2022 Biomarkers Metastatic Breast Cancer Slides

Biomarkers for Systemic Therapy in Metastatic
Breast Cancer
ASCO Guideline Update
Henry et al.
www.asco.org/breast-cancer-guidelines ©American Society of Clinical Oncology (ASCO) 2022. All rights reserved worldwide.
For licensing opportunities, contact licensing@asco.org
2
Overview
1. Background & Methodology
• Introduction
• ASCO Guideline Development Methodology
• Clinical Questions
• Target Population and Audience
2. Summary of Recommendations
3. Discussion
• Patient and Clinician Communication
• Additional Resources
• Expert Panel Members
1 Background & Methodology
4
Introduction
• ASCO published a guideline in 2015 on the use of biomarkers to guide decisions on systemic
therapy for patients with metastatic breast cancer (MBC).1
• The updated guideline2 revisited recommendations from the 2015 guideline and expanded the
scope of the guideline to address topics that have emerged since the publication of the 2015
guideline:
▪ testing for PIK3CA and ESR1 somatic variants and germline BRCA1, BRCA2, and PALB2 pathogenic variants
to guide therapy
▪ testing tumors for homologous recombination deficiency, expression of PD-L1, dMMR/MSI, TMB, NTRK gene
fusions, and TROP2 expression to determine eligibility for selected treatments
▪ the use of cell-free, ctDNA and CTCs for monitoring treatment response
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ASCO Guideline Development Methodology

• The ASCO Evidence Based Medicine Committee (EBMC) guideline process includes:
▪ a systematic literature review by ASCO guidelines staff
▪ an expert panel provides critical review and evidence interpretation to inform
guideline recommendations
▪ final guideline approval by ASCO EBMC
• The full ASCO Guideline methodology manual can be found at: www.asco.org/guideline-
methodology
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Clinical Questions
This clinical practice guideline update addresses 11 clinical questions:
1. What is the role of PIK3CA mutation testing to guide the decision to use alpelisib in patients
with hormone receptor-positive metastatic breast cancer?
2. What is the role of testing for ESR1 mutations to guide therapy for hormone receptor-
positive, HER2-negative metastatic breast cancer?
3. What is the role of testing for germline BRCA 1/2 and PALB2 pathogenic mutations to guide
the decision to use an oral PARP inhibitor in patients with hormone receptor-positive or
hormone receptor-negative, HER2-negative metastatic breast cancer?
4. What is the role of testing tumors for homologous recombination deficiency in treatment
selection for patients with metastatic breast cancer?
5. What is the role of testing for expression of PD-L1 in the tumor and immune cells in patients
with locally recurrent unresectable or metastatic hormone receptor-negative and HER2-
negative breast cancer who are candidates for a treatment regimen that includes an immune
checkpoint inhibitor?
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Clinical Questions
6. What is the role of testing for dMMR/MSI-H in treatment selection for patients with
metastatic breast cancer to identify candidates for immune checkpoint inhibitor
monotherapy?
7. What is the role of testing for TMB for patients with metastatic breast cancer to identify
candidates for immune checkpoint inhibitor monotherapy?
8. What is the role of testing for NTRK fusions in treatment selection for patients with
metastatic breast cancer to identify candidates for treatment with tyrosine kinase inhibitors
(larotrectinib or entrectinib)?
9. What is the role of testing tumors for TROP2 expression to guide therapy with an anti-
TROP2 antibody-drug conjugate for hormone receptor-negative, HER2-negative metastatic
breast cancer?
10. What is the role of using ctDNA for monitoring response to treatment?
11. What is the role of using CTCs for monitoring response to treatment?
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Target Population and Audience
Target Population
• Patients with metastatic breast cancer being considered for systemic therapy or for
changes in the drug or regimen they are receiving.
Target Audience
• Oncology specialists, other health care providers (including primary care physicians,
specialists, nurses, social workers, and any other relevant member of a comprehensive
multidisciplinary cancer care team) caregivers, and patients.
2 Summary of Recommendations
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Summary of Recommendations
Clinical Question 1
• What is the role of PIK3CA mutation testing to guide the decision to use alpelisib in
patients with hormone receptor-positive metastatic breast cancer?
Recommendation 1.1 Evidence-based

benefits outweigh harms
• Patients with locally recurrent unresectable or metastatic hormone

Strength of
receptor-positive and HER2-negative breast cancer who are Evidence Quality
Recommendation
candidates for a treatment regimen that includes a PI3K inhibitor High Strong
and a hormonal therapy, should undergo testing for PIK3CA
mutations using next-generation sequencing of tumor tissue or ctDNA in plasma to determine
their eligibility for treatment with the PI3K inhibitor alpelisib plus fulvestrant. If no mutation is
found in ctDNA, testing in tumor tissue, if available, should be used as this will detect a small
number of additional patients with PIK3CA mutations.
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Clinical Question 2
• What is the role of testing for ESR1 mutations to guide therapy for hormone receptor-
positive, HER2-negative metastatic breast cancer?
Recommendation 2.1 Informal consensus
• There are insufficient data at present to recommend routine Evidence Quality

Strength of
testing for ESR1 mutations to guide therapy for hormone receptor- Recommendation
positive, HER2-negative MBC. Existing data suggest reduced Insufficient Moderate

efficacy of aromatase inhibitors compared to the SERD fulvestrant
in patients who have tumor or ctDNA with ESR1 mutations.
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Clinical Question 3
• What is the role of testing for germline BRCA 1/2 and PALB2 pathogenic mutations to
guide the decision to use an oral PARP inhibitor in patients with hormone receptor-
positive or hormone receptor-negative, HER2-negative metastatic breast cancer?

• Patients with metastatic HER2-negative breast cancer who are

Strength of
candidates for treatment with a PARP inhibitor should undergo Evidence Quality
Recommendation
testing for germline BRCA1 and BRCA2 pathogenic or likely High Strong
pathogenic mutations to determine their eligibility for treatment
with the PARP inhibitors olaparib or talazoparib.
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• There is insufficient evidence to support a recommendation either Evidence Quality

Strength of
for or against testing for a germline PALB2 pathogenic variant for Recommendation
the purpose of determining eligibility for treatment with PARP Low Moderate
inhibitor therapy in the metastatic setting. This recommendation is
independent of the indication for testing to assess cancer risk.
Qualifying Statements
• Small single-arm studies show that oral PARP inhibitor therapy demonstrates high response
rates in metastatic breast cancer encoding DNA repair defects, such as germline PALB2
pathogenic variants and somatic BRCA1/2 mutations. It should also be noted that the
randomized PARP inhibitor trials made no direct comparison with taxanes, anthracyclines, or
platinums; comparative efficacy against these compounds is unknown.3,4
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Clinical Question 4
• What is the role of testing tumors for homologous recombination deficiency in treatment
selection for patients with metastatic breast cancer?
• There are insufficient data at present to recommend routine Evidence Quality

Strength of
testing of tumors for HRD to guide therapy for metastatic breast Recommendation
cancer Low Moderate
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Clinical Question 5
• What is the role of testing for expression of PD-L1 in the tumor and immune cells in
patients with locally recurrent unresectable or metastatic hormone receptor-negative and
HER2-negative breast cancer who are candidates for a treatment regimen that includes
an immune checkpoint inhibitor?

• Patients with locally recurrent unresectable or metastatic hormone

Strength of
receptor-negative and HER2-negative breast cancer who are Evidence Quality
Recommendation
candidates for a treatment regimen that includes an immune Intermediate Strong
checkpoint inhibitor should undergo testing for expression of PD-L1
in the tumor and immune cells with an FDA-approved test to determine eligibility for treatment
with the immune checkpoint inhibitor pembrolizumab plus chemotherapy.
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Clinical Question 6
• What is the role of testing for dMMR/MSI-H in treatment selection for patients with metastatic
breast cancer to identify candidates for immune checkpoint inhibitor monotherapy?
• Patients with metastatic cancer who are candidates for a Evidence Quality
Strength of
treatment regimen that includes an immune checkpoint inhibitor Recommendation
should undergo testing for dMMR/MSI-H to determine eligibility for Low Moderate
dostarlimab-gxly or pembrolizumab.
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Clinical Question 7
• What is the role of testing for TMB for patients with metastatic breast cancer to identify
candidates for immune checkpoint inhibitor monotherapy?
• Patients with metastatic cancer who are candidates for treatment Evidence Quality
Strength of
with an immune checkpoint inhibitor should undergo testing for Recommendation
TMB to determine eligibility for pembrolizumab monotherapy. Low Moderate
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Clinical Question 8
• What is the role of testing for NTRK fusions in treatment selection for patients with metastatic
breast cancer to identify candidates for treatment with tyrosine kinase inhibitors (larotrectinib
or entrectinib)?
• Clinicians may test for NTRK fusions in patients with metastatic Evidence Quality
Strength of
cancer who are candidates for a treatment regimen that includes a Recommendation
TRK inhibitor to determine eligibility for larotrectinib or entrectinib. Low Moderate
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Clinical Question 9
• What is the role of testing tumors for TROP2 expression to guide therapy with an anti-TROP2
antibody-drug conjugate for hormone receptor-negative, HER2-negative metastatic breast
cancer?
• There are insufficient data to recommend routine testing of tumors Evidence Quality
Strength of
for TROP2 expression to guide therapy with an anti-TROP2 Recommendation
antibody-drug conjugate for hormone receptor-negative, HER2- Low Moderate

negative metastatic breast cancer.
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Clinical Question 10
• What is the role of using ctDNA for monitoring response to treatment?
• There are insufficient data to recommend routine use of ctDNA to Evidence Quality
Strength of
monitor response to therapy among patients with metastatic Recommendation
breast cancer. Low Moderate
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Clinical Question 11
• What is the role of using CTCs for monitoring response to treatment?
• There are insufficient data to recommend routine use of CTCs to Evidence Quality
Strength of
monitor response to therapy among patients with metastatic Recommendation
breast cancer. Low Moderate
3 Discussion
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Patient and Clinician Communication

• Metastatic breast cancer presents complicated and evolving treatment options.
• It is imperative that clinicians apply skills and tasks that optimize patient-provider
communication around the goals of treatment and treatment options, and check for patient
understanding. If practicable and acceptable to the patient, clinicians should include significant
others in the conversation and reassess the patient’s goals of care, quality of life priorities, and
tolerance for risk.
• See the Patient-Clinician Communication: ASCO Consensus Guideline for recommendations
and strategies to optimize patient-provider communication.5
• With respect to biomarker testing in particular, clinicians should educate patients, and/or
caregivers and family members about the results of pathology evaluations and specific
genomic tests, including how the results of this testing are used to develop a treatment plan
tailored to their cancer biology.6
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Patient and Clinician Communication

• The terminology around testing is complex; simplifying and explaining this terminology is
essential to enhancing patient understanding of the role of biomarker testing in cancer care.
• Clear definitions and understanding about known endpoints such as PFS are necessary to
ensure patients have the information they need for treatment decision-making.7 Asking
patients to repeat back key pieces of information, providing written or recorded notes, and
using visual aids can also help ensure information is effectively communicated.
• Patients should be provided with a copy of their pathology report and, if available, other test
results when useful. Clinicians should review the individual results with patients and offer to
discuss any questions about test interpretation or performance.6
• Conversations between the oncology team and the person with MBC need to include the
caveat that NGS and biomarker testing is a rapidly evolving field; that shared decision making
is paramount; and that, if there are questions about the role of or interpretation of NGS and/or
biomarker testing, consultation with a molecular tumor board or MBC expert should be
considered.
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Additional Resources
• More information, including a supplement and clinical tools and
resources, is available at www.asco.org/breast-cancer-
guidelines
• Patient information is available at www.cancer.net
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Guideline Panel Members

Name Affiliation/Institution Role/Area of Expertise
Angela DeMichele, MD (Co-Chair) University of Pennsylvania, Philadelphia, PA Medical Oncology

N. Lynn Henry, MD, PhD (Co-Chair) University of Michigan, Ann Arbor, MI Medical Oncology
Zoneddy Dayao, MD University of New Mexico Hospital, Albuquerque, NM Medical Oncology/PGIN Representative
Anthony Elias, MD University of Colorado Cancer Center, Aurora, CO Medical Oncology
Kevin Kalinsky, MD, MS Winship Cancer Institute at Emory University, Atlanta, GA Medical Oncology
Lisa M. McShane, PhD National Cancer Institute, NIH, Bethesda, MD Biostatistics
Beverly Moy, MD, MPH Massachusetts General Hospital, Boston, MA Medical Oncology
Ben Ho Park MD, PhD Vanderbilt-Ingram Cancer Center, Nashville, TN Medical Oncology
Kelly M. Shanahan, MD South Lake Tahoe, CA Patient Representative
Priyanka Sharma, MD University of Kansas Medical Center, Westwood, KS Medical Oncology
Rebecca Shatsky, MD University of California, San Diego School of Medicine, La Jolla, CA Medical Oncology
Erica Stringer-Reasor, MD University of Alabama at Birmingham, Birmingham, AL Medical Oncology
Melinda Telli, MD Stanford University, Palo Alto, CA Medical Oncology
Nicholas C. Turner, MD, PhD Breast Unit, Royal Marsden Hospital, London, UK Medical Oncology
Mark R. Somerfield, PhD American Society of Clinical Oncology, Alexandria, VA ASCO Practice Guideline Staff (Health Research Methods)
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Abbreviations
• ASCO, American Society of Clinical Oncology • MSI-H, microsatellite instability-high
• CTCs, circulating tumor cells • NGS, next-generation sequencing
• ctDNA, circulating tumor DNA • NTRK, neurotrophic tyrosine receptor kinase
• dMMR, deficient mismatch repair • PARP, poly (ADP-ribose) polymerase
• EBMC, Evidence Based Medicine Committee • PD-L1, programmed cell death ligand-1
• HER2, human epidermal growth factor • PFS, progression-free survival
receptor 2 • SERD, selective estrogen receptor degrader
• HRD, homologous recombination deficiency • TMB, tumor mutational burden
• MBC, metastatic breast cancer • TROP2, trophoblast cell-surface antigen 2
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References
1. Van Poznak C, Somerfield MR, Bast RC, et al: Use of Biomarkers to Guide Decisions on Systemic Therapy for Women With
Metastatic Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol 33:2695-704, 2015
2. Henry NL, Somerfield MR, Dayao Z, et al: Biomarkers for Systemic Therapy in Metastatic Breast Cancer: ASCO Guideline
Update. J Clin Oncol, 2022
3. Moy B, Rumble RB, Come SE, et al: Chemotherapy and Targeted Therapy for Patients With Human Epidermal Growth Factor
Receptor 2-Negative Metastatic Breast Cancer That is Either Endocrine-Pretreated or Hormone Receptor-Negative: ASCO
Guideline Update. J Clin Oncol 39:3938-3958, 2021
4. Burstein HJ, Somerfield MR, Barton DL, et al: Endocrine Treatment and Targeted Therapy for Hormone Receptor-Positive,
Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer: ASCO Guideline Update. J Clin Oncol
39:3959-3977, 2021
5. Gilligan T, Coyle N, Frankel RM, et al: Patient-Clinician Communication: American Society of Clinical Oncology Consensus
Guideline. J Clin Oncol 35:3618-3632, 2017
6. Andre F, Ismaila N, Allison KH, et al: Biomarkers for Adjuvant Endocrine and Chemotherapy in Early-Stage Breast Cancer:
ASCO Guideline Update. J Clin Oncol, 2022
7. Fallowfield LJ, Catt SL, May SF, et al: Therapeutic aims of drugs offering only progression-free survival are misunderstood by
patients, and oncologists may be overly optimistic about likely benefits. Support Care Cancer 25:237-244, 2017
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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 herein 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 information does not account for individual variation among patients. Recommendations
specify the level of 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” indicates 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 does not endorse third party drugs,
devices, services, or therapies used to diagnose, treat, monitor, manage, or alleviate health conditions. Any use of a brand
or trade name is for identification purposes only. ASCO provides this information on an “as is” basis and makes no
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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.

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Biomarkers for Systemic Therapy in Metastatic

ASCO Guideline Development Methodology

Target Population and Audience

Recommendation 1.1 Evidence-based

• Patients with locally recurrent unresectable or metastatic hormone

Recommendation 2.1 Informal consensus

• There are insufficient data at present to recommend routine Evidence Quality

positive, HER2-negative MBC. Existing data suggest reduced Insufficient Moderate

Recommendation 3.1 Evidence-based

• Patients with metastatic HER2-negative breast cancer who are

• There is insufficient evidence to support a recommendation either Evidence Quality

Recommendation 4.1 Informal consensus

• There are insufficient data at present to recommend routine Evidence Quality

cancer Low Moderate

Recommendation 5.1 Evidence-based

• Patients with locally recurrent unresectable or metastatic hormone

Recommendation 6.1 Informal consensus

Recommendation 7.1 Informal consensus

TMB to determine eligibility for pembrolizumab monotherapy. Low Moderate

Recommendation 8.1 Informal consensus

TRK inhibitor to determine eligibility for larotrectinib or entrectinib. Low Moderate

Recommendation 9.1 Informal consensus

antibody-drug conjugate for hormone receptor-negative, HER2- Low Moderate

Recommendation 10.1 Informal consensus

breast cancer. Low Moderate

Recommendation 11.1 Informal consensus

breast cancer. Low Moderate

Patient and Clinician Communication

Patient and Clinician Communication

• Patient information is available at www.cancer.net

Guideline Panel Members

Angela DeMichele, MD (Co-Chair) University of Pennsylvania, Philadelphia, PA Medical Oncology

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