VOLUME 36 • NUMBER 23 • AUGUST 10, 2018

JOURNAL OF CLINICAL ONCOLOGY A S C O S P E C I A L A R T I C L E

Selection of Optimal Adjuvant Chemotherapy and Targeted

Therapy for Early Breast Cancer: ASCO Clinical Practice
Guideline Focused Update
Neelima Denduluri, Mariana Chavez-MacGregor, Melinda L. Telli, Andrea Eisen, Stephanie L. Graff, Michael J.
Hassett, Jamie N. Holloway, Arti Hurria, Tari A. King, Gary H. Lyman, Ann H. Partridge, Mark R. Somerfield,
Maureen E. Trudeau, Antonio C. Wolff, and Sharon H. Giordano

Author affiliations and support information

(if applicable) appear at the end of this
article.
Published at jco.org on May 22, 2018.
Clinical Practice Guideline Committee
Approved: March 8, 2018
This ASCO Clinical Practice Guideline
provides recommendations, with
comprehensive review and analyses of
the relevant literature for each
recommendation. Additional information,
including a Data Supplement with
additional evidence tables, a Methodology
Supplement, slide sets, clinical tools and
resources, and links to patient information
at www.cancer.net, is available at www.
asco.org/breast-cancer-guidelines
Corresponding Author: American Society
of Clinical Oncology, 2318 Mill Rd, Suite
800, Alexandria, VA 22314; e-mail:
guidelines@asco.org.
© 2018 by American Society of Clinical
Oncology
0732-183X/18/3623w-2433w/$20.00
A B S T R A C T
Purpose
To update key recommendations of the ASCO guideline adaptation of the Cancer Care Ontario
guideline on the selection of optimal adjuvant chemotherapy regimens for early breast cancer and
adjuvant targeted therapy for breast cancer.
Methods
An Expert Panel conducted targeted systematic literature reviews guided by a signals approach
to identify new, potentially practice-changing data that might translate to revised practice
recommendations.
Results
The Expert Panel reviewed phase III trials that evaluated adjuvant capecitabine after completion of
standard preoperative anthracycline- and taxane-based combination chemotherapy by patients with
early-stage breast cancer HER2-negative breast cancer with residual invasive disease at surgery; the
addition of 1 year of adjuvant pertuzumab to combination chemotherapy and trastuzumab for pa-
tients with early-stage, HER2-positive breast cancer; and the use of neratinib as extended adjuvant
therapy for patients after combination chemotherapy and trastuzumab-based adjuvant therapy with
early-stage, HER2-positive breast cancer.
Recommendations
Patients with early-stage HER2-negative breast cancer with pathologic, invasive residual disease at
surgery following standard anthracycline- and taxane-based preoperative therapy may be offered up
to six to eight cycles of adjuvant capecitabine. Clinicians may add 1 year of adjuvant pertuzumab to
trastuzumab-based combination chemotherapy in patients with high-risk, early-stage, HER2-positive
breast cancer. Clinicians may use extended adjuvant therapy with neratinib to follow trastuzumab in
patients with early-stage, HER2-positive breast cancer. Neratinib causes substantial diarrhea, and
diarrhea prophylaxis must be used.
Additional information can be found at www.asco.org/breast-cancer-guidelines.

J Clin Oncol 36:2433-2443. © 2018 by American Society of Clinical Oncology

This focused update of the 2016 guide-

INTRODUCTION
In 2016, ASCO published an adaptation of the
Cancer Care Ontario guideline on the selection of
ASSOCIATED CONTENT optimal adjuvant chemotherapy regimens for early
Appendix breast cancer and adjuvant targeted therapy for human
DOI: https://doi.org/10.1200/JCO. epidermal growth factor receptor 2 (HER2)–positive
2018.78.8604
breast cancers.1 ASCO updates its guidelines at in-
Data Supplement
tervals determined by an Update Steering Group of
DOI: https://doi.org/10.1200/JCO.
2018.78.8604 the original Expert Panel. The recent publication
DOI: https://doi.org/10.1200/JCO.2018.
of phase III studies2-5 relevant to the clinical care of
78.8604 patients with breast cancer prompted this update.
line adaptation provides new recommenda-
tions for (1) the addition of adjuvant capecitabine
after completion of standard preoperative
anthracycline- and taxane-based combination
chemotherapy in patients with early-stage breast
cancer, HER2-negative breast cancer with residual
disease at surgery; (2) the addition of 1 year of
adjuvant pertuzumab to combination chemo-
therapy and trastuzumab; and (3) the use of
neratinib as extended adjuvant therapy in patients
with early-stage HER2-amplified or -overexpressed
breast cancer. The remaining recommendations

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 Denduluri et al

THE BOTTOM LINE

Selection of Optimal Adjuvant Chemotherapy and Targeted Therapy for Early Breast Cancer: ASCO Clinical
Practice Guideline Focused Update

Questions Addressed in Focused Update

• Should adjuvant capecitabine be given following completion of standard preoperative anthracycline- and taxane-based
combination chemotherapy in patients with early-stage HER2-negative breast cancer with residual invasive disease at surgery?
• Should 1 year of adjuvant pertuzumab be added to trastuzumab-based combination chemotherapy in patients with early
stage HER2-positive breast cancer?

• Should neratinib be offered as extended adjuvant therapy for patients after combination chemotherapy and trastuzumab-
based adjuvant therapy with early-stage, HER2-positive breast cancer?

Target Population
Patients who are being considered for, or who are receiving, systemic therapy following definitive surgery for early-stage invasive breast
cancer, defined largely as invasive cancer anatomic stages I to IIIC

Target Audience
Medical oncologists, pathologists, surgeons, oncology nurses, patients, and caregivers.

Methods
An Expert Panel was convened to develop clinical practice guideline recommendations based on a review of signals in the medical literature on
the optimal use of adjuvant cytotoxic chemotherapy and human epidermal growth factor receptor 2 (HER2)–directed therapy.

Focused Update Recommendations

Patients with early-stage HER2-negative breast cancer with pathologic invasive residual disease at surgery following standard
anthracycline- and taxane-based preoperative therapy may be offered up to six to eight cycles of adjuvant capecitabine. (Type:
evidence-based, benefits outweigh harms; Evidence quality: intermediate; Strength of recommendation: moderate.)

Qualifying statements. If clinicians decide to use capecitabine, then the Expert Panel preferentially supports the use of adjuvant
capecitabine in the subgroup of patients with hormone receptor–negative, HER2-negative disease. The capecitabine dosage used in the
CREATE-X study (1,250 mg/m2 twice daily) is associated with higher toxicity in patients $ 65 years old.
Clinicians may add 1 year of adjuvant pertuzumab to trastuzumab-based combination chemotherapy in patients with high-risk, early-
stage, HER2-positive breast cancer. (Type: evidence-based, benefits outweigh harms; Evidence quality: high; Strength of
recommendation: moderate.)

Qualifying statements. The Expert Panel preferentially supports pertuzumab in patients with node-positive, HER2-positive breast
cancer in view of the clinically insignificant absolute benefit observed among node-negative patients. After a median follow-up of 3.8
years, pertuzumab offered a modest disease-free survival (DFS) benefit. The first planned interim analysis did not show an overall
survival (OS) benefit in the trial population. There are no data to guide the duration of pertuzumab in patients who received
neoadjuvant pertuzumab and achieved a pathologic complete response.
Clinicians may use extended adjuvant therapy with neratinib to follow trastuzumab in patients with early-stage, HER2-positive breast
cancer. (Type: evidence-based, benefits outweigh harms; Evidence quality: high; Strength of recommendation: moderate.) Neratinib
causes substantial diarrhea, and diarrhea prophylaxis must be used.

Qualifying statements. The Expert Panel preferentially favors use of neratinib in patients with HER2-positive, hormone receptor–positive,
and node-positive disease. At a median follow-up of 5.2 years, no OS benefit has been observed. Patients who began neratinib within 1 year
of trastuzumab completion appeared to derive the greatest benefit.
There are no data on the added benefit of neratinib in patients who also received pertuzumab in the neoadjuvant or adjuvant
setting.
Refer to Table 1 for the full list of recommendations from the guideline adaptation.
(continued on following page)

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 Adjuvant Chemotherapy and Targeted Therapy for Breast Cancer

THE BOTTOM LINE (CONTINUED)

Additional Resources:
More information, including a Data Supplement with additional evidence tables, a Methodology Supplement with information
about evidence quality and strength of recommendations, slide sets, and clinical tools and resources, is available at www.asco.org/
breast-cancer-guidelines. Patient information is available at www.cancer.net.
ASCO believes that cancer clinical trials are vital to inform medical decisions and improve cancer care, and that all patients should
have the opportunity to participate.

from the 2016 ASCO guideline adaptation are unchanged because
there were no new potentially practice-changing data to support
substantive revisions.
FOCUSED GUIDELINE UPDATE QUESTIONS
Question 1: Should adjuvant capecitabine be given following
completion of standard preoperative anthracycline- and
taxane-based combination chemotherapy in patients with
early-stage, HER2-negative breast cancer with residual in-
vasive disease at surgery?
Question 2: Should 1 year of adjuvant pertuzumab be added to
trastuzumab-based combination chemotherapy in patients
with early-stage, HER2-positive breast cancer?
Question 3: Should neratinib be offered as extended adjuvant
therapy for patients after combination chemotherapy and
trastuzumab-based adjuvant therapy with early-stage, HER2-
positive breast cancer?
METHODS
Guideline Update Process
ASCO uses a “signals” approach to facilitate guideline updating.6 This
approach identifies new, potentially practice-changing data—signals—that
might translate into revised practice recommendations. The approach
relies on targeted literature searching and the expertise of ASCO guideline
panel members to identify signals.
For this focused update, three phase III, randomized, adjuvant trials
addressing capecitabine, pertuzumab, and neratinib provided the signals.2-5
Based in large part on these signals, the ASCO Breast Cancer Advisory Group
ranked updating the adjuvant therapy guideline adaptation among its highest
priorities. To that end, ASCO convened an Expert Panel to review the
evidence and to formulate updated recommendations for practice.
This systematic, review-based guideline product was developed by
a multidisciplinary Expert Panel, which included a patient representative and
an ASCO guidelines staff member with health research methodology ex-
pertise. The Expert Panel conducted a search of the PubMed database to
identify any additional randomized controlled trials that addressed the fo-
cused update’s three clinical questions. Additional information about the
results of the updated literature search and search strategy strings and results,
as well as a discussion of ASCO’s signals approach to guideline updating, are
available at www.asco.org/breast-cancer-guidelines in the Data Supplement 1
and Methodology Supplement, respectively. The Data Supplement also in-
cludes QUORUM diagrams of the updated search and the clinical questions.
The entire Expert Panel (Appendix Table A1, online only) contributed
to the development of the guideline, provided critical review, and finalized
the guideline recommendations. The ASCO Clinical Practice Guidelines
Committee reviews and approves all ASCO guidelines. All funding for the
administration of the project was provided by ASCO.
Guideline Disclaimer
The clinical practice guidelines and other guidance published herein are
provided by the American Society of Clinical Oncology, Inc. (“ASCO”) to
assist providers in clinical decision-making. The information therein should
not be relied upon as being complete or accurate, nor should it be considered
as inclusive of all proper treatments or methods of care or as a statement of
the standard of care. With the rapid development of scientific knowledge,
new evidence may emerge between the time information is developed and
when it is published or read. The information is not continually updated and
may not reflect the most recent evidence. The information addresses only the
topics specifically identified therein and is not applicable to other interventions,
diseases, or stages of diseases. This information does not mandate any particular
course of medical care. Further, the information is not intended to substitute for
the independent professional judgment of the treating provider, as the in-
formation does not account for individual variation among patients. Recom-
mendations reflect high, moderate or low confidence that the recommendation
reflects the net effect of a given course of action. The use of words like “must,”
“must not,” “should,” and “should not” indicate that a course of action is
recommended or not recommended for either most or many patients, but there
is latitude for the treating physician to select other courses of action in individual
cases. In all cases, the selected course of action should be considered by the
treating provider in the context of treating the individual patient. Use of the
information is voluntary. ASCO provides this information on an “as is” basis, and
makes no warranty, express or implied, regarding the information. ASCO
specifically disclaims any warranties of merchantability or fitness for a particular
use or purpose. ASCO assumes no responsibility for any injury or damage to
persons or property arising out of or related to any use of this information or for
any errors or omissions.
Guideline and Conflicts of Interest. The Expert Panel was assembled in
accordance with ASCO’s Conflict of Interest Policy Implementation for
Clinical Practice Guidelines (“Policy,” found at http://www.asco.org/rwc). All
members of the Expert Panel completed ASCO’s disclosure form, which
requires disclosure of financial and other interests, including relationships
with commercial entities that are reasonably likely to experience direct
regulatory or commercial impact as a result of promulgation of the guideline.
Categories for disclosure include employment; leadership; stock or other
ownership; honoraria, consulting or advisory role; speaker’s bureau; research
funding; patents, royalties, other intellectual property; expert testimony;
travel, accommodations, expenses; and other relationships. In accordance
with the Policy, the majority of the members of the Expert Panel did not
disclose any relationships constituting a conflict under the Policy.
RESULTS
The PubMed search for reports published from July 2015 to
December of 2017 on studies addressing the three clinical ques-
tions yielded a total of 54 records: 21 records related to

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 Denduluri et al

Table 1. Complete List of Recommendations from 2016 ASCO Guideline Adaptation and from the ASCO 2018 Focused Guideline Update
Recommendations From 2018 Focused Guideline Update
Recommendation Evidence Rating
Patients with early-stage, HER2-negative breast cancer with pathologic invasive residual disease at Type: evidence-based, benefits outweigh harms
surgery following standard anthracycline- and taxane-based preoperative therapy may be Evidence quality: intermediate
offered up to six to eight cycles of adjuvant capecitabine Strength of recommendation: moderate
Qualifying Statements. If clinicians decide to use capecitabine, then the Expert Panel
preferentially supports the use of adjuvant capecitabine in patients with hormone receptor-
negative, HER2-negative breast cancer. The capecitabine dosage used in the CREATE-X study
(1,250 mg/m2 twice daily) is associated with higher toxicity in patients $ 65 years old.
Clinicians may add 1 year of adjuvant pertuzumab to trastuzumab-based combination Type: evidence-based, benefits outweigh harms
chemotherapy for patients with early-stage, HER2-positive breast cancer. Evidence quality: high
Strength of recommendation: moderate
Qualifying Statements. The Expert Panel preferentially supports pertuzumab in the node-positive,
HER2-positive population in view of the clinically insignificant absolute benefit observed
among node-negative patients. After a median follow-up of 3.8 years, pertuzumab was found
to offer a modest disease-free survival benefit; the first planned interim analysis did not show
an overall survival benefit. There are no data to guide the duration of pertuzumab treatment for
patients who received neoadjuvant pertuzumab and achieved a pathologic complete response.
Clinicians may use extended adjuvant therapy with neratinib for patients with early-stage, HER2- Type: evidence-based, benefits outweigh harms
positive breast cancer. Neratinib causes substantial diarrhea, and diarrhea prophylaxis must be Evidence quality: high
used. Strength of recommendation: moderate

Qualifying Statements. The Expert Panel preferentially favors use of neratinib treatment for
hormone receptor–positive and node-positive patients. At 5.2-years of follow-up, no overall
survival benefit has been observed. Patients who began receiving neratinib within 1 year of
trastuzumab completion appeared to derive the greatest benefit. There are no data on the
added benefit of neratinib treatment for patients who also received pertuzumab in the
neoadjuvant or adjuvant setting.
Recommendations Unchanged From 2016 Guideline Adaptation
In patients who can tolerate it, use of a regimen containing anthracycline-taxane is considered the optimal strategy for adjuvant chemotherapy, particularly for patients
deemed to be at high risk.
For patients with high-risk disease who will not receive a taxane, an optimal-dose, anthracycline, three-drug regimen (cumulative dose of doxorubicin $ 240 mg/m2 or epirubicin $
600 mg/m2 but not . 720 mg/m2) that contains cyclophosphamide is recommended. The cumulative dose of doxorubicin in two-drug regimens should not exceed 240 mg/m2.
The addition of gemcitabine or capecitabine to an anthracycline-taxane regimen is not recommended for adjuvant chemotherapy.
In patients age $ 65 years, capecitabine is not recommended as an adjuvant chemotherapy option in lieu of standard regimens such as doxorubicin-cyclophosphamide
or cyclophosphamide-methotrexate-fluorouracil (with oral cyclophosphamide).
For patients in whom anthracycline-taxane is contraindicated, cyclophosphamide-methotrexate-fluorouracil (with oral cyclophosphamide) is an acceptable
chemotherapy alternative to doxorubicin-cyclophosphamide. Of note, the ASCO Panel recommends classic cyclophosphamide-methotrexate-fluorouracil (oral
cyclophosphamide days 1 to 14 with IV methotrexate-fluorouracil days 1 and 8, repeated once every 28 days for six cycles) as the default adjuvant
cyclophosphamide-methotrexate-fluorouracil regimen. However, the Panel also recognizes that an all-IV cyclophosphamide-methotrexate-fluorouracil regimen
once every 21 days is often used in clinical practice and was accepted by some clinical trials (eg, TAILORx) on the basis of convenience and tolerability despite the
absence of efficacy data from randomized controlled trials.
These adjuvant chemotherapy regimens can be used for patients with early breast cancer:
• Fluorouracil-epirubicin-cyclophosphamide 3 3 → docetaxel 3 3 (superior to fluorouracil-epirubicin-cyclophosphamide 3 6)
• Doxorubicin-cyclophosphamide 3 4 → docetaxel 3 4 (superior to doxorubicin-cyclophosphamide 3 4)
• Docetaxel-doxorubicin-cyclophosphamide 3 6 (superior to fluorouracil-doxorubicin-cyclophosphamide 3 6)
• Doxorubicin-cyclophosphamide 3 4 → paclitaxel administered once per week
• Dose-dense doxorubicin-cyclophosphamide → paclitaxel administered once every 2 weeks
• Dose-dense epirubicin 90 mg/m2, cyclophosphamide 600 mg/m2 every 2 weeks for 4 cycles → paclitaxel 175 mg/m2 every 2 weeks for 4 cycles
Docetaxel-cyclophosphamide 3 4 is recommended as an alternative to doxorubicin-cyclophosphamide 3 4 and offers improved disease-free survival and overall
survival. Classic cyclophosphamide-methotrexate-fluorouracil with oral cyclophosphamide for six cycles is another option. As mentioned, the ASCO Panel
recommends classic cyclophosphamide-methotrexate-fluorouracil (oral cyclophosphamide days 1 to 14 with IV methotrexate-fluorouracil days 1 and 8, repeated
once every 28 days for six cycles) as the default adjuvant cyclophosphamide-methotrexate-fluorouracil regimen. However, the Panel also recognizes that an all-IV
cyclophosphamide-methotrexate-fluorouracil regimen once every 21 days is often used in clinical practice and was accepted by some clinical trials (eg, TAILORx)
on the basis of its convenience and tolerability despite the absence of efficacy data from randomized controlled trials.
Only patients with HER2-positive breast cancer (overexpressed based on immunohistochemistry [3+] or amplified based on in situ hybridization [ratio $ 2.0 or average
HER2 copy number $ 6.0]) should be offered adjuvant trastuzumab.
Trastuzumab plus chemotherapy is recommended for all patients with HER2-positive, node-positive breast cancer and for patients with HER2-positive, node-negative
breast cancer (. 1 cm)
Trastuzumab therapy can be considered in small, node-negative tumors (# 1 cm).
Trastuzumab can be administered with any acceptable adjuvant chemotherapy regimen.
The administration of trastuzumab concurrently with the anthracycline component of a chemotherapy regimen is not recommended, because of the potential for
increased cardiotoxicity.
Trastuzumab should be preferentially administered concurrently (not sequentially) with a nonanthracycline chemotherapy regimen.
Less cardiotoxicity is seen with docetaxel-carboplatin-trastuzumab than with doxorubicin-cyclophosphamide → docetaxel-trastuzumab, and docetaxel-carboplatin-
trastuzumab is recommended for patients at higher risk for cardiotoxicity.
No phase III evidence exists for the addition of trastuzumab to some chemotherapy regimens, such as docetaxel-cyclophosphamide. However, those regimens might
be in use and are reasonable options, particularly for mitigating cardiotoxicity in certain patients.
Patients should be offered 1 year total of adjuvant trastuzumab with regular assessments of cardiac function during that period.

Abbreviations: IV, intravenous; TAILORx, Trial Assigning Individualized Options for Treatment (Rx).

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 Adjuvant Chemotherapy and Targeted Therapy for Breast Cancer
capecitabine, 29 related to pertuzumab, and four related to ner-
atinib (Data Supplement 2). After review of the identified abstracts,
four full-text articles reporting on three phase III clinical trials were
selected for review by the Expert Panel.
One article reported the results of the CREATE-X (Capecitabine
for Residual Cancer as Adjuvant Therapy) trial2 of adjuvant capeci-
tabine after preoperative chemotherapy in patients with HER2-
negative breast cancer and residual invasive disease after pathologic
evaluation testing (Table 2). Another article reported the results of the
APHINITY (Study of Pertuzumab in Addition to Chemotherapy and
Trastuzumab as Adjuvant Therapy in Participants With Human
Epidermal Growth Receptor 2 [HER2]-Positive Primary Breast
Cancer) trial3 of adjuvant pertuzumab added to trastuzumab-based
combination chemotherapy in early-stage, HER2-positive breast
cancer (Table 3). Finally, two articles reported the results of the
ExteNET (Neratinib After Trastuzumab-Based Adjuvant Therapy in
Patients With HER2-Positive Breast Cancer) trial of neratinib4,5 after
adjuvant trastuzumab treatment (Table 4). Chan et al4 reported results
after a median of 2 years of follow-up; more recently, Martin et al5
reported the results of 5-year analyses of the trial data.
FOCUSED UPDATE RECOMMENDATIONS
Clinical Question 1
Should adjuvant capecitabine be given following completion
of standard preoperative anthracycline- and taxane-based com-
bination chemotherapy in patients with early-stage, HER2-
negative breast cancer with residual invasive disease at surgery?
Recommendation. Patients with early-stage, HER2-negative
breast cancer with pathologic invasive residual disease at surgery
following standard anthracycline- and taxane-based preoperative
therapy may be offered up to six to eight cycles of adjuvant cape-
citabine. (Type: Evidence-based, benefits outweigh harms; Evidence
quality: intermediate; Strength of recommendation: moderate)
Qualifying Statements. If clinicians decide to use capecitabine,
then the Expert Panel preferentially supports the use of adjuvant
capecitabine in patients with hormone receptor–negative, HER2-
negative breast cancer. The capecitabine dosage used in the
CREATE-X study (1,250 mg/m2 twice daily) is associated with
higher toxicity in patients $ 65 years old.
Literature review and analysis. The CREATE-X randomized,
phase III clinical trial assessed the impact of six to eight cycles of
adjuvant capecitabine on disease-free survival (DFS) and overall
survival (OS) among 910 Asian patients with stages I to IIIB, HER2-
negative breast cancer treated with curative intent with neoadjuvant
anthracycline, taxane, or combined anthracycline and taxane
therapy.2 Eligible patients had centrally confirmed residual invasive
disease at surgery in the breast and/or axillary nodes following
standard combination chemotherapy. Patients randomly assigned to
the capecitabine arm received six to eight cycles of oral capecitabine
at a dosage of 1,250 mg/m2 orally twice daily on days 1 through 14 of
a 21-day cycle. Patients with hormone receptor–positive (n = 601;
68%) and hormone receptor–negative (n = 286; 32%) disease were
enrolled and, notably, 57% of patients were premenopausal at study
entry. Patients received a number of neoadjuvant regimens, with
about 95% receiving sequential or concurrent anthracycline- and
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taxane-based therapy; intravenous fluorouracil was administered in
about 60% of patients as part of the neoadjuvant therapy. Adjuvant
endocrine therapy was administered to all hormone receptor–
positive patients.
The trial was terminated early after the primary end point of
DFS was met; median follow-up at the time of final analysis was 3.6
years. The rate of DFS at 5 years was 74.1% in the capecitabine arm
and 67.6% in the control arm (hazard ratio [HR], 0.70; 95% CI,
0.53 to 0.92; P = .01) for all patients, with an absolute difference of
6.5%. OS, a secondary end point, was also better in the capeci-
tabine group, at 89.2% versus 83.6% (HR, 0.59; 95% CI, 0.39 to
0.90; P = .01), with an absolute difference of 5.6%.2
Patients with triple-negative breast cancer (DFS: 69.8% v
56.1%, HR, 0.58, 95% CI, 0.39 to 0.87; OS: 78.8% v 70.3%, HR,
0.52, 95% CI, 0.30 to 0.90) and hormone receptor–positive breast
cancer (DFS: 76.4% v 73.5%, HR, 0.81, 95% CI, 0.55 to 1.17; OS:
93.4% v 90%, HR, 0.73, 95% CI, 0.38 to 1.40) derived a benefit
from capecitabine. Although the effect size was numerically larger
in patients with hormone receptor–negative disease, the interac-
tion test for treatment effect by hormone receptor status was not
statistically significant (P = .21).2
CREATE-X was the first adjuvant capecitabine trial to select
high-risk patients on the basis of residual disease at surgery following
standard neoadjuvant combination chemotherapy. Several other
studies have assessed the added the addition of capecitabine in
combination with standard anthracycline- and taxane-based adju-
vant therapy in otherwise unselected patients with breast cancer.
The phase III, randomized Finland Capecitabine (FinXX) trial
enrolled 1,500 patients with stages II to III disease who were un-
selected for estrogen receptor, progesterone receptor, and HER2
status.7 Patients were randomly assigned to received adjuvant doce-
taxel plus capecitabine for three cycles followed by cyclophosphamide,
epirubicin, and capecitabine for three cycles versus docetaxel for three
cycles followed by cyclophosphamide, epirubicin, and fluorouracil for
three cycles. Capecitabine was dosed at 900 mg/m2 orally twice daily
on days 1 through 14 of a 21-day cycle. After a median of 4.9 years,
recurrence-free survival did not differ significantly between the
groups. In an exploratory analysis, after a median follow-up of 10.3
years, patients with triple-negative breast cancer had improved
recurrence-free survival and OS with the capecitabine-containing
regimen (HR, 0.53, P = .02; and HR 0.55, P = .03).8
O’Shaughnessy and colleagues9 evaluated doxorubicin and
cyclophosphamide followed by docetaxel with or without the addition
of capecitabine 825 mg/m2 orally twice daily on days 1 through 14 of
a 21-day cycle in a phase III adjuvant study that included 2,611 patients.
In the overall trial, the primary end point of DFS was not significantly
improved with the addition of capecitabine (DFS: HR, 0.84; P = .125);
however, OS was significantly improved in a prespecified exploratory
analysis (HR, 0.68; P = .011). An exploratory subgroup analysis
among 780 patients with triple-negative disease also showed an OS
advantage with capecitabine (HR, 0.62; 95% CI, 0.41 to 0.94).
A trial-level meta-analysis of eight studies of adjuvant or
neoadjuvant capecitabine added to standard chemotherapy com-
prising 9,302 patients was recently reported.10 In otherwise un-
selected patients, capecitabine did not improve DFS or OS (DFS:
HR, 0.99, P = .93; OS: HR, 0.90, P = .36). However, in the subset of
patients with triple-negative versus non–triple-negative disease, DFS
was significantly improved (HR, 0.72 v 1.01; P for interaction = .02),
© 2018 by American Society of Clinical Oncology 2437
 Denduluri et al

Table 2. Results of Phase III Trial of Adjuvant Capecitabine After Standard Preoperative Anthracycline and Taxane-Based Combination Chemotherapy in Patients with
HER2-Negative Breast Cancer and Residual Invasive Disease: CREATE-X
No. of Survival*
Primary Patients Quality
Study Intervention/Comparisons End Points Evaluated OS PFS of Life Safety Outcomes
Masuda Capecitabine plus standard Primary: 443 Median: 89.2 Median: 74.1 NA Hand–foot syndrome was
et al2 therapy (endocrine DFS the most frequent ad-
therapy in patients with verse event, occurring in
ER+ disease plus RT, if 325 patients (73.4%),
indicated) including 49 (11.1%)
Standard therapy alone Secondary: 444 Median: 83.6 Median: 67.6 with a grade 3 event in
OS HR for death, 0.59; HR for recurrence, second the capecitabine group v
95% CI, 0.39 to 0.90; cancer, or death, 0.70; 0% across grades in
P = .01 95% CI, 0.53 to 0.92; standard therapy group.
P = .01

Abbreviations: DFS, disease-free survival; ER+, estrogen-receptor positive; HR, hazard ratio; NA, not applicable; OS, overall survival; PFS, progression-free survival; RT,
radiotherapy.
*Data given as percentage unless otherwise indicated.

and regression analyses showed that adding capecitabine to standard
chemotherapy improved OS in studies with a higher proportion of
patients with triple-negative breast cancer (R = 20.967; P = .007).
Capecitabine is not without meaningful toxicities, particularly
among older patients.11 In CREATE-X, patients in the capecitabine
group had a higher rate of adverse events; grade 3/4 events of
interest included neutropenia in 6.3%, diarrhea in 2.9%, and
hand–foot syndrome in 11.1%. In the meta-analysis, capecitabine
increased the odds of grade 3/4 diarrhea and hand–foot syndrome
and resulted in higher rates of treatment discontinuation. Notably,
the median age in CREATE-X was 48 years; the study excluded
those patients with age $ 75 years and majority of those with
creatinine clearance , 50 mL/min.
CALGB 49907, a phase III clinical trial that evaluated adjuvant
capecitabine in patients $ 65 years of age in North America who had
early-stage breast cancer, there was a 34% rate of grade 3 or higher
toxicity, including two protocol-related deaths among the first 56 patients
treated with the dose of 1,250 mg/m2 orally twice daily on days 1 through
14 of a 21-day cycle.12 Due to this unacceptable toxicity, the protocol was
amended and all subsequent patients were treated at a starting dose of
1,000 mg/m2 orally twice daily without escalation of dose.
Clinical interpretation. Based on the results of the CREATE-X
phase III clinical trial, we recommend that patients with residual
invasive disease at surgery after standard preoperative anthracycline-
and taxane-based chemotherapy may be offered up to six to eight
cycles of postoperative capecitabine. Although the meta-analysis
suggests benefit of capecitabine is limited to the triple-negative
population, a significant interaction by hormone receptor status
was not observed in the CREATE-X trial; therefore, a small benefit
cannot be excluded in the hormone receptor–positive population.
This treatment strategy must be balanced against potential tox-
icities. Despite the convenience of oral administration, capecitabine can
be associated with life-threatening toxicity. The starting dosage of 1,
250 mg/m2 orally twice daily was found to be excessively toxic in
a population of predominantly non-Asian patients age 65 and older.
The findings from CREATE-X are now being extended in the
ongoing phase III EA1131 trial of adjuvant capecitabine versus
platinum chemotherapy for patients with triple-negative breast
cancer, with a particular interest in the subset of patients with
a basal-like molecular subtype, who have residual invasive disease
after preoperative taxane therapy with or without anthracycline
chemotherapy (ClinicalTrials.gov identifier: NCT02445391).
Clinical Question 2
Should 1 year of adjuvant pertuzumab be added to
trastuzumab-based combination chemotherapy for patients with
early-stage, HER2-positive breast cancer?
Recommendation. Clinicians may add 1 year of adjuvant
pertuzumab to trastuzumab-based combination chemotherapy in
patients with high-risk, early-stage, HER2-positive breast cancer
(Type: evidence-based, benefits outweigh harms; Evidence quality:
high; Strength of recommendation: moderate.)
Qualifying statements. The Expert Panel preferentially supports
pertuzumab in the node-positive, HER2-positive population in view of
the clinically insignificant absolute benefit observed among node-
negative patients. After a median follow-up of 3.8 years, pertuzu-
mab was found to offer a modest DFS benefit; the first interim analysis
did not show an OS benefit in the overall trial population. There are no
data to guide the duration of pertuzumab in patients who received
neoadjuvant pertuzumab and achieved a pathologic complete response.
Literature review and analysis. In 2013, the Food and Drug
Administration (FDA) granted accelerated approval of up to six
cycles of pertuzumab in combination with trastuzumab and doce-
taxel for the neoadjuvant treatment of patients with HER2-positive,
locally advanced, inflammatory or early-stage breast cancer (either
. 2 cm in diameter or node positive) as part of a complete treatment
regimen for early breast cancer. The accelerated approval was based on
a higher observed rate of pathologic complete response when pertu-
zumab was added to trastuzumab-based chemotherapy regimens.13,14
The results of APHINITY, a large phase III clinical trial eval-
uating the survival benefit of 1 year of pertuzumab in the adjuvant
setting, were recently published and led to full FDA approval.3
Following mastectomy or lumpectomy, 4,805 patients with HER2-
positive, early-stage breast cancer were randomly assigned to receive
a maximum of 18 weeks of standard adjuvant chemotherapy with
HER2-targeted therapy (trastuzumab and placebo or trastuzumab
and pertuzumab) followed by continuation of trastuzumab and
placebo or trastuzumab and pertuzumab to complete 1 year of
HER2-targeted therapy. The primary end point of the study was

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 jco.org
Table 3. Results of Phase III Trial of Pertuzumab Added to Trastuzumab-Based Combination Chemotherapy in Early-Stage, HER2-Positive Breast Cancer: APHINITY
Survival
Intervention/
Study Comparisons Primary End Points No. of Patients Evaluated OS PFS Quality of Life Safety Outcomes
von Minckwitz et al3 Chemotherapy Primary: iDFS* 2,400 n = 80 (3.3%) pts in 3-year iDFS, 94.1% Baseline functional Grade 3 or higher
and 1 year of (excluding the pertuzumab health-related diarrhea was
treatment second primary group died QOL scores more frequent
with nonbreast were similar with
trastuzumab cancer) between the pertuzumab
plus treatment than with
pertuzumab groups. The placebo (9.8%
scores remained v 3.7%)
Chemotherapy Secondary: OS, 2,404 n = 89 (3.7%) pts in In node-positive pts, 3-year stable during The largest
and 1 year of DFS (including the placebo iDFS, 92.0% treatment, differences
treatment noninvasive group died except for between the
with breast cancers), No statistically 3-year iDFS, 93.2% a temporary groups for all
trastuzumab iDFS (including significant In node-positive pts, clinically grades of
plus placebo second primary treatment effect 3-year iDFS, 90.2% meaningful adverse
nonbreast at first interim OS decrease at the events were
HR for invasive-disease
cancer), RFI, survival analysis end of taxane diarrhea
event, 0.81 (95% CI,
distant RFI, (HR, 0.89; 95% treatment. (71.2% with
0.66 to 1.00; P = .045)
safety, and CI, 0.66 to 1.21; in favor of pertuzumab pertuzumab
health-related P = .47) in overall population. and 45.2%
QOL with placebo)
HR invasive-disease
and rash
event, 0.77 (95% CI,
(25.8% with
0.62 to 0.96; P = .02)
pertuzumab
for node-positive pts
and 20.3%
HR, 1.13 (95% CI, 0.68
with placebo).
to 1.86; P = .64 for
Adjuvant Chemotherapy and Targeted Therapy for Breast Cancer

node-negative pts

Abbreviations: DFS, disease-free survival; HR, hazard ratio; iDFS, invasive disease-free survival; OS, overall survival; PFS, progression-free survival; pts, patients; QOL, quality of life; RFI, recurrence-free interval.

Copyright © 2019 American Society of Clinical Oncology. All rights reserved.

*Defined as the time from randomization until the date of the first occurrence of one of the following events: recurrence of ipsilateral invasive breast tumor, recurrence of ipsilateral locoregional invasive disease,
a distant disease recurrence, contralateral invasive breast cancer, or death from any cause.

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© 2018 by American Society of Clinical Oncology
2439
 2440
Table 4. Results of Phase III Trial of Neratinib Therapy for Patients After Combination Chemotherapy and Trastuzumab-Based Adjuvant Therapy with Early-Stage, HER2-Positive Breast Cancer: ExteNET
Survival
Intervention/ No. of Patients
Study Comparisons Primary End Points Evaluated OS PFS Quality of Life Safety Outcomes
4
Chan et al Neratinib after Primary: iDFS 1,420 Data were not 2-year iDFS rate, 93.9% Health-related QOL Serious AEs in 103 pts(7%) in the
neoadjuvant and Secondary: DFS mature and there was an exploratory neratinib group and 85 (6%) in the
adjuvant including DCIS, time was no provision end point. placebo group.
trastuzumab to distant recurrence, in the protocol for
therapy up to 2 distant DFS, any analyses
years before cumulative incidence before the
randomization of CNS recurrences, predetermined
Placebo after OS, and safety 1,420 target number of 2-year iDFS rate, 91.6% After the first month,
neoadjuvant and events being QOL for pts in both
adjuvant reached. groups recovered
trastuzumab toward baseline
therapy up to 2 levels. The

© 2018 by American Society of Clinical Oncology

years before difference between
randomization groups was less
pronounced.
At 2-year follow-up, 70 iDFS events QOL differences Most common serious AEs in the
occurred in neratinib group v 109 deemed not clinically neratinib group were diarrhea
events in placebo group important (n = 22 v n = 1 in the placebo
(stratified HR, 0.67; 95% CI, 0.50 group), vomiting (n = 12 v n = 1),
to 0.91; P = .0091). and dehydration (n = 9 v n = 1)
Prespecified subgroup analysis of
iDFS showed that neratinib
provided greater benefit to pts
with hormone receptor–positive
breast cancer (HR, 0.51, 95% CI,
0.33 to 0.77; P = .0013) than to
those with hormone
receptor–negative disease (0.93,
Denduluri et al

95% CI. 0.60 to 1.43; P = .74;

P for interaction = .054)
Martin et al5 Neratinib after Primary: iDFS 1420 OS analysis 5-year iDFS rate, 90.2% Detailed health-related Treatment-emergent serious AEs
neoadjuvant and planned after 248 QOL data from the occurred in 103 women (7%) in the
adjuvant events study will be neratinib group and 85 (6%) in the
trastuzumab reported separately. placebo group.
therapy up to 2
years before
randomization
Placebo after Secondary: DFS 1420 5-year iDFS rate, 87.7% Most common grade 3-4 AEs
neoadjuvant and including DCIS, time (without diarrhea prophylaxis) in
adjuvant to distant recurrence, the neratinib group, compared with
trastuzumab distant DFS, the placebo group, were diarrhea

Copyright © 2019 American Society of Clinical Oncology. All rights reserved.

therapy up to 2 cumulative incidence (neratinib: grade 3, n = 561 [40%];

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years before of CNS recurrences, grade 4, n = 1 [,1%]) v placebo:
randomization OS, and safety grade 3, n = 23 [2%]), vomiting
(neratinib: grade 3: n = 47 [3%] v
placebo: n = 5 [,1%]), and nausea
(neratinib: grade 3: n = 26 [2%] v
placebo: n = 2 [,1%])
At 5-year follow-up, 116 iDFS No evidence of increased risk of long-
events occurred in neratinib term toxicity or long-term adverse
group v 163 events in placebo consequences of neratinib-
group (stratified HR, 0.73; 95% associated diarrhea were identified
CI, 0.57 to 0.92; P = .0083) with neratinib v placebo.

Abbreviations: AE, adverse event; DCIS, ductal carcinoma in situ; DFS, disease-free survival; HR, hazard ratio; iDFS, invasive disease-free survival; OS, overall survival; PFS, progression-free survival; pt, patient; QOL,
quality of life.

JOURNAL OF CLINICAL ONCOLOGY

 Adjuvant Chemotherapy and Targeted Therapy for Breast Cancer

Table 5. Estimated Prices for Capecitabine, Neratinib, and Pertuzumab in the United States
Total Price Per Treatment Cycle
Agent, Route Dose Schedule Price Per Dose (USD) (USD)
Capecitabine*, 1,250 mg/m2 Delivered twice daily for 14 days, then $11.486 (daily dose price, $22.97; Eight-cycle price: $2,572.64($321.58/
oral 7 days off for six to eight cycles per-cycle price, $321.58) cycle)
Neratinib*, oral 240 mg Delivered daily continuously over 1 $11,500.00/month† $138,000.00/year†
year
Pertuzumab, 840 mg loading dose, 420 mg Every 3 weeks for 17 doses after Loading subsequent doses, Loading dose plus subsequent doses:
intravenous subsequent doses initial dose $11.433 $89,024.88 ($9603.72 for loading
dose + $81,631.62)

NOTE. Drug prices are dynamic; thus, prices listed in the table may not reflect current prices.
*Prices for capecitabine and pertuzumab reimbursed through Medicare Part B only were identified from the fourth quarter 2017 Medicare Payment Allowable Part B
Drugs Average Sales Price (ASP) Data (https://www.cms.gov/Medicare/Medicare-Fee-for-Service-Part-B-Drugs/McrPartBDrugAvgSalesPrice/2018ASPFiles.html. Drug
price may vary by plan and by pharmacy where a medication is filled (eg, preferred or nonpreferred pharmacies).
†Prices based on Lexi-Drugs. Lexicomp. Riverwoods, IL, Wolters Kluwer Health, http://online.lexi.com. Accessed October 24, 2017.

invasive disease-free survival (iDFS). After a median follow-up of
almost 4 years, 171 patients (7.1%) in the pertuzumab group ex-
perienced an iDFS event, compared with 210 patients (8.7%) in the
placebo group. The 3-year iDFS was 94.1% among patients in the
pertuzumab group and 93.2% in the placebo group (HR, 0.81; 95%
CI, 0.66 to 1.00) for an absolute overall iDFS benefit of 0.9%. In all,
63% of the patients enrolled in the trial had lymph node in-
volvement and 36% had hormone receptor–negative tumors. Results
from subgroup analyses suggest a numerically greater benefit from
pertuzumab among patients with node-positive disease: The 3-year
iDFS rate was 92% with pertuzumab versus 90.2% with placebo (HR,
0.77; 95% CI, 0.62 to 0.96) with an absolute benefit of 1.8%. Among
patients with node-negative cancer, the iDFS rate was 97.5% in the
pertuzumab-treated group and 98.4% in the placebo group (HR, 1.13;
95% CI, 0.68 to 1.86). In the cohort of patients with hormone
receptor–negative disease, 8.2% in the pertuzumab group and 10.6%
in the placebo group had iDFS events (HR, 0.76; 95% CI, 0.56 to 1.04);
in the hormone receptor–positive cohort, 6.5% in the pertuzumab
group and 7.7% in the placebo group experienced iDFS events (HR,
0.86, 95% CI, 0.66 to 1.13). There was no observed statistical in-
teraction between pertuzumab benefit and hormone receptor status.3
The treatment with pertuzumab was well tolerated, though
severe diarrhea was more frequent in the pertuzumab arm (9.8% v
3.7%) and almost exclusively during chemotherapy administration. There
was a higher numeric difference in the frequency of primary cardiac events
observed among patients treated with pertuzumab (0.7% v 0.3%).3
Clinical interpretation. Based on the phase III APHINITY
data, we recommend that 1 year of pertuzumab may be offered in
addition to trastuzumab and combination chemotherapy for pa-
tients with high-risk, early-stage breast cancer, such as those with
node-positive disease. The APHINITY data showed no clinically
meaningful benefit among patients with node-negative breast
cancer. The first planned interim analysis did not show an OS
benefit. There are no data to guide the duration of pertuzumab
treatment in patients who received neoadjuvant pertuzumab and
achieved a pathologic complete response.
Clinical Question 3
Should neratinib be offered as extended adjuvant therapy for
patients after combination chemotherapy and trastuzumab-based
adjuvant therapy with early-stage, HER2-positive breast cancer?
Recommendation. Clinicians may use extended adjuvant
therapy with neratinib to follow trastuzumab in patients with
early-stage, HER2-positive breast cancer. (Type: evidence-based,
benefits outweigh harms; Evidence quality: high; Strength of
recommendation: moderate.) Neratinib causes substantial di-
arrhea, and diarrhea prophylaxis must be used.
Qualifying Statements. The Expert Panel preferentially favors
use of neratinib in patients with HER2-positive, hormone
receptor–positive and node-positive disease. At a median follow-up
of 5.2 years, no OS benefit has been observed. Patients who began
neratinib within 1 year of trastuzumab completion appeared to
derive the greatest benefit. There are no data on the added benefit
of neratinib in patients who also received pertuzumab in the
neoadjuvant or adjuvant setting.
Literature review and analysis. The FDA approved neratinib for
the extended adjuvant treatment of adult patients with early-stage
HER2-overexpressed or amplified breast cancer to follow standard
adjuvant trastuzumab-based therapy. Approval was based on results of
the ExteNET trial,5 a multicenter, randomized, double-blind, placebo-
controlled trial of neratinib following adjuvant trastuzumab treatment.
Multiple amendments were instituted throughout the course of this
trial. Eligibility was restricted to women with node-positive disease after
initially allowing those with node-negative disease. The interval between
completion of trastuzumab and enrollment was reduced from 2 years to
1 year. The analysis was changed from an event-driven analysis to
a time-driven analysis. Another amendment allowed an exploratory
iDFS analysis at 5 years.
Women (N = 2,840) with early-stage, HER2-positive breast
cancer who were within 2 years of completing adjuvant trastu-
zumab were randomly assigned to receive either neratinib (n =
1,420) or placebo (n = 1,420) for 1 year. The major efficacy
outcome measure was 2-year iDFS defined as the time between the
randomization date to the first occurrence of invasive recurrence,
distant recurrence, or death from any cause. After a median of 2
years of follow-up, iDFS was 94.2% in patients treated with ner-
atinib compared with 91.9% in those receiving placebo (HR, 0.66;
95% CI, 0.49 to 0.90; P = .008).4 Extended follow-up after patients
gave reconsent was recently reported among 2,117 of the original
2,840 patients (74.5%).5 The estimated iDFS rate after at 5 years of
median follow-up was 90.2% in the neratinib arm and 87.7% in the
placebo arm (HR, 0.73; 95% CI, 0.57 to 0.92).

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 Denduluri et al
In subgroup analyses, the observed benefit of neratinib was
greater among patients with hormone receptor–positive tumors (HR,
0.60; 95% CI, 0.43 to 0.83) among those with involvement of four or
more lymph nodes (HR, 0.67; 95% CI, 0.46 to 0.96) and among those
treated with neratinib within 1 year of completion of trastuzumab
(HR, 0.70; 95% CI, 0.54 to 0.90). The most common side effect
associated with neratinib was diarrhea. Ninety-five percent of patients
experienced grades 1 to 4 diarrhea, 40% experienced grade 3 or 4
diarrhea, and diarrhea was also the most common adverse reaction
leading to treatment discontinuation (16.8%) in the neratinib arm. In
view of concerns about its tolerability, there is an ongoing phase II
clinical trial (ClinicalTrials.gov identifier: NCT02400476) evaluating
different antidiarrheal prophylaxis regimens. Initial reports suggest
that prophylaxis initiated with the first neratinib dose and continued
during the first two cycles of treatment and as needed thereafter
significantly decreased the incidence and severity of diarrhea.
There is an ongoing clinical trial to assess the safety and tol-
erability of neratinib treatment in patients with metastatic HER2-
positive breast cancer who are $ 60 years of age (ClinicalTrials.gov
identifier: NCT02673398).
Clinical interpretation. The addition of 1 year of neratinib
improved iDFS in patients with HER2-positive early breast cancer
after trastuzumab for 1 year. The observed benefit was higher in
hormone receptor-positive and node-positive patients, and no OS
advantage has been observed thus far. Patients who began neratinib
within 1 year of trastuzumab completion appeared to derive the
greatest benefit. There are no reported data on the incremental
benefit offered by neratinib in patients who completed up to a year of
pertuzumab in the neoadjuvant or adjuvant setting. The substantial
diarrhea toxicity warrants routine antidiarrheal prophylaxis in pa-
tients receiving neratinib, per the package insert.
COST CONSIDERATIONS IN THE SELECTION OF OPTIMAL
ADJUVANT CHEMOTHERAPY AND ADJUVANT TARGETED
THERAPY FOR BREAST CANCER
Increasingly, individuals with cancer are required to pay a larger pro-
portion of their treatment costs through deductibles and coinsurance.
Higher patient out-of-pocket costs have been shown to be a barrier to
initiating and adhering to recommended cancer treatments.15,16
Table 5 shows estimated prices for capecitabine, neratinib, and
pertuzumab. Of note, medication prices of these agents vary
markedly, depending on negotiated discounts and rebates. Dis-
cussion of cost can be an important part of shared decision-making.
Clinicians should exercise judgment and, whenever it is practical and
feasible, discuss with patients the use of less-expensive alternatives
when considering two or more treatment options that are com-
parable in terms of benefits and harms.17
Depending on a patient’s particular insurance coverage, re-
imbursement for the various agents may originate in their medical or
pharmacy benefit, which may have different cost-sharing arrange-
ments. Patients should be aware that different products may be
preferred or covered by their particular insurance plan. Even with the
same insurance plan, the price may vary between different phar-
macies. Patients should be asked about their financial concerns by
their caregivers and be offered financial counseling to address this
complex and heterogeneous landscape.17
2442 © 2018 by American Society of Clinical Oncology
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Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
OPEN COMMENT
The draft recommendations and any corresponding qualifying
statements were released to the public for open comment from
January 10, 2018, through January 24, 2018. Response categories of
“Agree as written,” “Agree with suggested modifications,” and
“Disagree, see comments” were captured for every proposed rec-
ommendation with five written comments received across draft
recommendations. A total of 90% of the 10 respondents agreed
(70%) or agreed with slight modifications (20%; one written
comment) with the draft capecitabine recommendation; 10% of the
respondents disagreed (one written comment). For the pertuzumab
recommendation, 100% of the 11 respondents either agreed (73%)
or agreed with slight modifications (27%; one written comment)
with the draft recommendation. Finally, for the draft neratinib
recommendation, 100% of the 10 respondents either agreed (50%)
or agreed with slight modifications (50%; two written comments).
The Expert Panel Co-Chairs reviewed comments from all sources
and determined whether to maintain the original draft recom-
mendations, to revise with minor language changes, or to consider
major recommendation revisions. In two cases, draft recommen-
dations or corresponding qualifying statements were revised with
minor language changes. All changes were incorporated prior to
Clinical Practice Guidelines Committee final review and approval.
ADDITIONAL RESOURCES
Additional information, including data supplements, evidence
tables, and clinical tools and resources can be found at www.asco.
org/breast-cancer-guidelines. Patient information is available
there and at www.cancer.net.
Related ASCO Guidelines
• Patient-Clinician Communication (http://ascopubs.org/
doi/10.1200/JCO.2017.75.2311)
• Use of Biomarkers to Guide Decisions on Adjuvant
Systemic Therapy for Women With Early-Stage Invasive
Breast Cancer (http://ascopubs.org/doi/10.1200/
JCO.2017.74.0472)
• Interventions to Address Sexual Problems in People
With Cancer (http://ascopubs.org/doi/10.1200/
JCO.2017.75.8995)
• Prevention and Monitoring of Cardiac Dysfunction in
Survivors of Adult Cancers (http://ascopubs.org/doi/
10.1200/JCO.2016.70.5400)
• Outpatient Management of Fever and Neutropenia in
Adults Treated for Malignancy (http://ascopubs.org/doi/
10.1200/JCO.2017.77.6211)
JOURNAL OF CLINICAL ONCOLOGY
 Adjuvant Chemotherapy and Targeted Therapy for Breast Cancer

Manuscript writing: All authors

AUTHOR CONTRIBUTIONS Final approval of manuscript: All authors

Administrative support: Mark R. Somerfield

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Affiliations
Neelima Denduluri, The US Oncology Network, Virginia Cancer Specialists; Jamie N. Holloway, Georgetown Breast Cancer
Advocates, Arlington; Mark R. Somerfield, American Society of Clinical Oncology, Alexandria, VA; Mariana Chavez-MacGregor and
Sharon H. Giordano, University of Texas MD Anderson Cancer Center, Houston, TX; Melinda L. Telli, Stanford University School of
Medicine, Stanford; Arti Hurria, City of Hope, Duarte, CA; Andrea Eisen and Maureen E. Trudeau, Sunnybrook Odette Cancer Centre;
Andrea Eisen and Maureen E. Trudeau, Cancer Care Ontario, Toronto, Ontario, Canada; Stephanie L. Graff, Sarah Cannon Cancer
Institute HCA Midwest Health, Kansas City, MO; Michael J. Hassett, Tari A. King, and Ann H. Partridge, Dana-Farber Cancer Institute;
Tari A. King, Brigham & Women’s Cancer Center, Boston, MA; Gary H. Lyman, Fred Hutchinson Cancer Research Center, Seattle, WA;
Antonio C. Wolff, Johns Hopkins Kimmel Cancer Center, Baltimore, MD.

nnn

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 Denduluri et al

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Selection of Optimal Adjuvant Chemotherapy and Targeted Therapy for Early Breast Cancer: ASCO Clinical Practice Guideline Focused Update
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are
self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more
information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc.
Neelima Denduluri Tari A. King
Research Funding: Amgen (Inst), Novartis (Inst), Genentech (Inst) Honoraria: Genomic Health
Mariana Chavez-MacGregor Gary H. Lyman
Employment: MD Anderson Physicians Network Leadership: Generex Biotechnology
Consulting or Advisory Role: Pfizer, Roche Consulting or Advisory Role: Halozyme, G1 Therapeutics, Coherus
Research Funding: Novartis (Inst) Biosciences
Travel, Accommodations, Expenses: Pfizer Research Funding: Amgen (Inst)
Melinda L. Telli Ann P. Partridge
Consulting or Advisory Role: Vertex, AstraZeneca, Tesaro, PharmaMar, No relationship to disclose
Celldex, Pfizer
Research Funding: Novartis (Inst), PharmaMar (Inst), Abbvie (Inst), Mark R. Somerfield
Calithera Biosciences (Inst), Genentech (Inst), Medivation (Inst), OncoSec No relationship to disclose
(Inst), Vertex (Inst), Biothera (Inst), Tesaro (Inst), Pfizer (Inst) Maureen E. Trudeau
Andrea Eisen Stock or Other Ownership: RNA Diagnostics
Research Funding: Genomic Health (Inst) Consulting or Advisory Role: RNA Diagnostics
Other Relationship: Cancer Care Ontario (government agency) Research Funding: Roche Canada (Inst), Novartis (Inst), Pfizer (Inst),
Eisai (Inst), AstraZeneca (Inst), Astellas Pharma (Inst)
Stephanie L. Graff
Consulting or Advisory Role: Genomic Health Antonio C. Wolff
Research Funding: Pfizer (Inst)
Michael Hassett Patents, Royalties, Other Intellectual Property: Antonio Wolff has been
No relationship to disclose named as inventor on one or more issued patents or pending patent
applications relating to methylation in breast cancer, and has assigned his
Jamie N. Holloway rights to Johns Hopkins University, and participates in a royalty sharing
Employment: Cure Forward, Science37 agreement with Johns Hopkins University.
Stock or Other Ownership: Merck
Sharon H. Giordano
Arti Hurria No relationship to disclose
Consulting or Advisory Role: GTx, Boehringer Ingelheim, On Q Health,
Sanofi, OptumHealth Care Solutions, Pierian Biosciences, MJH Healthcare
Holdings
Research Funding: GlaxoSmithKline, Celgene, Novartis

© 2018 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

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 Adjuvant Chemotherapy and Targeted Therapy for Breast Cancer

Acknowledgment

The Expert Panel thanks Gregg E. Franklin, Charles L. Shapiro, and the Clinical Practice Guidelines Committee for their thoughtful
reviews and insightful comments on this guideline. The Panel also thanks Shannon McKernin for editorial assistance.

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 Denduluri et al

Appendix

Table A1. Expert Panel Membership

Member Affiliation
Neelima Denduluri, MD (Co-Chair) The US Oncology Network, Virginia Cancer Specialists,
Arlington, VA
Sharon H. Giordano, MD (Co-Chair) University of Texas MD Anderson Cancer Center, Houston, TX
Mariana Chavez-MacGregor, MD University of Texas MD Anderson Cancer Center, Houston, TX
Andrea Eisen, MD, FRCPC Sunnybrook Odette Cancer Centre; Cancer Care Ontario,
Toronto, Canada
Stephanie L. Graff, MD (Practical Guidelines Implementation Sarah Cannon Cancer Institute HCA Midwest Health, Kansas
Network representative) City, MO
Michael J. Hassett, MD Dana-Farber Cancer Institute, Boston, MA
Jamie N. Holloway, PhD (patient advocate) Georgetown Breast Cancer Advocates, Arlington, VA
Arti Hurria, MD City of Hope, Duarte, CA
Tari A. King, MD Dana-Farber Cancer Institute and Brigham and Women’s
Cancer Center, Boston, MA
Gary H. Lyman, MD, MPH Fred Hutchinson Cancer Research Center, Seattle, WA
Ann H. Partridge, MD Dana-Farber Cancer Institute, Boston, MA
Melinda L. Telli, MD Stanford University, Palo Alto, CA
Maureen E. Trudeau, MD, MA Sunnybrook Odette Cancer Centre; Cancer Care Ontario,
Toronto, Ontario, Canada
Antonio C. Wolff, MD Johns Hopkins Kimmel Comprehensive Cancer Center,
Baltimore, MD
Mark R. Somerfield, Staff, Health Research Methodologist American Society of Clinical Oncology, Alexandria, VA

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