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 womenâ€™s health research.
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
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).1The 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).
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.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.
The BRCA1 and BRCA2 genes code for proteins that play a critical role in the high fidelity, homologous recombination repair of DNA damage in normal cells. Cancer cells also use these proteins to attempt repair of the significant number of mutations present in the cancer cell DNA.
The amount of DNA damage in the cancer cell is too much to allow complete repair, but enough occurs that the cancer cell can survive. However, in a cancer that developed in a patient with a deleterious mutation in BRCA1 or BRCA2, one of the BRCA proteins is absent, so this primary repair mechanism is not available. As a result, the cancer cells must depend on an alternative DNA repair pathway that uses the PARP enzyme for survival. If this enzyme can be inhibited, BRCA-deficient cancer cells may die due to loss of the ability to adequately repair their abnormal DNA, a process referred to as synthetic lethality.There are several PARP inhibitors in development, and the FDA approved olaparib in December 2014 as monotherapy for patients with advanced ovarian cancer with deleterious germline mutations in BRCA1 or BRCA2. Olaparib monotherapy has also shown promise in patients with pretreated metastatic breast cancer with BRCA germline mutations, although the data have not been strong enough to seek approval in this indication from the FDA.
Now, the OlympiAD trial2 is currently enrolling patients with germline BRCA mutations and pretreated metastatic breast cancer to receive olaparib versus chemotherapy of investigator’s choice. This study will determine the utility of olaparib in patients with BRCA-associated metastatic breast cancer.
A second trial, OlympiA, is a landmark, global collaboration between the National Clinical Trials Network, which is led by NRG Oncology and sponsored by the National Cancer Institute (NCI), and the Breast International Group, which is sponsored by AstraZeneca, the manufacturer of olaparib.
This phase III clinical trial is investigating the efficacy and safety of adjuvant olaparib following completion of standard therapies for high-risk, HER2-negative patients with breast cancers that harbor germline mutations of the BRCA1 or BRCA2 gene. Initially launched as a trial limited to patients with triple-negative breast cancer, an amendment is in process to expand eligibility to patients with high-risk hormone receptor (HR)—positive/HER2-negative breast cancer.
This is the first time a major adjuvant study has been launched to evaluate a therapy specifically targeting patients with BRCA mutation-associated breast cancer. The study is being led by leading experts in BRCA-associated breast cancer from around the world, including Andrew Tutt, MBChB, PhD, Judy E. Garber, MD, MPH, and Bella Kaufman, MD. It is my privilege to serve as co-principal investigator on this trial with these outstanding investigators.
OlympiA participants are required to complete all standard treatments including chemotherapy and surgery and, if needed, radiation therapy. Chemotherapy can be administered as neoadjuvant or adjuvant therapy. Participants will be randomized 1:1 to receive either olaparib or a placebo for a year.
Since standard therapy will have been completed by the time patients enter OlympiA, the placebo controlled-design is both appropriate and necessary to understand the benefits and side effects of olaparib in this potentially curative patient population. Patients will be followed for disease recurrence and new cancers for approximately 10 years following randomization to determine the efficacy of adjuvant treatment with olaparib on invasive disease-free survival.
Secondary endpoints include overall survival, distant disease-free survival, and the incidence of new invasive breast primary cancer and/or a new epithelial ovarian cancer. An important secondary aim of the trial is to study how olaparib affects patient quality of life (QoL) by measuring patient-reported outcomes using the FACIT fatigue scale and EORTC QLQ-C30 QoL scale.
Since only women and men with germline BRCA mutations who develop high-risk but potentially curable breast cancer are eligible for OlympiA, timely completion of accrual of the 1500 patients required for the study will be challenging. The trial is being conducted in 23 countries. In North America, the trial is open to all investigators participating in the National Clinical Trials Network, which consists of four academic research bases (NRG Oncology, Alliance, ECOG-ACRIN, and SWOG) and the NCI Community Oncology Research Program (NCORP). The trial is actively recruiting eligible women and men diagnosed with triple-negative breast cancer with an inherited BRCA1 or BRCA2 gene mutation, and will soon include those with HR-positive, HER2-negative cancers as well.
On behalf of my co-principal investigators, the members of the Scientific Steering Committee, and the hereditary breast and ovarian community, I want to encourage physician investigators across North America to join this global effort and provide your patients who meet the eligibility criteria the opportunity to participate in OlympiA.