Prevalence of germline BRCA mutations in HER2-negative metastatic breast cancer: global results from the real-world, observational BREAKOUT study

Joyce O'Shaughnessy, Christine Brezden-Masley, Marina Cazzaniga, Tapashi Dalvi, Graham Walker, James Bennett, Shozo Ohsumi, Joyce O'Shaughnessy, Christine Brezden-Masley, Marina Cazzaniga, Tapashi Dalvi, Graham Walker, James Bennett, Shozo Ohsumi

Abstract

Background: The global observational BREAKOUT study investigated germline BRCA mutation (gBRCAm) prevalence in a population of patients with human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC).

Methods: Eligible patients had initiated first-line cytotoxic chemotherapy for HER2-negative MBC within 90 days prior to enrollment. Hormone receptor (HR)-positive patients had experienced disease progression on or after prior endocrine therapy, or endocrine therapy was considered unsuitable. gBRCAm status was determined using baseline blood samples or prior germline test results. For patients with a negative gBRCAm test, archival tissue was tested for somatic BRCAm and homologous recombination repair mutations (HRRm). Details of first-line cytotoxic chemotherapy were also collected.

Results: Between March 2017 and April 2018, 384 patients from 14 countries were screened and consented to study enrollment; 341 patients were included in the full analysis set (median [range] age at enrollment: 56 [25-89] years; 256 (75.3%) postmenopausal). Overall, 33 patients (9.7%) had a gBRCAm (16 [4.7%] in gBRCA1 only, 12 [3.5%] in gBRCA2 only, and 5 [1.5%] in both gBRCA1 and gBRCA2). gBRCAm prevalence was similar in HR-positive and HR-negative patients. gBRCAm prevalence was 9.0% in European patients and 10.6% in Asian patients and was higher in patients aged ≤ 50 years at initial breast cancer (BC) diagnosis (12.9%) than patients aged > 50 years (5.4%). In patients with any risk factor for having a gBRCAm (family history of BC and/or ovarian cancer, aged ≤ 50 years at initial BC diagnosis, or triple-negative BC), prevalence was 10.4%, versus 5.8% in patients without these risk factors. HRRm prevalence was 14.1% (n = 9/64) in patients with germline BRCA wildtype.

Conclusions: Patient demographic and disease characteristics supported the association of a gBRCAm with younger age at initial BC diagnosis and family history of BC and/or ovarian cancer. gBRCAm prevalence in this cohort, not selected on the basis of risk factors for gBRCAm, was slightly higher than previous results suggested. gBRCAm prevalence among patients without a traditional risk factor for harboring a gBRCAm (5.8%) supports current guideline recommendations of routine gBRCAm testing in HER2-negative MBC, as these patients may benefit from poly(ADP-ribose) polymerase (PARP) inhibitor therapy.

Trial registration: NCT03078036 .

Keywords: BRCA; Breast cancer susceptibility genes; Observational; Prevalence.

Conflict of interest statement

Dr. Joyce O’Shaughnessy has received honoraria for consulting and advisory boards from AbbVie, Agendia, Amgen, AstraZeneca, Bristol-Myers Squibb, Celgene Corporation, Eisai, Eli Lilly, Genentech, Genomic Health, GRAIL, Heron Therapeutics, Immunomedics, Ipsen Biopharmaceuticals, Jounce Therapeutics, Merck, Myriad, Novartis, Odonate Therapeutics, Pfizer, Puma Biotechnology, Roche, Seattle Genetics, and Syndax Pharmaceuticals.

Dr. Christine Brezden-Masley has received honoraria for consulting and advisory boards from Amgen, AstraZeneca, Eli Lilly, Genomic Health, Merck, Myriad, Novartis, Pfizer, Roche, and Taiho. She has received travel grants from Amgen, AstraZeneca, and Roche.

Dr. Marina Cazzaniga reports no competing interests.

Dr. Tapashi Dalvi, Dr. Graham Walker, and Dr. James Bennett are employees or contracted employees of AstraZeneca and may own stock.

Dr. Shozo Ohsumi has received honoraria for lecture fees from AstraZeneca.

Figures

Fig. 1
Fig. 1
BREAKOUT study design. BRCA, breast cancer susceptibility gene; CT, chemotherapy; gBRCAm, germline BRCA mutation; HER2, human epidermal growth factor receptor-2; HRRm, homologous recombination repair gene mutation; OS, overall survival; PFS, progression-free survival; sBRCAm, somatic BRCA mutation. *Blood/tumor testing occurred concurrently to the extent possible. †Foundation Medicine Inc. (Cambridge, Massachusetts, USA) Lynparza HRR assay was used to test for HRR gene mutations. ‡Positive: deleterious mutation; suspected deleterious. Negative: no deleterious mutation detected; no mutation detected; favor polymorphism; variant of uncertain significance; BRCA wildtype
Fig. 2
Fig. 2
Patient disposition. FAS, full analysis set. *39 patients did not meet eligibility criteria; 29 patients had not initiated treatment with first-line systemic cytotoxic chemotherapy for metastatic breast cancer in the past 90 days and, at that time, were considered to have exhausted endocrine therapy options if hormone receptor-positive; 9 patients had no evidence of metastatic disease; and 1 patient consented after the termination of the study
Fig. 3
Fig. 3
Prevalence of sBRCAm and other HRR gene mutations (subgroup for exploratory analysis). BRCA1, breast cancer susceptibility gene 1; BRCA2, breast cancer susceptibility gene 2; HRRm, homologous recombination repair gene mutation; sBRCAm, somatic BRCA mutation; sBRCA1, somatic BRCA1 mutation; sBRCA2, somatic BRCA2 mutation

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