While the field of cancer genetics may seem pretty recent, ancient Greek physicians observed that the occurrence of breast cancer was more common in certain families.1 In the late 1800s, Paul Broca, the famous French surgeon and anthropologist, best known for discovering the speech production center in the frontal lobe, was one of the first to formally recognize genetic pedigrees in breast cancers.2
In 1992, King and her colleagues used linkage analysis of 11 markers in breast and ovarian cancer families to localize the BRCA1 gene to chromosome 17 q12-q21.3 The discovery of the BRCA2 gene on chromosome 13q12-13 soon followed, employing similar techniques.4
Functionally, BRCA1 and BRCA2 are tumor-suppressor genes responsible for repair of double-stranded DNA breaks by homologous recombination, a generally error-free approach. Cells lacking the BRCA1 or BRCA2 protein cannot participate in this DNA repair process; thus, alternative pathways that are more error prone must be used, leading to accelerated rates of mutation and chromosomal rearrangement. The BRCA1 protein also serves other potential tumor suppressor functions, including assembly of the mitotic spindle, control of the cell cycle, and remodeling of chromatin at the double-strand DNA breaks. Defective homologous repair of BRCA genes also can result from mutations in other genes, such as those involved in the Fanconi anemia pathway, including RAD50, PALB2, and BRIP1.
Despite the recognition of the basic tumor-suppressive roles of BRCA1 and BRCA2, the complete mechanism of action of these genes is still under study. However, we do know that cells deficient in BRCA1 or BRCA2 are exceedingly sensitive to certain therapeutic agents that induce double-stranded DNA breaks such as the alkylating-like agents cisplatin and carboplatin. The success of poly(ADP-ribose) polymerase (or PARP) inhibitors in treating hereditary BRCA-associated pelvic serous carcinoma has significantly accelerated the pace of PARP inhibitor drug approval and the search for additional biomarkers that can identify the best candidates for these new targeted agents. In December 2014, olaparib received Food and Drug Administration (FDA) approval for women with hereditary BRCA-associated recurrent ovarian/tubal or peritoneal carcinomas. In April 2015, rucaparib, another PARP inhibitor, received breakthrough designation from the FDA for further study in women with advanced ovarian cancer. Further study will elucidate the optimal identification of homologous repair-deficient ovarian cancers and the best candidates for PARP inhibitor therapy.
Genetic mutations and risk of ovarian cancer
In women with BRCA1 mutations the cumulative lifetime risk of developing ovarian cancer is reported to be in the range of 39% to 54%; the risk with BRCA2 is lower, 11% to 23%.5 The overall prevalence of BRCA1/BRCA2 mutations in the general population is estimated at between 1 in 400 and 1 in 800. BRCA germline mutations are present in up to 13% to 15% of women with epithelial ovarian cancer, the most common and lethal type of ovarian cancer. However, 25% of women with serous ovarian carcinomas carry germline BRCA mutations and additional 9% to 40% have somatic mutations in BRCA or mutations in other genes involved in homologous repair. Taken together, a large proportion of high-grade serous and endometrioid ovarian carcinomas appear to have homologous recombination defects which correlate with the highest responses to PARP inhibitors.
Complicating screening efforts is the large number of potential BRCA1 and BRCA2 mutations identified in the general population. In 1 study, 1,731 deleterious mutations in BRCA1 and BRCA2 were identified in 10,000 at-risk individuals,6 but among patients of Ashkenazi Jewish heritage, there is a higher prevalence (1 in 40) of BRCA1/BRCA2 mutations, principally due to the presence of 3 founder mutations.5
While these BRCA mutations clearly confer an increased risk of ovarian cancer, conventional wisdom held that since these defects also limited the DNA-repair functions of ovarian cancer cells, patients with homozygous BRCA1 or BRCA2 mutations in their tumors would have improved responses to chemotherapeutic agents that further damaged DNA, such as cisplatin, because of the accumulation of a fatal level of new mutations (ie, lethal genetic instability). However, definitive proof of this hypothesis has been hard to come by because of conflicting results from generally small, and/or methodologically flawed studies. A large prospective study suggests the cumulative risk of developing breast and ovarian cancer by age 70 among BRCA1 carriers is 60% (95%CI: 44–75%) and 59% (95%CI: 42–76), respectively. For BRCA2, the risks are lower, 55% (95%CI: 41–70) and 16.5% (95%CI: 7.5–34), respectively.7
In addition, BRCA2 carriers clearly have a lower lifetime risk of ovarian and fallopian tube cancer than BRCA1 carriers, and ovarian cancer in BRCA2 carriers tends to occur later in life.5 These findings suggest that BRCA2 confers a lesser oncological “hit” than BRCA1 mutations, and thus, perhaps, an improved prognosis. However, again there is a dearth of high-quality studies comparing ovarian cancer survival in women with BRCA1 and BRCA2 mutations. Fortunately, a recent study by Yang and associates provides far deeper insights into the variable prognosis and biology of these 2 hereditary causes of ovarian cancer.8