Olaparib Studies Put Focus on BRCA-Positive Breast Cancers

Charles E. Geyer Jr, MD
Published: Saturday, Jan 30, 2016
VCUCharles E. Geyer Jr, MD
Charles E. Geyer Jr, MD
Associate Director, Clinical Research
VCU Massey Cancer Center
Professor, Division of Hematology, Oncology and Palliative Care
VCU School of Medicine
Richmond, VAStrategic Partnership
The identification of the BRCA1 and BRCA2 tumor suppressor genes and the recognition that inherited loss of function (deleterious) mutations in one of these important genes places women at high risk for the development of breast, ovarian, and other cancers are major advances in women’s health research.

Efforts are now under way to utilize this knowledge through clinical trials testing olaparib (Lynparza), a poly (ADP-ribose) polymerase (PARP) inhibitor that is the first anticancer therapy approved for patients with tumors that harbor BRCA mutations, in individuals with breast cancer.

I am serving as a co-principal investigator on the OlympiA trial, the first major adjuvant study to evaluate a therapy specifically targeting patients with BRCA mutation-associated breast cancer (Figure).1

BRCA1/2 Mutations: Prevalence and Impact

The presence of a deleterious germline BRCA1 mutation is associated with a 60% to 70% lifetime risk of breast cancer and a 20% to 45% lifetime risk of ovarian cancer. A deleterious BRCA2 mutation is associated with a 40% to 60% lifetime risk of breast cancer and a 10% to 20% lifetime risk of ovarian cancer.

Additionally, these BRCA mutation-associated cancers typically occur at a younger age than similar sporadic cancers in women without these mutations.

Identification of women with deleterious mutations in the BRCA genes before they develop cancer provides an opportunity for initiating enhanced early detection programs such as MRI-based breast cancer screening, as well as consideration for risk reduction surgeries such as bilateral salpingooophorectomy and bilateral mastectomies.

Deleterious germline BRCA mutations are present in only a small minority of women who develop breast cancer. Approximately 5% of breast cancers are associated with a germline mutation in the BRCA1 or BRCA2 gene (3% with the BRCA1 gene and 2% with the BRCA2 gene).

Figure. OlympiA Schema for Patients With Triple-Negative Breast Cancer With Germline BRCA Mutations1

OlympiA Schema for Patients With Triple-Negative Breast Cancer
With Germline BRCA Mutations

gBRCA indicates germline BRCA mutation; MRI, magnetic resonance imaging; pCR, pathologic complete response; TNBC, triple-negative breast cancer.

The majority of cancers that develop in women with BRCA1 mutations are the triple-negative phenotype (70%) while women with mutations in the BRCA2 gene are more likely to develop estrogen receptor—positive breast cancer (70%).

Given the small size of the subpopulation of patients with deleterious BRCA mutations in breast cancer, information comparing the outcomes of these patients with the outcomes in the overall breast cancer population is relatively limited. However, the available evidence suggests that once baseline prognostic factors (such as hormone receptor and HER2 status) and treatment are taken into account, patients with BRCA mutations have similar outcomes with standard therapies for breast cancer as do women with sporadic breast cancer.

Historically, patients with germline BRCA mutations have been included in clinical trials evaluating new cancer therapies appropriate for the subtype of breast cancer they have developed, so they are treated according to their hormone receptor and HER2 status. Until recently, there have been very few clinical trials evaluating potential new therapies specifically in patients with BRCA mutations.

Rationale for PARP Inhibition

Women and men who inherit a deleterious mutation in a BRCA gene from one parent still have a normal functioning BRCA gene from the other parent in the normal cells throughout their body.

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