Last week the Lasker Foundation bestowed their prestigious Lasker-Koshland Special Achievement Award in Medical Science to geneticist Mary-Claire King for her role in discovering the genetic basis of certain forms of breast cancer, due to mutations in the genes BRCA1 and BRCA2. Dr. King took advantage of the attention around this award to send a bold and important public health message: that every woman over 30 years old should be screened for mutations in these cancer genes.
Most breast cancer is not inherited, but for the 5 to 10 percent of breast cancers that are inherited, about half of those are due to mutations in BRCA1 and BRCA2. These genes also increase a woman’s risk of ovarian cancer. For women who test positive, their lifetime risk of breast cancer or ovarian cancer is around 80 percent. Options for women who test positive include increased screenings (mammograms, ultrasounds), chemopreventive medicines (Tamoxifen, Raloxifene), and prophylactic surgery to remove the breasts (mastectomy) and/or ovaries (oophorectomy).
Since the BRCA gene discoveries in the early 1990s, women have been offered testing only if they had a family history. A new research study led by King and colleagues found that among a large population of women screened for BRCA1 and BRCA2 mutations, half of the mutation carriers had no family history of breast cancer. This means that the current screening guidelines would miss half of the women in the population carrying a mutation in these genes.
So why don’t we already just screen every woman? Part of the rationale stems from the fact that there have been several thousand different genetic variants described in these genes that can lead to breast/ovarian cancer, so-called “pathogenic variants,” along with an equally large number of genetic variants that probably have no effect on the disease but represent benign variation. The problem is distinguishing between the two types of variants. The majority of breast cancer variants are exceedingly rare, sometimes found in only one family with the disease. In a woman with a family history who tests positive for a BRCA gene variant, if her affected relatives also carry the variant, it is more likely to be deemed pathogenic. Without an affected relative to compare to, assigning pathogenicity can be difficult. These variants will then be classified as “variants of unknown significance.”
The question is whether to report these variants of unknown significance to women undergoing BRCA screening. The danger is that they will misinterpret these variants, assigning more importance to them than is warranted, and make health decisions based on the presence of an unvalidated variant. A study published in May confirms this very fear. In the study, among women carrying known pathogenic variants, three-quarters went on to have prophylactic mastectomies and/or oophorectomies. Among women with variants of unknown significance, over a third of them also chose to undergo these radical, possibly unnecessary interventions. Dr. King’s recommendation addresses the danger of variants of uncertain significance by specifically calling for reporting of only well-validated known pathogenic variants.
Universal screening for BRCA mutations may be advantageous to society. Through it, we may gain a better understanding of the exact risk associated with presence of a pathogenic BRCA variant, which until now has been estimated from a somewhat biased subset of the population. There is also an enormous opportunity to improve classification of variants of unknown significance. Universal screening methods would likely involve gene sequencing, which would identify both pathogenic and variants of unknown significance, with reporting of only the known pathogenics. Over time, as these women are followed, the status of their variants of unknown significance will change, either being confirmed as benign or deemed pathogenic. But this information only becomes valuable if it is shared with others in the medical community. Universal screening, coupled with universal sharing of results in medical databases, has the potential to dramatically improve the accuracy of screening for all patients.
Whatever happens in personalized medicine seems to happen in cancer first, in particular breast cancer. The BRCA journey is the furthest we’ve come in genetic testing for a common disease. The journey touches on medical, ethical, legal, economic, and policy issues, and the decisions we make now will pave the way for how we conduct genetic testing in the future. Congratulations to my mentor, Mary-Claire King, for her pioneering achievements in breast cancer research and her bold advancement of the field of personalized medicine.