HER2 Targeted Therapy For Metastatic Breast Cancer

HER2 Targeted Therapy for Metastatic Breast Cancer
Related Summaries
● Breast Cancer in Women
● In ammatory Breast Cancer
● Surgery for Metastatic Breast Cancer
● Radiation Therapy for Metastatic Breast Cancer
● Endocrine Therapy for Metastatic Breast Cancer
● Chemotherapy for Metastatic Breast Cancer
● HER2 Targeted Therapy for Early and Locally Advanced Breast Cancer
● Cardiotoxicities of Chemotherapeutic Agents
Overview
● human epidermal growth factor receptor 2 (HER2) is a transmembrane receptor protein that is
overexpressed in about 20% of breast cancers and associated with more aggressive disease in the
absence of HER2 directed therapy; HER2 plays a role in cell growth and di erentiation
● HER2 inhibitors used for treatment of HER2 positive metastatic breast cancer include
⚬ trastuzumab
⚬ pertuzumab
⚬ ado-Trastuzumab Emtansine
⚬ lapatinib
● HER2 targeted inhibitors are typically given in combination with chemotherapy or endocrine therapy,
but can sometimes be given alone or in combination with a second HER2 targeted agent
● pretreatment evaluation
⚬ assessment at time of diagnosis for patients presenting with metastatic recurrence or stage IV
disease may include
– history, physical exam, and blood tests (NCCN Category 2A; ESO/ESMO Grade A, Level II)
– diagnostic imaging of primary site and distant metastatic sites, including
● chest computed tomography (CT) (NCCN Category 2A; ESO/ESMO Grade A, Level II for
imaging of chest)
● abdominal CT (with or without pelvic CT) or magnetic resonance imaging (MRI) with contrast
(NCCN Category 2A; ESO/ESMO Grade A, Level II for imaging of abdomen)
● skeletal X-rays of symptomatic regions and long and weight-bearing bones that appear
abnormal on bone scan (NCCN Category 2A; ESO/ESMO Grade A, Level II for imaging of
bone)
● brain MRI if central nervous system symptoms are present (NCCN Category 2A)
● spine MRI with contrast if back pain or symptoms of spinal cord compression are present
(NCCN Category 2A)
– biopsy of metastatic disease at presentation or rst recurrence (NCCN Category 2A)
– determination of metastatic tumor hormone receptor (estrogen receptor [ER] and progesterone
receptor [PR]) status and HER2 status (NCCN Category 2A; ESO/ESMO Grade C, Level II)
● HER2 targeted therapy
⚬ for use in HER2 positive breast cancer

⚬ recommendations for use of HER2 targeted therapy are based on hormone receptor (HR) status,
menopausal status, prior therapies, burden of metastatic disease, and balance of toxicities
⚬ National Comprehensive Cancer Network (NCCN) recommendations for systemic treatment of
HER2 positive metastatic disease
– for HR positive, HER2 positive breast cancer
● if prior endocrine therapy within 1 year (NCCN Category 2A)
⚬ in premenopausal women, options include
– chemotherapy plus HER2 targeted therapy with any of pertuzumab plus trastuzumab
plus taxane (preferred), ado-trastuzumab emtansine (T-DM1), trastuzumab plus
chemotherapy, or other HER2 targeted therapies
– ovarian ablation or suppression plus endocrine therapy with or without HER2 targeted
therapy as for postmenopausal women
⚬ in postmenopausal women, o er chemotherapy plus HER2 targeted therapy (as above) or
consider di erent endocrine therapy with or without HER2 targeted therapy
● if no prior endocrine therapy within 1 year (NCCN Category 2A)
⚬ in premenopausal women, options include chemotherapy plus HER2 targeted therapy

with any of pertuzumab plus trastuzumab plus taxane (preferred), T-DM1, trastuzumab
plus chemotherapy (avoid concurrent use of trastuzumab and pertuzumab with
anthracycline due to signi cant cardiac toxicity), and other HER2 targeted therapies
⚬ ovarian ablation or suppression plus endocrine therapy with or without HER2 directed
therapy as for postmenopausal women
⚬ selective ER modulators with or without HER2 targeted therapy
⚬ in postmenopausal women, options include
– chemotherapy plus HER2 targeted therapy with any of pertuzumab plus trastuzumab
plus taxane (preferred), T-DM1, trastuzumab plus chemotherapy (avoid concurrent use
of trastuzumab and pertuzumab with anthracycline due to signi cant cardiac toxicity),
and other HER2 targeted therapies
– aromatase inhibitor with or without HER2 targeted therapy
– selective ER modulators with or without HER2 targeted therapy
– selective ER downregulator with or without HER2 targeted therapy
● continue until progression or intolerable toxicity, then
⚬ if rst-line therapy was endocrine therapy, consider additional endocrine therapy (if not
endocrine refractory) with or without HER2 targeted therapy (NCCN Category 2A)
– if no bene t following 3 sequential endocrine therapy regimens with or without HER2
targeted therapy or symptomatic visceral disease present, o er chemotherapy plus
HER2 targeted therapy until progression (NCCN Category 2A)
– if no clinical bene t after 3 sequential chemotherapy plus HER2 targeted therapy
options or ECOG performance status ≥ 3, consider supportive care without further
chemotherapy (NCCN Category 2A)
⚬ if rst-line therapy was chemotherapy plus HER2 targeted therapy, o er di erent
chemotherapy plus HER2 targeted therapy
– continue HER2 targeted therapy until progression (NCCN Category 2A)
– if no clinical bene t after 3 sequential targeted therapy options or ECOG performance
status ≥ 3, consider supportive care without further chemotherapy (NCCN Category 2A)
– for HR negative, HER2 positive breast cancer
● o er chemotherapy plus HER2 targeted therapy with any of pertuzumab plus trastuzumab
plus taxane (preferred), T-DM1, trastuzumab, or other HER2 targeted therapies (NCCN
Category 2A)
● if progression or unacceptable toxicity, o er another line of chemotherapy plus HER2
targeted therapy
● if no clinical bene t after 3 sequential targeted therapy options or ECOG performance status
≥ 3, consider supportive care without further chemotherapy (NCCN Category 2A)
⚬ European Society for Medical Oncology (ESMO) recommendations for systemic treatment of HER2
positive metastatic disease
– for ER positive breast cancer
● rst-line treatment
⚬ for patients previously untreated with HER2 targeted therapy, options include
– chemotherapy plus trastuzumab plus pertuzumab as standard therapy (ESO/ESMO

Grade A, Level I)
– chemotherapy plus trastuzumab only (if pertuzumab not available); vinorelbine or a
taxane are preferred chemotherapy agents absent pertuzumab after considering
di erences in toxicity and patient preferences (ESO/ESMO Grade A, Level I)
⚬ for patients previously treated with neoadjuvant and/or adjuvant HER2 targeted therapy,
options include
– chemotherapy plus pertuzumab plus trastuzumab (ESO/ESMO Grade A, Level I)
– chemotherapy plus trastuzumab; vinorelbine or a taxane are is preferred
chemotherapy agent absent pertuzumab after considering di erences in toxicity and
patient preferences (ESO/ESMO Grade A, Level I)
⚬ in highly selected patients receiving rst-line endocrine therapy plus HER2 targeted
therapy, dual agent HER2 targeted therapy may be used (ESO/ESMO Grade B, Level I)
⚬ for patients unsuitable for chemotherapy, or with minimal disease burden, long disease-
free interval, and/or strong HR expression, and for whom biomarkers are not available,
endocrine therapy plus HER2 targeted therapy in an option
● subsequent treatment is based on response to therapy
⚬ if no disease progression, it is reasonable to o er maintenance with endocrine therapy

plus HER2 targeted therapy (ESO/ESMO Grade B, for patients with metastatic disease who
received rst-line therapy with chemotherapy plus HER2 targeted therapy)
⚬ if disease progression, o er T-DM1 as second-line therapy (ESO/ESMO Grade A, Level I);
later-line therapy options include trastuzumab plus unused chemotherapy followed by
maintenance endocrine therapy plus HER2 targeted therapy (ESO/ESMO Grade A, Level II)
or trastuzumab plus lapatinib plus endocrine therapy in selected patients (ESO/ESMO
Grade B, Level I); for patients progressing on HER2 targeted therapy plus chemotherapy
or endocrine therapy, o er additional HER2 targeted therapy with any subsequent
treatment, except in presence of contraindications (ESO/ESMO Grade A, Level I)
– for ER negative breast cancer
● rst-line therapy
– chemotherapy plus trastuzumab plus pertuzumab is standard therapy (ESO/ESMO
Grade A, Level I)
– chemotherapy plus trastuzumab only (if pertuzumab not available); vinorelbine or a
taxane may be used after considering di erences in toxicity and patient preferences
(ESO/ESMO Grade A, Level I)
⚬ for patients previously treated with neoadjuvant and/or adjuvant HER2 targeted therapy,
options include
– chemotherapy plus pertuzumab plus trastuzumab (ESO/ESMO Grade A, Level I)
– chemotherapy plus trastuzumab; vinorelbine or a taxane may be used after
considering di erences in toxicity and patient preferences (ESO/ESMO Grade A, Level I)
⚬ for patients unsuitable for chemotherapy, or with minimal disease burden and long
disease-free interval, HER2 targeted therapy alone is an option
● subsequent treatment is based on response to therapy 3
⚬ if no disease progression, o er maintenance therapy with HER2 targeted therapy

⚬ if disease progression
– T-DM1 preferred in patients with disease progression through ≥ 1 line trastuzumab-

based therapy (ESO/ESMO Grade A, Level I)
– later line therapy options include trastuzumab plus unused chemotherapy (ESO/ESMO
Grade A, Level II), or trastuzumab plus lapatinib (ESO/ESMO Grade A, Level I)
– for patients progressing on HER2 targeted therapy plus chemotherapy, o er additional
HER2 targeted therapy with any subsequent treatment, except in presence of
contraindications (ESO/ESMO Grade A, Level I)
⚬ American Society of Clinical Oncology (ASCO) recommendations for systemic treatment of HER2
positive metastatic disease
– rst-line treatment
● o er HER2 targeted therapy, except for highly selected patients with hormone receptor
positive disease for whom endocrine therapy alone may be used (ASCO Strong
recommendation, High-quality evidence)
● trastuzumab plus pertuzumab plus a taxane is recommended preferred rst-line therapy
unless patient has contraindication to taxanes (ASCO Strong recommendation, High-quality
evidence)
– for second-line treatment upon progression during or after rst-line HER2 targeted therapy,
o er HER2 targeted therapy (ASCO Strong recommendation, High-quality evidence); T-DM1
recommended as preferred second-line treatment option (ASCO Strong recommendation, High-
quality evidence)
– for third-line treatment or greater upon progression during or after second-line or greater HER2
targeted therapy may o er HER2 targeted therapy (ASCO Moderate recommendation,
Intermediate quality evidence); third-line treatment regimens include
● in patients who received no prior T-DM1, o er T-DM1 (ASCO Strong recommendation, High-
quality evidence)
● in patients who received no prior pertuzumab, may o er pertuzumab (ASCO Weak
recommendation, Insu cient evidence)
● in patients who received prior pertuzumab and T-DM1, may o er lapatinib plus capecitabine,
trastuzumab plus other chemotherapy combinations, lapatinib plus trastuzumab, or
endocrine therapy in patients with HR positive disease (ASCO Weak recommendation,
Insu cient evidence)
– for patients with HER2 positive and HR positive advanced breast cancer, rst-line treatment
options also include
● HER2 targeted therapy plus chemotherapy (ASCO Strong recommendation, High-quality
evidence)
● endocrine therapy plus trastuzumab or lapatinib (in select cases) (ASCO Moderate
● endocrine therapy alone (in selected cases) (ASCO Weak recommendation, Intermediate-
quality evidence)
● perform periodic monitoring of symptoms and cancer burden to determine if treatment is providing
bene t and patient does not have toxicity from an ine ective therapy (NCCN Category 2A)
● adverse e ects associated with HER2 targeted therapies include cardiac toxicity, diarrhea, skin
toxicities, cognitive decline, weight gain, venous thromboembolism, infection, and fatigue
General Information
● HER2 targeted therapy is for use only in breast cancers that overexpress HER2 1
● HER2 is a transmembrane receptor protein of the human epidermal growth factor receptor (EGFR)
family
⚬ overexpressed in about 20% of breast cancers and associated with more aggressive disease in the
absence of HER2 targeted therapy
⚬ normally plays a role in cell growth and di erentiation
⚬ intracellular portion is a tyrosine kinase
⚬ HER2 has no known ligand; normal activation of HER2 occurs through dimerization with other
EGFR family receptors (HER1 [EGFR], HER2, and HER3) that have bound ligand
⚬ activation of HER2 starts a signal transduction cascade using PI3K/Akt and Ras/Raf/MEK/MAPK
pathways
⚬ overexpression of the HER2 receptor allows for dimerization/activation independent of ligand
⚬ Reference - Breast Cancer 2015 Mar;22(2):101
● metastatic breast cancer is also called advanced breast cancer and refers to either 1 , 2 , 3
⚬ de novo stage IV (any T, any N, M1) breast cancer (metastatic disease beyond the regional lymph
nodes at time of initial diagnosis)
⚬ metastatic (beyond regional lymph nodes) recurrence of breast cancer
● recommendations for use of HER2 targeted therapy are based on hormone receptor (HR) status,
menopausal status, prior therapies, and balance of toxicities 2 , 3
Pretreatment Assessment
Recommendations for pretreatment assessment
National Comprehensive Cancer Network (NCCN)
● NCCN recommendations for assessment at time of diagnosis for patients presenting with recurrent or
stage IV disease 2
⚬ history and physical exam (NCCN Category 2A)
⚬ blood tests (NCCN Category 2A)
– complete blood count

– comprehensive metabolic panel, including liver function tests and alkaline phosphatase
assessment
⚬ diagnostic imaging studies of primary site and distant metastatic sites
– chest computed tomography (CT) (NCCN Category 2A)

– abdominal CT (with or without pelvic CT) with contrast or magnetic resonance imaging (MRI)
with contrast (NCCN Category 2A)
– uorodeoxyglucose (FDG) positron emission tomography (PET)/CT is an option for select
patients (NCCN Category 2A)
● may be performed at same time as diagnostic CT
● may be most helpful when standard studies are equivocal or suspicious
– skeletal X-rays of symptomatic regions and long and weight-bearing bones that appear
abnormal on bone scan (NCCN Category 2A)
– spine MRI with contrast if back pain or symptoms of spinal cord compression are present
(NCCN Category 2A)
– brain MRI if central nervous system symptoms are present (NCCN Category 2A)
⚬ biopsy
– biopsy of metastatic disease at presentation or rst recurrence (NCCN Category 2A)

– determination of metastatic tumor hormone receptor (estrogen receptor [ER] and progesterone
receptor [PR]) status and HER2 status (NCCN Category 2A)
● false negative ER and/or PR determinations do occur, as well as discordance between ER
and/or PR determinations on primary and metastatic tumors due to tumor heterogeneity or
testing discrepancies; if clinical course suggestive of a hormone receptor positive cancer,
may consider endocrine therapy to treat asymptomatic visceral metastasis or nonvisceral
metastasis
● if biopsy cannot be safely obtained, may start treatment based on hormone receptor and
HER2 status of primary tumor
European School of Oncology/Society for Medical Oncology (ESO/ESMO)
● ESO-ESMO recommendations for advanced breast cancer 3
⚬ history and physical exam, hematology and biochemistry tests, and imaging of chest, abdomen
and bone as minimal staging workup (ESO/ESMO Grade A, Level II)
⚬ brain imaging should not be routinely performed in asymptomatic patients (ESO/ESMO Grade D,
Level II)
⚬ tumor markers may be used to aid in evaluation of treatment response especially in patients with
nonmeasurable metastatic disease, but should not be used alone to initiate treatment change
(ESO/ESMO Grade C, Level II)
⚬ biopsy should be obtained of the metastasis, if possible, to con rm diagnosis and obtain hormone
receptors and HER2 receptor status (ESO/ESMO Grade B, Level I)
National Institute for Health and Clinical Excellence (NICE)
● NICE recommendations for diagnosis and treatment of advanced breast cancer
⚬ use combination of x-ray, ultrasound, computed tomography (CT), and magnetic resonance
imaging (MRI) to assess presence and extent of visceral metastases
⚬ use CT, MRI, or bone scintigraphy to assess presence and extent of metastases in axial skeleton
⚬ use bone scintigraphy and/or x-ray in patients with evidence of bone metastases to evaluate
pathological fracture risk in proximal limb bones
⚬ use MRI to assess for bony metastases if imaging is equivocal for metastatic disease or if more
information needed (for example, lytic metastases encroaching on spinal canal)
⚬ PET-CT should only be used to make new diagnosis of metastases for patients with breast cancer
whose imaging is suspicious but not diagnostic
⚬ consider reassessment of ER and HER2 status if change in receptor status will lead to change in
management
⚬ Reference - National Institute for Health and Care Excellence guideline on diagnosis and treatment
of advanced breast cancer (NICE 2009 Feb:CG81 PDF )
American Society of Clinical Oncology (ASCO)
● ASCO recommendations on use of biomarkers to guide decisions on systemic therapy for women with
metastatic breast cancer
⚬ o er biopsy to patients with accessible, newly diagnosed metastases from primary breast cancer
to con rm disease process and test for estrogen receptor (ER), progesterone receptor (PR), and
human epidermal growth factor receptor 2 (HER2) status (ASCO Moderate recommendation,
Insu cient evidence)
– inform patients that if discordances identi ed, evidence is lacking to determine whether
outcomes are better with treatment regimens based on receptor status in the metastases or
the primary tumor
– if discordant results between primary and metastatic tissues, preferentially use ER, PR, and HER
status from metastasis to direct therapy if supported by clinical scenario and patient goals
⚬ for women with metastatic breast cancer and known ER and HER2 status (ASCO Evidence-based,
Moderate recommendation, Low-quality evidence)
– initiation of systemic therapy should be based on clinical evaluation, judgment, and patient
preferences
– no evidence that initiating therapy solely on basis of biomarkers beyond ER, PR, and HER2
improves health outcomes
⚬ for women with metastatic breast cancer and known ER, PR, and HER2 status
– for tissue biomarkers (ASCO Evidence-based, Moderate recommendation, Low-quality evidence)
● if already receiving systemic therapy for metastatic breast cancer, decisions on changing to a
new drug or regimen or discontinuing treatment should be based on patient's goals and
clinical evaluation and judgment of disease progression or response
● no evidence that changing therapy solely on basis of biomarkers beyond ER, PR, and HER2
improves health outcomes, quality of life, or cost-e ectiveness
– for circulating tumor markers (ASCO Evidence-based, Moderate recommendation, Intermediate-
quality evidence)
● if already receiving systemic therapy for metastatic breast cancer, decisions on changing to a
new drug or regimen or discontinuing treatment should be based on patient's goals and
clinical evaluation and judgment of disease progression or response
● no evidence that changing therapy solely on circulating biomarkers improves health
outcomes, quality of life, or cost-e ectiveness
– CEA, CA 15-3, and CA 27.29 may be used as adjunctive assessments to contribute to decisions
regarding therapy for metastatic breast cancer (ASCO Informal consensus, Moderate
Recommendation, Insu cient Evidence)
● insu cient data to recommend use of these biomarkers alone for monitoring treatment
response
⚬ decisions for systemic therapy should be in uenced by ER, PR, and HER2; clinical utility of
biomarkers beyond ER, PR, and HER2 has not been demonstrated (ASCO Informal consensus,
Strong Recommendation, Low-quality Evidence)
⚬ Reference - ASCO guideline on use of biomarkers to guide decisions on systemic therapy for
women with metastatic breast cancer (J Clin Oncol 2015 Aug 20;33(24):2695 full-text ),
summary can be found at ASCO Jul 2015 PDF
National Academy of Clinical Biochemistry (NACB)
● NACB recommendations on use of biomarkers to guide decisions on systemic therapy for women
with breast cancer
⚬ estrogen receptor and progesterone receptor testing recommended in all patients with breast
cancer (NACB Grade A, Level I)
– primary role is to identify patients who can be treated with endocrine therapy (NACB Grade A,
Level I)
– may be used with tumor stage, tumor grade and lymph node status to determine short-term
prognosis in patients with newly diagnosed breast cancer (NACB Grade B, Level III)
⚬ human epidermal growth factor receptor 2 testing recommended in all patients with invasive
breast cancer (NACB Grade A, Level I)
– primary role is to identify patients who may be treated with trastuzumab (NACB Grade A, Level
I)
⚬ cancer antigen (CA) 15-3, CA 27.29 (also called BR 27.29), and carcinoembryonic antigen
– should not routinely be used in asymptomatic patients for early detection of recurrence or
metastases after surgery (NACB Grade B, Level III)
– may be used in conjunction with radiology and clinical exam to monitor chemotherapy in
patients with advanced breast cancer; for patients with otherwise nonassessable disease,
sustained increases in concentration suggest progressive disease (NACB Grade B, Level III)
⚬ Reference - NACB guideline on use of tumor markers in testicular, prostate, colorectal, breast and
ovarian cancers (Clin Chem 2008 Dec;54(12):e11 full-text )
Hormone receptor (HR) testing and prediction of therapeutic response
● tumor estrogen receptor (ER) predicts potential bene t from endocrine therapy; tumor progesterone
receptor (PR) is primarily prognostic
⚬ positive ER test (≥1%) predicts bene t from endocrine therapy; data is limited in patients with low
positive ER (1-10%)
⚬ negative ER test (<1%) predicts no bene t from endocrine therapy
⚬ Reference - J Clin Oncol 2020 Apr 20;38(12):1346
● HR status for estrogen and progesterone receptors (PR) is usually performed by
immunohistochemical (IHC) staining 1 , 2 , 3
● American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) recommendations

for IHC testing of estrogen and progesterone receptors in breast cancer
⚬ estrogen receptor (ER) and PR testing indicated for all invasive breast cancers and breast cancer
recurrences
⚬ optimal HR testing
– perform on large, multiple core biopsies if they are representative of tumor (grade and type) at
resection
– laboratory must provide documentation of
● initial validation of positive and negative ER or PR categories and concordance (90% for
positive, and 95% for negative ER/PR) with clinically validated assays
● ongoing internal quality assurance procedures
● participation in external pro ciency testing
● accreditation through a valid accrediting agency every 2 years
– de nitions of ER and PR testing results
● positive de ned as ≥ 1% of tumor cell nuclei are immunoreactive

● negative de ned as < 1% of tumor cell nuclei are immunoreactive with positive intrinsic
controls
● uninterpretable de ned as no tumor nuclei are immunoreactive and internal epithelial
elements present in sample or separately submitted from same sample lack any nuclear
staining
⚬ Reference - J Clin Oncol 2010 Jun 1;28(16):2784 full-text
HER2 testing and prediction of therapeutic response
● HER2 (also called ERBB2) gene reported to have ampli ed expression in 15%-20% of primary breast
cancers (J Clin Oncol 2013 Nov 1;31(31):3997 )
● HER2 predicts for potential bene t from HER2 targeted therapies
⚬ tumors with HER2 ampli cation (HER2 positive) may bene t from HER2 targeted therapy
⚬ tumors without HER2 ampli cation (HER2 negative) unlikely to bene t from HER2 targeted therapy
⚬ Reference - J Clin Oncol 2018 Jul 10;36(20):2105
● American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) recommendations

for HER2 testing in breast cancer
⚬ HER2 testing recommended for every newly diagnosed invasive breast cancer to guide decisions
about pursuing HER2 targeted therapy (ASCO/CAP Strong recommendation, High-quality evidence)
⚬ HER 2 testing of metastatic site also recommended if metastatic recurrence occurs and tissue
sample available (ASCO/CAP Strong recommendation, High-quality evidence)
⚬ optimal HER2 testing (ASCO/CAP Strong recommendation, High-quality evidence)
– performed with FDA-approved immunohistochemistry (IHC) or in situ hybridization (ISH)
● IHC stains the HER2 protein on the cell membrane for measurement
● ISH identi es the HER2 gene in the cell nucleus for measurement of gene copy number
● list of cleared or approved companion diagnostic devices for determining utility of anti-HER2
targeted therapy can be found at United States FDA
– laboratories accredited by CAP or other accrediting entity may use laboratory developed tests,
but must document and make available the analytical performance and validity of its assay
⚬ IHC result reporting
– positive test de ned as IHC 3+ and based on complete, intense circumferential membrane
staining in > 10% of tumor cells (ASCO/CAP Strong recommendation, High-quality evidence)
– equivocal test de ned as IHC 2+ and based on weak/moderate complete membrane staining in
> 10% of tumor cells (ASCO/CAP Strong recommendation, High-quality evidence); in case of IHC
2+ result, perform ISH using same specimen or retest with new specimen using either IHC or
ISH (ASCO/CAP Strong recommendation, High-quality evidence)
– negative test de ned as either (ASCO/CAP Strong recommendation, High-quality evidence)
● IHC 1+ and based on incomplete, faint membrane staining within > 10% of tumor cells
● IHC 0 and based on either no staining, or incomplete, faint membrane staining in ≤ 10% of
tumor cells
⚬ ISH
– dual probe assay preferred over single probe assay

– pathologist should scan entire ISH slide prior to counting ≥ 20 cells or use IHC to de ne areas of
potential HER2 ampli cation (ASCO/CAP Strong recommendation, High-quality evidence)
● if second population of HER2 ampli ed cells and cell population > 10% of tumor cells on the
slide, must perform and report on a separate counting of ≥ 20 nonoverlapping cells
● if bright eld ISH used, comparison between pattern in tumor cells and normal breast should
be performed when counting to avoid counting artifactual patterns
– positive test de ned as (ASCO/CAP Strong recommendation, High-quality evidence)
● in single probe assay, average HER2 copy number ≥ 6 signals/cell

● in dual probe assay, HER2/CEP17 ratio ≥ 2 and average HER2 copy number ≥ 4 signals/cell
– negative test de ned as (ASCO/CAP Strong recommendation, High-quality evidence)
● in single probe assay, average HER2 copy number < 4 signals/cell

● in dual probe assay, HER2/CEP17 ratio < 2 and average HER2 copy number < 4 signals/cell
– equivocal test requiring further testing including IHC (if not already assessed) using same tissue
sample from ISH, and view both ISH and IHC concomitantly
● in single probe assay, average HER2 copy number ≥ 4 but < 6 signals/cell (ASCO/CAP Strong
⚬ test positive if either or both
– concurrent IHC 3+
– concurrent dual-probe ISH is HER2/CEP17 ratio ≥ 2 and average HER2 copy number ≥ 4
signals/cell
⚬ test negative if either or both
– concurrent IHC 0 or 1+
– concurrent dual-probe ISH is HER2/CEP17 ratio < 2 and average HER2 copy number < 4
signals/cell
⚬ perform dual probe assay for nal result if IHC 2+
● in dual probe assay
⚬ if HER2/CEP17 ratio ≥ 2 and average HER2 copy number < 4 signals/cell (ASCO/CAP Strong
recommendation, Intermediate-quality evidence)
– test positive if IHC 3+
– test negative if IHC 0 or 1+ and include comment "evidence is currently limited on
e cacy of HER2 targeted therapy in patients with HER2/CEP17 ratio of ≥ 2 and average
HER2 copy number < 4 signals/cell"
– perform recount of ≥ 20 cells by observer blinded to previous results if IHC 2+
– test negative if recount remains HER2/CEP17 ratio ≥ 2 and average HER2 copy
number < 4 signals/cell and include comment "evidence is currently limited on
e cacy of HER2 targeted therapy in patients with HER2/CEP17 ratio of ≥ 2 and
average HER2 copy number < 4 signals/cell"
– adjudicate result through internal procedure if recount changes ISH category
⚬ if HER2/CEP17 ratio < 2 and average HER2 copy number ≥ 6 signals/cell (ASCO/CAP Strong
recommendation, Intermediate-quality evidence)
– test negative if IHC 0 or 1+ and include comment "insu cient evidence on e cacy of
HER2 targeted therapy in patients with HER2/CEP17 ratio of < 2 in absence of protein
overexpression"
– test positive if recount remains HER2/CEP17 ratio is < 2 and average HER2 copy
number ≥ 6 signals/cell
⚬ if HER2/CEP17 ratio < 2 and average HER2 copy number ≥ 4 but < 6 signals/cell (ASCO/CAP
Strong recommendation, Intermediate-quality evidence)
– test negative if IHC 0 or 1+ and include comment "evidence is currently limited on
e cacy of HER2 targeted therapy in patients with HER2/CEP17 ratio of < 2 and average
HER2 copy number ≥ 4 but < 6 signals/cell in absence of protein overexpression (IHC
3+)"
– test negative if recount remains HER2/CEP17 ratio < 2 and average HER2 copy
number ≥ 4 but < 6 signals/cell and include comment "evidence is limited on
e cacy of HER2 targeted therapy in patients with HER2/CEP17 ratio of < 2 and
average HER2 copy number ≥ 4 but < 6 signals/cell in absence of protein
overexpression (IHC 3+)"
⚬ for both IHC and ISH, report a test as indeterminate when technical issues prevent a report of
positive, negative, or equivocal, such as
– for IHC (ASCO/CAP Strong recommendation, High-quality evidence)
● controls not as expected

● artifacts (crush or edge artifacts) make interpretation di
cult
● normal breast ductal cells have strong membrane straining (internal control)
– for ISH (ASCO/CAP Strong recommendation, High-quality evidence)
● controls not as expected

● observer cannot nd and count ≥ 2 areas of invasive tumor
● > 25% of signals are unscorable due to weak signal
● > 10% of signals occur over cytoplasm
● poor nuclear resolution
● strong auto uorescence
⚬ Reference - J Clin Oncol 2018 Jul 10;36(20):2105
● National Comprehensive Cancer Network (NCCN) endorses the ASCO/CAP recommendations for HER2
testing in breast cancer (NCCN Category 2A) 2
Performance status evaluation
● performance status evaluation to aid treatment decisions
Table 1. ECOG or WHO Performance Status Scale

Gra Criteria
de
0 Fully active; able to carry on all predisease performance without restriction
1 Restricted in physically strenuous activity but ambulatory and able to carry

out work of a light or sedentary nature (such as light housework or o ce
work)
2 Ambulatory and capable of all self-care but unable to carry out any work
activities; up and about > 50% of waking hours
3 Capable of only limited self-care; con ned to bed or chair > 50% of waking
hours
4 Completely disabled; cannot carry on any self-care; totally con ned to bed
or chair
5 Dead
Abbreviations: ECOG, Eastern Cooperative Oncology Group; WHO, World Health Organization.
Reference - Am J Clin Oncol 1982 Dec;5(6):649 .
Table 2. Karnofsky Performance Status Scale
De nitions Rating Criteria
Able to carry on normal 100% Normal; no complaints; no evidence of

activity; no special care disease
needed
90% Able to carry on normal activity; minor
signs or symptoms of disease
80% Normal activity with e ort; some signs or

symptoms of disease
Unable to work; able to 70% Cares for self; unable to carry on normal
live at home and care for activity or do active work
most personal needs;
De nitions Rating Criteria
varying amount of
60% Requires occasional assistance but is able
assistance needed
to care for most personal needs
50% Requires considerable assistance and

frequent medical care
Unable to care for self; 40% Disabled; requires special care and
requires equivalent of assistance
institutional or hospital
care; disease may be 30% Severely disabled; hospital admission is
progressing rapidly indicated although death not imminent
20% Very sick; hospital admission necessary;

active supportive treatment necessary
10% Moribund; fatal processes progressing

rapidly
0% Dead
Reference - J Gerontol 1991 Jul;46(4):M139 , Cancer 1994 Apr 15;73(8):2087 .
HER2 Targeted Therapy Principles and Regimens
Principles of HER2 targeted therapy for metastatic breast cancer
● HER2 inhibitors are typically given in combination with chemotherapy or endocrine therapy 1 , 2
● HER2 inhibitors in combination with chemotherapy associated with increased overall survival,
progression-free survival, and response rate compared with chemotherapy alone (Breast Cancer 2015
Mar;22(2):101 )
● HER2 inhibitors for metastatic breast cancer include 1 , 2
⚬ trastuzumab
⚬ pertuzumab
⚬ ado-trastuzumab emtansine
⚬ lapatinib
⚬ neratinib
● choice of regimen for HER2 targeted therapy varies with patient circumstances including 1 , 2 , 3
⚬ presence of brain metastases

⚬ disease burden
⚬ comorbidities
⚬ length of disease-free interval
⚬ disease progression
⚬ unacceptable toxicity
⚬ visceral disease
⚬ HR status
⚬ prior treatments
HER2 inhibitors
IMAGE 1 OF 1
EGFR pathway
● HER2 inhibitors for metastatic breast cancer include
⚬ trastuzumab, a humanized monoclonal antibody speci c for extracellular domain of HER2

receptors
– common adverse e ects include fever, vomiting, diarrhea, infections, increased cough,
headache, fatigue, dyspnea, rash, neutropenia, and anemia
– serious adverse e ects include cardiomyopathy, pulmonary toxicity, infusion reactions, and
febrile neutropenia
– trastuzumab biosimilars include
● in the United States
⚬ MYL-1401O (Ogivri) FDA approved for treatment of patients with HER2 positive breast
cancer
– common side e ects include headache, diarrhea, nausea, chills, fever, infection,
congestive heart failure, insomnia, cough, and rash
– serious adverse events include worsened chemotherapy-induced neutropenia
– increased risk of cardiomyopathy, infusion reactions, pulmonary toxicity, and embryo-
fetal toxicity
– Reference - FDA Press Release 2017 Dec 1
⚬ trastuzumab-qyyp (Trazimera) FDA approved for treatment of patients with HER2 positive
breast cancer (FDA Label 2019 Mar PDF )
● in Europe, the European Medicines Agency (EMA) has authorized
⚬ trastuzumab (SB3, Ontruzant) (EMA 2017 Nov 15 ; EMA Label 2017 Nov )
⚬ trastuzumab (Zercepac) (EMA 2020 Jul 28 ; EMA Label 2020 Jul )
– subcutaneous trastuzumab approved in Europe by EMA for use in patients with early or
metastatic breast cancer EMA 2013 Oct 25
– pertuzumab/trastuzumab/hyaluronidase-zzxf (Phesgo) FDA approved for use in combination
with docetaxel for treatment of HER2-positive metastatic breast cancer in adults who have not
received prior anti-HER2 targeted therapy or chemotherapy for metastatic disease
● pertuzumab/trastuzumab/hyaluronidase-zzxf (Phesgo) is a xed dose combination product
consisting of HER2 targeted therapies (pertuzumab and trastuzumab) and hyaluronidase, an
endoglycosidase used to increase subcutaneous dispersion and absorption of concurrently
administered drugs
● e cacy based on FeDeriCa trial comparing subcutaneous
pertuzumab/trastuzumab/hyaluronidase vs. IV pertuzumab plus trastuzumab in 500 patients
treated with neoadjuvant and/or adjuvant chemotherapy; non-inferiority of subcutaneous
pertuzumab/trastuzumab/hyaluronidase established based on similar serum trough levels
● dosing and administration
⚬ start with pertuzumab/trastuzumab/hyaluronidase (1,200 mg/600 mg/30,000 units)

subcutaneously over approximately 8 minutes, followed by
pertuzumab/trastuzumab/hyaluronidase (600 mg/600 mg/20,000 units) subcutaneously
over approximately 5 minutes every 3 weeks
⚬ for metastatic disease, subcutaneous injection is given with docetaxel every 3 weeks until
disease progression or unmanageable toxicity (whichever occurs rst); recommended
initial dose of docetaxel is 75 mg/m2, which may be increased to 100 mg/m2, given by IV
infusion every 3 weeks if initial dose is well-tolerated
● adverse e ects (in > 30% with metastatic breast cancer, based on IV pertuzumab in
combination with trastuzumab and docetaxel) include diarrhea, alopecia, neutropenia,
nausea, fatigue, rash, and peripheral neuropathy
● Reference - FDA Press Release 2020 Jun 29 , FDA Label 2020 Jun
– see Trastuzumab for additional information
⚬ pertuzumab, a humanized monoclonal antibody speci c for extracellular domain II of HER2

receptors
– typically given in combination with trastuzumab
– most common grade 3-4 adverse e ects for pertuzumab in combination with trastuzumab
included neutropenia, febrile neutropenia, diarrhea, decreased neutrophil count, anemia,
decreased white blood cell count, leukopenia, fatigue, nausea, and stomatitis
– pertuzumab/trastuzumab/hyaluronidase-zzxf (Phesgo) FDA approved for use in combination
with docetaxel for treatment of HER2-positive metastatic breast cancer in adults who have not
received prior anti-HER2 targeted therapy or chemotherapy for metastatic disease (FDA Press
Release 2020 Jun 29 , FDA Label 2020 Jun )
– see Pertuzumab for additional information
⚬ fam-trastuzumab deruxtecan-nxki (Enhertu) FDA approved for treatment of adults with

unresectable or metastatic HER2 positive breast cancer
– fam-trastuzumab deruxtecan-nxki is an antibody drug conjugate (topoisomerase inhibitor plus
trastuzumab) approved for patients who have received ≥ 2 prior anti-HER2-based regimens
– e cacy based on clinical study in 184 women with HER2 positive, unresectable, and/or
metastatic breast cancer receiving fam-trastuzumab deruxtecan-nxki
● overall response rate 60.3% with mean duration of response 14.8 months
● all patients had received prior treatment with anti-HER2 therapy (between 2-17 prior
regimens)
– dosing: 5.4 mg/kg given as IV infusion once every 3 weeks until disease progression or
unacceptable toxicity
– do not substitute fam-trastuzumab deruxtecan-nxki for or with trastuzumab or ado-
trastuzumab emtansine
– adverse e ects may include nausea, fatigue, vomiting, cough, alopecia, anemia, constipation,
decreased appetite, neutropenia, diarrhea, leukopenia, and thrombocytopenia
– boxed warnings include risk of interstitial lung disease and embryo-fetal toxicity
– References - FDA Press Release 2019 Dec 20 , FDA DailyMed 2019 Dec
⚬ ado-trastuzumab emtansine, an anti-HER2 antibody drug conjugate (cytotoxic DM1 plus
trastuzumab)
– typically used as monotherapy in patients with HER2 positive metastatic breast cancer who have
already been treated with trastuzumab and/or taxane, or following recurrence
– should not be substituted for trastuzumab
– common adverse e ects include headache, constipation, nausea, fatigue, musculoskeletal pain,
hemorrhage, and thrombocytopenia
– serious adverse e ects include left ventricular cardiac dysfunction, injection site extravasation,
anaphylactoid reaction, grade 3-4 peripheral nerve disease, dyspnea, interstitial lung disease,
pneumonitis, and hematologic complications
– see Ado-Trastuzumab Emtansine for additional information
⚬ lapatinib, a dual EGFR (HER1)/HER2 reversible small molecule tyrosine kinase inhibitor which blocks
HER1 and HER2 at the intracellular tyrosine kinase portion of the receptors
– common adverse e ects include diarrhea, rash, nausea, fatigue, hepatotoxicity, and cardiac
dysfunction
– see Lapatinib for additional information
⚬ neratinib, an intracellular kinase inhibitor which irreversibly binds to epidermal growth factor
receptors (HER2 and HER4) receptors
HER2 targeted therapy regimens for metastatic breast cancer
Preferred regimens for HER2 positive disease
● preferred regimens for human epidermal growth factor receptor 2 (HER2) positive metastatic breast
cancer include 2
⚬ pertuzumab plus trastuzumab plus docetaxel (NCCN Category 1)
⚬ pertuzumab plus trastuzumab plus paclitaxel (NCCN Category 2A)
● patients previously treated for metastatic disease with chemotherapy plus trastuzumab absent
pertuzumab may be considered for one line of trastuzumab plus pertuzumab with or without
chemotherapy (such as vinorelbine or taxane) 2
● dosing schedules for preferred regimens for HER2 positive tumors 2
⚬ pertuzumab plus trastuzumab plus docetaxel (NCCN Category 2A)
– pertuzumab 840 mg IV on day 1, then 420 mg IV every 21 days

– trastuzumab 8 mg/kg IV on day 1, then 6 mg/kg IV every 21 days
– docetaxel 75-100 mg/m2 IV on day 1 every 21 days
⚬ pertuzumab plus trastuzumab plus paclitaxel (NCCN Category 2A)
– pertuzumab 840 mg IV on day 1, then 420 mg IV every 21 days

– trastuzumab, either one of the following
● 4 mg/kg IV on day 1, then 2 mg/kg IV weekly

● 8 mg/kg IV on day 1, then 6 mg/kg IV every 21 days
– paclitaxel, either one of the following

● 80 mg/m2 IV on day 1 weekly
● 175 mg/m2 IV on day 1 every 21 days
Alternate regimens for HER2 positive disease
● other regimens for HER2 positive metastatic breast cancer (NCCN Category 2A) 2
⚬ ado-Trastuzumab Emtansine (T-DM1)

⚬ trastuzumab plus any of
– paclitaxel with or without carboplatin

– docetaxel
– vinorelbine
– capecitabine
– lapatinib (without cytotoxic therapy)
– other single agents, preferably nonanthracycline based agents recommended for recurrent or
metastatic breast cancer
⚬ lapatinib plus capecitabine
● patients previously treated for metastatic disease with chemotherapy plus trastuzumab absent
pertuzumab may be considered for one line of trastuzumab plus pertuzumab with or without
chemotherapy (such as vinorelbine or taxane)
● avoid concurrent use of trastuzumab plus pertuzumab plus anthracycline due to risk of signi cant
cardiotoxicity
● dosing schedules for alternate regimens for HER2 positive metastatic breast cancer 2
⚬ T-DM1 3.6 mg/kg IV on day 1 every 21 days

⚬ trastuzumab plus paclitaxel plus carboplatin

– paclitaxel 175 mg/m2 IV on day 1 every 21 days

– carboplatin area under curve (AUC) 6 IV on day 1 every 21 days
⚬ trastuzumab plus weekly paclitaxel plus carboplatin

– paclitaxel 80 mg/m2 IV on days 1, 8, and 15 every 28 days

– carboplatin AUC 2 IV on days 1, 8, and 15 every 28 days
⚬ trastuzumab plus paclitaxel

– paclitaxel, either one of the following
● 175 mg/m2 IV on day 1 every 21 days

● 80-90 mg/m2 IV on day 1 weekly
⚬ trastuzumab plus docetaxel


– docetaxel, either one of the following
● 80-100 mg/m2 IV on day 1 every 21 days

● 35 mg/m2 IV on days 1, 8, and 15 weekly
⚬ trastuzumab plus vinorelbine

– vinorelbine, either one of the following
● 25 mg/m2 IV on day 1 weekly

● 30-35 mg/m2 IV on days 1 and 8 every 21 days
⚬ trastuzumab plus capecitabine

– capecitabine 1,000-1,250 mg/m2 orally twice daily on days 1-14 every 21 days
⚬ trastuzumab plus lapatinib

– lapatinib 1,000 mg orally daily
⚬ lapatinib plus capecitabine
– lapatinib 1,250 mg orally daily on days 1-21 every 21 days

– capecitabine 1,000 mg/m2 orally twice daily on days 1-14 every 21 days
⚬ neratinib plus capecitabine
– neratinib (Nerlynx) receives expanded FDA approval in combination with capecitabine for
treatment of advanced or metastatic HER2 positive breast cancer in adults who have received ≥
2 prior anti-HER2 based regimens in metastatic setting
● neratinib is an intracellular kinase inhibitor which irreversibly binds to epidermal growth
factor receptor (EGFR), HER2, and HER4 receptors and demonstrates antitumor activity by
reducing autophosphorylation and downstream activation of MAPK and AKT cell signaling
pathways
● e cacy based on 1 randomized trial without blinding evaluating addition of neratinib or
lapatinib to capecitabine in 621 patients; comparing neratinib vs. lapatinib
⚬ median progression free survival (PFS) 5.6 months vs. 5.5 months (hazard ratio [HR] 0.76,
95% CI 0.63-0.93)
⚬ PFS at 12 months in 29% vs. 15%
⚬ median overall survival was 21 months vs. 18.7 months (not signi cant)
⚬ median duration of response was 8.5 months vs. 5.6 months
● dosing and administration
⚬ 240 mg (6 tablets) orally once daily with food on days 1-21 in combination with
capecitabine 750 mg/m2 orally twice daily on days 1-14 of 21-day cycle
⚬ give antidiarrheal prophylaxis with loperamide for rst 2 cycles and continue as needed
thereafter to maintain 1-2 bowel movements per day
⚬ reduce starting dose to 80 mg/day in patients with severe hepatic impairment
⚬ other dose interruption, reduction, and/or discontinuation recommended based on
safety and tolerability
– dose modi cation (stepwise increments, such as decreasing to 200 mg [5 tablets] per
day, then 160 mg [4 tablets] per day, and then 120 mg [3 tablets] per day) may be
required for adverse reactions; hold dose for grade 3 toxicity (until recovery to grade ≤
1, or to baseline if within 3 weeks of stopping treatment) and resume at next lower
dose increment
– discontinue treatment permanently for grade 4 toxicity
● adverse e ects (reported in ≥ 5%) include diarrhea, nausea, abdominal pain, fatigue,
vomiting, rash, stomatitis, decreased appetite, muscle spasms, dyspepsia, increased liver
enzymes, nail disorders, dry skin, abdominal distension, epistaxis, decrease in weight, and
urinary tract infection
● References - FDA Press Release 2020 Feb 26 , FDA Label 2020 Feb
HER2 targeted therapy plus endocrine therapy
● if prior endocrine therapy within 1 year (NCCN Category 2A) 2
⚬ for premenopausal women
– ovarian ablation or suppression plus a di erent endocrine therapy plus HER2 targeted therapy
as for postmenopausal women
● aromatase inhibitor (anastrozole, letrozole, or exemestane) plus trastuzumab
● aromatase inhibitor plus lapatinib
● aromatase inhibitor plus lapatinib plus trastuzumab
● fulvestrant plus trastuzumab
● tamoxifen plus trastuzumab
⚬ for postmenopausal women, options include
– di erent endocrine therapy plus HER2 targeted therapy such as any of

⚬ see Endocrine therapy for metastatic breast cancer for additional information
● if no prior endocrine therapy within 1 year (NCCN Category 2A) 2
⚬ for premenopausal women
– ovarian ablation or suppression plus endocrine therapy plus HER2 targeted therapy as for
postmenopausal women
– tamoxifen plus HER targeted therapy

– aromatase inhibitor (anastrozole, letrozole, or exemestane) plus trastuzumab

– aromatase inhibitor plus lapatinib
– aromatase inhibitor plus lapatinib plus trastuzumab
– tamoxifen plus trastuzumab
– fulvestrant plus trastuzumab
⚬ see Endocrine therapy for metastatic breast cancer for additional information
Recommendations from Professional Organizations
National Comprehensive Cancer Network (NCCN)
HR positive, HER2 positive disease
● if prior endocrine therapy within 1 year (NCCN Category 2A) 2
⚬ for premenopausal women, options include
– chemotherapy plus HER2 targeted therapy with any of the following
● pertuzumab plus trastuzumab plus taxane (preferred)

● ado-trastuzumab emtansine (T-DM1)
● trastuzumab plus chemotherapy; avoid concurrent use of trastuzumab and pertuzumab with
anthracycline due to signi cant cardiac toxicity
● other HER2 targeted therapies
– ovarian ablation or suppression plus systemic therapy as for postmenopausal women
– consider di erent endocrine therapy regimen with or without HER2 targeted therapy such as
any of
● aromatase inhibitor with or without trastuzumab
● aromatase inhibitor with or without lapatinib
● aromatase inhibitor with or without lapatinib plus trastuzumab
● fulvestrant with or without trastuzumab
● tamoxifen with or without trastuzumab
– chemotherapy plus HER2 targeted therapy with any of

● T-DM1
⚬ continue therapy until disease progression or unacceptable toxicity
● if no prior endocrine therapy within 1 year (NCCN Category 2A) 2
⚬ for premenopausal women, options include

● T-DM1
● other HER2 directed therapies
– ovarian ablation or suppression plus endocrine therapy with or without HER2 targeted therapy
as for postmenopausal women
– selective estrogen receptor (ER) modulators with or without HER2 targeted therapy
– aromatase inhibitor with or without HER2 targeted therapy

– selective ER modulators with or without HER2 targeted therapy
– selective ER downregulator with or without HER2 targeted therapy

● T-DM1
⚬ continue therapy until disease progression or unacceptable toxicity
● for progression or intolerable toxicity
⚬ if rst-line therapy was endocrine therapy, consider additional endocrine therapy (if not endocrine
refractory) with or without HER2 targeted therapy (NCCN Category 2A)
– if no bene t following 3 sequential endocrine therapy regimens with or without HER2 targeted
therapy or symptomatic visceral disease present, o er chemotherapy plus HER2 targeted
therapy until progression (NCCN Category 2A)
– if no clinical bene t after 3 sequential chemotherapy plus HER2 targeted therapy options or
ECOG performance status ≥ 3, consider supportive care without further chemotherapy (NCCN
Category 2A)
⚬ if rst-line therapy was chemotherapy plus HER2 targeted therapy, o er di erent chemotherapy
plus HER2 targeted therapy
– continue HER2 targeted therapy until progression (NCCN Category 2A)
– if no clinical bene t after 3 sequential targeted therapy regimens or ECOG performance status ≥
3, consider supportive care without further chemotherapy (NCCN Category 2A)
HR negative, HER2 positive disease
● chemotherapy plus HER2 targeted therapy with (NCCN Category 2A) 2
⚬ pertuzumab plus trastuzumab plus taxane (preferred)

⚬ ado-trastuzumab emtansine (T-DM1)
⚬ trastuzumab plus chemotherapy; avoid concurrent use of trastuzumab and pertuzumab with
⚬ other HER2 targeted therapies
● continue until progression or unacceptable toxicity occurs, then consider additional line of
chemotherapy plus HER2 targeted therapy 2
● if no clinical bene t after 3 sequential lines of targeted therapy or ECOG performance status ≥ 3,
consider no further cytotoxic therapy and continue supportive care 2
European School of Oncology/Society for Medical Oncology (ESO/ESMO)
General recommendations
● patients treated with neoadjuvant and/or adjuvant HER2 targeted therapy should remain candidates
for HER2 targeted therapies and should be eligible for enrollment in clinical trials for HER2 positive
metastatic breast cancer (ESO/ESMO Grade B, Level I)
● o er HER2 targeted therapy early as rst-line treatment to all patients with HER2 positive advanced
breast cancer unless contraindicated (ESO/ESMO Grade A, Level I)
● in patients with HER2 positive advanced breast cancer previously untreated with trastuzumab or
treated in the adjuvant setting and with > 12 months disease free interval, rst-line chemotherapy
plus trastuzumab is superior to chemotherapy plus lapatinib for progression-free survival and overall
survival (ESO/ESMO Grade A, Level I)
● for later lines of therapy, trastuzumab can be administered with several chemotherapy agents
including vinorelbine (if not given in rst line), taxanes (if not given in rst line), capecitabine, eribulin,
liposomal anthracyclines, platinum, gemcitabine, or metronomic cyclophosphamide plus
methotrexate; decision should be individualized and take into account toxicity pro les, previous
exposure, patient preferences, and availability (ESO/ESMO Grade A, Level II)
Estrogen receptor (ER) positive disease
● rst-line therapy 3
– chemotherapy plus trastuzumab plus pertuzumab is standard rst-line therapy (ESO/ESMO

Grade A, Level I); chemotherapy agents to combine with trastuzumab plus pertuzumab include
● docetaxel (ESO/ESMO Grade A, Level I)
● paclitaxel (ESO/ESMO Grade B, Level I)
● vinorelbine (ESO/ESMO Grade A, Level II)
● nab-paclitaxel (ESO/ESMO Grade B, Level II)
● capecitabine (ESO/ESMO Grade A, Level II)
– chemotherapy plus trastuzumab only, if pertuzumab not available
● vinorelbine or a taxane may be used after considering di erences in toxicity and patient
preferences (ESO/ESMO Grade A, Level I)
● other chemotherapy agents can be administered with trastuzumab but are not preferred
⚬ for patients previously treated with neoadjuvant and/or adjuvant HER2 targeted therapy, options
include
– chemotherapy plus pertuzumab plus trastuzumab (ESO/ESMO Grade A, Level I); chemotherapy
agents to combine with trastuzumab plus pertuzumab include
– chemotherapy plus trastuzumab
● vinorelbine or a taxane may be used after considering di erences in toxicity and patient
preferences (ESO/ESMO Grade A, Level I)
⚬ for patients unsuitable for chemotherapy, or with minimal disease burden, long disease-free
interval, and/or strong HR expression, or for whom biomarkers are not available, endocrine
therapy plus HER2 targeted therapy in an option
– HER2 targeted options include trastuzumab or lapatinib
– in highly selected patients receiving rst-line endocrine therapy plus HER2 targeted therapy,
dual agent HER2 targeted therapy may be used (ESO/ESMO Grade B, Level I)
● options include
⚬ pertuzumab plus trastuzumab

⚬ lapatinib plus trastuzumab
● decision should be balanced against higher side e ects, higher costs, and lack of overall
survival bene t when compared with endocrine therapy plus HER2 targeted monotherapy
⚬ if no disease progression with rst-line therapy of chemotherapy plus HER2 targeted therapy, it is
reasonable to o er maintenance therapy with endocrine therapy plus HER2 targeted therapy
(ESO/ESMO Grade B); in patients achieving complete remission
– duration of maintenance therapy should be until progression, unacceptable toxicity, or patient
request (ESO/ESMO Grade B)
● for patients achieving complete remission (ESO/ESMO Grade C, Expert opinion)
⚬ optimal duration of maintenance therapy unknown and should be balanced against

treatment toxicity, logistical burden, and cost
⚬ stopping HER2 targeted therapy may be considered in select patients with complete
remission over several years, especially if treatment rechallenge is available in case of
disease progression
– no evidence to decide between single-agent or dual agent HER2 targeted therapy to combine
with maintenance endocrine therapy (ESO/ESMO Grade B)
– second-line therapy, o er ado-trastuzumab emtansine (T-DM1) (ESO/ESMO Grade A, Level I)
● superior e cacy relative to other second-line HER2 targeted therapies (lapatinib plus
capecitabine) after rst-line trastuzumab-based therapy
● preferred in patients with disease progression through ≥ 1 line trastuzumab-based therapy
● insu cient evidence on use of T-DM1 after trastuzumab plus pertuzumab
– later line therapy options include
● trastuzumab plus unused chemotherapy (ESO/ESMO Grade A, Level II), followed by

maintenance endocrine therapy plus HER2 targeted therapy with either trastuzumab or
trastuzumab and lapatinib (if not used previously); chemotherapy agents include
⚬ vinorelbine (if not used for rst-line treatment)
⚬ taxanes (if not used for rst-line treatment)
⚬ capecitabine
⚬ eribulin
⚬ liposomal anthracyclines,
⚬ platinum-containing agents
⚬ gemcitabine
⚬ metronomic chemotherapy
● trastuzumab plus lapatinib plus endocrine therapy in selected patients
⚬ trastuzumab plus lapatinib is reasonable option in selected patients who progressed on

trastuzumab-based therapy (ESO/ESMO Grade B, Level I)
⚬ insu cient evidence on use of trastuzumab plus lapatinib after progression on
pertuzumab or T-DM1
– o er additional HER2 targeted therapy with any subsequent treatment, except in presence of
contraindications (ESO/ESMO Grade A, Level I)
Estrogen receptor (ER) negative disease
● rst-line therapy 3
⚬ if previously untreated with HER2 targeted therapy, options include
– chemotherapy plus trastuzumab plus pertuzumab is standard rst-line therapy (ESO/ESMO

Grade A, Level I); chemotherapy agents to combine with trastuzumab plus pertuzumab include
– chemotherapy plus trastuzumab only, if pertuzumab not available
● when pertuzumab is not given, vinorelbine or a taxane may be used in combination with
trastuzumab; consider di erences in toxicity and patient preferences (ESO/ESMO Grade A,
Level I)
⚬ if previously treated with neoadjuvant and/or adjuvant HER2 targeted therapy, options include
– chemotherapy plus pertuzumab plus trastuzumab (ESO/ESMO Grade A, Level I); chemotherapy
agents to combine with trastuzumab plus pertuzumab include
– chemotherapy plus trastuzumab
● when pertuzumab is not given, vinorelbine or a taxane may be used in combination with
trastuzumab; consider di erences in toxicity and patient preferences (ESO/ESMO Grade A,
Level I)
⚬ if unsuitable for chemotherapy, or with minimal disease burden and long disease-free interval,
options include
– trastuzumab alone
– trastuzumab plus pertuzumab
– trastuzumab plus lapatinib
⚬ if no disease progression
– o er maintenance HER2 targeted therapy

– in patients achieving complete remission (ESO/ESMO Grade C, Expert opinion)
● optimal duration of maintenance therapy is unknown and should be balanced against

treatment toxicity, logistical burden, and cost
● stopping HER2 targeted therapy may be considered in select patients, especially if treatment
rechallenge is available in case of disease progression
– second-line therapy is ado-trastuzumab emtansine (T-DM1) (ESO/ESMO Grade A, Level I)
● superior e cacy relative to other second-line HER2 targeted therapies (lapatinib plus
capecitabine) after rst-line trastuzumab-based therapy
● preferred in patients with disease progression through ≥ 1 line trastuzumab-based therapy
● insu cient evidence on use of T-DM1 after trastuzumab plus pertuzumab
⚬ later line therapy includes
– trastuzumab plus a chemotherapy agent not previously used (ESO/ESMO Grade A, Level II);
chemotherapy options include
● vinorelbine (if not given in rst line)
● taxanes (if not given in rst line)
● capecitabine
● eribulin
● liposomal anthracyclines
● platinum
● gemcitabine
● metronomic chemotherapy
– for patients progressing on HER2 targeted therapy plus chemotherapy, o er additional HER2
targeted therapy plus di erent chemotherapy, except in presence of contraindications
(ESO/ESMO Grade A, Level I)
– trastuzumab plus lapatinib
● trastuzumab plus lapatinib is reasonable option in selected patients who progressed on

trastuzumab-based therapy (ESO/ESMO Grade B, Level I)
● insu cient evidence on use of trastuzumab plus lapatinib after progression on pertuzumab
or T-DM1
American Society of Clinical Oncology (ASCO)
● rst-line treatment
⚬ o er HER2 targeted therapy as rst-line treatment, except in highly selected patients with
hormone receptor (HR) positive disease for whom endocrine therapy alone may be used (ASCO
Strong recommendation, High quality evidence)
⚬ trastuzumab plus pertuzumab plus a taxane is recommended as rst-line treatment, unless patient
has contraindication to taxanes (ASCO Strong recommendation, High quality evidence)
⚬ for patients with HER2 positive and HR positive advanced breast cancer, options also include
– HER2 targeted therapy plus chemotherapy (ASCO Strong recommendation, High quality
evidence)
– endocrine therapy plus trastuzumab or lapatinib (in selected cases) (ASCO Moderate
recommendation, High quality evidence)
– endocrine therapy alone (in selected cases) (ASCO Weak recommendation, Intermediate quality
evidence); rst-line endocrine therapy may be used in special circumstances such as low
disease burden, presence of comorbidities such as congestive heart failure, and/or presence of
long disease-free interval (ASCO Weak recommendation, Intermediate quality evidence)
● second-line treatment for disease progression during or after rst-line HER2 targeted therapy
⚬ o er HER2 targeted therapy as second-line treatment (ASCO Strong recommendation, High quality
evidence)
⚬ trastuzumab emtansine (T-DM1) is recommended as second-line treatment (ASCO Strong
recommendation, High quality evidence)
● third-line or greater treatment for disease progression during or after second-line or greater HER2
targeted therapy
⚬ may o er HER2 targeted therapy as third-line treatment or greater (ASCO Moderate
recommendation, Intermediate quality evidence)
⚬ recommended regimens
– in patients who received no prior T-DM1, o er T-DM1 (ASCO Strong recommendation, High
quality evidence)
– in patients who received no prior pertuzumab, may o er pertuzumab (ASCO Weak
recommendation, Insu cient evidence)
– in patients who received prior pertuzumab and T-DM1, may o er any of the following (ASCO
Weak recommendation, Insu cient evidence)
● lapatinib plus capecitabine
● trastuzumab plus other chemotherapy combinations
● lapatinib plus trastuzumab
● endocrine therapy, in patients with HR positive disease
● if prior trastuzumab-based treatment in neoadjuvant or adjuvant setting and if
⚬ ≤ 12 months after completion, may follow second-line HER2 targeted therapy recommendations
(ASCO Moderate recommendation, Intermediate evidence)
⚬ > 12 months after completion, follow rst-line HER2 targeted therapy recommendations (ASCO
Strong recommendation, High quality evidence)
● for patients receiving combinations of HER2 targeted therapy plus chemotherapy
⚬ consider continuing chemotherapy ≥ 4-6 months and/or until maximal response, unless disease
progression or unacceptable toxicity (ASCO Moderate recommendation, Intermediate evidence)
⚬ when stopping chemotherapy, consider continuing HER2 targeted therapy with no further change
in regimen until disease progression or unacceptable toxicity (ASCO Moderate recommendation,
Intermediate evidence)
⚬ when chemotherapy ends and/or cancer progresses, may add endocrine therapy to HER2 targeted
therapy (ASCO Weak recommendation, Insu cient evidence)
● Reference - J Clin Oncol 2018 Sep 10;36(26):2736 full-text , summary can be found in J Oncol Pract
2018 Aug;14(8):501 full-text
Efficacy of HER2 Targeted Therapies for Metastatic Breast Cancer
Trastuzumab
Trastuzumab as first- or later-line therapy
STUDY
● SUMMARY
trastuzumab as first-line treatment may improve survival but may increase risk of heart failure
in women with HER2 positive metastatic breast cancer DynaMed Level 2
COCHRANE REVIEW: Cochrane Database Syst Rev 2014 Jun 12;(6):CD006242
Details
⚬ based on Cochrane review of trials without blinding
⚬ systematic review of 7 randomized trials comparing trastuzumab alone or in combination with
chemotherapy, hormonal therapy, or targeted agents vs. same regimen used in intervention group
without trastuzumab (control) in 1,497 women with HER2 positive metastatic breast cancer
⚬ 5 trials evaluated adjuvant trastuzumab as rst-line treatment until disease progression, trials
evaluated trastuzumab as adjuvant to chemotherapy (4 trials) or letrozole (1 trial)
⚬ trastuzumab as rst-line treatment associated with
– improved overall survival (hazard ratio [HR] for mortality 0.79, 95% CI 0.67-0.94) in analysis of 3
trials with 865 women
– improved progression-free survival (HR for relapse 0.56, 95% CI 0.49-0.65) in analysis of 5 trials
with 1,045 women
– increased heart failure in analysis of 5 trials with 1,013 women
● risk ratio (RR) 3.3 (95% CI 1.71-6.37)

● NNH 11-88 with heart failure in 1.6% of control group
– increase in left ventricular ejection fraction decline in analysis of 3 trials with 492 women
● RR 2.4 (95% CI 1.17-4.91)

● NNH 10-235 with left ventricular ejection fraction decline in 2.5% of control group
– nonsigni cant increase in neutropenia (RR 1.48, 95% CI 1.02-2.14) in analysis of 2 trials with 309
women
⚬ no signi cant di erences in neutropenic fever (2 trials with 309 women) and anemia (3 trials with
773 women)
⚬ brain metastases in 17.9% with trastuzumab vs. 9% with control (p < 0.05, NNH 11) in 1 trial with
469 women
⚬ Reference - Cochrane Database Syst Rev 2014 Jun 12;(6):CD006242
⚬
DynaMed Commentary
Because brain metastases typically occur later in the disease course, the increase in brain
metastases associated with trastuzumab is thought likely due to improved control of extra-
central nervous system disease with little or no e ect on the brain.
STUDY
● SUMMARY
addition of trastuzumab to lapatinib or capecitabine may improve progression-free survival but
might increase decline in left ventricular ejection fraction in women with HER2 positive,
trastuzumab-refractory metastatic breast cancer DynaMed Level 2
COCHRANE REVIEW: Cochrane Database Syst Rev 2014 Jun 12;(6):CD006242
Details
⚬ based on Cochrane review of trials without blinding of patients or personnel
⚬ systematic review of 7 randomized trials comparing trastuzumab alone or in combination with
chemotherapy, hormonal therapy, or targeted agents vs. same regimen used in intervention group
without trastuzumab (control) in 1,497 women with HER2 positive metastatic breast cancer
⚬ 2 trials evaluated trastuzumab as adjuvant to lapatinib or capecitabine in patients with disease
progression during prior trastuzumab-based therapy
⚬ adjuvant trastuzumab after disease progression associated with
– improved progression-free survival (hazard ratio [HR] for progression 0.72, 95% CI 0.59-0.88) in
analysis of 2 trials with 452 women
– nonsigni cant increase in left ventricular ejection fraction decline (risk ratio [RR] 3.21, 95% CI
1.19-8.64) in analysis of 2 trials with 446 women
⚬ no signi cant di erences in
– overall survival (HR for death 0.87, 95% 0.68-1.12) in analysis of 2 trials with 452 women
– heart failure (RR 5.31, 95% CI 0.87-32.2) in analysis of 2 trials with 446 women
– neutropenia, neutropenic fever, or anemia with addition of trastuzumab to capecitabine in 1
trial with 151 women
⚬ Reference - Cochrane Database Syst Rev 2014 Jun 12;(6):CD006242
Trastuzumab plus chemotherapy
Trastuzumab plus taxane or anthracycline
STUDY
● SUMMARY
addition of trastuzumab to chemotherapy may improve survival and time to disease progression
compared to chemotherapy alone in women with HER2 positive metastatic breast cancer that
did not receive prior chemotherapy in metastatic setting DynaMed Level 2
RANDOMIZED TRIAL: N Engl J Med 2001 Mar 15;344(11):783 | Full Text
Details
⚬ based on randomized trial without blinding
⚬ 469 women (mean age 52.8 years) with HER2 positive metastatic breast cancer and no prior
chemotherapy in metastatic setting were randomized to trastuzumab plus chemotherapy vs.
chemotherapy alone until disease progression
– trastuzumab plus chemotherapy group received trastuzumab 4 mg/kg loading dose followed by
2 mg/kg weekly, plus either
● an anthracycline (doxorubicin 60 mg/m2 or epirubicin 75 mg/m2) plus cyclophosphamide 600
mg/m2 once every 21 days for 6 cycles, for 143 women (30.5%) who did not receive any prior
anthracycline
● paclitaxel 175 mg/m2 once every 21 days for 6 cycles, for 92 women (19.6%) who had
previously received adjuvant anthracycline
– chemotherapy alone group received either
● an anthracycline (doxorubicin 60 mg/m2 or epirubicin 75 mg/m2) plus cyclophosphamide 600
mg/m2 once every 21 days for 6 cycles, for 138 women (29.4%) who did not receive any prior
anthracycline
● paclitaxel 175 mg/m2 once every 21 days for 6 cycles, for 96 women (20.5%) who had
previously received adjuvant anthracycline
⚬ 66% of women in chemotherapy alone group were allowed to cross over to trastuzumab arm upon
disease progression
⚬ median follow-up 30 months
⚬ comparing trastuzumab plus chemotherapy vs. chemotherapy alone
– median survival (not adjusted for crossover) 25.1 months vs. 20.3 months (p = 0.046)
– median time to disease progression 7.4 months vs. 4.6 months (p < 0.001); disease progression
de ned as > 25% increase in size of any measurable lesion
– median time to treatment failure 6.9 months vs. 4.5 months (p < 0.001); treatment failure
de ned as composite of disease progression, death, discontinuation of treatment, and use of
other antitumor therapy
– overall response in 50% vs. 32% (p < 0.001, NNT 6)
– adverse events (no p value reported)
● heart failure in 22% vs. 5%

● infection in 47% vs. 29%
● leukopenia in 41% vs. 26%
● anemia in 27% vs. 19%
⚬ in retrospective analysis of all cardiac dysfunction cases, cardiac dysfunction in
– 27% of women receiving trastuzumab plus anthracycline plus cyclophosphamide

– 13% of women receiving trastuzumab plus paclitaxel
– 8% of women receiving anthracycline plus cyclophosphamide
– 1% of women receiving paclitaxel
⚬ 2 deaths potentially related to trastuzumab treatment

⚬ Reference - N Engl J Med 2001 Mar 15;344(11):783 full-text
Trastuzumab plus antimetabolite
STUDY
● SUMMARY
trastuzumab plus capecitabine may not improve overall survival compared to capecitabine alone
in women with HER2 positive locally advanced or metastatic breast cancer that progressed on
prior trastuzumab treatment DynaMed Level 2
RANDOMIZED TRIAL: Eur J Cancer 2011 Oct;47(15):2273
Details
⚬ 156 women with HER2 positive locally advanced or metastatic breast cancer that progressed on
trastuzumab with or without rst-line chemotherapy were randomized to trastuzumab plus
capecitabine vs. capecitabine alone until disease progression or unacceptable toxicity
– trastuzumab 8 mg/kg IV loading dose, then 6 mg/kg, on day 1 plus capecitabine 1,250 mg/m2
orally twice daily on days 1-14 every 21 days
– capecitabine 1,250 mg/m2 orally twice daily on days 1-14 every 21 days
⚬ all women had prior trastuzumab ≥ 12 weeks and completed treatment < 6 weeks from start of trial
⚬ median follow-up 20.7 months
⚬ comparing trastuzumab plus capecitabine vs. capecitabine alone
– no signi cant di erences in median overall survival or median progression-free survival

– outcomes for third-line treatment following disease progression
● in subgroup analysis of 84 women compared according to initial randomization, no

signi cant di erences in overall survival
● in subgroup analysis of 140 women compared according to third-line treatment received,
median postprogression survival 18.8 months vs. 13.3 months (p = 0.02)
⚬ Reference - GBG 26/BIG 03-05 trial (Eur J Cancer 2011 Oct;47(15):2273 )
Trastuzumab plus lapatinib
STUDY
● SUMMARY
addition of trastuzumab to lapatinib may improve overall survival compared to lapatinib alone
in women with HER2 positive metastatic breast cancer that progressed on trastuzumab-based
therapy DynaMed Level 2
RANDOMIZED TRIAL: J Clin Oncol 2012 Jul 20;30(21):2585
Details
⚬ 296 women (median age 51-52 years) with HER2 positive metastatic breast cancer that progressed
on trastuzumab-based therapy were randomized to trastuzumab plus lapatinib vs. lapatinib alone
– trastuzumab 4 mg/kg IV loading dose, then 2 mg/kg weekly, plus lapatinib 1,000 mg orally daily
– lapatinib 1,500 mg orally daily
⚬ all women had progression while receiving trastuzumab plus anthracycline- or taxane-based
regimen
⚬ 77 women (52%) in lapatinib alone group crossed over to trastuzumab plus lapatinib after disease
progression ≥ 4 weeks on monotherapy; e cacy analysis based on 291 patients as randomly
assigned
⚬ comparing trastuzumab plus lapatinib vs. lapatinib alone
– median overall survival 14 months vs. 9.5 months (p = 0.026)

– median progression-free survival 11.1 weeks vs. 8.1 weeks (p = 0.01)
– factors associated with increased overall survival in subgroup analysis
● ECOG performance score 0 (HR 0.44 95% CI 0.34-0.58)

● < 3 metastatic sites (hazard ratio [HR] 0.44, 95% CI 0.33-0.57)
● no visceral disease (HR 0.59, 95% CI 0.43-0.81)
● no bone metastases (HR 0.74, 95% CI 0.56-0.96)
● no brain metastases (HR 0.64, 95% CI 0.44-0.92)
● no liver metastases (HR 0.58, 95% CI 0.45-0.76)
⚬ most common adverse events included diarrhea, nausea, rash, fatigue, and vomiting
⚬ Reference - EGF104900 trial ( J Clin Oncol 2012 Jul 20;30(21):2585 )
Trastuzumab plus other targeted therapy
STUDY
● SUMMARY
abemaciclib plus trastuzumab plus fulvestrant might improve progression-free survival
compared to single-agent chemotherapy plus trastuzumab in women with hormone receptor-
positive, HER2-positive advanced breast cancer with unresectable, locally advanced, recurrent,
or metastatic disease DynaMed Level 2
RANDOMIZED TRIAL: Lancet Oncol 2020 Jun;21(6):763
Details
⚬ based on randomized trial with con dence interval that includes di erences that are not clinically
important
⚬ 237 women (median age 55 years) with hormone receptor-positive, HER2-positive unresectable,
locally advanced, recurrent, or metastatic breast cancer were randomized to 1 of 3 treatments,
each given in 21-day cycles
– abemaciclib plus trastuzumab plus fulvestrant
● abemaciclib 150 mg orally every 12 hours

● trastuzumab 8 mg/kg IV on day 1 of cycle 1 and then 6 mg/kg on day 1 of all subsequent 21-
day cycles
● fulvestrant 500 mg intramuscularly on days 1 and 15 of cycle 1 and on day 8 of cycle 2 and
then once every 4 weeks for all subsequent cycles
– abemaciclib plus trastuzumab
– single-agent chemotherapy plus trastuzumab
⚬ additional inclusion criteria
– ≥ 2 previous HER2-targeted therapies for advanced breast cancer (alone or in combination with
chemotherapy or endocrine therapy)
– no prior treatment with fulvestrant
⚬ 87% had measurable disease

⚬ primary outcome was progression-free survival, de ned as time to progression or death with
signi cance de ned as 2-sided p value of < 0.2
⚬ clinical bene t de ned as complete or partial treatment response or stable disease for ≥ 6 months
⚬ median follow-up of 19 months; all patients included in analysis
⚬ comparing abemaciclib plus trastuzumab plus fulvestrant vs. chemotherapy plus trastuzumab
– median progression-free survival 8.3 months vs. 5.7 months (hazard ratio 0.67, 95% CI 0.45-1, p
= 0.051), signi cant, but CI includes di erences that are not clinically important
– complete or partial treatment response in 33% vs. 14% (p = 0.0042, NNT 6)
– clinical bene t in 58% vs. 38% (p = 0.0032, NNT 5)
⚬ median progression-free survival 5.7 months with abemaciclib plus trastuzumab vs. 5.7 months
with chemotherapy plus trastuzumab (not signi cant; signi cance of other outcomes not tested)
⚬ overall survival data were immature at time of analysis
⚬ grade 3-4 adverse events comparing abemaciclib plus trastuzumab plus fulvestrant vs. abemaciclib
plus trastuzumab vs. chemotherapy plus trastuzumab (no p values reported)
– any treatment-related adverse event in 68% vs. 50% vs. 48%
– neutropenia in 27% vs. 22% vs. 26%
– thrombocytopenia in 11% vs. 7% vs. 3%
– leukopenia in 10% vs. 3% vs. 10%
– diarrhea in 9% vs. 7% vs. 3%
– anemia in 9% vs. 4% vs. 4%
⚬ 2 treatment-related deaths reported, 1 due to pulmonary brosis with abemaciclib plus

trastuzumab and 1 due to febrile neutropenia with standard chemotherapy plus trastuzumab
⚬ Reference - monarcHER trial (Lancet Oncol 2020 Jun;21(6):763 ), editorial can be found in Lancet
Oncol 2020 Jun;21(6):734
Trastuzumab plus endocrine therapy
STUDY
● SUMMARY
addition of trastuzumab to anastrozole may improve progression-free survival compared to
anastrozole alone in women with HER2 positive and hormone receptor positive metastatic breast
cancer DynaMed Level 2
RANDOMIZED TRIAL: J Clin Oncol 2009 Nov 20;27(33):5529

Details
⚬ 207 postmenopausal women (median age 54-56 years) with HER2 positive and hormone receptor
positive breast cancer were randomized to trastuzumab plus anastrozole vs. anastrozole alone
until disease progression
– trastuzumab 4 mg/kg IV on day 1 followed by 2 mg/kg weekly plus anastrozole 1 mg/day orally
– anastrozole 1 mg/day orally
⚬ 150 women (72.5%) had hormone receptor positive disease con rmed by central testing, and 57
women (27.5%) had HR status determined locally as de ned by institutional criteria
⚬ 73 women (70%) randomized to anastrozole group crossed over to a trastuzumab regimen after
disease progression; all women were analyzed as randomized
⚬ comparing trastuzumab plus anastrazole vs. anastrozole alone
– median overall survival 28.5 months vs. 23.9 months (not signi cant)
– median progression-free survival 4.8 months vs. 2.4 months (p = 0.0016)
– adverse events (no p value reported)
● all grade cardiac events in 13.6% vs. 1.9%

● serious cardiac events in 1.9% vs. 1%
– in subgroup analysis of women with con rmed hormone receptor positive disease, median
progression-free survival 5.6 months vs. 3.8 months (p = 0.006)
⚬ Reference - TAnDEM trial (J Clin Oncol 2009 Nov 20;27(33):5529 ), editorial can be found in J Clin
Oncol 2009 Nov 20;27(33):5492
Trastuzumab biosimilars
STUDY
● SUMMARY
addition of trastuzumab biosimilar to taxane-based chemotherapy associated with similar
overall response and survival rates compared to addition of trastuzumab in women with HER2
positive metastatic breast cancer DynaMed Level 2
RANDOMIZED TRIAL: JAMA 2017 Jan 3;317(1):37
Details
⚬ based on randomized trial with protocol amendment during trial
⚬ 500 women with HER2 positive metastatic breast cancer were randomized to addition of
trastuzumab biosimilar vs. trastuzumab to taxane-based chemotherapy for ≥ 8 cycles (≥ 24 weeks)
or until disease progression or unacceptable toxicity and were followed for ≥ 48 weeks
– biosimilar or trastuzumab regimen was 8 mg/kg IV loading dose followed by 6 mg/kg every 3
weeks
– chemotherapy regimen was docetaxel 75 mg/m2 IV every 3 weeks or paclitaxel 80 mg/m2 IV
weekly
– women who had response or stable disease after 8 cycles were allowed to continue biosimilar
or trastuzumab without additional chemotherapy until disease progression
⚬ equivalence margin de ned as 2-sided 95% CI between -15% and +15% for di erence in overall
response rate (ORR) or 2-sided 90% CI between 0.81 and 1.24 for ratio of ORRs between groups at
24 weeks
⚬ 8% had prior rst-line therapy and no longer met inclusion criteria after protocol amendment
⚬ 34% discontinued treatment (mostly for prespeci ed reasons), 92% included in analyses
⚬ comparing biosimilar vs. trastuzumab
– 24-week ORR 69.6% vs. 64% (95% CI for di erence -3.08% to +14.04% and 90% for ORR ratio
0.97-1.21, equivalence met)
– 48-week overall survival 89.1% vs. 85.1% (not signi cant)
– 48-week progression-free survival 44.3% vs. 44.7% (not signi cant)
– 48-week tumor progression at 48 weeks in 41.3% vs. 43% (not signi cant)
– ≥ 1 serious adverse event at 24 weeks in 38.1% vs. 36.2% (no p value reported)
⚬ most common serious adverse events in both groups were neutropenia, febrile neutropenia, and
leukopenia
⚬ Reference - HERITAGE trial ( JAMA 2017 Jan 3;317(1):37 , editorial can be found in JAMA 2017 Jan
3;317(1):33 and JAMA 2017 Jan 3;317(1):30
Timing of trastuzumab
STUDY
● SUMMARY
sequential trastuzumab followed by paclitaxel may have similar overall survival compared to
concurrent trastuzumab plus chemotherapy in women with HER2 positive metastatic breast
cancer who had no prior HER2 targeted therapy DynaMed Level 2
RANDOMIZED TRIAL: Ann Oncol 2017 Feb 1;28(2):305 | Full Text
Details
⚬ 175 women (median age 53-57 years) with HER2 positive advanced breast cancer and no previous
HER2 targeted therapy randomized to 1 of 2 treatments
– sequential treatment of trastuzumab 4 mg/kg IV on day 1, then 2 mg/kg IV weekly, followed (at
disease progression) by addition of paclitaxel 90 mg/m2 mg/kg IV weekly for 3 weeks every 28
days or physician's choice of chemotherapy (taxane, vinorelbine, cisplatin) at standard dosing
regimens
– concurrent treatment of trastuzumab 4 mg/kg IV on day 1, then 2 mg/kg IV weekly, plus
physician's choice of chemotherapy (taxane, vinorelbine, cisplatin) at standard dosing regimens
⚬ previous neoadjuvant and/or adjuvant chemotherapy completed ≥ 6 months before enrollment
allowed following protocol amendment, but no previous taxanes allowed
⚬ chemotherapy could be changed due to adverse events, stopped after ≥ 24 weeks in responding
women or if unacceptable toxicity occurred, or reintroduced if clinically indicated
⚬ comparing sequential trastuzumab plus paclitaxel vs. concurrent trastuzumab plus chemotherapy
– median overall survival 35.6 months vs. 36.3 months (not signi cant)
– median time to progression 12.2 months vs. 10.3 months (p = 0.1)
– grade 3-4 adverse events (no p value reported)
● neutropenia in 15% vs. 27%

● alopecia in 10% vs. 10%
– in post hoc subgroup analysis of women without visceral disease, median time to progression
21.8 months vs. 10.1 months (p = 0.03)
⚬ Reference - Ann Oncol 2017 Feb 1;28(2):305 full-text
Pertuzumab plus trastuzumab plus chemotherapy

● addition of pertuzumab to trastuzumab plus docetaxel increases progression-free survival and
4-year overall survival in women with HER2 positive metastatic breast cancer DynaMed Level 1
⚬ based on randomized trial and follow-up study

⚬ 808 patients (median age 54 years) with HER2 positive metastatic breast cancer randomized to
rst-line treatment with pertuzumab IV at xed loading dose 840 mg followed by 420 mg every 3
weeks until disease progression or development of toxic e ects vs. placebo
⚬ all patients received
– trastuzumab IV loading dose of 8 mg/kg followed by maintenance dose 6 mg/kg every 3 weeks
until disease progression or development of toxic e ects
– docetaxel IV at starting dose of 75 mg/m2 every 3 weeks with goal of ≥ 6 cycles (dose could be
decreased if toxic e ects or increased if well tolerated)
⚬ progression-free survival de ned as time to rst radiographic evidence of progressive disease or
death from any cause within 18 weeks after last independent assessment of tumors
⚬ interim analysis of overall survival was performed after 165 events (43% of prespeci ed total
number for nal analysis) had occurred
⚬ comparing pertuzumab vs. placebo at median follow-up 19.3 months
– median progression-free survival 18.5 months vs. 12.4 months (p < 0.001)
– mortality at interim analysis 17.2% vs. 23.6% (p = 0.005, not signi cant with criterion for
signi cant di erence de ned as p ≤ 0.0012 to correct for interim analysis)
⚬ all patients included in follow-up study at median follow-up 50 months
⚬ 11.8% in placebo group had crossed over to pertuzumab
⚬ comparing pertuzumab vs. placebo
– median overall survival 56.5 months vs. 40.8 months (p < 0.001)
– 4-year overall survival 57.6% vs. 45.4% (p < 0.05, NNT 9)
– adverse events (no p values reported)
● any-grade adverse events
⚬ diarrhea in 66.8% vs. 46.3%

⚬ rash in 33.7% vs. 24.2%
⚬ mucosal in ammation in 27.8% vs. 19.9%
⚬ febrile neutropenia in 13.8% vs. 7.6%
⚬ dry skin in 10.6% vs. 4.3%
● grade 3-4 adverse events
⚬ diarrhea in 7.9% vs. 5%

⚬ febrile neutropenia in 13.8% vs. 7.6%
⚬ consistent ndings in analysis adjusted for patient crossovers

⚬ References
– CLEOPATRA trial ( N Engl J Med 2012 Jan 12;366(2):109 full-text )

– follow-up study N Engl J Med 2015 Feb 19;372(8):724
⚬ consistent ndings regardless of patient age
– based on prespeci ed subgroup analysis of CLEOPATRA trial

– 808 patients with HER2 positive metastatic breast cancer who were randomized to pertuzumab
plus trastuzumab plus docetaxel vs. placebo plus trastuzumab plus docetaxel were analyzed
– 16% were ≥ 65 years old
– comparing pertuzumab plus trastuzumab plus docetaxel vs. placebo plus trastuzumab plus
docetaxel
● median progression-free survival 17.2 months vs. 12.5 months in subgroup of women < 65
years old (hazard ratio for progression 0.65, 95% CI 0.53-0.8)
● median progression-free survival 21.6 months vs. 10.4 months in subgroup of women ≥ 65
years old (hazard ratio for progression 0.52, 95% CI 0.31-0.86)
– Reference - Breast Cancer Res Treat 2013 Nov;142(1):89 full-text
STUDY
⚬ SUMMARY
pertuzumab not associated with increased incidence of central nervous system metastases
DynaMed Level 2
RANDOMIZED TRIAL: Ann Oncol 2014 Jun;25(6):1116
Details
– based on post hoc secondary analysis of CLEOPATRA trial
– all patients were evaluated for central nervous system (CNS) metastases as rst site of disease
progression
– comparing pertuzumab plus trastuzumab plus docetaxel vs. placebo plus trastuzumab plus
docetaxel
● incidence of CNS metastases 13.7% vs. 12.6% (not signi cant)
● median time to development of CNS metastases 15 months vs. 11.9 months (p = 0.0049)
● median overall survival 34.4 months vs. 26.3 months in patients with CNS metastases (not
signi cant)
– Reference - Ann Oncol 2014 Jun;25(6):1116 full-text
Pertuzumab plus trastuzumab plus aromatase inhibitor
STUDY
● SUMMARY
addition of pertuzumab to trastuzumab plus aromatase inhibitor may increase progression-free
survival in postmenopausal women with HER2 positive, hormone receptor-positive
metastatic/locally advanced breast cancer DynaMed Level 2
RANDOMIZED TRIAL: J Clin Oncol 2018 Oct 1;36(28):2826
Details
⚬ 258 postmenopausal women (median age 60 years) with HER2 positive, hormone receptor-positive
metastatic/locally advanced breast cancer and no prior systemic nonhormonal anticancer therapy
for advanced disease were randomized to pertuzumab 840 mg IV followed by 420 mg IV every 3
weeks plus trastuzumab 8 mg/kg IV followed by 6 mg/kg IV every 3 weeks plus aromatase inhibitor
(anastrozole 1 mg or letrozole 2.5 mg orally once daily) vs. trastuzumab plus aromatase inhibitor
⚬ 146 patients had induction chemotherapy at investigator discretion (docetaxel IV every 3 weeks or
paclitaxel IV weekly for 18-24 weeks)
⚬ 100% included in analysis of primary outcome and 97% in analysis of adverse events
⚬ comparing pertuzumab plus trastuzumab plus aromatase inhibitor vs. trastuzumab plus
aromatase inhibitor
– median progression-free survival
● 18.9 months vs. 15.8 months (p = 0.007) in analysis of all patients

● 21.7 months vs. 12.45 months (p < 0.05) in subgroup analysis of patients who did not have
induction chemotherapy
● 16.89 months vs. 16.85 months (not signi cant) in subgroup analysis of patients who had
induction chemotherapy
– serious adverse events in 33.1% vs. 19.4% (no p value reported)
– grade ≥ 3 adverse events in 50.4% vs. 38.7% (no p value reported)
⚬ median overall survival not reached in either group

⚬ most common (> 5%) grade ≥ 3 adverse events were hypertension, diarrhea, and neutropenia
⚬ Reference - PERTAIN trial (J Clin Oncol 2018 Oct 1;36(28):2826 )
Ado-trastuzumab emtansine (T-DM1)
STUDY
● SUMMARY
T-DM1 with or without pertuzumab may have similar overall and progression-free survival
compared to trastuzumab plus taxane in women with HER2 positive advanced or metastatic
breast cancer and no prior chemotherapy DynaMed Level 2
RANDOMIZED TRIAL: J Clin Oncol 2017 Jan 10;35(2):141 | Full Text
Details
⚬ based on randomized noninferiority trial without blinding
⚬ 1,095 patients (median age 52-55 years) with HER2 positive advanced or metastatic breast cancer
and no prior chemotherapy were randomized to 1 of 3 treatments
– T-DM1 3.6 mg/kg IV once every 3 weeks (T-DM1 alone arm)
– T-DM1 3.6 mg/kg IV once every 3 weeks plus pertuzumab 840 mg IV loading dose followed by
420 mg IV once every 3 weeks (T-DM1 plus pertuzumab arm)
– trastuzumab plus taxane, either docetaxel or paclitaxel (trastuzumab plus taxane arm)
● trastuzumab 8 mg/kg IV loading dose, then 6 mg/kg IV every 3 weeks, plus docetaxel 75-100
mg/m2 IV on day 1 every 3 weeks for ≥ 6 cycles (18 weeks) or until disease progression or
● trastuzumab 4 mg/kg IV loading dose, then 2 mg/kg IV every 3 weeks, plus paclitaxel 80
mg/m2 IV on day 1 weekly for ≥ 6 cycles (18 weeks) or until disease progression or
⚬ median follow-up about 35 months
⚬ noninferiority of T-DM1 de ned as hazard ratio (HR) < 1.1765 for progression-free survival
compared to trastuzumab plus taxane at limit of 97.5% CI
⚬ comparing T-DM1 alone vs. T-DM1 plus pertuzumab vs. trastuzumab plus taxane
Endpoints T-DM1 T-DM1 Plus Trastuzumab Plus

Pertuzumab Taxane
Median 14.1 months* 15.2 months** 13.7 months

progression-
free survival
Pertuzumab Taxane
Overall 59.7% 64.2% 67.9%

response***
Mean duration 20.7 months 21.2 months 12.5 months

of responses***
Any grade ≥ 3 45.4% 46.2% 54.1%

adverse
events***
Grade ≥ 3 4.4% 2.7% 19.8%

neutropenia***
Grade ≥ 3 0% 0% 6.5%
febrile
neutropenia***
Grade ≥ 3 0.3% 2.5% 4.2%

diarrhea***
Grade ≥ 3 4.4% 4.9% 3.1%

hypertension**
*
Grade ≥ 3 4.7% 6% 2.8%

anemia
Grade ≥ 3 4.4% 5.2% 0.8%

elevated ALT***
Grade ≥ 3 6.6% 3% 0.3%

elevated AST***
Grade ≥ 3 6.4% 7.9% 0%

thrombocytope
nia***
Pertuzumab Taxane
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; HR, hazard

ratio.
*For progression-free survival with T-DM1 alone compared to trastuzumab plus taxane, HR
0.94 (97.5% CI 0.76-1.16, noninferiority met).
**For progression-free survival with T-DM1 plus pertuzumab compared to trastuzumab plus
taxane, HR 0.85 (97.5% CI 0.69-1.06, noninferiority met).
***No p value reported.
⚬ Reference - MARIANNE trial (J Clin Oncol 2017 Jan 10;35(2):141 full-text )

⚬ based on follow-up of MARIANNE trial
– 1,095 patients (100%) included in analysis

– median follow-up about 54 months
– median overall survival
● 53.7 months with T-DM1 alone (not signi cant vs. trastuzumab plus taxane)
● 51.8 months with T-DM1 plus pertuzumab (not signi cant vs. trastuzumab plus taxane)
● 50.9 months with trastuzumab plus taxane
– any grade ≥ 3 adverse event (no p values reported)
● 47.1% with T-DM1 alone

● 48.6% with T-DM1 plus pertuzumab
● 55.8% with trastuzumab plus taxane
– median time to clinically important deterioration in neurotoxicity symptoms
● 6.2 months with T-DM1 alone (p < 0.05 vs. trastuzumab plus taxane)
● 4.2 months with T-DM1 plus pertuzumab (p < 0.05 vs. trastuzumab plus taxane)
● 2.1 months with trastuzumab plus taxane
– Reference - Cancer 2019 Jul 18 early online PDF
STUDY
● SUMMARY
T-DM1 may increase overall survival compared to lapatinib plus capecitabine in women with
HER2 positive locally advanced or metastatic breast cancer progressing after treatment with
trastuzumab and a taxane DynaMed Level 2
RANDOMIZED TRIAL: N Engl J Med 2012 Nov 8;367(19):1783
Details
⚬ 991 women (median age 53 years) with HER2 positive locally advanced or metastatic breast cancer
were randomized to 1 of 2 treatments
– T-DM1 3.6 mg/kg IV every 21 days
– lapatinib 1,250 mg/day orally plus capecitabine 1,000 mg/m2 orally every 12 hours on days 1-14
of each 21-day cycle
⚬ all women previously treated with trastuzumab and taxane at baseline
⚬ all analyses based on rst interim analysis (median follow-up about 13 months) except for overall
survival which was based on second interim analysis (median follow-up about 19 months)
⚬ progression-free survival de ned as time to progression or death from any cause
⚬ median overall survival at second interim analysis met pre-speci ed stopping boundary for e cacy
⚬ comparing T-DM1 vs. lapatinib plus capecitabine
– median overall survival 30.9 months vs. 25.1 months (p < 0.001)
– complete or partial objective response in 43.6% vs. 30.8% (p < 0.001, NNT 8)
– grade 3 or 4 adverse events in 41% vs. 57% (no p value reported)
⚬ Reference - EMILIA trial (N Engl J Med 2012 Nov 8;367(19):1783 ), correction can be found in N
Engl J Med 2013 Jun 20;368(25):2442, editorial can be found in N Engl J Med 2012 Nov
8;367(19):1847
⚬ consistent results in analysis of nal overall survival results
– based on follow-up of EMILIA trial

– 136 women (27%) in lapatinib plus capecitabine group crossed over to T-DM1 group after
second interim overall survival analysis
– median follow-up 47.8 months in T-DM1 group and 41.9 months in lapatinib plus capecitabine
group
– comparing T-DM1 vs. lapatinib plus capecitabine
● median overall survival 29.9 months vs. 25.9 months (hazard ratio 0.75, 0.64-0.88)
● grade 3 or 4 adverse events in 48% vs. 60% (no p value reported)
– Reference - Lancet Oncol 2017 Jun;18(6):732 full-text , editorial can be found in Lancet
Oncol 2017 Jun;18(6):696
STUDY
● SUMMARY
T-DM1 may increase progression-free survival compared to other treatments in women with
previously treated HER2 positive advanced breast cancer DynaMed Level 2
Details
⚬ 602 women with previously treated HER2 positive advanced breast cancer were randomized to T-
DM1 3.6 mg/kg IV once every 21 days vs. physician's treatment choice until disease progression or
⚬ physician's treatment choice included chemotherapy with any single drug, hormonal therapy with
1-2 drugs, or HER2-directed therapy alone or in combination with chemotherapy or hormonal
therapy
⚬ all patients had
– left ventricular ejection fraction ≥ 50% and Eastern Cooperative Oncology Group performance
status score 0-2 (lower score = better functional status)
– ≥ 2 prior HER2-directed regimens including trastuzumab plus lapatinib for advanced disease and
prior taxane therapy in any setting
⚬ 22% in physician's treatment choice group crossed over to T-DM1 group upon disease progression
⚬ median follow-up 7.2 months in trastuzumab emtansine group and 6.5 months in physician's
choice group
⚬ comparing T-DM1 vs. physician's treatment choice
– median progression-free survival (de ned as disease progression or death) 6.2 months vs. 3.3
months (p < 0.0001)
– median overall survival not reached vs. 14.9 months (p = 0.003) in interim analysis, but stopping
boundary not reached
– serious adverse events in 18% vs. 21% (no p value reported)
⚬ Reference - TH3RESA trial (Lancet Oncol 2014 Jun;15(7):689 ), editorial can be found in Lancet
Oncol 2014 Jun;15(7):668
STUDY
● SUMMARY
T-DM1 may increase overall survival compared to other treatments in women with previously
treated HER2 positive advanced breast cancer DynaMed Level 2
Details
⚬ based on nal analysis of overall survival data from TH3RESA trial
⚬ at data cuto , 133 patients (33%) in T-DM1 group and 41 patients (21%) in physician's treatment
choice group remained on study, and 93 women (47%) in physician's treatment choice group
crossed over to T-DM1 group; all results were based on intention-to-treat analysis population
⚬ median duration of treatment 5.22 months for T-DM1 group vs. 2.79 months for physician’s
treatment choice group
⚬ comparing T-DM1 vs. physician's treatment choice
– median overall survival 22.7 months vs. 15.8 months (p = 0.0007)

– grade 3-4 adverse events in 40% vs. 47% (no p value reported)
● thrombocytopenia in 6% vs. 3%
● hemorrhage of any type in 4% vs. < 1%
● neutropenia in 3% vs. 16%
● febrile neutropenia in < 1% vs. 4%
● diarrhea in 1% vs. 4%
⚬ Reference - Lancet Oncol 2017 Jun;18(6):743 , editorial can be found in Lancet Oncol 2017
Jun;18(6):696
Trastuzumab deruxtecan
● trastuzumab deruxtecan (DS-8201) is antibody-drug conjugate of anti-human epidermal growth factor

receptor 2 (HER2) antibody, cytotoxic topoisomerase I inhibitor, and cleavable tetrapeptide-based
linker
STUDY
● SUMMARY
trastuzumab deruxtecan reported to induce response in about 60% with median duration 15
months in women with previously-treated HER2 positive unresectable or metastatic breast
cancer DynaMed Level 3
UNCONTROLLED TRIAL: N Engl J Med 2019 Dec 11 early online
Details
⚬ based on uncontrolled trial
⚬ in part 1 of trial, 253 adults with HER2 positive unresectable or metastatic breast cancer previously
treated with trastuzumab emtansine (Eastern Cooperative Oncology Group [ECOG] performance
score 0-1) received trastuzumab deruxtecan IV every 3 weeks at 1 of 3 doses (5.4 mg/kg, 6.4 mg/kg,
7.4 mg/kg)
⚬ trastuzumab deruxtecan 5.4 mg/kg was chosen as recommended dose based on predicted bene t-
risk pro le
⚬ in part 2 of trial, 184 women (median age 55 years, 52.7% hormone receptor positive) received 5.4
mg/kg and were included in analysis
– median number of previous treatment regimens 6 (range 2-27)
– previous treatments included trastuzumab emtansine in 100%, trastuzumab in 100%,
pertuzumab in 65.8%, and other anti-HER2 therapies in 54.3%
⚬ median follow-up 11.1 months (range 0.7-19.9 months)
⚬ outcomes with trastuzumab deruxtecan 5.4 mg/kg
– objective response in 60.9%

– median response duration 14.8 months
– median progression-free survival 16.4 months
– interstitial lung disease in 13.6% (grade 3 in patient and grade 5 in 4 patients)
– most common adverse events ≥ grade 3
● decreased neutrophil count in 20.7%

● anemia in 8.7%
● nausea in 7.6%
⚬ consistent results for objective response rates in subgroups by hormone receptor status, number
of prior regimens, and presence of brain or visceral metastases
⚬ Reference - DESTINY-Breast01 trial (N Engl J Med 2019 Dec 11 early online )
Lapatinib
Lapatinib plus chemotherapy vs. chemotherapy alone
STUDY
● SUMMARY
addition of lapatinib to paclitaxel may improve overall survival in patients with newly diagnosed
HER2 positive metastatic breast cancer DynaMed Level 2
RANDOMIZED TRIAL: J Clin Oncol 2013 Jun 1;31(16):1947
Details
⚬ based on randomized trial with allocation concealment not stated
⚬ 444 patients (median age 50 years) with newly diagnosed HER2 positive metastatic breast cancer
randomized to lapatinib 1,500 mg once daily orally vs. placebo until disease progression or toxicity
and followed for ≥ 18 months
⚬ all patients received paclitaxel 80 mg/m2 IV once weekly for 3 weeks every 4 weeks for ≥ 6 cycles
⚬ 77% had prior treatment for nonmetastatic disease, including 1% who had adjuvant treatment with
trastuzumab
⚬ comparing lapatinib vs. placebo

– overall response rate 69% vs. 50% (p < 0.001)
– ≥ grade 3 diarrhea in 20% vs. 1% (no p value reported)
– ≥ grade 3 neutropenia in 51% vs. 20% (no p value reported)
⚬ Reference - J Clin Oncol 2013 Jun 1;31(16):1947 , commentary can be found in Nat Rev Clin Oncol
2013 Jun;10(6):312
STUDY
● SUMMARY
addition of lapatinib to paclitaxel may increase event-free survival in women with HER2
positive metastatic breast cancer DynaMed Level 2
RANDOMIZED TRIAL: J Clin Oncol 2008 Dec 1;26(34):5544 | Full Text
Details
⚬ based on post hoc analysis of randomized trial
⚬ 579 women (mean age 51.8 years) with metastatic breast cancer were randomized to paclitaxel 175
mg/m2 every 3 weeks plus lapatinib 1,500 mg/day vs. paclitaxel 175 mg/m2 plus placebo every 3
weeks
⚬ no signi cant di erences in overall survival, event-free survival, and time to progression in analysis
of intention-to-treat population
⚬ comparing lapatinib plus paclitaxel vs. paclitaxel in subgroup analysis of 86 women (14.8%) with
HER2 positive disease
– median event-free survival 35.1 weeks vs. 21.9 weeks (p = 0.004)
– median time to progression 36.4 weeks vs. 25.1 weeks (p = 0.005)
– median overall survival 104.6 weeks vs. 82.4 weeks (not signi cant)
⚬ serious adverse events in 35% vs. 22% (no p value reported)

⚬ Reference - J Clin Oncol 2008 Dec 1;26(34):5544 full-text , commentary can be found in J Clin
Oncol 2009 Apr 10;27(11):1919 and Nat Rev Clin Oncol 2009 Jun;6(6):308
STUDY
● SUMMARY
addition of lapatinib to capecitabine may reduce rate of progression in women with HER2
positive locally advanced or metastatic breast cancer that progressed on trastuzumab (level 2
[mid-level] evidence)
RANDOMIZED TRIAL: N Engl J Med 2006 Dec 28;355(26):2733 | Full Text
Details
⚬ 324 women with HER2 positive, locally advanced (stage IIIB or IIIC) or metastatic breast cancer that
had progressed after treatment with anthracycline, taxane, and trastuzumab were randomized to
lapatinib plus capecitabine vs. capecitabine alone
– combination therapy was lapatinib dose 1,250 mg/day on continuous basis, plus capecitabine
dose 2,000 mg/m2 /day in 2 divided doses on days 1-14 of 21-day cycle
– capecitabine monotherapy was 2,500 mg/m2 /day in 2 divided doses on days 1-14 of 21-day
cycle
⚬ comparing lapatinib plus capecitabine vs. capecitabine alone
– disease progression in 30.1% vs. 44.7% (p < 0.001, NNT 7)

– median time to progression 8.4 months vs. 4.4 months (p < 0.001)
– death 22.1% vs. 21.7% (not signi cant)
– disease progression or death from breast cancer in 36.2% vs. 46% (p = 0.002, NNT 11)
– median time to progression or death from breast cancer 5.9 months vs. 4.3 months (p = 0.002)
– diarrhea in 60% vs. 39% (p < 0.001, NNH 4)
– rash in 27% vs. 15% (p = 0.011, NNH 8)
– dyspepsia in 11% vs. 3% (p = 0.014, NNH 12)
⚬ Reference - N Engl J Med 2006 Dec 28;355(26):2733 full-text , correction can be found in N Engl
J Med 2007 Apr 5;356(14):1471; author reply 1471 , editorial can be found in N Engl J Med 2006
Dec 28;355(26):2783 , commentary can be found in N Engl J Med 2007 Apr 5;356(14):1471
Lapatinib plus chemotherapy vs. trastuzumab plus chemotherapy
STUDY
● SUMMARY
addition of lapatinib to taxane may decrease progression-free survival compared to addition of
trastuzumab to taxane in women with HER2 positive metastatic breast cancer DynaMed Level 2
RANDOMIZED TRIAL: J Clin Oncol 2015 May 10;33(14):1574
Details
⚬ based on randomized noninferiority trial without blinding
⚬ 652 women (median age 54.9 years) with HER2 positive metastatic breast cancer were randomized
to 1 of 2 treatments until disease progression
– lapatinib 1,250 mg/day orally plus a taxane for 24 weeks, then lapatinib 1,500 mg/day orally as
monotherapy after 24 weeks; taxane options included
● paclitaxel 80 mg/m2 IV weekly on days 1, 8, and 15, cycled every 28 days
● docetaxel 75 mg/m2 IV once every 3 weeks
– trastuzumab plus a taxane for 24 weeks, followed by trastuzumab 6 mg/kg IV once every 3
weeks as monotherapy; trastuzumab plus taxane options included
● trastuzumab 4 mg/kg IV loading dose, then 2 mg/kg IV, once weekly plus paclitaxel 80 mg/m2
IV weekly on days 1, 8, and 15, cycled every 28 days
● trastuzumab 8 mg/kg IV loading dose, then 6 mg/kg, once every 3 weeks plus docetaxel 75
mg/m2 once every 3 weeks
⚬ 537 patients (82%) had centrally con rmed HER2 positive disease
⚬ 644 patients (99%) had no prior (neo)adjuvant HER2 targeted or taxane-based therapy
⚬ noninferiority of lapatinib plus taxane de ned as hazard ratio < 1.25 for median progression-free
survival compared to trastuzumab plus a taxane at limit of 95% C
⚬ comparing lapatinib plus taxane vs. trastuzumab plus taxane
– median progression-free survival
● 9 months vs. 11.3 months (hazard ratio [HR] 1.37, 95% CI 1.13-1.65, noninferiority not met) in
intention-to-treat analysis population
● 9.1 months vs. 13.6 months (HR 1.48, 95% CI 1.2-1.83, noninferiority not met) in patients with
centrally con rmed HER2 positive tumors
– grade 3-4 adverse events
● diarrhea in 19% vs. 1% (p < 0.001, NNH 5)

● rash in 8% vs. 0% (p < 0.001, NNH 12)
● febrile neutropenia in 17.3% vs. 2% (no p value reported) in patients who received docetaxel
– estrogen receptor positive disease associated with improved progression-free survival in
multivariable analysis (p = 0.04)
⚬ Reference - NCIC CTG MA.31 trial (J Clin Oncol 2015 May 10;33(14):1574 ), editorial can be found
in J Clin Oncol 2015 May 10;33(14):1530
STUDY
● SUMMARY
addition of lapatinib to capecitabine is associated with lower overall survival and progression-
free survival compared to addition of trastuzumab to capecitabine in women with HER2 positive
metastatic breast cancer DynaMed Level 2
RANDOMIZED TRIAL: J Clin Oncol 2015 May 10;33(14):1564
Details
⚬ based on randomized trial without blinding and with early termination
⚬ 540 women (median age 55 years) with HER2 positive metastatic breast cancer and no central
nervous system metastases at baseline were randomized to 1 of 2 treatments
– lapatinib 1,250 mg orally daily plus capecitabine 2,000 mg/m2 /day orally on days 1-14 every 21
days
– trastuzumab 8 mg/kg IV loading dose followed by 6 mg/kg every 3 weeks plus capecitabine
2,500 mg/m2 /day on days 1-14 every 21 days
⚬ all women had prior anthracycline- or taxane-based treatment in (neo)adjuvant or metastatic
setting
⚬ study design amended to include interim analysis of safety and e cacy after ≥ 40% of patients had
been observed for ≥ 1 year, experienced disease progression, or died
⚬ trial terminated early due to lower than expected incidence of central nervous system metastases
after interim analysis of 475 patients; analysis based on intention-to-treat population
⚬ comparing lapatinib plus capecitabine vs. trastuzumab plus capecitabine
– median progression-free survival 6.6 months vs. 8.1 months (p = 0.021)

– incidence of central nervous system metastases in 3% vs. 5% (not signi cant)
– serious adverse events in 13% vs. 17% (no p value reported)
– grade 3-4 adverse events (no p value reported)
● hand-foot syndrome in 9.3% vs. 15.4%

● diarrhea in 5.9% vs. 7.9%
● neutropenia in 3.4% vs. 5.6%
⚬ Reference - CEREBEL trial (J Clin Oncol 2015 May 10;33(14):1564 ), editorial can be found in J Clin
Oncol 2015 May 10;33(14):1564
Lapatinib plus aromatase inhibitor
STUDY
● SUMMARY
addition of lapatinib to trastuzumab plus an aromatase inhibitor may improve progression-free
survival compared to trastuzumab plus an aromatase inhibitor in women with hormone receptor
positive, HER2 positive metastatic breast cancer that received prior endocrine therapy and/or
trastuzumab DynaMed Level 2
RANDOMIZED TRIAL: J Clin Oncol 2018 Mar 10;36(8):741

Details
⚬ 355 postmenopausal women (median age 54-57 years) with hormone receptor (HR) positive, HER2
positive metastatic breast cancer were randomized to 1 of 3 treatments and treated until disease
progression or unacceptable toxicity
– lapatinib 1,000 mg/day orally plus trastuzumab 8 mg/kg IV loading dose, followed by 6 mg/kg IV,
every 3 weeks plus an aromatase inhibitor (AI)
– lapatinib 1,500 mg/day orally plus AI
– trastuzumab 8 mg/kg IV loading dose, followed by 6 mg/kg, every 3 weeks plus AI
⚬ AIs included letrozole 2.5 mg/day orally, anastrazole 1 mg/day orally, or exemestane 25 mg/day
orally
⚬ 343 women (97%) had prior endocrine therapy and all women had prior trastuzumab
Table 3. Comparing Lapatinib Plus Trastuzumab Plus AI vs. Lapatinib Plus AI

vs. Trastuzumab Plus AI
Lapatinib Lapatinib Plus AI Trastuzumab

Plus Plus AI
Trastuzuma
b Plus AI
Median 11 months* 8.3 months** 5.7 months

progression-free
survival
Complete or partial 31.7%*** 18.6%**** 13.7%

response
Any grade 3-4 34% 17% 10%

adverse event (no p
values reported)
Diarrhea 13% 6% 0%
Rash 0% 3% 0%
Nausea 0% 2% 0%
Paronychia 0% 2% 0%
Lapatinib Lapatinib Plus AI Trastuzumab
Plus Plus AI
Trastuzuma
b Plus AI
Abbreviation: AI, aromatase inhibitor. *p = 0.0064 compared to trastuzumab plus AI.**p =

0.0361 compared to trastuzumab plus AI.***p = 0.0017 (NNT 6) compared to trastuzumab
plus AI.****No signi cant di erence compared to trastuzumab plus AI.
⚬ Reference - ALTERNATIVE trial (J Clin Oncol 2018 Mar 10;36(8):741 )
STUDY
● SUMMARY
addition of lapatinib to letrozole may increase progression-free survival in postmenopausal
women with HER2 positive, hormone receptor positive metastatic breast cancer
DynaMed Level 2
RANDOMIZED TRIAL: J Clin Oncol 2009 Nov 20;27(33):5538 | Full Text
Details
⚬ based on randomized trial with allocation concealment not stated
⚬ 219 postmenopausal women with HER2/hormone receptor-copositive metastatic breast cancer
were randomized to letrozole 2.5 mg/day plus lapatinib 1,500 mg/day orally vs. letrozole alone until
progression or withdrawal from trial
⚬ comparing letrozole plus lapatinib vs. letrozole alone
– median progression-free survival 8.2 months vs. 3 months (p = 0.019)

– clinical bene t (responsive or stable disease ≥ 6 months) in 48% vs. 29% (p = 0.003, NNT 6)
⚬ Reference - J Clin Oncol 2009 Nov 20;27(33):5538 full-text , editorial can be found in J Clin
Oncol 2009 Nov 20;27(33):5492 , also published in Oncologist 2010;15(2):122
Tucatinib
● tucatinib is an oral, highly selective HER-2 tyrosine kinase inhibitor
⚬ tucatinib (Tukysa) FDA approved for treatment of advanced unresectable or metastatic HER-2
positive breast cancer (in combination with trastuzumab plus capecitabine) in adults who have
received prior anti-HER-2 based regimens
– e cacy based on HER2CLIMB clinical trial
– dosing and administration
● 300 mg orally twice daily (in combination with trastuzumab plus capecitabine) until disease
progression or unacceptable toxicity
● tablets must be swallowed whole and not chewed, crushed, or split; broken tablets must not
be ingested
● dosing must be modi ed according to adverse e ects (see package insert for details)
– adverse e ects (in ≥ 20%) include diarrhea, palmar-plantar erythrodysesthesia, nausea, fatigue,
hepatotoxicity, vomiting, stomatitis, decreased appetite, abdominal pain, headache, anemia,
and rash
– Reference - FDA Press Release 2020 Apr 17
STUDY
● SUMMARY
in adult patients with human epidermal growth factor receptor 2 (HER2) positive metastatic
breast cancer with or without brain metastases and previously treated with trastuzumab,
pertuzumab, and trastuzumab emtansine, addition of tucatinib to trastuzumab plus capecitabine
improves overall and progression-free survival DynaMed Level 1
RANDOMIZED TRIAL: N Engl J Med 2019 Dec 11 early online
Details
⚬ based on randomized trial
⚬ 612 adults (median age 54 years, 99% women) with HER2 positive metastatic breast cancer with
(47.5%) or without brain metastases who had progression after trastuzumab, pertuzumab, and
trastuzumab emtansine were randomized to tucatinib 300 mg orally twice daily vs. placebo
– all patients given trastuzumab 6 mg/kg IV once every 21 days (initial loading dose 8 mg/kg)
(subcutaneous administration allowed) plus capecitabine 1,000 mg/m2 orally twice daily on days
1-14 of every 21-day cycle
– all patients had Eastern Cooperative Oncology Group (ECOG) score 0-1
⚬ tucatinib is selective inhibitor of the HER2 tyrosine kinase with minimal inhibition of epidermal
growth factor receptor
⚬ protocol amended to increase enrollment from 180 to 600 patients
⚬ primary outcome was progression-free survival among rst 480 (78%) randomized patients
(primary outcome population)
⚬ 100% included in analyses of secondary outcomes
⚬ comparing tucatinib vs. placebo
– in all patients
● median overall survival 21.9 months vs. 17.4 months (hazard ratio [HR] for death 0.66, 95% CI
0.5-0.88)
● estimated 2-year overall survival 44.9% vs. 26.6% (no p value reported)
● median progression-free survival 8.1 months vs. 5.5 months (HR for progression or death
0.54, 95% CI 0.42-0.68)
– in all patients with brain metastases
● median progression-free survival 7.6 months vs. 5.4 months (HR for disease progression or
death 0.48, 95% CI 0.34-0.69)
● estimated 1-year progression-free survival 24.9% vs. 0% (p < 0.05, NNT 4)
– in primary outcome population
● median progression-free survival 7.8 months vs. 5.6 months (HR for disease progression or
death 0.54, 95% CI 0.42-0.71)
● estimated 1-year progression-free survival 33.1% vs. 12.3% (p < 0.05, NNT 5)
– discontinuation due to adverse event in 5.7% vs. 3% (no p value reported)

– adverse event leading to death in 1.5% vs. 2.5% (no p value reported)
– any ≥ grade 3 adverse event in 55.2% vs. 48.7% (no p value reported)
● diarrhea in 12.9% vs. 8.6% (no p value reported)

● palmar-plantar erythrodysesthesia syndrome in 13.1% vs. 9.1% (no p value reported)
● alanine aminotransferase elevation in 5.4% vs. 0.5% (no p value reported)
● fatigue in 4.7% vs. 4.1% (no p value reported)
● aspartate aminotransferase elevation in 4.5% vs. 0.5% (no p value reported)
⚬ Reference - HER2CLIMB trial (N Engl J Med 2019 Dec 11 early online )
Neratinib
● neratinib plus capecitabine
⚬ neratinib (Nerlynx) receives expanded FDA approval in combination with capecitabine for
treatment of advanced or metastatic HER2 positive breast cancer in adults who have received ≥ 2
prior anti-HER2 based regimens in metastatic setting
– e cacy based on 1 randomized trial without blinding evaluating addition of neratinib or
lapatinib to capecitabine in 621 patients; comparing neratinib vs. lapatinib
● median progression free survival (PFS) 5.6 months vs. 5.5 months (hazard ratio [HR] 0.76,
95% CI 0.63-0.93)
● PFS at 12 months in 29% vs. 15%
● median overall survival was 21 months vs. 18.7 months (not signi cant)
● median duration of response was 8.5 months vs. 5.6 months
– References - FDA Press Release 2020 Feb 26 , FDA Label 2020 Feb
● neratinib plus other chemotherapy regimens
STUDY
⚬ SUMMARY
neratinib plus paclitaxel might not improve progression-free survival compared to
trastuzumab plus paclitaxel in women with previously untreated locally recurrent or
metastatic HER2 positive breast cancer DynaMed Level 2
RANDOMIZED TRIAL: JAMA Oncol 2016 Dec 1;2(12):1557
Details
– based on randomized trial without blinding and with inadequate statistical power
– 479 women (median age 54.5-55 years) with previously untreated inoperable recurrent or
metastatic HER2 positive breast cancer were randomized to 1 of 2 treatments until disease
progression
● neratinib 240 mg orally daily plus paclitaxel 80 mg/m2 IV on days 1, 8, and 15 every 28 days
● trastuzumab 4 mg/kg IV loading dose, then 2 mg/kg weekly, plus paclitaxel 80 mg/m2 IV on
days 1, 8, and 15 every 28 days
– at baseline 464 women (96.9%) had distant metastases including 18 (3.7%) in central nervous
system, 13 women (2.7%) had inoperable local recurrence, and 2 women (0.4%) had unknown
metastases status
– accrual goal reduced from planned 1,200 to 480 women, and hence study was no longer
powered for primary outcome(progression-free survival)
– median follow-up 23 months
– comparing neratinib plus paclitaxel vs. trastuzumab plus paclitaxel
● median progression-free survival 12.9 months vs. 12.9 months (not signi cant)
● symptomatic or progressive central nervous system events in 8.3% vs. 17.3% (p = 0.002, NNH
11 for trastuzumab plus paclitaxel)
● most common grade 3-4 adverse events (no p value reported)
⚬ diarrhea in 30.4% vs. 3.8%

⚬ neutropenia in 12.9% vs. 14.5%
⚬ leukopenia in 7.9% vs. 10.7%
– Reference - NEfERT-T trial (JAMA Oncol 2016 Dec 1;2(12):1557
Treatment Response
● World Health Organization (WHO) response evaluation criteria in solid tumors
⚬ evaluation of measurable disease
– complete response (CR) de ned as disappearance of all known disease determined by 2

observations ≥ 4 weeks apart
– partial response (PR) de ned as
● ≥ 50% decrease in
⚬ total target lesions determined by 2 observations ≥ 4 weeks apart

⚬ single lesion (multiplication of longest diameter by greatest perpendicular diameter)
⚬ multiple lesions (sum of products of perpendicular diameters)
⚬ linear tumor measurement
● no additional lesions or progression of any lesion
– progressive disease (PD) de ned as either of
● ≥ 25% increase in size of ≥ 1 lesion

● appearance of new lesions
– stable disease (SD) de ned as either of
● 50% decrease in total tumor size has not been established

● 25% increase in size of ≥ 1 lesion has not been demonstrated
⚬ evaluation of nonmeasurable disease
– CR de ned as disappearance of all known disease for ≥ 4 weeks

– PR de ned as estimated ≥ 50% decrease in tumor size for ≥ 4 weeks
– progressive disease de ned as either of
● estimated ≥ 25% increase in size of ≥ 1 lesion

– stable disease de ned as no signi cant change for ≥ 4 weeks, including
● estimated ≤ 50% decrease in total tumor size

● estimated ≤ 25% increase in size of ≥ 1 lesion
⚬ evaluation of bone metastases
– CR de ned as disappearance of all lesions on x-ray or scan for ≥ 4 weeks

– PR de ned as partial decrease in size of lytic lesions, recalci cation of lytic lesions, or decreased
density of blastic lesions for ≥ 4 weeks
– progressive disease de ned as either of
● increase in size of existent lesions

– stable disease de ned as no change for ≥ 8 weeks
⚬ Reference - Cancer 1981 Jan 1;47(1):207
● response evaluation criteria in solid tumors version 1.1 (RECIST 1.1)
⚬ evaluation of target lesions
– CR de ned as both of
● disappearance of all target lesions

● any pathological lymph nodes (either target or nontarget) must have reduction in short axis
to < 10 mm
– PR de ned as ≥ 30% decrease in sum of diameters of target lesions (from baseline sum
diameters)
– PD de ned as 1 of
● ≥ 20% increase in sum of diameters of target lesions (from whatever is the smallest sum on
record, including baseline sum if that is the smallest recorded) plus absolute increase of ≥ 5-
mm increase in sum of diameters of target lesions
● appearance of ≥ 1 new lesion(s)
– SD de ned as either of
● insu cient shrinkage to qualify for PR (from whatever is the smallest sum on record,
including baseline sum if that is the smallest recorded)
● insu cient increase to qualify for PD (from whatever is the smallest sum on record, including
baseline sum if that is the smallest recorded)
⚬ evaluation of nontarget lesions
– CR de ned as both of
● disappearance of all nontarget lesions and normalization of tumor marker level

● all lymph nodes must be de ned as nonpathological (short axis < 10 mm)
– non-CR/nonprogressive disease de ned as persistence of ≥ 1 nontarget lesions and/or

maintenance of tumor marker level above normal limit
– PD de ned as 1 of
● unequivocal progression (overall level of substantial worsening of existing nontarget lesions

such that, even with SD or PR in target disease, overall tumor burden has increased
su ciently to merit stopping therapy) of existing nontarget lesions
● appearance of ≥ 1 new lesion(s)
⚬ Reference - Eur J Cancer 2009 Jan;45(2):228
Surveillance
● monitoring metastatic disease
⚬ monitoring symptoms and cancer burden important during treatment to determine if treatment is
providing bene t and patient does not have toxicity from an ine ective therapy 2
⚬ components of monitoring include (NCCN Category 2A) 2
– periodic assessment of varied combinations of symptoms, physical exam, routine laboratory

tests, imaging studies, and blood biomarkers where appropriate
– classi cation of results during monitoring can be 1 of the following
● response/continued response to treatment

● stable disease
● uncertainty regarding disease status
● progression
⚬ clinician must assess and balance multiple di erent forms of information to make a determination
regarding whether disease is being controlled and if toxicity is acceptable 2
● de nition of disease progression 2

⚬ unequivocal evidence of progression of disease by ≥ 1 of these factors is required to establish
disease progression, either due to ine ective therapy or acquired resistance of disease to applied
therapy (progression may be identi ed through evidence of growth or worsening of disease at
previously known sites of disease and/or occurrence of new sites of metastatic disease)
– ndings suggestive of disease progression include
● worsening symptoms such as pain or dyspnea
● evidence of worsening or new disease on physical exam
● declining performance status
● unexplained weight loss
● increasing alkaline phosphatase, aspartate aminotransferase (ALT), alanine
aminotransferase (AST), or bilirubin
● hypercalcemia
● new radiographic abnormality or increase in the size of preexisting radiographic abnormality
● new areas of abnormality on functional imaging (for instance, bone scan, positron emission
tomography [PET]/computed tomography [CT] scan)
⚬ increasing tumor markers (for instance, carcinoembryonic antigen [CEA], cancer antigen [CA] 15-3,
and CA 27.29) may also be seen with responding disease, isolated increase in tumor markers
should rarely be used to declare disease progression; may be more helpful in patients with bone-
dominant metastatic disease
● use of objective criteria for response/stability/progression 2
⚬ most accurate assessments of disease activity typically occur when previously abnormal studies
are repeated on a serial and regular basis (NCCN Category 2A)
⚬ same method of assessment should be used over time (NCCN Category 2A)
⚬ some nonclinically important variation in measurement of abnormalities by all serial studies is
common and expected
⚬ use of objective and widely accepted criteria to de ne response, stability and progression of
disease are encouraged, such as (NCCN Category 2A)
– response evaluation criteria in solid tumors (RECIST) guideline, version 1.1
– World Health Organization (WHO) criteria
⚬ studies on functional imaging, such as radionuclide bone scans and PET imaging, are particularly
challenging when used to assess response (NCCN Category 2A)
– for bone scans, responding disease may result in are or increased activity on scan that may be
misinterpreted as disease progression, especially on rst follow-up bone scan after initiating
new therapy
– for PET imaging, absence of reproducible, validated, and widely accepted sets of standards for
disease activity assessment
● National Institute for Health and Care Excellence (NICE) recommends against
⚬ use of PET/CT to monitor advanced breast cancer

⚬ use of bone scintigraphy to monitor response of bone metastasis to treatment
⚬ Reference - National Institute for Health and Care Excellence guideline on diagnosis and treatment
of advanced breast cancer (NICE 2009 Feb:CG81 PDF )
● frequency of monitoring (NCCN Category 2A) 2
⚬ optimal frequency of repeat testing uncertain, and primarily based on monitoring strategies
utilized in breast cancer clinical trials
⚬ frequency of monitoring must balance need to detect progressive disease, avoid toxicity of
ine ective therapy, utilize resources, and determine cost
⚬ guidance should be modi ed for individual patient based on sites of disease, biology of disease,
length of time on treatment
⚬ reassessment of disease should be performed in patients with new or worsening signs or
symptoms, regardless of time interval from previous studies
⚬ depending on dynamics of disease, location and extent of metastatic involvement, and type of
treatment, evaluation of response to therapy includes
– symptom assessment, physical exam, performance status, weight, and blood tests generally
done prior to new therapy and every 1-3 months for endocrine therapy or prior to each cycle
for chemotherapy
– CT of chest/abdomen/pelvis with contrast generally done prior to new therapy or every 2-6
months for endocrine therapy or every 2-4 cycles for chemotherapy
– bone scan generally done prior to new therapy or every 4-6 months for endocrine therapy or
prior to every 4 cycles for chemotherapy
– PET/CT and tumor markers optional
– restaging done if concern for disease progression
Adverse Events of HER2 Targeted Therapy and their Management
General toxicity information
Table 4. Trastuzumab Toxicities
Common Serious
Cardiovascular NA Cardiac dysrhythmia,

heart failure, left
ventricular cardiac
dysfunction, myocardial
ischemia
Dermatologic Rash NA
Endocrine Weight loss NA
Gastrointestinal Diarrhea, nausea, NA

stomatitis, vomiting
Hematologic Anemia, neutropenia, Febrile neutropenia,

thrombocytopenia neutropenia,
thrombocytopenia,
thrombosis
Common Serious
Immunologic Infectious disease Hypersensitivity reaction
Neurologic Headache, insomnia NA
Renal NA Renal failure
Reproductive NA NA
Respiratory Cough Dyspnea, interstitial

pneumonia, pulmonary
hypertension, pulmonary
toxicity
Other Fatigue, fever, shivering Infusion reaction, tumor

lysis syndrome
Abbreviation: NA, not applicable.
● see also Trastuzumab
Table 5. Pertuzumab Toxicities
Common Serious
Cardiovascular NA Heart failure, left

ventricular cardiac
dysfunction
Dermatologic Alopecia, rash NA
Gastrointestinal Decreased appetite, NA

diarrhea, in ammatory
disease of mucous
membrane, nausea,
vomiting
Common Serious
Hematologic Anemia, neutropenia Anemia, febrile

neutropenia, leukopenia,
neutropenia,
thrombocytopenia
Immunologic NA Anaphylaxis,
hypersensitivity reaction
Neurologic Asthenia, headache, NA

peripheral neuropathy
Other Fatigue NA
● see also Pertuzumab
Table 6. T-DM1 Toxicities
Common Serious
Cardiovascular NA Left ventricular cardiac

dysfunction
Dermatologic NA Injection site

extravasation
Gastrointestinal Constipation, nausea NA
Hematologic Hemorrhage, Anemia, hemorrhage,

thrombocytopenia neutropenia,
thrombocytopenia
Hepatic Elevated liver enzymes Hepatotoxicity, elevated

liver enzymes, liver injury
Immunologic NA Anaphylactoid reaction

Common Serious
Musculoskeletal Musculoskeletal pain NA
Neurologic Headache Peripheral nerve disease
Respiratory NA Dyspnea, interstitial lung

disease, pneumonitis
Other Fatigue NA
Abbreviation: NA, not applicable; T-DM1, ado-trastuzumab emtansine.
● see also Ado-Trastuzumab Emtansine
Table 7. Lapatinib Toxicities
Common Serious
Cardiovascular NA Depressed left

ventricular systolic
function, prolonged QT
interval, torsades de
pointes
Dermatologic Hand foot syndrome, Skin disorder

rash
Gastrointestinal Diarrhea, indigestion, Diarrhea

nausea, vomiting
Hepatic NA Hepatotoxicity
Immunologic NA Hypersensitivity reaction
Musculoskeletal Backache, limb pain NA
Neurologic Headache, insomnia NA

Common Serious
Respiratory Dyspnea Interstitial lung disease,

pneumonitis
Other Fatigue NA
● see also Lapatinib
Common toxicities and their management
Cardiac toxicities
● cardiac toxicity is known risk in women treated with trastuzumab
⚬ naturally functioning HER2 is involved in cardiac stress response; when trastuzumab is used to
block HER2 function, it impairs ability of heart to respond to stress
⚬ evaluate left ventricular ejection fraction (LVEF) at baseline and every 3 months during treatment
with trastuzumab (NCCN Category 2A)
⚬ trastuzumab-induced cardiac dysfunction is typically reversible
⚬ trastuzumab should not be given concurrently with anthracyclines due to association with
signi cant cardiac toxicity (ESMO Grade B, Level I)
⚬ in patients at risk of cardiac complication
– nonanthracycline, taxane-based regimens (such as docetaxel plus cyclophosphamide) should be

used as alternative to anthracycline-based chemotherapy (ESMO Grade A, Level I)
– docetaxel plus carboplatin in combination with trastuzumab is an anthracycline-free alternative
reported to have signi cantly lower cardiac toxicity but also lower e cacy
⚬ Reference - Crit Rev Oncol Hematol 2017 Nov;119:113
● manage trastuzumab-related cardiac toxicities with appropriate monitoring and prevention strategies
including
⚬ obtaining a full medical history
⚬ performing physical exam including evaluation for edema and hepatomegaly
⚬ before starting trastuzumab, perform echocardiogram and assess LVEF
⚬ for LVEF < 50%, refer patient to cardiologist to optimize cardiac function; may consider
trastuzumab if LVEF > 50% on repeat measure
⚬ for patients receiving trastuzumab, regularly assess for
– increase in heart rate > 15%

– increase in weight ≥ 2 kg/week
– any cardiac signs and symptoms
– changes in LVEF; repeat assessment every 3 months
⚬ Reference - Crit Rev Oncol Hematol 2017 Nov;119:113
● perindopril (angiotensin-converting enzyme inhibitor) and bisoprolol (beta-blocker) are cardiac

medications that may be considered to decrease occurrence of trastuzumab-induced cardiac
dysfunction
● New York Heart Association (NYHA) classi cation for heart failure based on patient symptoms and
objective assessment includes
⚬ patient symptoms
– Class I de ned as patients without limitation of physical activity; ordinary physical activity does
not cause undue fatigue, palpitations, or dyspnea
– Class II de ned as patients with slight limitation of physical activity but comfortable at rest;
ordinary physical activity causes fatigue, palpitations, or dyspnea
– Class III indicates patients with notable limitation of physical activity but comfortable at rest;
less than usual physical activity causes fatigue, palpitations, or dyspnea
– Class IV indicates patients unable to participate in physical activity comfortably and have
symptoms of heart failure at rest; increased discomfort with any physical activity
⚬ objective assessment
– Class A indicates patients with no evidence of cardiovascular disease, no symptoms and no

limitation in ordinary physical activity
– Class B indicates patients with minimal cardiovascular disease, mild symptoms and slight
limitation during ordinary activity but they are comfortable at rest
– Class C indicates patients with moderately severe cardiovascular disease, with notable limitation
of physical activity related to symptoms during less than ordinary activity, and who are only
comfortable at rest
– Class D indicates patients with severe cardiovascular disease and sever limitations with
symptoms present even while at rest
⚬ Reference - American Heart Association accessed 2018 March 29
STUDY
● SUMMARY
dual therapy and monotherapy with HER2 inhibitors appear to have similar cardiac toxicities in
women with breast cancer DynaMed Level 2
SYSTEMATIC REVIEW: Int J Cancer 2013 Nov;133(9):2245
Details
⚬ based on systematic review with low event rates
⚬ systematic review of 6 randomized trials comparing dual HER2 inhibitor therapy vs. HER2 inhibitor
monotherapy in 2,615 women with breast cancer
– dual therapy was pertuzumab plus trastuzumab or trastuzumab plus lapatinib
– monotherapy was lapatinib, trastuzumab, or pertuzumab
⚬ women also received chemotherapy in 5 trials

⚬ 2 trials included women with metastatic disease, and 2 trials used HER2 inhibitors as neoadjuvant
therapy
⚬ pooled incidence of ≥ grade 3 heart failure
– 0.88% (95% CI 0.47%-1.64%) with dual therapy

– 1.49% (95% CI 0.98%-2.23%) with monotherapy
⚬ pooled incidence of left ventricular ejection fraction decline
– 3.1% (95% CI 2.2%-4.4%) with dual therapy

– 2.9% (2.1%-4.1%) with monotherapy
⚬ no signi cant di erences in
– grade ≥ 3 heart failure in analysis of 4 trials

– left ventricular ejection fraction decline in analysis of 5 trials
⚬ Reference - Int J Cancer 2013 Nov;133(9):2245
STUDY
● SUMMARY
lapatinib associated with ≤ 3% rate of cardiac toxicities in patients with breast cancer
DynaMed Level 2
SYSTEMATIC REVIEW: Breast Cancer Res Treat 2017 Dec;166(3):927
Details
⚬ based on systematic review limited by heterogeneity
⚬ systematic review of 45 trials evaluating cardiac events in 6,646 patients with cancer treated with
lapatinib
⚬ trials included various types of cancer however breast cancer was the most common
⚬ in analysis of all trials with all patients with cancer, lapatinib associated with
– any adverse cardiac event in 2.7% (95% CI 1.7%-4.5%), results limited by signi cant
heterogeneity
– left ventricular dysfunction in 1.6% (95% CI 1.3%-2%)
– decreased left ventricular ejection fraction in 2.2% (95% CI 1.3%-3.6%), results limited by
signi cant heterogeneity
⚬ in analysis of 26 trials with 5,462 patients with breast cancer, lapatinib associated with
– any adverse cardiac event in 3% (95% CI 1.5%-6.1%), results limited by signi cant heterogeneity
– left ventricular dysfunction in 1.7% (95% CI 1.3%-2.2%)
– decreased left ventricular ejection fraction in 1.8% (95% CI 0.8%-3.9%), results limited by
signi cant heterogeneity
⚬ Reference - Breast Cancer Res Treat 2017 Dec;166(3):927
Diarrhea
● European Society for Medical Oncology (ESMO) clinical practice guidelines on diarrhea in adult cancer
patients
⚬ diarrhea is common side e ect of targeted therapy and may become severe when targeted
therapies are combined with chemotherapy
⚬ tyrosine kinase inhibitors such as lapatinib and sunitinib reported to have higher risk of all-grade
and high-grade diarrhea than conventional regimens
⚬ prophylactic budesonide not recommended (ESMO Grade B, Level II)
⚬ recommendations for management of diarrhea
– in patients with mild-to-moderate (grade 1-2) diarrhea and no other complicating signs or
symptoms, manage with oral hydration and loperamide (ESMO Grade A, Level V)
● oral rehydration therapy is generally appropriate for mild diarrhea (ESMO Grade A, Level I);
2,200-4,000 mL/day of total uids, glucose and electrolytes indicated
● loperamide initial dose 4 mg followed by 2 mg every 4 hours or after each unformed stool,
up to maximum 16 mg/day (ESMO Grade B, Level II)
● include dietary modi cations (for example, elimination of lactose-containing products and
high-osmolar dietary supplements)
● use skin barriers to prevent skin irritation
● special attention to patients with stool incontinence due to risk of pressure ulcer formation
● patient should report number of stools and potentially life-threatening symptoms such as
fever or dizziness on standing
– in patients with mild-to-moderate diarrhea complicated by moderate-to-severe cramping,
nausea, vomiting, diminished performance status, fever, sepsis, neutropenia, bleeding,
dehydration, and in patient with severe diarrhea, recommended management includes (ESMO
Grade A, Level V)
● hospitalization
● IV rehydration
⚬ typically with isotonic saline or balanced salt solution; choice of therapy in uenced by
concurrent abnormalities in serum sodium or potassium or presence of metabolic
acidosis
⚬ if patient has tachycardia and is potentially septic, give an initial uid bolus of 20 mL/kg
(ESMO Grade A, Level I)
● give loperamide (ESMO Grade A, Level V); initial dose 4 mg followed by 2 mg every 4 hours or
after each unformed stool, up to maximum 16 mg/day (ESMO Grade B, Level II)
● evaluate with complete blood count, electrolyte pro le, and stool work-up evaluating for
blood, Clostridium di cile, Salmonella, E. coli, Campylobacter, and infectious colitis (ESMO
Grade A, Level V)
● if severe dehydration, octreotide acetate 100-150 mcg subcutaneously or 25-50 mcg/hour IV
3 times daily, with dose escalation up to 500 mcg subcutaneously 3 times daily until diarrhea
is controlled, plus antibiotics such as uoroquinolone (ESMO Grade A, Level V)
● if fever, hypotension, peritoneal signs, neutropenia small intestinal bacterial overgrowth,
perianal sepsis, or bloody diarrhea, consider antibiotics such as uoroquinolone
● if severe diarrhea ≤ 96 hours of completing treatment with 5- uorouracyl or capecitabine,
consider uridine triacetate (ESMO Grade B, Level II); recommended dose 10 mg orally every
60 hours for 20 doses (ESMO Grade A, Level II)
– Reference - Ann Oncol 2018 Oct 1;29(Supplement_4):iv126
● see also Acute diarrhea in adults for additional information
STUDY
● SUMMARY
dual HER2 targeted therapy appears to increase incidence of diarrhea compared to HER2
targeted monotherapy in women with HER2 positive breast cancer DynaMed Level 2
SYSTEMATIC REVIEW: Tumour Biol 2014 May;35(5):4077
Details
⚬ based on systematic review limited by clinical heterogeneity
⚬ systematic review of 7 randomized trials comparing dual HER2 targeted therapy vs. HER2 targeted
monotherapy in 2,920 patients with HER2 positive breast cancer
– dual HER2 targeted therapy included any of
● trastuzumab plus pertuzumab

● trastuzumab plus lapatinib
– HER2 targeted monotherapy included any of
● trastuzumab alone
● pertuzumab alone
● lapatinib alone
⚬ HER2 targeted therapy varied across studies in dose, paired chemotherapy regimens, and timing
⚬ compared to HER2 targeted monotherapy, dual HER2 targeted therapy associated with increased
incidence of diarrhea in analysis of all trials, results limited by signi cant heterogeneity
– odds ratio (OR) 1.66 (95% CI 1.35-2.06)
– NNH 10-27 with incidence of diarrhea 12.3% in HER2 targeted monotherapy group
⚬ compared to trastuzumab monotherapy
– trastuzumab plus lapatinib dual therapy associated with increased incidence of diarrhea in
analysis of 4 trials with 972 patients
● OR 16.45 (95% CI 8.24-32.83)
● NNH 2-8 with incidence of diarrhea 1.9% in trastuzumab monotherapy group
– trastuzumab plus pertuzumab dual therapy associated with increased incidence of diarrhea in
analysis of 2 trials with 1,018 patients
● OR 1.81 (95% CI 1.08-3.04)
● NNH 11-274 with incidence of diarrhea 4.8% in trastuzumab monotherapy group
⚬ Reference - Tumour Biol 2014 May;35(5):4077
● for management of toxicities predominantly due to chemotherapy portion of regimen, see

Chemotherapy for metastatic breast cancer
Skin toxicities
● dual kinase inhibitors of epidermal growth factor receptor (EGFR) and HER2 (including lapatinib and
neratinib) are known to cause dermatologic toxicities
⚬ high EGFR expression occurs in epidermis, therefore these toxicities are expected with EGFR
inhibition
⚬ cutaneous adverse event reported to occur in 50%-90% of patients receiving EGFR inhibitors
⚬ most common cutaneous adverse events include
– papulopustular eruption (most common)
● reported to occur in > 75% of patients, severe reaction in < 10% of patients
● occurs 1-2 weeks after initiation of therapy and is dose-dependent
● may be confused with acne, however pruritus occurs with papulopustular eruptions
● management may include
⚬ antibiotics, antiseptic cream, or low potency corticosteroids may be useful for eruptions
involving < 10% of body surface area with or without pruritus
⚬ tetracyclines, penicillinase-resistant antibiotics, and isotretinoin may be useful for
eruptions involving ≥ 10% to 30% of body surface area, or those that are tender, involve
pruritus, or superinfection
⚬ systemic steroids are not recommended
– xerosis
● reported to occur in about 33% of patients

● progresses over weeks of therapy and is dose-dependent
● fragile skin may lead to ssures, easy bruising, pain, severe pruritus, or secondary skin
infection
⚬ thick emollient may be preventative

⚬ antihistamine or aprepitant may be useful with pruritus
⚬ topical gel used for papulopustular eruptions may worsen xerosis and may need to be
discontinued
– hair changes
● hair quality, texture, and growth may change after 2-3 months of treatment
● may e ect hair on scalp, eyelashes, eyebrows, upper lip, beard
⚬ cutting eyelashes to prevent keratitis

⚬ frequent brushing to scalp
⚬ depilatory creams or laser epilation for hypertrichosis
– mucositis
● exhibited on oral mucosa (aphthae, xerostomia, geographic tongue), genitalia (vulvovaginitis,

balanitis, aphthae), or as conjunctivitis, or keratitis
⚬ topical steroid, antiseptic wash, or anesthetic for aphthae

⚬ lubricants to relieve dryness
⚬ ophthalmologic consultation for chronic corneal irritation
– nail changes
● reported to occur in about 17% of patients

● may e ect nail bed, fold, or matrix and lead to superinfection
⚬ wet dressing, cushion inserts, topical or systemic antibiotics, antifungals, and pain control
⚬ preventative daily antiseptic soak, topical corticosteroids may be useful if in ammation
occurs
⚬ systemic antibiotic or antifungal may be considered for superinfection but paronychia
may not resolve completely while on EGFR inhibitor
– photosensitivity
● exhibited as telangiectasia, hyperpigmentation, and photosensitive eruption

⚬ hyperpigmentation gradually resolves after discontinuation of targeted therapy

⚬ encourage caution with sun exposure
⚬ vascular light devices or electrocoagulation may be useful with telangiectasia
⚬ most cutaneous toxicities resolve, although hair changes, pruritus, xerosis, and nail in ammation
may last ≥ 6 months
⚬ multidisciplinary approach with oncologist and dermatologist may lead to best management
⚬ Reference - J Am Acad Dermatol 2015 Feb;72(2):203
● for management of toxicities predominantly due to chemotherapy portion of regimen, see

Chemotherapy for metastatic breast cancer
Guidelines and Resources
Guidelines
United States guidelines
● National Comprehensive Cancer Network (NCCN) guidelines can be found at NCCN website (free
registration required), guidelines include
⚬ breast cancer
⚬ genetic/familial high-risk assessment of breast and ovarian cancer
⚬ cancer and chemotherapy-induced anemia
⚬ management of immunotherapy-related toxicities
⚬ prevention and treatment of cancer-related infections
⚬ safety of erythropoiesis-stimulating agents (ESAs) in cancer-induced anemia
⚬ cancer-associated venous thromboembolic disease
● American Society of Clinical Oncology (ASCO)
⚬ clinical practice guideline on systemic therapy for patients with advanced human epidermal growth
factor receptor 2 positive breast cancer can be found in J Clin Oncol 2014 Jul 1;32(19):2078
⚬ clinical practice guideline update on outpatient management of fever and neutropenia in adults
treated for malignancy can be found in J Clin Oncol 2018 May 10;36(14):1443 PDF
⚬ clinical practice guideline update on platelet transfusion for patients with cancer can be found in J
Clin Oncol 2018 Jan 20;36(3):283 PDF
⚬ clinical practice guideline update on antiemetics can be found J Clin Oncol 2017 Oct 1;35(28):3240
PDF
⚬ ASCO clinical practice guideline update on use of tumor markers in breast cancer can be found in J
Clin Oncol 2013 Nov 1;31(31):3997 full-text , editorial can be found in J Clin Oncol 2015 Apr
10;33(11):1301 full-text
● National Academy of Clinical Biochemistry (NACB) guideline on use of tumor markers in testicular,
prostate, colorectal, breast, and ovarian cancers can be found in Clin Chem 2008 Dec;54(12):e11
full-text
● American Cancer Society (ACS) guideline on nutrition and physical activity for cancer survivors can be
found in CA Cancer J Clin 2012 Jul;62(4):242 full-text , correction can be found in CA Cancer J Clin
2013 May;63(3):215
● Oncology Nursing Society (ONS) evidence-based interventions for chemotherapy-induced peripheral

neuropathy can be found in Clin J Oncol Nurs 2007 Dec;11(6):901
United Kingdom guidelines
● National Institute for Health and Care Excellence (NICE)
⚬ NICE guidance on abemaciclib with fulvestrant for treating hormone receptor-positive, HER2-
negative advanced breast cancer after endocrine therapy can be found at NICE 2019 May:TA579
PDF
⚬ National Institute for Health and Care Excellence (NICE) guideline on diagnosis and treatment of
advanced breast cancer can be found at NICE 2009 Feb:CG81 PDF (last update 2017 Aug)
⚬ NICE guidance on trastuzumab for treating advanced breast cancer can be found at NICE 2002
Mar:TA34 PDF
⚬ NICE guidance on pertuzumab with trastuzumab and docetaxel for treating HER2 positive
advanced breast cancer can be found at NICE 2018 Mar:TA509 PDF
⚬ NICE guidance on trastuzumab emtansine for treating HER2 positive advanced breast cancer after
trastuzumab and a taxane can be found at NICE 2017 Jul:TA458 PDF
⚬ NICE guidance on lapatinib or trastuzumab in combination with aromatase inhibitor for rst-line
treatment of hormone receptor positive breast cancer that overexpresses HER2 can be found at
NICE 2012 Jun:TA257 PDF
⚬ United Kingdom expert guidance document on treatment of metastatic breast cancer can be found
in Clin Oncol (R Coll Radiol) 2012 Apr;24(3):169
Canadian guidelines
● Cancer Care Ontario (CCO) Program in Evidence-Based Care guidelines on
⚬ continued use of trastuzumab beyond disease progression in patients with metastatic breast
cancer can be found at CCO 2009 Jun
⚬ role of trastuzumab (Herceptin) in treatment of women with HER2/neu-overexpressing metastatic
breast cancer can be found at CCO 2011 Sep
⚬ role of gemcitabine in management of metastatic breast cancer can be found at CCO 2011 Sep
⚬ use of bevacizumab in metastatic breast cancer can be found at CCO 2009 Apr
⚬ role of trastuzumab (herceptin) in treatment of women with HER2/neu-overexpressing metastatic
breast cancer can be found at CCO 2011 Sep 15 PDF
⚬ role of gemcitabine in management of metastatic breast cancer can be found at CCO 2011 Sep 15
PDF
⚬ vinorelbine in stage IV breast cancer can be found at CCO 2003 Nov PDF
⚬ continued use of trastuzumab beyond disease progression in patients with metastatic breast
cancer can be found at CCO 2009 Aug 17 PDF
⚬ fulvestrant for systemic therapy of locally advanced or metastatic breast cancer in postmenopausal
women can be found at CCO 2008 Sep 25 PDF
⚬ use of bisphosphonates for women with metastatic breast cancer can be found in CCO 2017 Oct
PDF
● Alberta Health Services (AHS) clinical practice guideline on optimal use of taxanes in metastatic breast
cancer can be found at AHS 2013 Sep PDF
European guidelines
● European Society for Medical Oncology (ESMO) clinical practice guidelines on diarrhea in adult cancer
patients can be found in Ann Oncol 2018 Oct 1;29(Supplement_4):iv126
● Multinational Association of Supportive Care in Cancer/European Society of Medical Oncology

(MASCC/ESMO) guideline on prevention of chemotherapy-induced nausea and vomiting and nausea
and vomiting in advanced cancer patients can be found in Ann Oncol 2016 Sep;27(suppl 5):v119
● Central European Cooperative Oncology Group (CECOG) third consensus on medical treatment of
metastatic breast cancer can be found in Ann Oncol 2009 Nov;20(11):1771 , commentary can be
found in Ann Oncol 2010 Mar;21(3):665
● Central European consensus statement on current standards in treatment of metastatic breast cancer
with focus on lapatinib can be found in Wien Klin Wochenschr 2010 Jun;122(11-12):368
● Spanish Society for Medical Oncology (SEOM) clinical guideline on treatment of metastatic breast
cancer can be found in Clin Transl Oncol 2010 Nov;12(11):719
Australian and New Zealand guidelines
● Cancer Australia clinical practice guideline on use of chemotherapy for treatment of advanced breast
cancer can be found at Cancer Australia 2010 Jul PDF
● Cancer Australia clinical practice guideline on management of central nervous system (CNS)
metastases in women with secondary breast cancer can be found at Cancer Australia 2014 May PDF
Middle Eastern guidelines
● Bahrain Government/Think Pink Nongovernment Organization (NGO) mapping study and

recommendations on breast cancer can be found in J Evid Based Med 2019 Aug;12(3):209 full-text
Review articles
● review of HER2 positive breast cancer can be found in Lancet 2017 Jun 17;389(10087):2415
● review of treatment of advanced HER2 positive breast cancer can be found in Cancer Treat Rev 2018
Jun;67:10
● review of current treatment options for HER2-directed therapy can be found in Breast Cancer 2015
Mar;22(2):101
● review of treatment of HER2 positive breast cancer can be found in Breast 2014 Apr;23(2):128 full-
text
● review of e cacy of HER2 targeted therapy in metastatic breast cancer can be found in Breast 2013
Feb;22(1):1
● review of treatment with trastuzumab emtansine (T-DM1) can be found in Crit Rev Oncol Hematol
2016 Jan;97:96
● review of immunotherapy for breast cancer, past, present, and future can be found in Cancer
Metastasis Rev 2016 Dec;35(4):525
● review of therapeutic approach to management of HER2 positive breast cancer metastatic to brain
can be found in Cancer Lett 2015 Mar 28;358(2):93
● review of emerging therapeutic options for HER2 positive breast cancer can be found in Am Soc Clin
Oncol Educ Book 2016;35:e64
● review of changing scenarios in HER2 positive metastatic breast cancer can be found in Crit Rev Oncol
Hematol 2015 Jul;95(1):78
● review of emerging approaches for treating HER2 positive metastatic breast cancer beyond
trastuzumab can be found in Ann Oncol 2013 Oct;24(10):2492
MEDLINE search
● to search MEDLINE for (HER 2 targeted therapies for metastatic breast cancer) with targeted search
(Clinical Queries), click therapy , diagnosis , or prognosis
References
General references used
1. Harbeck N, Gnant M. Breast cancer. Lancet. 2017 Mar 18;389(10074):1134-1150

2. Gradishar WJ, Anderson BO, Abraham J, et al. Breast cancer. Version 3.2018. In: National
Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology (NCCN Guidelines).
NCCN 2018 Oct from NCCN website (free registration required)
3. Cardoso F, Senkus E, Costa A., et al. 4th ESO-ESMO International Consensus Guidelines for Advanced
Breast Cancer (ABC 4). Ann Oncol 2018 Aug 1;29(8):1634-1657
Recommendation grading systems used
● National Academy of Clinical Biochemistry Laboratory Medicine (NACB) grading system for
recommendations
⚬ strength of recommendations
– Grade A - high - further research very unlikely to change Panel’s con dence in estimate of e ect
– Grade B - moderate - further research likely to have important impact on Panel's con dence in
estimate of e ect and likely to change estimate
– Grade C - low - further research very likely to have important e ect on Panel's con dence in
estimate of e ect and likely to change estimate
– Grade D - very low - any estimate of e ect very uncertain
⚬ levels of evidence
– Level I - evidence from single, high-powered, prospective, controlled study speci cally designed
to test marker, or evidence from meta-analysis, pooled analysis, or overview of level II or III
studies
– Level II - evidence from study in which marker data are determined in relationship to
prospective therapeutic trial performed to test therapeutic hypothesis but not speci cally
designed to test marker utility
– Level III - evidence from large prospective studies
– Level IV - evidence from small retrospective studies
– Level V - evidence from small pilot studies
– Expert opinion
⚬ Reference - NACB guideline on use of tumor markers in testicular, prostate, colorectal, breast, and
ovarian cancers (Clin Chem 2008 Dec;54(12):e11 full-text )
● American Society of Clinical Oncology (ASCO)
⚬ type of recommendation
– Evidence based - su cient evidence from published studies to inform a recommendation to

guide clinical practice
– Formal consensus - insu cient available evidence to inform a recommendation to guide clinical
practice; considered best current guidance for practice based on formal consensus process
– Informal consensus - insu cient available evidence to inform a recommendation to guide
clinical practice; considered best current guidance for practice based on informal consensus
process, formal consensus not necessary based on literature review and discussion
– No recommendation - insu cient evidence, con dence, or agreement to provide a
recommendation to guide clinical practice
⚬ strength of recommendation
– Strong - high con dence that recommendation re ects best practice; strong evidence that
bene ts exceed harms, consistent results with no or minor exceptions, minor or no concerns
about study quality
– Moderate - moderate con dence that recommendation re ects best practice; good evidence
that bene ts exceed harms, consistent results with minor or few exceptions, minor or few
concerns about study quality
– Weak - some con dence that recommendation re ects best practice; limited evidence that
bene ts exceed harms, consistent results but with important exceptions, concerns about study
quality
⚬ strength of evidence
– High - high con dence that available evidence re ects balance of bene t vs. harm, further
research very unlikely to change net e ect
– Intermediate - moderate con dence that available evidence re ects balance of bene t vs. harm,
further research unlikely to change net e ect but might alter magnitude of net e ect
– Low - low con dence that available evidence re ects balance of bene t vs. harm, further
research may change bene t vs. harm and/or net e ect
– Insu cient - insu cient evidence to discern bene t vs. harm, further research needed,
consensus opinion
⚬ Reference - ASCO clinical practice guideline on systemic therapy for patients with advanced human
epidermal growth factor receptor 2 positive breast cancer (J Clin Oncol 2014 Jul 1;32(19):2078 )
⚬ ASCO/CAP clinical practice guideline on human epidermal growth factor receptor 2 testing in
breast cancer: focused update (J Clin Oncol 2018 Jul 10;36(20):2105 )
● European School of Oncology/European Society of Medical Oncology (ESO/ESMO) levels of evidence

and grades of recommendation
⚬ grades of recommendation
– Grade A - strong evidence for e cacy with substantial clinical bene t, strongly recommended
– Grade B - strong or moderate evidence for e cacy but with a limited clinical bene t, generally
recommended
– Grade C - insu cient evidence for e cacy or bene t does not outweigh the risk or the
disadvantages, optional
– Grade D - moderate evidence against e cacy or for adverse outcomes, generally not
recommended
– Grade E - strong evidence against e cacy or for adverse outcomes, never recommended
⚬ levels of evidence
– Level I - evidence from ≥ 1 large, randomized, controlled trial of good methodological quality
(low potential for bias) or meta-analyses of well-conducted randomized trials without
heterogeneity
– Level II - small randomized trials or large randomized trials with a suspicion of bias (lower
methodological quality) or meta-analyses of such trials or of trials with demonstrated
heterogeneity
– Level III - prospective cohort studies
– Level IV - retrospective cohort studies or case-control studies
– Level V - studies without control group, case reports, expert opinions
⚬ References -
– ESO/ESMO International consensus guidelines for advanced breast cancer (ABC 4) (Ann Oncol
2018 Aug 1;29(8):1634 )
– ESMO clinical practice guidelines on diarrhoea in adult cancer patients (Ann Oncol 2018 Oct
1;29(Supplement_4):iv126 )
– ESMO clinical practice guidelines for diagnosis, treatment and follow-up of primary breast
cancer (Ann Oncol 2015 Sep;26 Suppl 5:v8 )
● Multinational Association of Supportive Care in Cancer (MASCC) levels of scienti c con dence
⚬ levels of consensus
– High
– Moderate
– Low
⚬ levels of con dence
– High - repeated, randomized trials that were appropriately sized and well conducted
– Moderate - ≥ 1 randomized trial, supported by well conducted, phase II trials, or possibly several
well-conducted phase II studies
– Low - formal clinical trials of a level less than that expressed above
– Very Low - clinical impression only
– No con dence possible
⚬ Reference - MASCC/ESMO guideline update for prevention of chemotherapy- and radiotherapy-

induced nausea and vomiting and of nausea and vomiting in advanced cancer patients (Ann Oncol
2016 Sep;27(suppl 5):v119 )
● National Comprehensive Cancer Network (NCCN) categories of evidence and consensus
⚬ Category 1 - based on high-level evidence, there is uniform NCCN consensus that intervention is
appropriate
⚬ Category 2A - based on lower-level evidence, there is uniform NCCN consensus that intervention is
appropriate
⚬ Category 2B - based on lower-level evidence, there is NCCN consensus that intervention is
appropriate
⚬ Category 3 - based on any level of evidence, there is major NCCN disagreement that intervention is
appropriate
⚬ Reference - NCCN Categories of Evidence and Consensus
DynaMed Editorial Process
● DynaMed topics are created and maintained by the DynaMed Editorial Team and Process .
● All editorial team members and reviewers have declared that they have no nancial or other
competing interests related to this topic, unless otherwise indicated.
● DynaMed content includes Practice-Changing Updates, with support from our partners, McMaster
University and F1000.
Special Acknowledgements
● DynaMed topics are written and edited through the collaborative e orts of the above individuals.
Deputy Editors, Section Editors, and Topic Editors are active in clinical or academic medical practice.
Recommendations Editors are actively involved in development and/or evaluation of guidelines.
● Editorial Team role de nitions
Topic Editors de ne the scope and focus of each topic by formulating a set of clinical
questions and suggesting important guidelines, clinical trials, and other data to be
addressed within each topic. Topic Editors also serve as consultants for the
DynaMed internal Editorial Team during the writing and editing process, and review
the nal topic drafts prior to publication.
Section Editors have similar responsibilities to Topic Editors but have a broader role
that includes the review of multiple topics, oversight of Topic Editors, and systematic
surveillance of the medical literature.
Deputy Editors are employees of DynaMed and oversee DynaMed internal

publishing groups. Each is responsible for all content published within that group,
including supervising topic development at all stages of the writing and editing
process, nal review of all topics prior to publication, and direction of an internal
team.
How to cite
National Library of Medicine, or "Vancouver style" (International Committee of Medical Journal Editors):
● DynaMed [Internet]. Ipswich (MA): EBSCO Information Services. 1995 - . Record No. T922341, HER2
Targeted Therapy for Metastatic Breast Cancer; [updated 2018 Dec 03, cited place cited date here].
Available from https://www.dynamed.com/topics/dmp~AN~T922341. Registration and login required.
Published by EBSCO Information Services. Copyright © 2020, EBSCO Information Services. All rights reserved. No part of
this may be reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying,
recording, or by any information storage and retrieval system, without permission.
EBSCO Information Services accepts no liability for advice or information given herein or errors/omissions in the text. It is
merely intended as a general informational overview of the subject for the healthcare professional.

HER2 Targeted Therapy For Metastatic Breast Cancer

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

HER2 Targeted Therapy For Metastatic Breast Cancer

Uploaded by

Copyright:

Available Formats

HER2 Targeted Therapy for Metastatic Breast Cancer

● Breast Cancer in Women

● In ammatory Breast Cancer

● Surgery for Metastatic Breast Cancer

● Radiation Therapy for Metastatic Breast Cancer

● Endocrine Therapy for Metastatic Breast Cancer

● Chemotherapy for Metastatic Breast Cancer

● Cardiotoxicities of Chemotherapeutic Agents

● HER2 targeted therapy

⚬ for use in HER2 positive breast cancer

● if prior endocrine therapy within 1 year (NCCN Category 2A)

⚬ in premenopausal women, options include

⚬ in premenopausal women, options include chemotherapy plus HER2 targeted therapy

● continue until progression or intolerable toxicity, then

– chemotherapy plus trastuzumab plus pertuzumab as standard therapy (ESO/ESMO

⚬ if no disease progression, it is reasonable to o er maintenance with endocrine therapy

⚬ if no disease progression, o er maintenance therapy with HER2 targeted therapy

– T-DM1 preferred in patients with disease progression through ≥ 1 line trastuzumab-

menopausal status, prior therapies, and balance of toxicities 2 , 3

Recommendations for pretreatment assessment

National Comprehensive Cancer Network (NCCN)

– complete blood count

– chest computed tomography (CT) (NCCN Category 2A)

– biopsy of metastatic disease at presentation or rst recurrence (NCCN Category 2A)

European School of Oncology/Society for Medical Oncology (ESO/ESMO)

● ESO-ESMO recommendations for advanced breast cancer 3

National Institute for Health and Clinical Excellence (NICE)

● NICE recommendations for diagnosis and treatment of advanced breast cancer

American Society of Clinical Oncology (ASCO)

– for tissue biomarkers (ASCO Evidence-based, Moderate recommendation, Low-quality evidence)

National Academy of Clinical Biochemistry (NACB)

Hormone receptor (HR) testing and prediction of therapeutic response

● HR status for estrogen and progesterone receptors (PR) is usually performed by

immunohistochemical (IHC) staining 1 , 2 , 3

● American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) recommendations

– de nitions of ER and PR testing results

● positive de ned as ≥ 1% of tumor cell nuclei are immunoreactive

HER2 testing and prediction of therapeutic response

● HER2 predicts for potential bene t from HER2 targeted therapies

● American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) recommendations

– performed with FDA-approved immunohistochemistry (IHC) or in situ hybridization (ISH)

– dual probe assay preferred over single probe assay

● in single probe assay, average HER2 copy number ≥ 6 signals/cell

– negative test de ned as (ASCO/CAP Strong recommendation, High-quality evidence)

● in single probe assay, average HER2 copy number < 4 signals/cell

● in dual probe assay

● controls not as expected

– for ISH (ASCO/CAP Strong recommendation, High-quality evidence)

● controls not as expected

⚬ Reference - J Clin Oncol 2018 Jul 10;36(20):2105

testing in breast cancer (NCCN Category 2A) 2

Performance status evaluation

● performance status evaluation to aid treatment decisions

Table 1. ECOG or WHO Performance Status Scale

0 Fully active; able to carry on all predisease performance without restriction

1 Restricted in physically strenuous activity but ambulatory and able to carry

Reference - Am J Clin Oncol 1982 Dec;5(6):649 .

Table 2. Karnofsky Performance Status Scale

De nitions Rating Criteria

Able to carry on normal 100% Normal; no complaints; no evidence of

80% Normal activity with e ort; some signs or

50% Requires considerable assistance and

20% Very sick; hospital admission necessary;