Genetic Cancer Screening for All?: The Evolving BRCA1/BRCA2 Story

Andre Goy, MD

Editor-in-Chief of

Oncology & Biotech News

Chairman and Director Lymphoma Division Chief John Theurer Cancer Center at HackensackUMC Chief Science Officer and Director of Research and Innovation Regional Cancer Care Associates Professor of Medicine, Georgetown University

Numerous epidemiological factors affect the likelihood of developing breast and ovarian cancer, but no other predictor is as powerful as an inherited mutation in BRCA1 or BRCA2, genes involved in both tumor suppression and DNA repair.

Although hereditary breast cancer accounts for only 5% to 10% of all breast cancer cases, individuals carrying mutations in one of these genes have an approximately 60% to 85% lifetime risk for breast cancer and a 10% to 40% risk for ovarian cancer (a much higher risk over their lifetime compared with the general population: 12% for breast cancer and 1.5% for ovarian cancer).

Consequently, since the identification of BRCA1 and BRCA2 genes in 1994 and 1995, respectively, patients with a strong personal and/or family history of breast and/or ovarian cancer have been counseled to seek molecular genetic testing. For those who test positive, the treatment decision can range from close monitoring for early detection to bilateral prophylactic mastectomy and/or prophylactic salpingo-oophorectomy, procedures that have been shown to reduce the risk of both ovarian and breast cancer and reduce overall mortality, as well.

There are clearly differences in the reported incidences of BRCA1 and BRCA2 that reflect true variability in populations from different geographic regions and ethnicities.

There is an ongoing discussion regarding cohort selection criteria and mutation ascertainment methods that might be very critical in explaining some of these discrepancies. Additionally, most studies reported so far—by definition— have looked at women tested because of their family history/risk factors, though there are also mutations of BRCA1 and BRCA2 in the “non—high-risk” population, as well. One could argue that “identifying a woman as a carrier only after she develops cancer is a failure of cancer prevention,”1 said Mary-Claire King, PhD, who was recently awarded the 2014 Lasker-Koshland Special Achievement Award in Medical Science for her pioneer work in identifying the BRCA1 gene and its oncogenic role in the early 90s. Among Ashkenazi Jewish populations, BRCA1 and BRCA2 mutations are equally common in males and females and are inherited at equal rates from mothers and fathers. In Israel, three inherited founder mutations in BRCA1 and BRCA2 cause 11% of breast cancers and 40% of ovarian cancers in Ashkenazi Jews.

For carriers of these mutations, risk-reducing salpingooophorectomy significantly reduces morbidity and mortality. An important new study recently reported by Gabai- Kapara attempted to look at breast and ovarian cancer risk among BRCA1/BRCA2 carriers in the general population compared with that among carriers who had been tested because they had cancer or had a family history of breast or ovarian cancer.²

In the study, families harboring mutations in BRCA1 or BRCA2 were ascertained by identifying mutation carriers among more than 8000 healthy Ashkenazi Jewish males recruited from health screening centers and outpatient clinics. Female relatives of the carriers were then enrolled, genotyped, and followed.

Results showed that female relatives with BRCA1 or BRCA2 mutations developed either breast or ovarian cancer at the same rate as women from families with a history of cancer. Though by design—prior history of cancer was not a prerequisite—authors reported that about half of the families (85/167) harboring BRCA1 or BRCA2 mutations had little or no history of relevant cancer. Gabai-Kapara et al concluded that general screening would identify and potentially benefit many carriers who are not evaluated by current genetic testing based on family history criteria. In a recent editorial in JAMA, King and two coauthors recommended that genetic screening for BRCA1 and BRCA2 should be offered routinely to every woman at about age 30, with special screening and counseling for women with these mutations.¹

A number of comments from experts in the field suggest being more cautious, given the complexity of the issue, including the remaining uncertainties regarding the best recommendation with a positive genetic screening result. In addition, it is debatable to use data from a high-risk population based on ethnicity and apply it to the average person. Furthermore, in the non-Jewish population, the range of mutations is much wider than the three genes examined in that study (testing would thus be more complex and costly). Finally, there are many more genes that can put women at risk outside BRCA1 and BRCA2.

The debate is certainly not closed, and Angelina Jolie’s decision to receive a double mastectomy based on a positive BRCA1 mutation status sparked an enormous increase in women seeking genetic screening. A number of issues remain unresolved: Will broader sequencing (especially as it becomes cheaper) help target better populations truly at risk? Will early proteomics facilitate earlier and better intervention? Can targeted chemoprevention and/or behavioral changes help compensate/neutralize some of the genetic risk factors in oncology? Hopefully, the answers to some of these questions will come from the emerging science of applied systems biology and its fascinating potential.

References

1. King MC, Levy-Lahad E, Lahad A. Population-based screening for BRCA1 and BRCA2: 2014 Lasker Award [published online September 8, 2014]. JAMA. doi:10.1001/jama.2014.12483.
2. Gabai-Kapara E, Lahad A, Kaufman B, et al. Population-based screening for breast and ovarian cancer risk due to BRCA1 and BRCA2 [published online September 5, 2014]. Proc Natl Acad Sci USA. pii: 201415979.