ASCO Updated Guideline of Biomarkers in Metastatic Breast Cancer Supports PIK3CA, BRCA1/2, PD-L1 Testing

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ASCO has issued a new practice guideline update on the use of biomarkers in the management of metastatic breast cancer.1 The updated guideline revisits recommendations from the 2015 guideline and addresses topics that have emerged since then in the move toward personalized medicine in metastatic breast cancer.2

After reviewing relevant clinical trials published from 2015–2022, the expert panel found the strongest support for widespread testing for PIK3CA somatic variants, germline BRCA1/2 mutations, and PD-L1 expression. The updated guideline makes a total of 11 recommendations, including in cases in which the panel found insufficient evidence to recommend routine testing for specific biomarkers.

The Evolution of Biomarkers

“The sheer number of recommendations in the guideline is remarkable and tells us that biomarkers now play an extremely significant role in treatment selection for patients with metastatic breast cancer,” said Expert Panel Co-Chair Angela DeMichele, MD, MSCE, of the University of Pennsylvania. “We may think we’ve already identified the most important biomarkers, but they are continuing to evolve and must do so in concert with new drugs as they’re developed.”

Angela DeMichele, MD, MSCE

Angela DeMichele, MD, MSCE

As an example of this evolution, Dr. DeMichele pointed to the DESTINY-Breast04 study, which established the antibody-drug conjugate fam-trastuzumab deruxtecan-nxki as a new standard of care for HER2 IHC (immunohistochemistry) 1+ or 2+/in situ hybridization–negative metastatic breast cancer.3

“We saw the DESTINY-Breast04 investigators take the existing biomarker HER2 and define an entirely new group of patients who can benefit from a new class of drugs,” she said. “Yet those findings didn’t make it into the guideline yet because they’re too new, so we remind all clinicians that ASCO guidelines are continually updated as new data become available.”

Testing for PIK3CA Mutations

The Panel determined that patients with locally recurrent unresectable or metastatic hormone receptor–positive and HER2-negative breast cancer who are candidates for a PI3K inhibitor and a hormonal therapy should be tested for PIK3CA mutations. Clinicians should use next-generation sequencing of tumor tissue or circulating tumor DNA in plasma to determine patients’ eligibility for alpelisib plus fulvestrant.

This recommendation was based on the SOLAR-1 trial, which used biomarker testing to identify patients with hormone receptor–positive, HER2-negative metastatic breast cancer who had PIK3CA mutations.4 Patients who received alpelisib plus fulvestrant had a median progression-free survival 5.3 months longer than those who received placebo plus fulvestrant (11.0 vs 5.7 months; hazard ratio [HR] for disease progression or death = 0.65). “SOLAR-1 demonstrated improved patient outcomes from the use of a tumor biomarker test result to select treatment strategy,” said Expert Panel Co-Chair N. Lynn Henry, MD, PhD, of the University of Michigan.

N. Lynn Henry, MD, PhD

N. Lynn Henry, MD, PhD

Dr. Henry noted that, in most cases, PIK3CA mutations develop early in the disease process and are therefore present in both primary and metastatic tumor samples. “Therefore, if no mutation is found in circulating tumor DNA, testing of tumor tissue from either primary or metastatic biopsies should be used, as this will detect a small number of additional patients with PIK3CA mutations,” she said.

Testing for PD-L1 Expression

The guideline recommends that patients with locally recurrent unresectable or metastatic hormone receptor–negative, HER2-negative breast cancer who are candidates for a treatment with an immune checkpoint inhibitor should receive PD-L1 testing of the tumor and immune cells with an U.S. Food and Drug Administration (FDA)-approved test to determine eligibility for treatment with pembrolizumab plus chemotherapy.

This recommendation is based on data from two phase III trials: KEYNOTE-355 and KEYNOTE-119. KEYNOTE-355 found that the use of pembrolizumab plus chemotherapy in patients with untreated metastatic triple-negative breast cancer and a PD-L1 combined positive score of ≥ 10 resulted in a median progression-free survival of 9.7 months compared with 5.6 months for patients who received placebo plus chemotherapy (HR for disease progression or death = 0.65).5

KEYNOTE-119 compared pembrolizumab monotherapy with single-drug chemotherapy as second- or third-line treatment of patients with metastatic triple-negative breast cancer.6 There was no significant improvement in overall survival observed for pembrolizumab monotherapy compared with chemotherapy, but a post hoc, exploratory analysis of the pembrolizumab treatment effect in study participants with a PD-L1 combined positive score ≥ 20—about 18% of the overall study population—found median overall survival was 14.9 months for the pembrolizumab group and 12.5 months for the chemotherapy group (HR = 0.58).

The guideline notes that PD-L1 testing is complex since different assays can yield different results. “This variability stems from the use of different antibodies, as well as from testing different cell types, including tumor cells, lymphocytes, and macrophages in the tumor and/or stroma,” Dr. Henry said, noting the FDA-approved pembrolizumab in combination with chemotherapy for treatment of triple-negative breast cancer that has tested positive for PD-L1 using the specific 22C3 companion assay.

Testing for BRCA1/2 Mutations

Another area of evolution is the use of germline testing as biomarkers for therapy. “It used to be that we looked for germline mutations in BRCA1/2 simply to understand a patient’s risk of developing cancer,” Dr. DeMichele said. “But now, we are utilizing germline testing so eligible patients don’t miss the opportunity to get one of the PARP inhibitors, which have outperformed traditional chemotherapy in this setting and are much less toxic.”

This change was based on the results of two phase III clinical trials: OlympiAD and EMBRACA. OlympiAD found that women with HER2-negative metastatic breast cancer and a germline BRCA mutation who received olaparib had significantly longer progression-free survival than those who received physician’s choice single-agent chemotherapy (7.0 vs 4.2 months; HR = 0.58).7

EMBRACA found that women with advanced breast cancer and a germline BRCA1/2 mutation who received talazoparib had significantly longer progression-free survival than those who received standard single-agent chemotherapy (8.6 vs 5.6 months; HR = 0.54). Benefits were seen in patients with either triple-negative or estrogen receptor–positive disease.8

Using the Correct Assay

One theme that runs throughout the updated guideline is the importance of keeping current with the assays used to identify biomarkers. “As oncologists, we all must talk to our pathologists to ensure the assay being used is the correct one to identify patients who might respond to the specific treatment,” Dr. DeMichele said. “We’re now in a situation of needing to match the assay to the biomarker to the treatment, which can include a steep learning curve.”

Additionally, the panel acknowledged the widespread use of commercial assays that test for multiple biomarkers simultaneously. “These panels are easy to use, and we know that many community oncologists are using them for a variety of cancers, so we pointed out instances when this approach is and is not appropriate and where the limitations of those tests may lie,” Dr. Henry said. 


1. Henry NL, Somerfield MR, Dayao Z, et al: Biomarkers for systemic therapy in metastatic breast cancer: ASCO guideline update. J Clin Oncol. June 27, 2022 (early release online).

2. 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 33:2695-2704, 2015.

3. Modi S, Jacot W, Yamashita T, et al: Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. N Engl J Med 387:9-20, 2022.

4. Andre F, Ciruelos E, Rubovszky G, et al: Alpelisib for PIK3CA-mutated, hormone receptor-positive advanced breast cancer. N Engl J Med 380:1929-1940, 2019.

5. Cortes J, Cescon DW, Rugo HS, et al: Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable
or metastatic triple-negative breast cancer (KEYNOTE-355): A randomised, placebo-controlled, double-blind, phase 3 clinical trial. Lancet 396:1817-1828, 2020.

6. Winer EP, Lipatov O, Im SA, et al: Pembrolizumab versus investigator-choice chemotherapy for metastatic triple-negative breast cancer (KEYNOTE-119): A randomised, open-label, phase 3 trial. Lancet Oncol 22:499-511, 2021.

7. Robson M, Im SA, Senkus E, et al: Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N Engl J Med 377:523-533, 2017.

8. Litton JK, Hurvitz SA, Mina LA, et al: Talazoparib versus chemotherapy in patients with germline BRCA1/2-mutated HER2-negative advanced breast cancer: Final overall survival results from the EMBRACA trial. Ann Oncol 31:1526-1535, 2020.

Originally published in ASCO Daily News. © American Society of Clinical Oncology. ASCO Daily News, July 15, 2022. All rights reserved.