NCCN Guidelines for Breast Cancer V.1.
2021 – Annual on 08/27/20
Guideline Page
and Request
General
External request:
Submission from Christina Rosati on 02/25/20 to
consider recommending ER-α36 testing of all breast
cancer tumors (initial presentation and recurrences) in
addition to current ER-α66 testing, as a prerequisite to
recommendation or exclusion of tamoxifen therapy in
light of potential for increased risk of metastases in ER-
α36 positive breast cancer patients.
Multiple Pages
External requests:
Submission from ASTRO on 07/20/20 requesting multiple
changes:
• IBC-2 and BINV-I – Either in a footnote on IBC-2 or
under “Chest Wall Radiation” section of BINV-I, a
dose recommendation of 66 Gy should be added as
a special consideration for inflammatory breast
cancer.
• BINV-13 and BINV-14 – Add footnote about high-risk
features that increase consideration of giving a boost
to the tumor bed.
• BINV-1 – Provide guidance on treatment for cT0N1
since mentioned at beginning of algorithm for work-
up, but not mentioned in any subsequent treatment
algorithms.
• BINV-F: Create a brief table to be included on the
bottom half of page “BINV-F 2 OF 2” summarizing all
of the margin recommendations from the text
included in this section.
See Submission for additional specific changes
requested.
Institution Vote
Panel Discussion/References
YES NO ABSTAIN ABSENT
Based on a review of the data and discussion, the 0 28 0 3
panel consensus did not support the inclusion of
ER-α36 testing of all breast cancer tumors (initial
presentation and recurrences), as a prerequisite to
recommendation or exclusion of tamoxifen therapy,
due to insufficient available data.
Based on a review of the data and discussion, the 28 0 0 3
panel consensus supported the following edits
• BINV-I: Modified chest wall RT dose to 60-
66Gy
• BINV-13, footnote added: Strongly consider RT
boost for high-risk features (eg, high-grade
disease, age <50 years).
• BINV-1: For treatment of cT0,N+,M0 disease, a
link has been added to NCCN Guidelines for
Occult Primary
• BINV-F (2 of 2): Table added with margin
recommendations.
The panel consensus did not support the inclusion
of the other specific changes requested.
See Submission for references.
NCCN Guidelines for Breast Cancer V.1.2021 – Annual on 08/27/20

BINV-5/BINV-15/BINV-L Based on a review of the data and discussion, the 0 28 0 3

External request:
Submission from Puma Biotechnology on 10/05/20 to
consider including neratinib in the treatment algorithm (as
opposed to the footnote) as extended adjuvant treatment
for patients with HER-2 positive, HR-positive disease in
the following sections:
• Systemic Adjuvant Treatment: Hormone Receptor-
Positive - HER2-Positive Disease (BINV-5)
• Adjuvant Systemic Therapy after Preoperative
Systemic Therapy (BINV-15)
• Preoperative/Adjuvant Therapy Regimens: HER2-
Positive (BINV-L 2/6)
BINV-6/BINV-7/BINV-N
External request:
Submissions from Myriad Genetics on 01/27/20 and
08/01/20 to consider specific changes to correct
discrepancies on BINV-6/BINV-7 with the following
statement that appeared on BINV-N:
“The [12-gene] risk score is predictive of chemo-benefit
based on a prospective analysis of 3,746 archived, HR-
positive, HER2-negative, T1-T3 tumors from chemo-
endocrine and endocrine-only cohorts, that included
women with lymph node-negative and lymph node-
positive disease13”, indicating that the 12-gene
EndoPredict assay can be used to predict chemo-benefit.
panel consensus was not to make changes to the
current recommendations.
See Submission for references.
Based on a review of the data and discussion, the 28 0 0 3
panel consensus supported the following edits on
BINV-N (3 of 5):
• For patients...The assay is prognostic in
endocrine and chemo-endocrine treated
patients. The risk score is predictive of
chemo-benefit based on a prospective
analysis of 3,746 archived, HR-positive,
HER2-negative, T1–T3 tumors from
chemo-endocrine and endocrine-only
cohorts, that included women with lymph
node-negative and lymph node-
positivedisease.
• Changed recurrence risk to: “Low (≤3.3)”
and “High (>3.3)”.

BINV-N (3 of 4): In the row for the 12-gene assay it The panel consensus did not support the inclusion
states “Low (<3.33)” and “High (>3.33)”. Request this be of the other specific changes requested.
changed to “EPclin Low (≤3.3)” and “EPclin High (>3.3)”.
The 12-gene test reports an EP molecular score and an See Submissions for references.
EPclin score. It is important and accurate to clarify EPclin
and to state “3.3” (not “3.33) and include “≤” and “>” in
the correct locations.

See Submissions for additional specific changes

requested.
NCCN Guidelines for Breast Cancer V.1.2021 – Annual on 08/27/20
BINV-11/BINV-M
External requests:
Submission from Exact Sciences on 07/28/20 to consider
these requests:
• Add the use of the 21-gene RT-PCR in the
preoperative work-up in women with operable ER+,
HER2(-) breast cancer if she is under consideration
for neoadjuvant systemic therapy, as reflected in
BINV-11.
• Add language in BINV-M as follows: Preoperative
endocrine therapy alone may be considered for
patients with ER+, HER2(-) breast cancer with a 21-
gene RT-PCR assay result <18 that has been shown
to significantly improve breast conserving surgery
rates without evidence of progression, and for whom
there is no adjuvant systemic chemotherapy benefit
for both N0 and N1 disease.
BINV-15
External request:
Submission from Genentech on 08/05/20 to consider
applying the following footnote on page BINV-15, which
allows for concomitant radiation as part of adjuvant
therapy after preoperative systemic therapy, to ado-
trastuzumab emtansine based on the KATHERINE
protocol and subgroup analysis.
• Footnote: If HER2-targeted therapy and/or endocrine
therapy is indicated, it may be administered
concurrently with radiation. If indicated, capecitabine
should follow completion of RT.
Based on a review of the data and discussion, the 28 0 0 3
panel consensus supported the inclusion of the
following footnote on BINV-11:
• If considering preoperative therapy, consider
use of a gene expression assay during workup
for postmenopausal patients with cN0,
operable ER-positive, HER2-negative disease.
(Iwata H, et al. Breast Cancer Res Treat
2019;173,123-133; Pease AM, et al. Ann Surg
Oncol 2019;26:366-371.)
Based on a review of the data and discussion, the 28 0 0 3
panel consensus was to include the footnote with
ado-trastuzumab emtansine as part of adjuvant
therapy for HR-negative/HER2-positive disease, if
ypT1-4 or ypN>1 after preoperative therapy.
The footnote has been modified: “HER2-targeted
therapy and/or endocrine therapy may be delivered
concurrently with RT, while capecitabine should
follow completion of RT.”
See Submission for references.
NCCN Guidelines for Breast Cancer V.1.2021 – Annual on 08/27/20
BINV-17
External request:
Submission from Society of Interventional Oncology on
07/30/20 to consider the following requests:
• Recommending PET/CT to monitor disease
progression rather than specifying it as optional and
including embolotherapies for treatment of refractory
hepatic metastasis.
• Including locoregional embolotherapy with
radioembolization as a treatment for refractory
hepatic metastasis.
BINV-17/BINV-21&23/BINV-A
External requests:
Submission from Zionexa US Corp on 07/29/20 to
consider the inclusion of FES PET on various pages in
the NCCN Guidelines for Breast Cancer.
See Submission for specific changes requested.
Based on a review of the data and discussion, the 0 28 0 3
panel consensus was not to make changes to the
current recommendations for PET/CT on BINV-17.
The panel consensus supported the removal of the 28 0 0 3
word “optional” from the PET/CT recommendation
on IBC-1.
Based on a review of the data and discussion, the 0 28 0 3
panel consensus was not to include locoregional
embolotherapy with radioembolization as a
treatment for refractory hepatic metastasis, due to
limited data.
See Submission for references.
Based on a review of the data and discussion, the 0 28 0 3
panel consensus did not support the addition of
these specific recommendations into the
Guidelines.
See Submission for references.
NCCN Guidelines for Breast Cancer V.1.2021 – Annual on 08/27/20

BINV-A/BINV-R Based on a review of the data and discussion, the 28 0 0 3

Internal request:
Comment to consider recent data on pembrolizumab in
metastatic TNBC and reevaluating the definition of PD-L1
testing (for pembro PD-L1 C > 10 using the combined
tumor/lymphocyte score was used).
External request:
panel consensus supported the inclusion of TMB-H
(> 10 muts/mb), using NGS to inform the use of
pembrolizumab (on page BINV-R).
Based on a review of the data and discussion, the 0 28 0 3
panel consensus did not support the addition of
“HER2 testing by validated next-generation
sequencing (NGS) assay” into the Guidelines.

Submission from Foundation Medicine on 08/06/20 and Reference:

09/15/20 to consider the following requested changes: Marabelle A, Fakih M, Lopez J, et al. Association of
1. Include “HER2 testing by validated next-generation tumour mutational burden with outcomes in
sequencing (NGS) assay” as an additional method to patients with advanced solid tumours treated with
determine HER2 status in “Principles of Biomarker pembrolizumab: prospective biomarker analysis of
Testing: HER2 Testing” on page BINV-A, page 1 of the multicohort, open-label, phase 2 KEYNOTE-
2. 158 study. Lancet Oncol. 2020;21(10):1353-1365.
2. Include next-generation sequencing (NGS) and
comprehensive genomic profiling (CGP) as a method
of detection for BRCA1/2 mutations, PIK3CA
mutations, MSI-H status and dMMR mutations in the
table “Biomarkers Associated with FDA-approved
Therapies” on page BINV-R, page 1 of 3.
3. Include tumor mutational burden (TMB) as
determined by validated and/or FDA approved next-
generation sequencing panel to inform the use of
pembrolizumab in the table “Biomarkers Associated
with FDA-approved Therapies” on page BINV-R,
page 1 of 3.
4. Add footnote on page BINV-R, page 1 of 3, to
indicate that “tumor/somatic profiling via large
validated NGS panels (>50 genes) or comprehensive
genomic profiling is recommended to determine rare
and actionable mutations and fusions for which
effective drugs may already be available, or to
appropriately counsel patients regarding the
availability of clinical trials.”
NCCN Guidelines for Breast Cancer V.1.2021 – Annual on 08/27/20

BINV-E The panel consensus did not support the addition 0 28 0 3

External request: of these specific recommendations into the
Guidelines.
Submission from ImpediMed Limited on 08/05/20 to
request the language be amended in BINV-E : See Submission for references.

From: Lymphedema is a potential side effect after the

treatment of axillary lymph node surgery resulting from
damage to the lymphatic system. Early
detection/diagnosis of lymphedema is key for optimal
management. Consider pretreatment measurement of
both arms as a baseline for patients with risk factors
for lymphedema. See NCCN Guidelines for
Survivorship: Lymphedema (SLYMPH-1).
To: Lymphedema is a potential side effect after the
treatment of axillary lymph node surgery resulting from
damage to the lymphatic system. Early
detection/diagnosis of lymphedema is key for optimal
management. Endeavor to obtain a pretreatment
measurement of both arms as a baseline for patients
with risk factors for lymphedema, and establish a
program of regular follow up using an objective,
reproducible tool such as L-Dex. See NCCN
Guidelines for Survivorship: Lymphedema (SLYMPH-1).
BINV-L Based on a review of the data and discussion, the 0 28 0 3
Internal request: panel consensus did not support the inclusion of
atezolizumab or pembrolizumab as a neoadjuvant
Comment to consider addition of PDL1 targeting agents, treatment options for TNBC. The Panel consensus
atezolizumab or pembrolizumab, as neoadjuvant was to defer the submission until FDA approval.
treatment options for TNBC based on KEYNOTE-35 and
IMpassion031. Reference:
Mittendorf EA, Zhang H, Barrios CH, et al.
External request: Neoadjuvant atezolizumab in combination with
sequential nab-paclitaxel and anthracycline-based
Submission from Genentech on 10/02/20 to consider the chemotherapy versus placebo and chemotherapy
enclosed IMpassion031 publication to support inclusion in patients with early-stage triple-negative breast
of atezolizumab (Tecentriq) plus nab-paclitaxel for the cancer (IMpassion031): a randomised, double-
neoadjuvant treatment of patients with early triple- blind, phase 3 trial. Lancet. 2020;396(10257):1090-
negative breast cancer (TNBC). 1100.
NCCN Guidelines for Breast Cancer V.1.2021 – Annual on 08/27/20
BINV-L
Internal request:
Comment to consider adding pembrolizumab +
combination chemotherapy for 1st line, PDL1 CPS> 10
TNBC and recommend AGAINST therapy in subset with
lower CPS based on KEYNOTE-522 data.
External request:
Submission from Merck & Co., Inc., on 03/18/20 to
request that pembrolizumab in combination with
platinum-based chemotherapy be added as a
preoperative therapy regimen for patients with early
triple-negative breast cancer.
BINV-N
Internal request:
Comment to consider the new evidence regarding the
Breast Cancer Index and alter the algorithm accordingly.
External request:
Submission from BioTheranostics on 08/05/20 to include
revisions to the BINV-N Table to include
• Changes to the title to add adjuvant extended
endocrine therapy
• A change from “No” to “Yes” for BCI validated
Predictive ability, and
• Addition of BCI results from the MA.17 and IDEAL
studies in the treatment implications (requested
changes highlighted in yellow in submission).
Based on a review of the data and discussion, the 0 28 0 3
panel consensus did not support the inclusion of
pembrolizumab in combination with platinum-based
chemotherapy as a preoperative/adjuvant therapy
regimen for patients with early triple-negative
breast cancer due to limited data. The Panel
consensus was to defer the submission until FDA
approval.
Based on a review of the data and discussion, the 28 0 0 3
panel consensus was to include the following
changes on BINV-N:
• Page title changed to: Gene Expression
Assays for Consideration of Adjuvant Systemic
Therapy
• BCI Predictive ability changed to: Predictive of
benefit of extended adjuvant endocrine therapy
• Updates to BCI treatment implications on
BINV-N (4 of 5)
Reference:
Noordhoek I, Treuner K, Putter H, et al. Breast
Cancer Index predicts extended endocrine benefit
to individualize selection of HR+ early stage breast
cancer patients for 10 years of endocrine therapy.
Clin Cancer Res 2020 Oct 27. doi: 10.1158/1078-
0432.CCR-20-2737. Online ahead of print.
NCCN Guidelines for Breast Cancer V.1.2021 – Annual on 08/27/20

BINV-P/BINV-R Based on a review of the data and discussion, the 28 0 0 3

External request: panel consensus supported the following edits on
to the footnote on BINV-P:

Submission from Novartis on 05/12/20 to consider the “If there is disease progression while on a CDK4/6
following requests: or PI3K inhibitor, there are limited data to support
an additional line of therapy with another CDK4/6-
• Consider adding “For PIK3CA-mutated tumors, see or PIK3CA-containing regimen…”
additional targeted therapy options (see BINV-R)” to
the list of Preferred Regimens for First-Line Therapy The panel consensus did not support the inclusion 0 28 0 3
as a systemic treatment option for HR+/HER2- of the other specific changes requested.
recurrent or Stage IV breast cancer in BINV-P.
• Consider adding the footnote “If there is disease
progression while on an alpelisib-containing regimen,
there are no data to support an additional line of See Submission for references.
therapy with another alpelisib regimen” to the bullet
“For PIK3CA-mutated tumors...” under the list of
Preferred Regimens for Second- and Subsequent-
Line Therapy.
• Consider changing the NCCN Category of
Preference for alpelisib + fulvestrant to “Preferred”
instead of “Preferred second-line therapy” in BINV-R.
BINV-Q/BINV-R Based on a review of the data and discussion, the 28 0 0 3
External request: panel consensus supported the inclusion of
pembrolizumab + chemotherapy (albumin-bound
Submission from Merck & Co., Inc., on 05/29/20 and paclitaxel, paclitaxel, or gemcitabine and
11/16/20 to consider the addition of pembrolizumab in carboplatin) as an option for those with recurrent or
combination with chemotherapy as a first-line therapy stage IV (M1) triple negative breast cancer, if PD-
regimen for patients with locally recurrent inoperable or L1 positive with a combined positive score > 10.
metastatic triple-negative breast cancer. This is a category 1, preferred first-line therapy
option.

Reference:
Cortes J, Cescon DW, Rugo HS, et al. KEYNOTE-
355: Randomized, double-blind, phase 3 study of
pembrolizumab + chemotherapy versus placebo +
chemotherapy for previously untreated locally
recurrent inoperable or metastatic triple-negative
breast cancer. Presented at ASCO 2020; May 29,
2020; Abstract 1000.
NCCN Guidelines for Breast Cancer V.1.2021 – Annual on 08/27/20
BINV-R
External requests:
Submission from Merck & Co., Inc., on 06/17/20 to
consider the inclusion of pembrolizumab as a treatment
option for patients with advanced tumor mutational
burden-high (TMB-H) breast cancer who have
progressed following prior treatment and have no
satisfactory alternative treatment.
Submission from Foundation Medicine Inc., on 06/22/20
requesting the following changes:
• Amend “Additional Targeted Therapies and
Associated Biomarker Testing for Recurrent or Stage
IV (M1) Disease” section on page BINV-R 1 of 3
include TMB testing by validated and/or FDA
approved targeted next generation sequencing panel
to inform the use of pembrolizumab. (refence Merino
2020 for validation standards)
• Add pembrolizumab as a treatment option for
patients with unresectable or metastatic tumors with
tissue tumor mutational burden-high (tTMB-H) >10
mutations/megabase, as determined by an FDA-
approved test, who have progressed following prior
treatment and who have no satisfactory alternative
treatment options.
BINV-R
External request:
Submission from Puma Biotechnology on 08/05/20 to
consider including neratinib-based therapy as a
treatment option for patients with somatic HER2mut in
the following section: Additional targeted therapies and
associated biomarker testing for recurrent or Stage IV
(M1) disease.
Based on a review of the data and discussion, the 28 0 0 3
panel consensus supported the inclusion of
pembrolizumab as a treatment option for patients
with advanced tumor mutational burden-high (TMB-
H) breast cancer who have progressed following
prior treatment and have no satisfactory alternative
treatment. This is a category 2A, useful in certain
circumstances recommendation.
The panel consensus did not support the inclusion 0 28 0 3
of TMB testing by validated and/or FDA approved
targeted next generation sequencing panel to
inform the use of pembrolizumab.
Reference:
Marabelle A, Fakih M, Lopez J, et al. Association of
tumour mutational burden with outcomes in
patients with advanced solid tumours treated with
pembrolizumab: prospective biomarker analysis of
the multicohort, open-label, phase 2 KEYNOTE-
158 study. Lancet Oncol. 2020;21(10):1353-1365.
Based on a review of the data and discussion, the 0 28 0 3
panel consensus was not to make changes to the
current recommendations.
See Submission for references.
NCCN Guidelines for Breast Cancer V.1.2021 – Annual on 08/27/20

BINV-R Based on a review of the data and discussion, the 28 0 0 3

External request: panel consensus was to include the following
changes:
Submission from Guardant on 08/06/20 to consider the 1. BINV-R: Added NGS as a detection
following changes: method for TMB-H tumors (on BINV-R).
• Tissue or liquid. Please consider suggesting that a 2. BINV-17, modified: Biomarker testing
well validated plasma-based next-generation Comprehensive germline and somatic
sequencing (NGS) assay be used in advanced profiling to identify candidates for additional
(recurrent or stage IV) breast cancer to support targeted therapies, see Additional Targeted
current Guideline-recommended testing in any Therapies and Associated Biomarker
cancer subtype for BRCA1/2, NTRK fusions, and Testing for Recurrent or Stage IV (M1)
MSI-H when (a) these predictive biomarkers have not Disease (BINV-R)
been evaluated, or (b) tissue biopsy is infeasible or
yields an insufficient sample. Such a suggestion is The panel consensus did not support the inclusion
aligned with the current recommendation to use of the other specific changes requested.
“tumor or liquid biopsy” to assess for PIK3CA
mutations for HR+/HER2- breast cancer, with the See Submission for references.
admonition “if liquid biopsy is negative, tumor tissue
testing is recommended.”1
• Liquid as a noninvasive alternative. Elsewhere, the
Guidelines recommend repeat biopsy to assess for
changes in ER/PR/HER2 status in the metastatic
tumor,2 but often doing so is infeasible, especially
when the metastases are predominantly bony.
Therefore, please consider suggesting that when
repeat tissue biopsy “cannot safely be obtained”
liquid biopsy be considered to assess for any change
in HER2 (ERBB2 gene amplification) status before
commencing treatment otherwise based solely (and
suboptimally) on the historical status of the primary
tumor. Liquid biopsy (as a safer, less invasive
alternative) has been recommended in similar
scenarios for lung and pancreatic cancers for some
time,3,4 and recently so for gastric and esophageal
and esophagogastric junction cancers.