Update on BRCA and ovarian cancer

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

NEXT: Is there a difference between ovarian cancers linked to BRCA1 and BRCA2?

Are ovarian cancers associated with BRCA1 and BRCA2 different diseases?

Yang and colleagues studied multidimensional genomic and clinical data on 316 high-grade serous ovarian cancer patients enrolled in The Cancer Genome Atlas project.⁸ Of these patients, 219 had wild-type BRCA genes: 35 had BRCA1 somatic and/or germline mutations, 27 had BRCA2 somatic and/or germline mutations, and 2 had both BRCA1 and BRCA2 mutations. They then evaluated the association between BRCA1 and BRCA2 deficiencies and patients’ overall and progression-free survival and chemotherapy response. Patients with BRCA1 mutations were younger at diagnosis (mean age, 55.9 years) than those with either wild-type BRCA genes (61.8 years; P=.006) or BRCA2 mutations (mean age, 60.9 years; P=.03). Surprisingly, the authors found that only BRCA2 was associated with improved 5-year survival rates compared with ovarian cancer patients whose tumors had the wild-type BRCA genes. Among BRCA2 mutation carriers, 5-year survival was 61% (95% Confidence Interval [CI], 43%-87%), compared with wild-type BRCA patients whose 5-year survival rates were only 25% (Hazard Ratio [HR]=0.33; 95% CI, 0.16-0.69; P=.003). In contrast, patients with BRCA1 mutations did not have a significantly different 5-year survival compared with patients without BRCA mutations when adjusting for their younger age.

The authors also found that patients with BRCA2 mutations had significantly improved primary chemotherapy responses compared with those with BRCA1 mutations or patients without BRCA mutations. In contrast, patients with BRCA1 mutations had no statistically significant enhanced primary chemotherapy sensitivity compared with wild-type BRCA patients. Yang et al used platinum-free duration as another measure of cancer resistance, with shorter durations reflecting increased resistance. Again they noted that patients with BRCA2 mutations had significantly longer median platinum-free duration than either patients with BRCA1 mutations or those without BRCA mutations (18.0 months vs 12.5 months for BRCA1-mutated cases and 11.7 months for wild-type BRCA cases; P<0.05).⁸

The findings of Yang et al suggest that BRCA1 plays a more robust role in preventing cancer-causing mutations that lead to ovarian cancer and/or in impeding the progress of cancers once such mutations occur. Conversely, patients with somatic and/or germline BRCA1 mutations develop ovarian cancer earlier and have as severe a disease as those with non-BRCA-associated cancers. However, BRCA2 is associated with a delayed onset of ovarian cancers, better survival, and improved responses to therapy.

Practical recommendations

Armed with knowledge from the study by Yang et al, investigators may now be able to target newer therapies such as the use of PARP inhibitors that exacerbate genetic instability to enhance cancer cell death. Different strategies for early detection or prevention may also be suggested and counseling women at risk for hereditary ovarian cancer now will be more accurate, and in the case of BRCA2 carriers, perhaps a little less intimidating.

Currently, the National Comprehensive Cancer Network (NCCN) recommends that affected women with BRCA1 or BRCA2 mutations have clinical breast exams every 6 to 12 months and annual breast magnetic resonance imaging (MRI) screening beginning at age 25, or earlier depending on family history. At age 30, mammography should be added and alternated with breast MRI every 6 months, until age 75.⁹ Use of both modalities improves detection rates over MRI alone.¹⁰ Management of women older than 75 should be individualized. Risk-reducing or prophylactic bilateral mastectomy decreases the incidence of breast cancer by more than 90% in BRCA1 and BRCA2 carriers and should be discussed.¹¹

Strategies for preventing ovarian cancer are more controversial. It is unclear whether twice-yearly CA-125 and transvaginal ultrasound evaluations (preferably on day 5–10 of the menstrual cycle), beginning at age 30, or earlier depending on family history, reduce deaths from ovarian cancer. However, salpingo-oopherectomy at age 35 to 40 and after childbearing is clearly indicated.⁹

REFERENCES

1. Holtz A. The role of genetic mutations in breast and ovarian cancer. National Association of Science Writers Web site. http://www.nasw.org/users/holtza/SHNBRCA12.html. Accessed March 6, 2012.

2. Check W. BRCA: what we now know. College of American Pathologists Web site. http://capstaging.cap.org/apps/cap.portal?_nfpb=true&cntvwrPtlt_actionOverride=%2Fportlets%2FcontentViewer%2Fshow&_windowLabel=cntvwrPtlt&cntvwrPtlt%7BactionForm.contentReference%7D=cap_today%2Ffeature_stories%2F0906BRCA.html&_state=maximized&_pageLabel=cntvwr. Published September 2006. Accessed March 6, 2012.

3. Hall JM, Friedman L, Guenther C, et al. Closing in on a breast cancer gene on chromosome 17q. Am J Hum Genet. 1992;50(6):1235-1242.

4. Wooster R, Neuhausen SL, Mangion J, et al. Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13. Science. 1994;265(5181):2088-2090.

5. Petrucelli N, Daly MB, Feldman GL. Hereditary breast and ovarian cancer due to mutations in BRCA1 and BRCA2. Genet Med. 2010;12(5):245-259.

6. Frank TS, Deffenbaugh AM, Reid JE, et al. Clinical characteristics of individuals with germline mutations in BRCA1 and BRCA2: analysis of 10,000 individuals. J Clin Oncol. 2002;20(6):1480-1490.

7. Mavaddat N, Peock S, Frost D, et al. Cancer risks for BRCA1 and BRCA2 mutation carriers: results from prospective analysis of EMBRACE. J Natl Cancer Inst. 2013;105(11):812-822.

8. Yang D, Khan S, Sun Y, et al. Association of BRCA1 and BRCA2 mutations with survival, chemotherapy sensitivity, and gene mutator phenotype in patients with ovarian cancer. JAMA. 2011;306(14):1557-1565. Erratum in: JAMA. 2012;307(4):368.

9. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: Genetic/familial high-risk assessment: breast and ovarian. http://www.nccn.org/professionals/physician_gls/pdf/genetics_screening.pdf

10. Warner E, Messersmith H, Causer P, Eisen A, Shumak R, Plewes D. Systematic review: using magnetic resonance imaging to screen women at high risk for breast cancer. Ann Intern Med. 2008;148(9):671–679.

11. Rebbeck TR, Friebel T, Lynch HT, et al. Bilateral prophylactic mastectomy reduces breast cancer risk in BRCA1 and BRCA2 mutation carriers: the PROSE Study Group. J Clin Oncol. 2004;22(6):1055–1062.

Dr. Lockwood, Editor-in-Chief of Contemporary OB/GYN, is Senior Vice President, USF Health, and Dean, Morsani College of Medicine, University of South Florida, Tampa.

Dr. Cass is Vice Chair and Associate Clinical Professor, Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, Los Angeles, California. She is also on the editorial board of Contemporary OB/GYN.