On 8/10/15 we will discuss genetic testing for breast cancer risk with Drs. Mark Robson and Steven Katz. This Fact Sheet from the National Cancer Institute contains information about BRCA 1 and 2 mutations. This post by Dr. Robson discusses next generation genetic testing including important considerations. Dr. Steven Katz recently co-authored Treatment Decision Making and Genetic Testing for Breast Cancer: Mainstreaming Mutations. Please join us at 9pm ET for what should be a very informative discussion.

Here is an outline of the topics:
T1 – BRCA Basics
– What does the BRCA gene actually do? What does it mean when you have a mutation or a variant of uncertain significance?
– Hereditary red flags – who should consider counseling / testing
– How many people are affected, % of all breast cancers, % of male breast cancers; mutations have been described in all racial/ethnic groups
– Are BRCA-associated breast cancers different?
– Does having a mutation mean cancer will always develop?

T2 – Beyond BRCA – What about other mutations
– Discuss the other mutations linked to breast cancer, including what treatment options are recommended

T3 – Options for Mutation carriers
– Active surveillance, tamoxifen, prophylactic surgery
– Effect of oophorectomy on subsequent breast cancer risk
– Surveillance recommendations for other associated cancers
– Considerations for family members

T4 – Future directions
– PROMPT registry
– Should everyone be tested?
– Other areas of research

Genetic testing for breast cancer risk: new wine, new bottles?
Guest Post by Dr. Mark Robson

The advent of so-called “next-generation” sequencing (NGS) technology has massively disrupted the field of clinical cancer genetics. In the past, people (mainly women) would seek evaluation because of a personal or family history of cancer that suggested the possibility that the history was due to a mutation in a single gene. They would be evaluated by a genetics professional, who would determine what gene or genes should be evaluated, and order the test.  If the test didn’t find anything, the genetics provider would either order more tests, looking for mutations in other genes, or would consider the testing to be uninformative and make follow-up recommendations on the basis of the clinical presentation and family history.

The ability to evaluate multiple genes using NGS has led to a broad reconsideration of this approach to genetic risk assessment. Now, a single test can look for mutations in any number of genes, and a number of commercial laboratories have offerings in the marketplace. These tests, called multigene or multiplex panels,  are the topic of much discussion regarding their appropriate place in the cancer geneticists’ armamentarium. Some believe that anyone undergoing a cancer risk assessment should be offered a multigene panel, while others (myself among them) argue for a more deliberative approach.

The challenge of the multigene panels is not the concept of multiplicity itself. After all, testing for BRCA1 and BRCA2 is a form of panel testing, as is testing for the four genes associated with Lynch Syndrome. Rather, the discussion about the panels relates to the genes included on the panels. Some of the genes are what are known as “high penetrance,” and would have been the genes tested before the availability of the multigene panels (examples are BRCA1, BRCA2, PTEN, TP53). However, the panels also include “moderate penetrance” genes that confer much less risk than the high penetrance genes. In general, these genes (such as CHEK2 and ATM) are associated with 2 to 3-fold increases in risk. Learning about mutations in these genes often does not lead to changes in clinical management in people who have family histories of diseases associated with these genes, and family members without mutations may still be at risk. For these individuals and families, learning that there is a mutation in one of these genes may not be helpful. Indeed, if they or their doctors believe that they should be treated as if there is a mutation in a high penetrance gene (for instance, recommending prophylatic mastectomy), these families may experience a type of harm.

The bigger challenge of the panel testing, however, is when a mutation is discovered in a gene that would not have been suggested by the family history, or if the family history is remote and would not, under other circumstances, have led to testing. In these cases, the individuals tested have essentially undergone opportunistic population screening, which is a particular issue when the mutation is found in a high penetrance gene. The published risk estimates for mutations in the high penetrance genes may not apply in these settings, and management recommendations that were developed for individuals with family histories consistent with a hereditary syndrome may not be appropriate for individuals identified through this kind of broad screening. This is an especially thorny challenge for a gene called CDH1, for which the traditional recommendation is preventive gastrectomy when it is found in the setting of a strong family history of stomach cancer. But the same uncertainties apply for other high (and indeed even moderate) genes.

So, how to move forward? Panels are widely available and widely used, and it is not practical to suggest that they only be used in the context of a clinical trial (which is the usual way of evaluating a new technology). That said, they should not yet be considered the standard of care, either. We should acknowledge that we have not yet figured out the best way to apply the information that we obtain for the benefit of those undergoing testing, and that there are large deficits in our knowledge base. Prospective studies such as PROMPT (Prospective Registry of Multiplex Testing) are needed to assess outcomes of individuals with mutations identified in this way, and, in an era of increasing health care costs, to determine the most cost-effective follow-up strategies. Unfortunately, those studies will not generate answers immediately. In the meantime, it is critical that the medical community, and the community of individuals undergoing this testing, understand that a “one size fits all” approach is particularly inappropriate here. A CHEK2 mutation is very different from a BRCA1 mutation. A CDH1 mutation found in a person with no family history of stomach cancer is potentially very different from a CDH1 mutation found in a person from a Hereditary Diffuse Gastric Cancer kindred. The interpretation of these test results and management of these individuals should be informed by experienced cancer genetics professionals while we are gathering the knowledge we need to allow the formation of evidence-based management guidelines.

Transcript from 8/10/15 TweetChat

Dr. Mark Robson is a medical oncologist and Director of the Clinical Genetics Service at the Memorial Sloan Kettering Cancer Center in New York. His research focuses on the best ways to use genetic information to improve the outcomes of those with or at risk for hereditary cancers of all types. Follow him on twitter: @MarkRobsonMD

Dr. Steven Katz is a Professor of Medicine and Health Management & Policy at the University of Michigan. He studies how treatment decisions are made during clinical encounters between patients newly diagnosed with cancer and their clinicians, including factors that drive patient treatment decisions. Follow him on twitter: @DrStevenKatz