Study Supports Population Screening for BRCA1 and BRCA2

Other Experts Disagree

Janis C. Kelly

September 11, 2014

Ashkenazi Jewish women who carried BRCA1 or BRCA2 mutations but had no personal or family history of cancer developed breast and ovarian cancers at the same rate as women from families with a history of cancer and would have benefit from population-based screening for the cancer genes, according the authors of a new study reported online September 5 in Proceedings of the National Academy of Sciences of the United States of America.

But 2 experts contacted by Medscape Medical News cautioned against the idea of population-based screening for these cancer genes.

The study authors were led by Mary-Claire King, PhD, professor of genome sciences, University of Washington, Seattle, and Ephrat Levy-Lahad, MD, director of the Medical Genetics Institute, Shaare Zedek Medical Center, Jerusalem, Israel.

Dr. King was recently awarded the 2014 Lasker-Koshland Special Achievement Award in Medical Science for her discovery that a single gene, BRCA1, causes a form of hereditary breast cancer.

The new study was designed to determine how the 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 came from a family with a history of breast or ovarian cancer.

Similar cancer rates would suggest that some type of population-based screening might identify many previously unsuspected carriers in time to offer them potentially life-saving treatment.

Presymptomatic salpingo-oophorectomy can reduce breast cancer risk, ovarian cancer risk, and overall mortality, but many mutation carriers are identified only after they have already developed cancer, according to the authors.

Among Ashkenazi Jewish populations, BRCA1 and BRCA2 are equally common in males and females and are inherited at equal rates from mothers and fathers. In Israel, 3 inherited founder mutations in BRCA1 and BRCA2 cause 11% of breast cancers and 40% of ovarian cancers in Ashkenazi Jews. The researchers screened 8195 healthy Ashkenazi Jewish men for the 3 loss-of-function mutations. Family history of cancer was not considered in selecting participants. The screen identified 175 men as mutation carriers, including 1.14% who carried BRCA1, 1.03% who carried BRCA2, and 2.17% who carried both mutant alleles.

All female relatives of these 175 male BRCA1/BRCA2 carriers (from 172 families) were then offered genetic testing, and 211 of the 431 women tested were found to be mutation carriers.

The researchers reported that women with BRCA1 had a cumulative risk for breast cancer or ovarian cancer of 0.60 by age 60 years and 0.83 by age 80 years. Carriers of BRCA2 had a cumulative risk for breast cancer or ovarian cancer of 0.33 by age 60 and 0.76 by age 80.

Carriers of BRCA1 had a cumulative risk for breast cancer of 0.41 by age 60 and 0.60 by age 80. Carriers of BRCA2 had a cumulative risk for breast cancer of 0.26 by age 60 and 0.40 by age 80.

Carriers of BRCA1 had a cumulative risk for ovarian cancer of 0.27 by age 60 and 0.53 by age 80. Carriers of BRCA2 had a cumulative risk for ovarian cancer of 0.07 by age 60 and 0.62 by age 80.

The authors write, "In this study, 51% (85 of 167) families harboring BRCA1 or BRCA2 mutations had little or no history of relevant cancer. These families were small and included few females with mutations who had reached the ages of highest cancer risk. Young women in these families would not have been tested in the absence of a general screening program."

The analysis also uncovered an interesting birth cohort effect: higher breast cancer risks among younger BRCA1 and BRCA2 carriers. For example, cumulative combined incidence for breast and ovarian cancer by age 50 was 0.22 for women born in or before 1958 and 0.84 for women born after 1958.

"Age-specific cancer risks, controlled for gene, were 3.8-fold higher for carriers in the younger vs. the older birth cohort," the authors write. They suggested that the birth cohort effects might mean that published risk estimates for BRCA1 and BRCA2 underestimate risk to carriers among present-day young women and that this also would support population screening to identify all carriers of the "unambiguously damaging founder mutations in BRCA1 and BRCA2."

Not Everyone Agrees

In a Viewpoint published online September 8 in JAMA in honor of the Lasker-Koshland award, Dr. King and 2 coauthors urged 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. But other experts are more cautious about this recommendation, which would mark a significant change to current US Preventive Services Task Force (USPSTF) guidelines on BRCA1 and BRCA2 testing.

The authors did not consider the potential harms from widespread genetic testing, Timothy R. Rebbeck, PhD, told Medscape Medical News. He was not involved in the BRCA1/BRCA2 study and is professor of epidemiology at the University of Pennsylvania, Philadelphia.

"Genetic information is complex and can have negative consequences to those being tested. Explaining the risks, benefits and harms of genetic information, dealing with the prevention and medical issues, and handling the psychosocial consequences of knowledge of genetic risk require expertise that some clinicians may not have," said Dr. Rebbeck.

Dr. Rebbeck added, "I believe if you ask most specialists in this area, they would say that a good proportion of their time is spent dealing with genetically tested women who were given incorrect or incomplete information. This is an important issue because the healthcare system is not ready for a large influx of women receiving testing."

Confusing terminology is another challenge in implementing population screening, said Lisa Madlensky, PhD, director of the Family Cancer Genetics Program at the University of California, San Diego, Cancer Center, La Jolla.

Dr. Madlensky, who was also not involved in the study, told Medscape Medical News that the term "BRCA testing" could mean testing for only the 3 founder mutations (which could be justified in individuals with no family history of breast or ovarian cancer, particularly if the family is small or has few females)."

However, this term could also mean "full sequencing of both BRCA1 and BRCA2, which would not be justified," she added.

Dr. Madlensky also pointed out that in the United States, consideration of genetic admixture will become increasingly important with each generation because fewer and fewer people are defined by a single ancestral origin.

"For example, would someone with 1 Jewish grandparent be appropriate for testing? Family history is still the strongest predictor of having a BRCA1/2 mutation, regardless of ancestry," Dr. Madlensky said.

Drs. King, Levy-Lahad, and Lahad argued in their JAMA essay that the gains of broader population screening for BRCA1/BRCA2 outweigh the risks. "Women do not benefit by practices that 'protect' them from information regarding their own health. They should have the choice to learn if they carry an actionable mutation in BRCA1 or BRCA2," they write.

The authors did not respond to Medscape Medical News' requests for comment.

The authors and commentators have disclosed no relevant financial relationships.

Proc Natl Acad Sci U S A. Published online September 5, 2014. Abstract

JAMA. Published online September 8, 2014. Abstract

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