Breast Cancer

BRCA1 and BRCA2

  • BRCA1 DNA repair associated (BRCA1) and BRCA2 DNA repair associated (BRCA2); encode tumor suppressor proteins central to homologous recombination repair (HRR) of DNA double-strand breaks
  • Gene Location: Chromosome 17 (17q21.31) for BRCA1; Chromosome 13 (13q13.1) for BRCA2

Biology

  • In an HRR-proficient cell, BRCA1 coordinates cell-cycle checkpoint control and DNA end resection, while BRCA2 loads RAD51 onto resected single-stranded DNA, enabling error-free repair of double-strand breaks.1
  • Tumorigenesis follows a two-hit pattern: an inherited loss-of-function allele plus somatic loss of the remaining wild-type allele leaves the tumor, but not normal tissue, HRR-deficient. Cells are forced onto error-prone backup repair pathways, producing the genomic instability that creates the therapeutic window.2
  • PARP inhibitors block PARP1 catalytic activity and trap PARP1 on DNA at single-strand break sites. The trapped complexes collapse replication forks into double-strand breaks that an HRR-deficient tumor cannot repair, producing synthetic lethality. The same deficiency underlies sensitivity to platinum chemotherapy.3,4

Etiology and Epidemiology

  • Germline BRCA1/2 pathogenic variants are inherited and present from birth, not acquired under treatment pressure. Status is established once and does not require retesting at progression, in contrast to acquired markers such as ESR1 mutations.
  • Germline BRCA mutations are found in approximately 5% to 10% of all patients with breast cancer.5
  • BRCA1-associated tumors are predominantly triple-negative and basal-like, whereas BRCA2-associated tumors are more often hormone receptor-positive. Carriers are enriched among patients with young-onset disease, bilateral disease, and a suggestive family history.2
  • Triple-negative breast cancer carries the highest carrier frequency of the major subtypes.2

Testing

When to Test:

  • Testing must be performed on germline DNA from blood or saliva. Tumor-only next-generation sequencing cannot distinguish germline from somatic origin and does not establish eligibility for the germline-restricted PARP inhibitor indications; a BRCA finding on a tumor panel requires germline confirmation.3,4
  • Per ASCO-SSO, offer BRCA1/2 testing to all patients diagnosed with breast cancer at or below age 65. Above age 65, offer testing to patients who are candidates for PARP inhibitor therapy, have triple-negative disease, were assigned male sex at birth, or have a personal or family history suggestive of a pathogenic variant.6
  • Offer testing regardless of age to any patient with local or metastatic recurrent breast cancer who is a candidate for PARP inhibitor therapy, and to patients with a second primary in the contralateral or ipsilateral breast.6

Testing Methodologies:

  • Multigene panel next-generation sequencing on germline DNA, combining sequence analysis with large-rearrangement and copy-number analysis. Deletion and duplication testing matters, since large rearrangements are a meaningful minority of BRCA1 pathogenic variants and are missed by sequencing alone.
  • BRACAnalysis CDx (Myriad Genetic Laboratories) is the FDA-approved companion diagnostic for both olaparib and talazoparib in breast cancer, covering the metastatic indications and the adjuvant olaparib indication.3,4
  • Panels typically also report the high-penetrance genes PALB2, TP53, PTEN, STK11, and CDH1, and the moderate-penetrance genes ATM, CHEK2, BARD1, RAD51C, and RAD51D. Moderate-penetrance findings inform second-primary and family risk but do not create an approved treatment option in breast cancer.6
  • Variants of uncertain significance are common and are not actionable. A VUS should not be treated as a positive result in therapy selection or in risk-reducing surgical planning.6

Guideline Recommendations

  • ASCO and the Society of Surgical Oncology published a joint germline testing guideline for breast cancer in 2024, which sets the age-65 threshold and directs additional predisposition-gene testing based on personal and family history.6
  • NCCN includes germline BRCA1/2 status in the workup of recurrent or stage IV HER2-negative disease and of high-risk early-stage disease where adjuvant olaparib is under consideration, with detailed testing criteria in the NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate.7

Targeted Therapy

Approved Agents

  • Two oral PARP inhibitors are FDA-approved specifically for germline BRCA-mutated, HER2-negative breast cancer: olaparib (Lynparza) and talazoparib (Talzenna). Both require selection by an FDA-approved companion diagnostic performed on germline DNA.3,4
  • On January 12, 2018, the FDA approved olaparib for germline BRCA-mutated, HER2-negative metastatic breast cancer based on the phase 3 OlympiAD trial, which demonstrated improved progression-free survival versus physician's choice chemotherapy. On March 11, 2022, the indication was extended to the adjuvant treatment of high-risk early breast cancer based on the phase 3 OlympiA trial.8,9
  • On October 16, 2018, the FDA approved talazoparib for germline BRCA-mutated, HER2-negative locally advanced or metastatic breast cancer based on the phase 3 EMBRACA trial. Talazoparib has no adjuvant breast cancer indication.10
  • Olaparib is the only PARP inhibitor with an early breast cancer indication, and the only one to have demonstrated an overall survival benefit in breast cancer, in the adjuvant OlympiA setting.3,9

Olaparib (Lynparza)

  • FDA-Approved Indication:
    • Adults with deleterious or suspected deleterious germline BRCA-mutated, HER2-negative metastatic breast cancer previously treated with chemotherapy in the neoadjuvant, adjuvant, or metastatic setting. Patients with hormone receptor-positive disease should have received prior endocrine therapy or be considered inappropriate for it.3
    • Adjuvant treatment of adults with deleterious or suspected deleterious germline BRCA-mutated, HER2-negative high-risk early breast cancer previously treated with neoadjuvant or adjuvant chemotherapy.3
  • Mechanism of Action:
    • Oral inhibitor of PARP1, PARP2, and PARP3 that blocks catalytic activity and traps PARP at sites of DNA damage.3
    • Trapped PARP-DNA complexes collapse replication forks into double-strand breaks that HRR-deficient tumor cells cannot repair, producing synthetic lethality.3

Drug Information:

Learn more about Olaparib ›

Patient Resources:

https://www.lynparza.com/

Talazoparib (Talzenna)

  • FDA-Approved Indication:
    • Adults with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm), HER2-negative locally advanced or metastatic breast cancer. Patients must be selected based on an FDA-approved companion diagnostic.4
  • Mechanism of Action:
    • Oral PARP inhibitor with potent PARP-trapping activity, blocking PARP1 and PARP2 catalytic function and stabilizing PARP-DNA complexes.4
    • The resulting replication-associated double-strand breaks cannot be repaired in HRR-deficient tumor cells.4

Drug Information:

Learn more about Talazoparib ›

Patient Resources:

https://www.talzenna.com/

Related Considerations

  • HRR deficiency also predicts platinum sensitivity, and platinum agents remain a common comparator and sequencing consideration in germline BRCA-mutated disease. They are not biomarker-gated by label.
  • PALB2 germline pathogenic variants produce a comparable HRR-deficient phenotype, and small single-arm studies have shown high response rates to PARP inhibition. There is currently no FDA-approved PARP inhibitor indication for PALB2 in breast cancer; use in that setting is off-label.6

References

1. Roy R, Chun J, Powell SN. BRCA1 and BRCA2: different roles in a common pathway of genome protection. Nat Rev Cancer. 2011;12(1):68-78. doi:10.1038/nrc3181

2. BRCA1 and BRCA2: Cancer Risks and Management (PDQ). National Cancer Institute. Accessed July 2026.

3. LYNPARZA (olaparib) tablets. Prescribing information. AstraZeneca Pharmaceuticals LP. Accessed July 2026.

4. TALZENNA (talazoparib) capsules. Prescribing information. Pfizer Inc. Accessed July 2026.

5. Merck & Co, Inc. LYNPARZA (olaparib) reduced risk of death by 32% in patients with germline BRCA-mutated, HER2-negative high-risk early breast cancer in the phase 3 OlympiA trial. News release. Accessed July 2026.

6. Bedrosian I, Somerfield MR, Achatz MI, et al. Germline testing in patients with breast cancer: ASCO-Society of Surgical Oncology guideline. J Clin Oncol. 2024;42(5):584-604. doi:10.1200/JCO.23.02225

7. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Breast Cancer V.5.2026, and for Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate V.3.2026. © National Comprehensive Cancer Network, Inc. 2026. All rights reserved. Accessed July 2026. To view the most recent and complete version of the guideline, go online to NCCN.org.

8. US Food and Drug Administration. FDA approves olaparib for germline BRCA-mutated metastatic breast cancer. January 12, 2018. Accessed July 2026.

9. US Food and Drug Administration. FDA approves olaparib for adjuvant treatment of high-risk early breast cancer. March 11, 2022. Accessed July 2026.

10. US Food and Drug Administration. FDA approves talazoparib for gBRCAm HER2-negative locally advanced or metastatic breast cancer. October 16, 2018. Accessed July 2026.