METASTATIC BREAST

DISEASE
PRESENTER: DR ABDI OSMAN M.

SUPERVISOR: DR D. KIPTOON
OUTLINE
• Introduction
• Mode of spread
• Sites of metastasis
• Diagnostic evaluation
• Treatment options
INTRODUCTION
The aim of treatment is to:
• Palliate symptoms
• Prolong survival
• Maintain quality of life
• Treatment associated with minimal toxicities should be preferred
INTRODUCTION
• Despite the strides that were made in early diagnosis of breast cancer,
about 5% of patients still have metastatic disease at presentation
• Primary breast tumor can be reservoir of cancer stem cells, its removal
can decrease the probability of developing new metastatic sites
(Bermas 2009).
• The primary tumor can secrete growth factors such as tumor growth
factors(TGF), which can send signals that favour implantation and
growth of metastatic sites( Karnoub 2007)
CONT…..
• Retrospective data suggest that the surgical removal of the primary
tumor may improve overall survival in metastatic breast
cancer( Blanchard 2008; Fields 2007;Gnerlich 2008; Khan 2002;
Rapiti 2006).
• A study at the Aga Khan University Hospital in Nairobi by Asim
Jamal et al(2012-2018) to describe the sociodemographic and clinical
characteristics of Kenyan women with metastatic breast cancer
concluded that 32% of all the patients seen in that duration had
metastasis at diagnosis.
MODE OF SPREAD
Metastasis can either be limited or extensive disease or visceral crisis
Mode of spread
• Local
• Hematogenous
• Lymphatics
SITES OF SPREAD
• Bone is the commonest site of metastasis with spread to the vertebrae,
femur, pelvis, upper end of humerus and ribs.
• Spread to the vertebrae commonly occurs through the posterior
intercostal veins and Batson’s venous plexus
• Bone metastasis is associated with pathological fractures , spinal
compression and paraplegia.
SITES OF SPREAD…….CONT
• Lungs metastasis causes canon ball secondaries, respiratory distress
and failure.
• Liver secondaries present with jaundice, elevated liver enzymes,
abdominal pain, loss of appetite, nausea and vomiting.
• Brain secondaries present with features of increased intracranial
pressures like headaches, convulsions and vomiting.
DIAGNOSTIC EVALUATION
• Patients with a previous diagnosis of primary breast cancer who present with
findings suspicious for recurrent metastatic disease should be strongly considered for
diagnostic biopsy, especially if there has been a long disease-free interval. Role of
repeat biopsy?????

• A biopsy is helpful in excluding benign processes that frequently masquerade as

metastases and in ruling out the development of other cancers. Furthermore, the
tissue can be assayed for ER, PR, HER2/neu and other markers, to assist in
treatment decisions.

• Further assess tumors for presence of mutations in breast cancer susceptibility gene
1 or 2 (BRCA1 or BRCA2)
• Diagnostic tests and staging procedures are directed by the organ sites
most frequently involved in metastatic breast cancer and by patient
signs and symptoms.
• History and physical examination should focus on the detection of
metastases on the chest wall, skin, remaining breast, regional and
distant lymph nodes, axial skeleton, lungs, liver, and central nervous
system.
• Laboratory evaluation should include a complete blood count, a
platelet count, serum calcium, and liver and renal function studies.
• A chest x-ray and bone scan are obtained in most patients because
these sites are commonly involved with metastatic breast cancer.
• Suspicious lesions on bone scan need confirmation by x-ray or by
other diagnostic tests because of the high false-positive rate.
Computed tomography or magnetic resonance imaging are also
commonly used for this purpose. In the presence of bone pain
unexplained by results of the bone scan, radiographs or MRI of the
symptomatic area should be performed.
ASSESSMENT FOR DISTANT
METASTASIS
• Examination of opposite axilla-breast
• Abdominal exam for secondaries in the liver, ascites and krukenberg
tumours
• Rectal examination-deposits in the rectouterine pouch
• Respiratory system- pleural effusion
• Bone tenderness- spine,long bones ,skull etc
TREATMENT OF METASTATIC
BREAST CANCER
AIMS OF THE TREATMENT
• Improves quality of life
• To relieve pain of secondaries like bone and lungs
• To relieve neurological problems like convulsions, space occupying
lesions
• Other symptomatic relief
General therapeutic guidelines
• The management of metastatic breast cancer is complex and therefore
involvement of all appropriate specialties in a multidisciplinary team
is crucial
• From the time of diagnosis, patients should be offered appropriate
psychosocial care, supportive and symptoms related interventions as a
routine part of their care
• Assess the extent of metastasis and to determine, based on available
clinical information, the likelihood of rapid progression, which
could cause vital organ failure or other catastrophic complications
• Low risk Vs High Risk
General therapeutic guidelines
• Low risk: long disease-free interval ,limited metastatic disease, often
located in soft tissues or osseous sites. Some patients with limited visceral
disease may also qualify. More often than not, low-risk patients are older
and postmenopausal, and their tumors are hormone receptor positive
• High risk :The disease-free interval for patients with high-risk or
aggressive metastatic disease is typically short (less than 2 years), and the
tumor is frequently ER negative
• Carcinomatous meningitis, extensive liver metastases, lymphangitic lung
metastases, or brain metastases almost always signify aggressive disease
that is unresponsive to endocrine therapy. 
Prediction of response
• Hormone receptor status and HER2 overexpression are the most
important predictors of treatment response
• Patients who are carriers of genetic alterations in breast cancer
susceptibility genes 1 or 2 (BRCA1 or BRCA2) are more likely to
respond to PARP inhibitors. Germline testing ???
• In regards to response to chemotherapy, consistent predictors of poor
response are progression with prior chemotherapy for advanced
disease, relapse within 12 months of completing adjuvant
chemotherapy, poor performance status, and multiple disease sites,
especially visceral involvement
SYSTEMIC TREATMENT GENERAL
PRINCIPLES
Endocrine therapy is favoured over chemotherapy as initial treatment
for most patients with hormone receptor-positive, HER2-negative MBC,
but in patients presenting with frank visceral crisis, chemotherapy should be
favoured.
When using endocrine therapy, addition of certain targeted therapies for
hormone receptor-positive cancers is often appropriate. Examples include;
 cyclin-dependent kinase (CDK) 4/6 inhibitors
inhibitors of mechanistic target of rapamycin (mTOR)
phosphoinositide 3-kinase (PI3K) inhibitors for those whose tumors harbor
mutations in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit
alpha (PIK3CA)
PRINCIPLES CONT’D
• Hormone receptor-positive, HER2-negative patients — In general, endocrine therapy (with or
without CDK 4/6 inhibition) is very likely to be beneficial for these patients, with fewer side
effects compared with chemotherapy. Therefore, these options should be used as initial treatment
for most patients with hormone receptor-positive
• Hormone receptor-positive, HER2-positive patients — Therapeutic options for these patients
include chemotherapy, endocrine therapy, and human epidermal growth factor receptor 2
(HER2)-directed therapy
• Hormone receptor-negative, HER2-negative patients — Many patients with triple-negative
(ER-negative, PR-negative, human epidermal growth factor receptor 2 [HER2]-negative) breast
cancer have a particularly aggressive subtype, and first-line chemotherapy is recommended,
with or without immunotherapy
• Hormone receptor-negative, HER2-positive patients — The combination of human epidermal
growth factor receptor 2 (HER2)-directed therapy and chemotherapy is recommended for
treatment-naϊve patients.
Targeted therapy for HER2-positive breast
cancer
1. Monoclonal antibodies:Trastuzumab (Herceptin, others),
Pertuzumab (Perjeta), trastuzumab and hyaluronidase injection 
2. Antibody-drug conjugates:Ado-trastuzumab emtansine (Kadcyla
or TDM-1, Fam-trastuzumab deruxtecan (Enhertu)
3. Kinase inhibitors :Lapatinib (Tykerb) ,Neratinib (Nerlynx),
Tucatinib (Tukysa)
Targeted therapy for hormone receptor-
positive breast cancer
1. CDK4/6 inhibitors :Palbociclib (Ibrance), ribociclib (Kisqali),
and abemaciclib (Verzenio) 
2. mTOR inhibitor:Everolimus (Afinitor) is a targeted drug known
as an mTOR inhibitor. It blocks mTOR, a protein in cells that
normally helps them grow and divide.
3. PI3K inhibitor:Alpelisib (Piqray) is a targeted drug known as a
PI3K inhibitor. It blocks a form of the PI3K protein in cancer cells,
which can help stop them from growing.
Targeted therapy for women with BRCA
gene mutations
• Polyadenosine diphosphate-ribose polymerase [PARP]
inhibitors:PARP proteins normally help repair damaged DNA inside
cells. The BRCA genes (BRCA1 and BRCA2) also help repair DNA (in
a slightly different way), but mutations in one of those genes can stop
this from happening. PARP inhibitors work by blocking the PARP
proteins. Because tumor cells with a mutated BRCA gene already have
trouble repairing damaged DNA, blocking the PARP proteins often
leads to the death of these cells. Olaparib
(Lynparza) and talazoparib (Talzenna
Targeted therapy for HER2-negative and
hormone receptor-negative breast cancer
• Antibody-drug conjugate:Sacituzumab govitecan-hziy
(Trodelvy): In the case of sacituzumab, instead of HER2, the
monoclonal antibody attaches to the Trop-2 protein and brings the
chemo (irinotecan) directly to the breast cancer cell. (Trop-2 is a
protein that some breast cancer cells make too much of. Trop-2 causes
breast cancer cells to grow and spread quickly.) By delivering the
chemo this way, you can give more chemo than through an IV but
with less severe side effects.
Cytotoxic Chemotherapy for Metastatic
Breast Cancer
• Chemotherapy is used in patients with aggressive disease who are
not candidates for endocrine therapy and in those with tumours
that no longer respond to endocrine therapy
• A large tumor burden involving visceral organs and threatening organ
function
• In general, it is preferred not to administer chemotherapy with
endocrine therapy for women with hormone receptor-positive disease
in order to minimize side effects, including an increased risk of
thromboembolic events
Single agent vs combination therapy
• Combination chemotherapy (rather than single-agent sequential
therapy) is most appropriate when the higher chance of response is
assessed to be more important than the potential for higher treatment
toxicity, due to concerns about impending organ dysfunction from
existing or rapidly progressing disease burden
SINGLE-AGENT CHEMOTHERAPY
• Taxanes — Taxanes are among the most active agents for metastatic breast
cancer. Agents in this class include:
Docetaxel – Docetaxel can be administered every three weeks (80 to 100
mg/m2) or weekly (30 to 40 mg/m2 weekly for three weeks followed by one
week off) 
Paclitaxel – Paclitaxel can be administered weekly (80 to 100 mg/m2 on days
1, 8, and 15 of a 28-day cycle) or every three weeks (175 mg/m2)
• Anthracyclines — The anthracyclines are important agents for the treatment
of breast cancer. However, their use in the adjuvant context often limits their
application in women with metastatic disease
•  myelosuppression, neural toxicity, hepato toxicity,
• Doxorubicin (60 to 75 mg/m2 every three weeks, or 20 mg/m2 weekly
for three weeks followed by one week off)
• Epirubicin (75 to 100 mg/m2 every three weeks, or 20 to 30
mg/m2 weekly for three weeks followed by one week
• One potential downside of using anthracycline regimens is the risk for
cumulative cardiac toxicity, which may limit the duration of
anthracycline-based therapy. However, for patients who are
responding to treatment and otherwise are tolerating therapy, the use
of dexrazoxane may minimize the risk of treatment-related cardiac
damage
• Anthracycline versus taxane — There is no evidence of superiority
of either anthracyclines or taxanes in the metastatic setting
OTHER SINGLE AGENTS:
• Capecitabine — In our practice, single-agent capecitabine (1000 to
1250 mg/m2 twice daily for 14 days followed by seven days of rest) is
a frequent choice as a first-line treatment for metastatic breast
cancer, particularly in patients with bone-predominant, estrogen
receptor-positive metastatic disease who have progressed despite at
least two trials of endocrine therapy
COMBINATION CHEMOTHERAPY
Anthracycline-containing regimens — Anthracycline-based
chemotherapy regimens are associated with response rates of up to 60
percent in previously untreated patients with metastatic breast cancer
Among the available regimens, an anthracycline plus taxane
combination results in a higher response rate compared with non-
taxane containing regimens
Non-anthracycline, taxane-based regimens — For patients who are
not suitable candidates for anthracyclines, taxane-based regimens can
be administered. The choice among the taxanes is usually determined
by the prior treatment history.
ADJUNCTIVE THERAPY
• Pain medications and osteoclast inhibitors
• In advanced tumour stages, skeletal mets with diffuse pain occur
frequently. If pain is refractory to analgesic, there are two alternative
radiation therapy that is recommended namely:
• Half body irradiation-Salazer et al
• Radionucleide therapy
• Pleurodesis in Malignant pleural effusion was efficacious in
controlling malignant pleural effusion
MONITORING
• History and physical exam prior to the start of each treatment cycle (ie, day
one of a new 21- or 28-day treatment cycle).

• Repeat imaging studies (using the same imaging modality throughout) after
completion of two cycles of therapy (ie, after cycle two, cycle four, etc).

• Serial assay for serum tumor markers (eg, cancer antigen [CA] 15-3, CA
27.29, and/or carcinoembryonic antigen [CEA]) if they were elevated at
baseline.Typically reevaluate them at the beginning of each treatment cycle.
DEFINITION OF TREATMENT
FAILURE
RECIST criteria —Response Evaluation Criteria in Solid Tumors
1. A 20 percent or more increase in the sum of measurable target
lesions compared with the smallest sum previously recorded

2. The appearance of any new lesions

3. Worsening of existing non-target lesions, for example, bone

metastases
REFERENCES
• 5th ESO-ESMO international guidelines for advanced breast cancer,
vol 31- Dec 2020.
• NCCN guidelines
• Medscape