Pathological Complete 
Response in Neoadjuvant 
Treatment of High-Risk 
Early-Stage Breast Cancer: 
Use as an Endpoint to 
Support Accelerated 
Approval 
Guidance for Industry 
 
  
  
  
  
  
  
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Oncology Center of Excellence 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
July 2020 
Clinical/Medical 
Revision 1 
 
   
 
 
Pathological Complete 
Response in Neoadjuvant 
Treatment of High-Risk 
Early-Stage Breast Cancer:  
Use as an Endpoint to Support 
Accelerated Approval 
Guidance for Industry 
 
Additional copies are available from:   
Office of Communications, Division of Drug Information   
Center for Drug Evaluation and Research   
Food and Drug Administration    
10001 New Hampshire Ave., Hillandale Bldg., 4th floor   
  Silver Spring, MD 20993-0002      
Tel: 855-543-3784 or 301-796-3400; Fax: 301-847-8714; Email: druginfo@fda.hhs.gov   
 https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs 
and/or 
Office of Communication, Outreach, and Development  
Center for Biologics Evaluation and Research 
Food and Drug Administration 
10903 New Hampshire Ave., Bldg. 71, Rm. 3128 
Silver Spring, MD  20993-0002 
Phone: 800-835-4709 or 240-402-8010; Email: ocod@fda.hhs.gov 
https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics/biologics-
guidances  
  
U.S. Department of Health and Human Services 
Food and Drug Administration 
Oncology Center of Excellence 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
  
July 2020  
Clinical/Medical   
Revision 1 
   
TABLE OF CONTENTS    
  
 
I.       INTRODUCTION ............................................................................................................. 1 
II.        BACKGROUND ................................................................................................................ 2 
A.    Rationale for Neoadjuvant Therapy ............................................................................................. 2 
B.    The Accelerated Approval Program ............................................................................................. 3 
C.    Implementation of the Guidance ................................................................................................... 4 
III.      ENDPOINTS FOR NEOADJUVANT TRIALS ............................................................. 4 
IV.      CLINICAL TRIAL DESIGN AND STATISTICAL CONSIDERATIONS ................. 6 
A.    Rationale for Use of Pathological Complete Response in Neoadjuvant Trials as an    
Endpoint for Accelerated Approval .............................................................................................. 6 
B.    Trial Designs in the Neoadjuvant Setting ..................................................................................... 7 
1. Clinical Trials to Support Accelerated Approval ............................................................................. 7 
2. Outcome Assessment ........................................................................................................................ 8 
3. Postoperatie Therapy ....................................................................................................................... 9 
4. Clinical Trials to Verify and Describe Clinical Benefit (Confirmatory 
Trials).............................110 
5. Selecting a Development Strategy:  Single Trial Model vs. Multiple Trial Model ...................... 112 
C.    Patient Populations for Neoadjuvant Breast Cancer Trials to Support 
Accelerated Approval .................................................................................................................. 13 
D.    Characterization of Drug Safety ................................................................................................. 13 
E.     Recommendations for Pathology Standard Operating Procedures ........................................ 14 
V.   POTENTIAL FOR UNINTENDED EFFECT ON DRUG DEVELOPMENT ......... 15 
VI.   CONCLUSION ............................................................................................................... 16 
REFERENCES ........................................................................................................................... 17 
 
  
   Contains Nonbinding Recommendations  
Pathological Complete Response in Neoadjuvant Treatment of  
 
High-Risk Early-Stage Breast Cancer:  Use as an Endpoint to  
Support Accelerated Approval  
 
Guidance for Industry1  
 
 
  
 
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on 
this topic.  It does not establish any rights for any person and is not binding on FDA or the public.  You 
can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.  
To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the 
title page. 
   
 
  
  
I.   INTRODUCTION   
  
This guidance is intended to assist sponsors in designing trials to support marketing approval of 
drugs and biological products for the treatment of high-risk early-stage breast cancer in the 
neoadjuvant (preoperative) setting.2  The main focus of the guidance is to discuss the use of 
pathological complete response (pCR) in high-risk early-stage breast cancer as a potential 
endpoint to support approval under the accelerated approval regulations (21 CFR part 314, 
subpart H, for new drug applications and 21 CFR part 601, subpart E, for biologics license 
applications).  The objectives of the guidance are to:    
  
  Describe acceptable definitions of pCR for regulatory purposes  
  
  Briefly summarize what is currently known about the relationship between pCR and 
prognosis  
  
  Describe trial designs and patient populations in which pCR may be accepted as  
reasonably likely to predict clinical benefit    
  
  Provide guidance regarding trial designs to verify clinical benefit in support of traditional 
approval    
  
This guidance does not address trials of neoadjuvant endocrine therapy for breast cancer, nor 
does it address use of pCR as an endpoint for approval of drugs to treat tumor types other than 
                                                 
1 You may submit comments on this guidance at any time.  Submit comments to Docket No.  
FDA-2012-D-0432. 
2 The terms drug and systemic therapy refer to both drugs and biological products regulated by CDER and CBER.  
   1    Contains Nonbinding Recommendations  
breast cancer.  This guidance primarily describes potential pathways to accelerated approval for 
drugs for the treatment of high-risk early-stage breast cancer.  Sponsors should consult the FDA 
as early as possible regarding their development strategy when seeking a neoadjuvant breast 
cancer indication.  
  
Specific terms and phrases used in this guidance are defined as follows:   
  
  The phrase early-stage breast cancer refers to invasive breast cancer without distant 
metastases   
  
  The phrase high-risk refers to patients with early-stage breast cancer who continue to 
have a high risk of distant disease recurrence and death despite use of optimal modern 
local and systemic adjuvant therapy  
  
  The terms neoadjuvant and preoperative are used interchangeably to refer to systemic 
therapy that is given before lumpectomy or mastectomy to reduce the risk of breast 
cancer recurrence   
  
  The term clinical benefit in an early-stage breast cancer population refers to a clinically 
meaningful and statistically significant improvement in event-free survival (EFS), 
disease-free survival (DFS), or overall survival (OS)  
  
This guidance is a revision of the final guidance of the same title that published in October 2014.  
This guidance replaces the October 2014 guidance of the same title. 
 
FDAs guidance documents, including this guidance, do not establish legally enforceable 
responsibilities.  Instead, guidances describe the Agencys current thinking on a topic and should 
be viewed only as recommendations, unless specific regulatory or statutory requirements are 
cited.  The use of the word should in Agency guidances means that something is suggested or 
recommended, but not required.    
  
  
II.   BACKGROUND  
  
  A.   Rationale for Neoadjuvant Therapy  
  
Adjuvant systemic therapies for breast cancer (i.e., drugs given to reduce the risk of breast cancer 
recurrence) historically have been administered following definitive breast surgery.  Preoperative 
or neoadjuvant systemic chemotherapy, once reserved for patients with locally advanced breast 
cancer in whom the goal was to render large breast cancers operable, has become increasingly 
common.  There are several potential reasons to consider neoadjuvant treatment for early-stage 
breast cancer.  Giving chemotherapy preoperatively permits breast conservation in some patients 
who would otherwise require mastectomy and may improve cosmesis in existing candidates for 
breast conservation.  Preoperative therapy also provides a real-time evaluation of tumor response 
to permit discontinuation of ineffective therapy.  Further, a patients response to neoadjuvant 
chemotherapy may provide prognostic information that can supplement conventional prognostic 
   2    Contains Nonbinding Recommendations  
data, such as initial staging, tumor grade, and estrogen receptor (ER), progesterone receptor 
(PR), and human epidermal growth factor receptor 2 (HER2) status.  Finally, the neoadjuvant 
setting offers investigators the unique opportunity to examine modulation of tissue, imaging, and 
other biomarkers from the time of biopsy to the time of definitive breast surgery following 
preoperative systemic therapy.  
  
  B.   The Accelerated Approval Program  
  
The FDAs accelerated approval program is intended to facilitate development of drugs for 
treatment of a serious or life-threatening disease that provide meaningful therapeutic benefit over 
available therapy.  We recognize that, despite advances in adjuvant systemic therapy of breast 
cancer over the past few decades, there remains a significant unmet medical need for certain 
high-risk or poor prognosis subsets of early-stage breast cancer patients.  Consideration of pCR 
as an acceptable study endpoint for accelerated approval in the neoadjuvant setting may 
encourage industry innovation and expedite the development of novel therapies to treat high-risk 
early-stage breast cancer.  
  
Section 506(c) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 356(b), as 
amended by the Food and Drug Administration Safety and Innovation Act of 2012, provides 
that:  
  
The FDA may grant accelerated approval . . . upon a determination that the product has an 
effect on a surrogate endpoint that is reasonably likely to predict clinical benefit, or on a 
clinical endpoint that can be measured earlier than an effect on irreversible morbidity or 
mortality, that is reasonably likely to predict an effect on irreversible morbidity or mortality 
or other clinical benefit, taking into account the severity, rarity, or prevalence of the 
condition and the availability or lack of alternative treatments.  
  
The accelerated approval regulations further provide that:3   
  
Approval under this section will be subject to the requirement that the sponsor study the drug 
further, to verify and describe its clinical benefit, where there is uncertainty as to the relation 
of the surrogate endpoint to clinical benefit, or of the observed clinical benefit to ultimate 
outcome.  Postmarketing studies would usually be studies already underway.  When required 
to be conducted, such studies must also be adequate and well-controlled.  The sponsor shall 
carry out any such studies with due diligence.4     
  
 
                                                 
3 See 21 CFR 314.510.  
4 See the guidance for industry Expedited Programs for Serious Conditions  Drugs and Biologics (May 2014), 
section VII.D.  We update guidances periodically.  To make sure you have the most recent version of a guidance, 
check the FDA drugs guidance web page at https://www.fda.gov/drugs/guidance-compliance-regulatory-
information/guidances-drugs.    
 
   3    Contains Nonbinding Recommendations  
C.   Implementation of the Guidance 
 
Since the draft version of this guidance was published in May 2012, the FDA has participated in 
public discussions regarding this pathway for drug development.  In March 2013, the FDA and 
the American Society of Clinical Oncology co-sponsored a public neoadjuvant breast cancer 
workshop to discuss the use of pCR to support accelerated approval.5  The panel concluded that a 
large improvement in pCR rate based upon analysis of a full intent-to-treat population was 
reasonably likely to predict clinical benefit, and that the potential advantages of granting 
accelerated approval based upon pCR from a neoadjuvant randomized controlled trial generally 
outweighed risks.  The panel emphasized that such trials should be limited to high-risk patients, 
and that a confirmatory trial should be ongoing at the time of accelerated approval.   
 
The first drug to be granted accelerated approval in the neoadjuvant setting for high-risk, early 
breast cancer was discussed at an Oncologic Drugs Advisory Committee (ODAC) meeting in 
September 2013.6  The favorable review of this application, both by the ODAC and the FDA, 
was based upon results of the submitted trials in the neoadjuvant setting taken in the context of 
the robustness of the development program.  The submitted application demonstrated a 
significant absolute improvement in pCR rate in the intent-to-treat population with acceptable 
safety.  Importantly, this application was supported by a statistically and clinically significant 
effect on OS in a separate trial in the metastatic setting, an extensive body of safety data from 
treatment of several thousand patients with metastatic breast cancer and an adjuvant 
confirmatory trial that was fully accrued at the time of accelerated approval in the neoadjuvant 
setting.7  The adjuvant confirmatory trial subsequently met its primary endpoint of disease-free 
survival, and the drug subsequently received regular approval for use in early breast cancer in 
both the neoadjuvant and adjuvant setting.    
 
The 2014 final guidance was revised to discuss the challenge that use of additional therapy in the 
setting of post neoadjuvant residual disease has the potential to confound interpretation of long-
term outcomes supporting confirmation of clinical benefit.  The revision also streamlines the 
guidance by removing information that is no longer current and information that is not specific 
to the focus of the guidance, as well as by including revised language to improve clarity.  
 
 
III.   ENDPOINTS FOR NEOADJUVANT TRIALS  
 
Randomized neoadjuvant trials comparing the same treatment regimen administered either 
preoperatively or postoperatively have suggested that pCR may predict long-term outcome in 
individual patients with early-stage breast cancer treated with preoperative systemic therapy 
(Cortazar et al. 2012, van der Hage et al. 2007, Rastogi et al. 2008, and Bear et al. 2006). While 
pathological complete response has been used as an endpoint in numerous trials of neoadjuvant 
                                                 
5 https://www.fdalive.com/agendas/PM032213/Agenda.pdf. 
6http://wayback.archive-
it.org/7993/20170113054202/http:/www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Dr
ugs/OncologicDrugsAdvisoryCommittee/UCM371011.pdf (January 13, 2020). 
7 http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/125409Orig1s051SumR.pdf. 
   4    Contains Nonbinding Recommendations  
systemic therapy for breast cancer, historically, there was not a uniform definition of pCR, which 
created challenges in reporting and interpreting data from neoadjuvant trials (Buzdar et al. 2005, 
von Minckwitz et al. 2010, Bear et al. 2006, Wolmark et al. 2001).  
  
To address these limitations, the FDA established a working group known as Collaborative Trials 
in Neoadjuvant Breast Cancer (CTneoBC).  Primary source data was obtained from nearly 
13,000 patients enrolled in large-scale neoadjuvant trials with clear definitions of pCR and 
available long-term follow-up, including U.S. and international trials.  Using these data, the FDA 
performed a pooled analysis to assess the relationship between pCR and long-term outcome 
(Cortazar et al. 2012).  The FDA compared the three most commonly used definitions of pCR 
(ypT0/Tis (absence of invasive cancer in the breast), ypT0/Tis ypN0 (absence of invasive cancer 
in the breast and axillary nodes), and ypT0 ypN0 (absence of invasive and in situ cancer in the 
breast and axillary nodes)) and their relationship to long-term patient outcome.  As expected, use 
of increasingly stringent definitions of pCR resulted in decreasing average pCR rates:  22 
percent, 18 percent, and 13 percent, respectively, in the trials included in the pooled analysis.  
Persistent nodal involvement following neoadjuvant therapy was associated with an increased 
risk of recurrence and death, whereas residual ductal carcinoma in situ did not have prognostic 
value.  Therefore, we recognize either of the following two definitions of pCR for the purposes 
of designing trials for U.S. marketing approval:  
  
1.  Pathological complete response (pCR) is defined as the absence of residual invasive 
cancer on hematoxylin and eosin evaluation of the complete resected breast specimen and 
all sampled regional lymph nodes following completion of neoadjuvant systemic therapy 
(i.e., ypT0/Tis ypN0 in the current AJCC staging system)    
  
or  
  
2.  Pathological complete response (pCR) is defined as the absence of residual invasive and 
in situ cancer on hematoxylin and eosin evaluation of the complete resected breast 
specimen and all sampled regional lymph nodes following completion of neoadjuvant 
systemic therapy (i.e., ypT0 ypN0 in the current AJCC staging system)    
  
The definitions reflect an evolving paradigm in surgical management of the axilla.  Axillary 
lymph node dissection (ALND) may not be required for patients with sentinel lymph node-
positive breast cancer in whom local and systemic therapies are unlikely to be affected by the 
finding of additional positive lymph nodes.  We therefore recommend using the phrase sampled 
regional lymph nodes, as indicated in our standard definitions of pCR.  These definitions permit 
flexibility in terms of the surgical approach to the axilla, but reflect the fact that the presence of 
any residual invasive cancer following neoadjuvant therapy portends a poorer prognosis.  Given 
that the primary endpoint includes the pathological status of the axilla and that an imbalance of 
ALND between arms has the potential to confound interpretation of pCR, an algorithm for 
surgical assessment of the axilla should be explicitly outlined in the protocol and discussed with 
the FDA before trial initiation.    
  
   5    Contains Nonbinding Recommendations  
For neoadjuvant trials, in which all patients by definition will have invasive cancer at the time of 
randomization, the long-term clinical benefit endpoints for traditional approval should be termed 
event free survival (EFS) or OS (see section IV).  
 
EFS should be defined as time from randomization to any of the following events:  progression 
of disease that precludes surgery, local or distant recurrence, or death due to any cause.   
 
For confirmatory trials conducted in the adjuvant setting, in which patients are presumed to be 
free of disease at the time of randomization, the long-term clinical benefit endpoints for 
traditional approval should be termed disease-free survival (DFS) or OS (see section IV).  
  
DFS should be defined as time from randomization until local or distant recurrence or death due 
to any cause. 
 
 
IV.   CLINICAL TRIAL DESIGN AND STATISTICAL CONSIDERATIONS  
  
We strongly encourage sponsors to meet with the FDA to discuss all neoadjuvant trial designs 
intended to support accelerated approval.  
  
A.   Rationale for Use of Pathological Complete Response in Neoadjuvant Trials 
as an Endpoint for Accelerated Approval  
  
Historically, new drugs for breast cancer have been developed and approved initially in the 
metastatic setting, with patients whose expected median OS was generally 2 years or less.  Trials 
to support adjuvant (postoperative) indications have followed development and approval in the 
metastatic setting and are much lengthier.  Existing adjuvant therapy for breast cancer will 
effectively delay or eliminate recurrence for many patients so that large sample sizes and 
prolonged follow-up in randomized trials are needed to demonstrate a difference in DFS or OS 
adequate to support drug approval in the adjuvant setting.  As a result, the time from initiation of 
a pivotal trial of a drug in metastatic breast cancer to approval for its use in an adjuvant 
population has often been a decade or more.   
  
The effectiveness of adjuvant therapy for breast cancer is well-established, but certain 
subpopulations of breast cancer patients continue to be at substantial risk of recurrence and 
death, even with optimal adjuvant therapy.  There is currently no early marker of potential 
efficacy in the adjuvant setting.  In contrast, when systemic therapy is given in the preoperative 
setting, pCR can be assessed within several months of initiation of an investigational drug.  Use 
of pCR as an endpoint to support accelerated approval in the neoadjuvant setting may help 
address unmet medical needs in high-risk populations in a far shorter time frame.    
  
Randomized neoadjuvant trials comparing the same treatment regimen administered either 
preoperatively or postoperatively have suggested that pCR may predict long-term outcome in 
individual patients with early-stage breast cancer treated with preoperative systemic therapy 
(Cortazar et al. 2012, van der Hage et al. 2007, Rastogi et al. 2008, and Bear et al. 2006).  
  
   6    Contains Nonbinding Recommendations  
An important limitation of these types of analyses, commonly referred to as responder analyses, 
is that they compare outcomes between two subpopulations (e.g., those who had a pCR and those 
who did not) irrespective of treatment assignment.  Although such data are informative at a 
patient level, indicating a more favorable prognosis for those with complete eradication of 
invasive tumor by preoperative therapy, they do not necessarily establish that a difference in 
pCR rates between treatment arms will predict a difference in efficacy endpoints, such as DFS, 
EFS, or OS, between two treatments.  Some trials that have shown a difference in pCR rate 
between arms have nonetheless failed to show a difference between arms in EFS when the entire 
intent-to-treat population is considered (Kaufmann et al. 2006).  The CTneoBC pooled analysis 
found no correlation between magnitude of difference in pCR rates between treatment arms and 
EFS or OS at a trial level (Cortazar et al. 2012).  A variety of potential explanations for this 
finding exist.  The trials included in the pooled analysis enrolled heterogeneous patient 
populations and, with one exception, compared various cytotoxic regimens to one another.  As a 
result, the absolute differences in pCR rate between treatment arms in the included trials ranged 
from 1 to 20 percent, but no trial other than the Neoadjuvant Herceptin (NOAH) trial had an 
absolute difference in pCR rate between arms of greater than 10 percent (Cortazar et al. 2012).  
The relationship between pCR and long-term outcome for immunotherapy and other targeted 
agents is an area of ongoing investigation.   
 
Given the substantial improvements in survival for individual patients who attain pCR, a novel 
agent administered with standard therapy that produces a marked absolute increase in pCR rate 
compared with standard therapy alone in the intent-to-treat population (i.e., all randomized 
patients) may be reasonably likely to result in long-term improvements in EFS or OS.  Different 
breast cancer subtypes may require different magnitudes of improvement in pCR rate to achieve 
clinically meaningful improvement in EFS or OS.  Therapies that modestly increase pCR rate are 
less likely to improve long-term outcomes in any subtype.  We emphasize that the analysis of 
neoadjuvant breast cancer trials for regulatory approval should compare pCR rates and long-term 
outcomes between treatment arms, using the intent-to-treat population, and should not be limited 
to those patients who achieve pCR, given that this is a nonrandomized patient subset determined 
by an outcome subsequent to randomization.    
  
  B.   Trial Designs in the Neoadjuvant Setting  
  
  1.   Clinical Trials to Support Accelerated Approval  
  
A trial to support accelerated approval should be a randomized, well-controlled trial intended to 
demonstrate superiority.  An add-on trial comparing the investigational drug plus standard 
neoadjuvant therapy to standard neoadjuvant therapy alone may be the most appropriate option 
when the standard of care regimen involves a limited number of agents.  For situations in which 
the standard of care for neoadjuvant therapy involves a large number of agents, alternatives to an 
add-on design may be considered. 
  
  Randomized, well-controlled trial    
  
The biological differences between the tumors of patients who achieve a pCR in response 
to neoadjuvant therapy and those who do not are still poorly understood, and there is 
   7    Contains Nonbinding Recommendations  
uncertainty about the use of pCR as an endpoint to evaluate an investigational drug in 
nonrandomized trials.  A high pCR rate in a single-arm trial may reflect the known and 
unknown biological characteristics of the tumors and other factors in the enrolled 
population, the efficacy of the investigational drug, the efficacy of conventional therapy 
delivered as part of neoadjuvant therapy, or some combination of the above.  
Randomized clinical trials are therefore necessary to establish treatment effects of the 
investigational drug.    
  
  Superiority design    
  
Neoadjuvant trials intended to support marketing approval should be designed to 
demonstrate superiority of the investigational drug over the standard of care for the trial 
population.   
  
Noninferiority trials are not appropriate for accelerated approval based on pCR.  Since an 
association between the absolute or relative increase in pCR that correlates with an 
improvement in long-term outcome has not been determined at a trial level, there is no 
basis for selection of an appropriate noninferiority margin for pCR rate.  Thus, such trials 
would expose patients to an unacceptable risk of inferior OS or EFS.  
  
  Add-on design    
  
Many individuals with early-stage breast cancer, including those identified as high risk at 
initial presentation, can be cured with available therapy; at present there appears to be no 
advantage, in terms of survival, to earlier (i.e., preoperative) administration of systemic 
therapy (Mauri et al. 2005).  Therefore, an add-on design, in which a standard adjuvant 
regimen is compared with the same regimen plus the investigational drug, is preferred 
when a standard of care treatment involves a limited number of agents.  Such a design 
ensures that high-risk patients are not denied effective therapy with curative potential and 
also permits isolation of the effects of the investigational drug.  In situations when there 
is substantial evidence of anti-tumor activity that is large in magnitude observed with an 
investigational drug in metastatic breast cancer, or when a standard of care regimen 
involves a large number of agents, a randomized superiority trial directly comparing 
standard neoadjuvant therapy with an investigational agent delivered preoperatively (i.e., 
omitting the standard therapy from the investigational arm) may be acceptable in lieu of 
an add-on design.  In these circumstances, omission of part or all of the standard therapy 
from the investigational arm may be acceptable because the risk of the investigational 
agent being inferior to standard therapy is relatively low and, in certain cases, may be 
offset by the benefit of avoiding the need for multiple agents. 
  
  2.   Outcome Assessment  
  
In all cases, pathologists interpreting surgical specimens for assessment of pCR should be 
blinded to treatment assignment.  We recommend that a summary note for each subject be 
provided to the blinded study pathologist that includes a general overview of the trial but no 
patient-level treatment information.  The note should include the major clinical, radiographic, 
   8    Contains Nonbinding Recommendations  
and operative findings, including a description or diagram of the original size and location of the 
tumor, the presence or absence of multifocality, the extent of preoperative lymph node 
involvement, the number of clips in the breast or nodes, hormone and HER2 receptor status, 
presence of calcifications if any, and type of surgery.  The summary note should also include a 
statement that pathologists are to remain blinded to treatment arm.  This summary note is 
intended to avoid the need for pathologists to access clinic notes and other documents that may 
result in their inadvertent unblinding to treatment arm. 
  
Although we appreciate that practices for identifying and evaluating the axillary nodes may vary 
between clinical centers and geographical regions, the nature and timing of nodal assessment 
should be standardized within a given trial to avoid confounding the primary endpoint.  We 
recommend an axillary ultrasound and pretreatment fine needle aspiration or core biopsy of any 
clinically or radiographically suspicious nodes before administration of any preoperative 
systemic therapy.  Any involved nodes should be marked with a metallic indicator or other 
standard approach before systemic therapy to ensure their removal at the time of definitive 
surgery.    
  
We strongly recommend that sentinel lymph node biopsy, using dual blue dye and radioisotope 
tracers, be performed at the time of definitive surgery and include resection of at least two nodes 
whenever possible (Boughey et al. 2012, Kuehn et al. 2012).  For global trials inclusive of 
geographic regions where the sentinel lymph node assessment is commonly performed before 
administration of systemic therapy, randomization may be stratified accordingly.  The protocol 
should provide guidelines for axillary lymph node dissection in patients found to have axillary 
nodal involvement.  Finally, the protocol should outline under what circumstances cytokeratin 
staining of the axillary nodes should be performed and state how patients found to have isolated 
tumor cells will be classified in terms of the primary endpoint.  
  
Since it is common for patients without any remaining palpable tumor in the breast or axilla after 
neoadjuvant therapy (i.e., those who have a clinical complete response (cCR)) to nonetheless 
have residual invasive breast cancer detected by pathology at the time of definitive breast surgery 
(von Minckwitz et al. 2001), a patient who has achieved cCR cannot be assumed to have 
achieved pCR.  Neoadjuvant trials intended to support a marketing application should require 
that all patients must receive local therapy consistent with current standards of care, at the 
completion of neoadjuvant systemic therapy (Davidson 2005).  
  
3.  Postoperative Therapy  
  
Criteria for radiotherapy should be prespecified in the protocol, and details of all radiation 
treatment should be captured in standardized manner in case report forms given the potential for 
local therapy to affect the risk of local and distant recurrence, as well as survival.   
  
It is important to recognize that many patients with high-risk early-stage breast cancer enrolled in 
neoadjuvant trials will not achieve pCR.  Patients with postneoadjuvant residual disease are at 
increased risk of distant recurrence (Cortazar et al. 2012).   
 
   9    Contains Nonbinding Recommendations  
The high rate of distant recurrence in patients with postneoadjuvant residual disease is of concern 
and underscores the need for future randomized trials in this patient population comparing novel 
therapies to one another or to the current standard of care.    
 
4.  Clinical Trials to Verify and Describe Clinical Benefit (Confirmatory Trials)  
  
To verify and describe the clinical benefit of a drug granted accelerated approval on the basis of 
pCR, the confirmatory trial should demonstrate a clinically meaningful and statistically 
significant improvement in EFS, DFS, or OS.  The confirmatory trial should be ongoing at the 
time of accelerated approval.  One acceptable approach, referred to as the single trial model, 
would be to follow the patients entered into a randomized neoadjuvant trial that supported the 
accelerated approval until EFS or OS data are mature.  This approach may enable a single, well-
controlled randomized trial, if adequately powered and with sufficiently compelling results, to 
serve as the basis for both accelerated and traditional approval, saving time and resources in drug 
development and expediting patient access to highly effective therapies for high-risk early-stage 
breast cancer.  The applicant should ensure adequate collection of long-term safety data and be 
prepared to provide interim safety data to the FDA on an ongoing basis so that serious safety 
signals can be quickly identified and mitigated.    
  
A single large neoadjuvant trial designed and powered to demonstrate both an improvement in 
pCR rate and an improvement in either EFS or OS may be capable of detecting pCR differences 
that are statistically significant without being clinically meaningful.  In this scenario, the 
statistical analysis plan for evaluating pCR should be prespecified, with the target magnitude of 
effect calculated based upon the sponsors best estimate of the magnitude of the difference in 
pCR rate between arms needed to result in a clinically and statistically significant difference in 
EFS or OS.  All patients should be enrolled in the trial before any efficacy analyses, including 
analyses of pCR, are performed.  Although prespecified interim analyses for EFS and/or OS 
performed for futility or for efficacy at the time of the definitive analysis of pCR are acceptable, 
interim efficacy analyses of pCR, which could impair the ability of the trial to complete accrual, 
should be avoided.  Interim analyses for futility with regards to the pCR endpoint would be 
acceptable.  
  
If a single trial is intended to support both accelerated and traditional approval, the statistical 
analysis plan should include a plan for controlling the false positive rate (type I error) for the 
primary endpoint, pCR, to support accelerated approval, as well as a plan for controlling the false 
positive rate for either of the primary endpoints, EFS or OS, to support traditional approval.  
Because the effect size on EFS or OS is likely to be smaller than the effect size on pCR rate, the 
statistical analysis plan for controlling the overall false positive rate (type I error) for all key 
efficacy objectives should be structured such that a greater portion of level of significance 
(alpha) is allocated to the comparisons of direct measure(s) of clinical benefit (i.e., EFS or OS), 
and a lesser portion to the pCR endpoint.  
  
An alternate development approach, referred to as the multiple trial model, would rely upon 
separate trials to support accelerated approval and traditional approval.  In this model, sponsors 
would conduct one or more neoadjuvant randomized trial(s), powered to detect a substantial 
absolute improvement in pCR rate between arms, to support accelerated approval.  A subsequent 
   10    Contains Nonbinding Recommendations  
larger trial, which may be conducted in either the neoadjuvant or adjuvant setting, powered for 
EFS (neoadjuvant), DFS (adjuvant), and/or OS (either disease setting), would be used to confirm 
clinical benefit and provide the basis for traditional approval in early breast cancer.    
  
5.  Selecting a Development Strategy:  Single Trial Model vs. Multiple Trial Model  
  
There are advantages and disadvantages to both the single trial and the multiple trial models.  
 
a.  Single Trial Model 
 
A single trial, which should be powered for both pCR and EFS or OS, will require a larger 
sample size than a trial intended only to support accelerated approval and may take longer to 
complete accrual.  A single large trial provides for an improved estimate of treatment effect on 
pCR, a better understanding of how pCR effect impacts long-term outcome in the same trial 
population, and a larger body of safety data from an early-stage high-risk breast cancer 
population at the time of initial accelerated approval, which will more fully characterize the 
toxicity of the drug.  Given that the trial should be fully accrued by the time of the pCR analysis, 
the single trial model also avoids the feasibility issues of conducting a separate confirmatory 
trial.  Furthermore, long-term outcome data is likely to be available earlier than if a separate trial 
to verify and describe clinical benefit had to be designed, conducted, and analyzed, which would 
shorten the time to satisfaction of the confirmatory study obligation, or withdrawal of the 
neoadjuvant breast cancer indication if clinical benefit is not confirmed.  The disadvantages of 
the single trial model include exposure of a large number of patients to potentially less effective 
and/or more toxic therapy, a potentially longer wait to initial U.S. approval compared with the 
multiple trial model, a lack of data on use of the drug in a strictly postoperative setting, and the 
potential for confounding by postoperative systemic therapy.  
 
A substantial challenge for confirmation of clinical benefit is the increasing use of drugs in the 
setting of postneoadjuvant residual disease, which has the potential to confound long-term 
outcomes such as EFS and OS.  For example, in the KATHERINE trial, patients with HER2 
positive breast cancer who had residual invasive cancer after neoadjuvant chemotherapy and 
trastuzumab had improved DFS if they switched to receive T-DM1 postoperatively rather than 
continuing trastuzumab (von Minckwitz et al. 2019).  In addition, there are ongoing randomized 
trials of multiple drug classes in patients with residual invasive cancer following preoperative 
therapy.  This issue should be anticipated and addressed proactively in the protocol and statistical 
analysis plan.  Designs that permit patients on the control arm to receive the investigational drug 
under study in the trial in the postoperative setting will confound EFS and OS and generally 
should be avoided.  Postoperative systemic therapy for all randomized patients irrespective of 
treatment arm that represents the current standard of care (e.g., HER2-directed therapy in 
patients with early-stage HER2+ breast cancer or endocrine therapy for women with hormone 
receptor-positive breast cancer) is acceptable.  The protocol should include a detailed and 
uniform plan to ensure that the approach to postoperative therapy is pre-specified and recorded in 
the case report form to assess the potential for confounding of long-term clinical outcomes. 
Sample size calculations should take into consideration this potential for confounding of the 
endpoint used to verify and describe the long-term clinical benefit by postoperative therapy, and 
sensitivity analyses to assess the effect of postoperative therapy should be pre-planned.  If 
   11    Contains Nonbinding Recommendations  
response-adaptive treatments are considered, a second randomization is recommended.  Given 
that EFS and OS results may be impacted by postoperative treatment, sponsors are encouraged to 
meet early with FDA to discuss selection of single versus multiple trial model, approach to use 
of postoperative systemic therapy in the setting of residual invasive cancer, and the details of the 
statistical analysis plan. 
 
b.  Multiple Trial Model 
 
The multiple trial model also has advantages and disadvantages.  The multiple trial model 
permits widespread access to highly effective drugs earlier because fewer patients need to be 
accrued before potentially granting accelerated approval based on the pCR endpoint.  
Demonstrating the efficacy of a drug provides greater assurance that the results are not due to 
chance alone.  The results of the neoadjuvant trial also may help to inform the design of the 
confirmatory trial.  In addition, there is less concern about confounding of results due to 
postneoadjuvant residual disease additional therapies.  Finally, the multiple trial model may 
facilitate study of the new drug combined with, or compared to, other standard therapy, or in a 
different patient population (e.g., lower risk patients, postoperative setting, or post-neoadjuvant 
residual disease setting), in the confirmatory trial.  The multiple trial model has as its principal 
disadvantage the feasibility issues involved in designing and conducting a second trial.  
Confirmatory trials that recapitulate the design and patient populations enrolled in the trial that 
supported accelerated approval would be expected to accrue poorly in the United States, and 
patient dropout or recommendations for patient cross-over are likely to occur following 
accelerated approval.  The effect of these issues may be mitigated by having a global adjuvant 
trial well underway at the time of accelerated approval.  
 
c.  Additional Considerations for Selecting a Development Strategy 
 
There is no single best development strategy for all drugs to treat high-risk, early breast cancer in 
the neoadjuvant setting.  Factors that can help to determine whether the single trial or the 
multiple trial model is more appropriate include:  the extent of prior clinical data with the drug, 
knowledge of efficacy and safety of the drug class, regulatory status of the drug (e.g., existing 
approvals for breast cancer, other malignancies, or non-oncologic indications), and the status of 
any ongoing development program in early-stage breast cancer.  In general, the multiple trial 
approach, in which accelerated approval would be granted on the basis of one or more small 
neoadjuvant randomized trials followed by a postapproval trial, is most appropriate for drugs 
with evidence of substantial efficacy in the metastatic setting, safety profiles that are well 
characterized and acceptable for the patient population in question, and ongoing or fully accrued 
large randomized adjuvant trials.  The multiple trial model also may be appropriate for drugs 
with evidence of unprecedented efficacy in breast cancer subtypes with significant unmet 
medical need.  Finally, the multiple trial model may be preferable in settings where use of 
standard of care systemic therapy to treat postneoadjuvant residual disease is expected, as this 
would confound the endpoints used to verify and describe the long-term clinical benefit in a 
single large neoadjuvant trial.  Selection of a neoadjuvant development plan should be tailored to 
the drug and patient population in question and should take place in consultation with the FDA.  
  
   
   12    Contains Nonbinding Recommendations  
 C.   Patient Populations for Neoadjuvant Breast Cancer Trials to Support  
Accelerated Approval  
  
Patient populations appropriate for trials of neoadjuvant systemic therapy for breast cancer with 
marketing intent are those judged to have a high risk of distant disease recurrence and mortality 
despite use of optimal therapy.  This is primarily because of excellent outcomes in patients 
without high-risk disease with available therapy where the potential risks of inferior DFS, EFS, 
or OS would be unacceptable.  Patients may be classified as high risk for recurrence on the basis 
of conventional histologic features or by appropriately validated genomic measures, but in 
general should have a 5-year EFS of less than 75 percent.  The decision to pursue accelerated 
approval via the neoadjuvant pathway should be made on the basis of strong biological and 
clinical rationale for a drugs activity in high-risk subtypes of breast cancer.  
  
The median follow-up in a neoadjuvant trial with pCR as its primary endpoint will be relatively 
immature at the time of accelerated approval.  Data that verify and describe, or fail to verify and 
describe, effects on DFS, EFS, or OS may require several years of additional follow-up to reach 
maturity.  It is also conceivable that the initial trial supporting the approval of an investigational 
drug, as an add-on to standard neoadjuvant chemotherapy, may be conducted in a development 
program that does not include large trials in the metastatic setting, further limiting supportive 
data on the anti-tumor activity or efficacy of the investigational drug in breast cancer at the time 
of approval.  Therefore, it is possible that a drug approved in the neoadjuvant setting could 
remain on the market for a prolonged period of time and subject patients with potential 
alternative options to a risk of inferior DFS, EFS, or OS.  
  
We recognize the risk of granting an initial approval in the setting of limited long-term efficacy 
and safety data from a neoadjuvant trial.  Although it is possible that such a risk may be 
appropriate in populations of breast cancer patients with significant unmet medical need, it is 
unlikely to be acceptable for populations having more favorable prognoses with existing therapy.  
For all of these reasons, we strongly recommend that patients with hormone receptor-positive 
tumors lacking high-risk features not be enrolled in neoadjuvant trials with pCR as the endpoint 
to support accelerated approval.     
  
  D.   Characterization of Drug Safety  
  
In a neoadjuvant trial relying upon pCR as the primary endpoint to support accelerated approval, 
long-term safety data will be limited.  Conventional adjuvant trials include several years of 
follow-up and, in addition, have historically been conducted only after one or more randomized 
trials in the metastatic setting have been performed.  The resultant safety database characterizes 
not only the incidence and severity of acute treatment-emergent adverse events, but also provides 
long-term data on the outcome of acute or cumulative adverse events, such as neuropathy, and 
the incidence of rare or late toxicities, such as secondary malignancy or heart disease.  Such a 
comprehensive safety assessment is critical in an early-stage breast cancer population, in whom 
long-term survival is common and indeed may result from local therapy alone.    
  
Given that a neoadjuvant trial to support accelerated approval could potentially occur in a 
development program that does not include a completed randomized trial or drug approval in the 
   13    Contains Nonbinding Recommendations  
metastatic setting, sponsors should discuss with the FDA the amount of safety data needed to 
proceed to a randomized neoadjuvant trial intended to support accelerated approval.  Before 
embarking on a such a neoadjuvant trial, sponsors should provide to the FDA at a minimum the 
same level of safety data on the investigational drug, administered alone and in combination with 
the regimen for which it will be studied, as would currently be needed to launch a trial intended 
to support approval in the metastatic setting.  Such data should be sufficient to establish that the 
dosage regimen(s) are reasonably safe and that preliminary pharmacology assessments have been 
conducted characterizing the pharmacokinetic profile with an emphasis on specific populations 
based on age and ethnicity, and the potential for drug interactions, QT prolongation, and food 
effects (for orally administered drugs).  The results of chronic nonclinical toxicology studies and 
preliminary assessments for effects on embryofetal development should have been submitted to 
FDA.  Based on the safety profile and extent of prior clinical experience with the investigational 
drug or other drugs in the same class, and the proposed trial population, additional safety or 
efficacy data may be required prior to the initiation of the randomized neoadjuvant trial.8   
  
Regulatory decisions on accelerated approval in the neoadjuvant setting would take into 
consideration the known, and potentially unknown, risks of a drug in the context of the observed 
improvement in pCR for the population under study.  Given these long-term safety 
considerations, the neoadjuvant setting should be designed to collect long-term safety data from 
a number of patients comparable to traditional adjuvant breast cancer trials.9  At the time of 
accelerated approval, applicants also may be required to conduct additional safety trials as 
postmarketing requirements under section 505(o)(3) of the FD&C Act.  
  
  E.   Recommendations for Pathology Standard Operating Procedures  
  
All protocols for neoadjuvant trials conducted to support a marketing application should include 
a detailed set of standard operating procedures (SOP) for collection, handling, and interpretation 
of pathology specimens, comparable to imaging charters for oncology trials with radiographic 
primary endpoints (see IV.B.2).  All neoadjuvant trial pathologists should receive formal training 
provided by the sponsor via webinar or on-site in a small number of centralized geographic 
locations.  A pathologist principal investigator with extensive prior experience interpreting 
postneoadjuvant specimens should be identified for each country or region to serve as an 
adjudicator for cases in which the study site pathologist is uncertain whether a given patient has 
achieved pCR.    
  
The SOP should include an approach to ensure localization of the tumor bed, including 
placement of a clip in the tumor bed and any involved lymph nodes at the time of biopsy, 
postoperative specimen radiographs to verify excision, and use of colored sutures or other 
approaches to orient the specimen (see also IV.B.2).  Pathological findings that may aid 
identification of the tumor bed, such as absence of glandular tissue, hyalinized vascular stroma, 
cell vacuolization, or foci of lymphocytic infiltration, should be described and illustrated.  
Acceptable standards for specimen handling and processing, such as a 1-hour maximum time of 
                                                 
8 See section 505(o)(3) of the FD&C Act. 
9 See the guideline for industry ICH-E1A The Extent of Population Exposure to Assess Clinical Safety: For Drugs 
Intended for Long-term Treatment of Non-Life-Threatening Conditions (March 1995). 
   14    Contains Nonbinding Recommendations  
specimen transit to the laboratory and a 24-hour minimum formalin fixation, also should be 
defined.     
  
The SOP should provide explicit guidelines for evaluation of specimens, particularly for those 
patients with cCR.  After entire specimens are inked for orientation, specimens from such 
patients should have a minimum of 1 block prepared per centimeter of pretreatment tumor size, 
or at least 10 blocks in total, whichever is greater, with 3 to 5 millimeter (mm) slices.  Review of 
both the radiologists interpretation of the specimen radiograph(s) and the pathologists 
assessment of the gross specimen(s) should be used to target areas deemed suspicious for 
potential residual disease.  Areas of concern identified by either discipline should be subjected to 
more extensive sectioning.  Given that tumors may shrink concentrically or irregularly, patients 
with no evidence of residual disease identified on initial evaluation should have additional blocks 
examined to ensure that no residual disease has been overlooked, and in particular, that no 
positive margins have been missed that may be surgically improved.   
  
All lymph nodes collected at the time of surgery should be assessed via serial gross sectioning.  
Nodes without residual disease apparent on gross inspection should be paraffin-embedded and 
cut in 2 to 3 mm slices.  At least one representative section per paraffin block should be analyzed 
after staining with hematoxylin and eosin.  The most reliable indicator of pCR in a lymph node is 
the presence of a well-defined scar in the absence of identifiable tumor cells.    
  
Both the SOP and the formal training for study pathologists should include guidance for 
situations when the presence of residual disease in the breast, lymph nodes, or lymphatics is in 
question.  Although cytokeratin staining should not be routinely performed on lymph nodes that 
are negative by gross inspection and hematoxylin and eosin staining, it may be helpful to assess 
lymph nodes where there are suspicious cells that preclude a final determination of nodal status 
by the pathologist.  Immunohistochemical staining also can help to distinguish epithelial cells 
(CK AE1/AE3, or CK7) from histiocytes (CD68).  If final determination of overall pCR status 
cannot be made by the sites study pathologist, the complete case should be submitted to the 
country/regions pathology principal investigator for formal adjudication.      
  
  
V.   POTENTIAL FOR UNINTENDED EFFECT ON DRUG DEVELOPMENT  
  
Although this pathway has the potential to provide high-risk early-stage breast cancer patients 
with earlier access to highly effective drugs compared to historical oncology drug development, 
there are potential limitations to this approach.    
  
First, long-standing practice involves characterizing the safety of oncology drugs first in patients 
with incurable disease.  Although investigational drugs are expected to continue to be studied 
initially in dose-finding and anti-tumor activity-estimating studies of patients with refractory 
metastatic cancer, the first large-scale randomized trials of an investigational drug under this 
pathway may be conducted in a curable population where the benefit/risk assessment differs 
from patients with incurable disease, particularly long-term risks, and the tolerance of physicians 
and patients for emerging serious safety signals will be lower.  Second, it is possible that a 
neoadjuvant trial could fail to demonstrate a significant difference in pCR rates and result in 
   15    Contains Nonbinding Recommendations  
abandoned development of an investigational drug that is, in fact, active in the adjuvant or 
metastatic breast cancer setting.  Finally, of concern to both patient advocacy groups and the 
FDA, there is a risk of failure to investigate investigational drugs in patients with metastatic 
breast cancer if companies assume that an approval for early-stage high-risk disease will result in 
widespread off-label use for patients with advanced breast cancer.  For all of these reasons, we 
wish to emphasize that formal study of new drugs in patients with metastatic breast cancer will 
continue to be important.  
  
  
VI.   CONCLUSION 
  
The FDA acknowledges that important regulatory questions persist regarding use of pCR to 
support accelerated approval in high-risk early-stage breast cancer.  A trial-level relationship 
between improvement in pCR and improvement in long-term outcome has not been established.  
If such a relationship exists, it is unknown whether the necessary magnitude of improvement in 
pCR will differ according to breast cancer subtype or drug class.  Hence, we recommend that 
sponsors pursuing a neoadjuvant indication meet early with the FDA to discuss their plans for 
designing a neoadjuvant trial in the context of a robust breast cancer drug development program.  
These discussions should include a justification for the proposed magnitude of improvement in 
pCR rate and long-term outcome, additional trials that would provide supporting evidence of 
clinical benefit in breast cancer, and the anticipated safety database to support the drugs use in a 
curative intent setting.  
  
   
   16    Contains Nonbinding Recommendations  
 
REFERENCES 
  
Bear H et al., 2006, Sequential Preoperative or Postoperative Docetaxel Added to Preoperative 
Doxorubicin Plus Cyclophosphamide for Operable Breast Cancer:  National Surgical Adjuvant 
Breast and Bowel Project Protocol B-27, J Clin Oncol, 24:2019-2027.  
  
Bottini A et al., 2005, Cytotoxic and Antiproliferative Activity of the Single Agent Epirubicin 
versus Epirubicin Plus Tamoxifen as Primary Chemotherapy in Human Breast Cancer:  A 
Single-Institution Phase III Trial, Endocr Relat Cancer, 12:383-392.  
  
Boughey J et al., 2012, The Role of Sentinel Lymph Node Surgery in Patients Presenting with 
Node Positive Breast Cancer (T0-T4, N1-2) who Receive Neoadjuvant Chemotherapy  Results 
from the ACOSOG Z1071 Trial, Cancer Res, 72 (24 Suppl): S2-1.  
  
Buzdar A et al., 2005, Significantly Higher Pathologic Complete Remission Rate after  
Neoadjuvant Therapy with Trastuzumab, Paclitaxel, and Epirubicin Chemotherapy:  Results of a 
Randomized Trial in Human Epidermal Growth Factor Receptor 2-Positive Operable Breast 
Cancer, J Clin Oncol, 23:3676-3685.  
  
Buzdar A et al., 2007, Neoadjuvant Therapy With Paclitaxel Followed By 5-Fluorouracil,  
Epirubicin, and Cyclophosphamide Chemotherapy and Concurrent Trastuzumab in Human  
Epidermal Growth Factor Receptor 2-Positive Operable Breast Cancer:  An Update of the Initial 
Randomized Study Population and Data of Additional Patients Treated With the Same Regimen, 
Clin Cancer Res, 13:228-233.  
  
Cortazar P et al., 2012, Meta-Analysis Results from the Collaborative Trials in Neoadjuvant 
Breast Cancer (CTneoBC), Cancer Res, 72 (24 Suppl): S1-11.    
  
Cortazar P et al., 2014, Pathological Complete Response and Long-Term Clinical Benefit in 
Breast Cancer: The CTNeoBC Pooled Analysis, Lancet, 384:164-172.  
  
Davidson N, 2005, Sometimes a Great Notion  An Assessment of Neoadjuvant Systemic 
Therapy for Breast Cancer, J Natl Cancer Inst, 97:159-161.  
  
Fisher B et al., 1998, Effect of Preoperative Chemotherapy on the Outcome of Women With 
Operable Breast Cancer, J Clin Oncol, 16:2672-2685.  
  
Gianni L et al., 2010, Neoadjuvant Chemotherapy With Trastuzumab Followed by Adjuvant  
Trastuzumab Versus Neoadjuvant Chemotherapy Alone, in Patients With HER2-Positive Locally 
Advanced Breast Cancer (The NOAH Trial): A Randomized Controlled Superiority Trial With a 
Parallel HER2-Negative Cohort, Lancet, 375:377-384.    
  
Hennessy B et al., 2005, Outcome After Pathologic Complete Eradication of Cytologically 
Proven Breast Cancer Axillary Node Metastases Following Primary Chemotherapy, J Clin 
Oncol, 23:9304-9311.  
   17    Contains Nonbinding Recommendations  
  
Kaufmann M et al., 2006, Recommendations from an International Expert Panel on the Use of 
Neoadjuvant (Primary) Systemic Treatment of Operable Breast Cancer:  An Update, J Clin 
Oncol, 24:1940-1949.  
  
Kuehn T et al., 2012, Sentinel Lymph Node Biopsy Before or After Neoadjuvant Chemotherapy:  
Final Results from the Prospective, German Multi-Institutional SENTINA Trial, Cancer Res, 72 
(24 Suppl): S2-2.  
  
Kuerer H et al., 1999, Clinical Course of Breast Cancer Patients With Complete Pathologic 
Primary Tumor and Axillary Lymph Node Response to Doxorubicin-Based Neoadjuvant 
Chemotherapy, J Clin Oncol, 17:460-469.  
  
Kuroi K et al., 2006, Issues in the Assessment of the Pathologic Effect of Primary Systemic 
Therapy for Breast Cancer, Breast Cancer, 13:38-48.  
  
Loi S et al., 2011, Proposals for Uniform Collection of Biosamples from Neoadjuvant Breast 
Cancer Clinical Trials:  Timing and Specimen Types, Lancet Oncol, 12:1162-1168.  
  
Liedtke C et al., 2008, Response to Neoadjuvant Therapy and Long-Term Survival in Patients 
With Triple-Negative Breast Cancer, J Clin Oncol, 26:1275-1281.  
  
Masuda et al., 2017, Adjuvant Capecitabine for Breast Cancer after Preoperative Chemotherapy, 
NEJM, 376: 2147-2159. 
 
Mauri D et al., 2005, Neoadjuvant versus Adjuvant Systemic Treatment in Breast Cancer:  A 
Meta-Analysis, J Natl Cancer Inst, 97:188-194.  
  
Mazouni C et al., 2007, Residual Ductal Carcinoma In Situ in Patients With Complete 
Eradication of Invasive Breast Cancer After Neoadjuvant Chemotherapy Does Not Adversely 
Affect Patient Outcome, J Clin Oncol, 25:2650-2655.  
  
McCready D et al., 1989, The Prognostic Significance of Lymph Node Metastases After 
Preoperative Chemotherapy for Locally Advanced Breast Cancer, Arch Surg, 124:21-25.  
  
Rastogi P et al., 2008, Preoperative Chemotherapy: Updates of National Surgical Adjuvant 
Breast and Bowel Project Protocols B-18 and B-27, J Clin Oncol, 26:778-785.  
  
Rouzier R et al., 2005, Breast Cancer Molecular Subtypes Respond Differently to Preoperative 
Chemotherapy, Clin Cancer Res, 11:5678-5685.  
  
Symmans WF et al., 2007, Measurement of Residual Cancer Burden to Predict Survival After 
Neoadjuvant Chemotherapy, J Clin Oncol, 25:4414-4422.  
  
van der Hage J et al., 2007, Preoperative Chemotherapy for Women With Operable Breast 
Cancer, Cochrane Database of Systematic Reviews, Issue 2, Art. No:  CD005002.  
   18    Contains Nonbinding Recommendations  
  
von Minckwitz G et al., 2001, Dose-Dense Doxorubicin, Docetaxel, and Granulocyte Colony-
Stimulating Factor Support With or Without Tamoxifen as Preoperative Therapy in Patients 
With Operable Carcinoma of the Breast:  A Randomized, Controlled, Open Phase IIb Study, J 
Clin Oncol, 19:3506-3515.  
  
von Minckwitz G et al., 2010, Capecitabine in Addition to Anthracycline- and Taxane-Based 
Neoadjuvant Treatment in Patients With Primary Breast Cancer:  Phase III Geparquattro Study, J 
Clin Oncol, 28:2015-2023.  
  
Von Minckwitz G et al., 2012, Definition and Impact of Pathologic Complete Response on 
Prognosis After Neoadjuvant Chemotherapy in Various Intrinsic Breast Cancer Subtypes, J Clin 
Oncol, 30:1796-804.  
 
Von Minckwitz G et al., 2017, Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive 
Breast Cancer, NEJM, 377:122-131.  
 
Von Minckwitz G et al., 2019, Trastuzumab Emtansine for Residual Invasive HER2-Positive 
Breast Cancer, NEJM, 380:617-628. 
  
Wolmark N et al., 2001, Preoperative Chemotherapy in Patients with Operable Breast Cancer:  
Nine-Year Results from National Surgical Adjuvant Breast and Bowel Project B-18, J Natl 
Cancer Inst Monogr, 30:96-102.  
  
   19