I once saw a woman with newly-diagnosed breast cancer at the age of 38. Her cancer was locally-advanced, meaning that it was not detected early as she had not been getting screened. She was told by her internist that her four paternal aunts who had all been diagnosed with breast cancer in their 30s did not constitute a significant family history because they were all on her father’s side of the family. Unfortunately, this woman was misinformed and ultimately diagnosed with a breast cancer that might have been prevented or caught earlier through genetic testing and early screening.
That was more than 5 years ago, but to this day, I still see patients who have been misinformed about their genetic risk by either friends and family or even their own doctors. As with many aspects of medicine, the world of cancer genetics is evolving at an incredibly rapid pace. Here’s a brief timeline to get you up to speed:
It’s now been two and a half decades since the first breast cancer gene, BRCA1, was identified by Dr. Mary Claire King at UC Berkeley. BRCA1 was identified as a tumor suppressor gene that, when mutated, could greatly increase a woman’s risk of developing breast and ovarian cancer. BRCA2 was later identified in 1994. Back then, and for the years that followed, we knew that women with these mutations were at high risk for developing cancer, but we lacked specific evidence-based guidelines on how to manage that risk. Fast forward a decade or so and we began having data to suggest that more aggressive surveillance measures, like breast MRI, and preventative surgery to remove the ovaries and fallopian tubes (BSO) actually improves survival in these high-risk women. Around this time as well, the Genetic Information Nondiscrimination Act of 2008 was signed by President Bush. This Act established protection against health insurance and employment discrimination based on genetic information. This Act was a huge advance in overcoming the skepticism associated with genetic testing, as many individuals had deferred testing due to concerns over such discrimination.
So, now that you have a little background, what’s changed? Why is genetic testing all over the news right now? Angelina Jolie, you say? Actually, while Angelina Jolie is to be commended for bringing positive attention to the world of hereditary breast and ovarian cancer, the Breast Cancer Genetics Revolution goes far beyond the Angelina Effect.
In June 2013, the Supreme Court unanimously ruled that Myriad Genetics, the lab which had patented BRCA1/2 testing, could actually not patent human genes. This ruling paved the way for an entirely new dynamic in the breast cancer genetics world. With the advent of next generation sequencing, a way of sequencing millions or billions of DNA strands in parallel, multiple biotech companies immediately came to market with various types of “panels” looking not only for the widely known and studied BRCA1 and BRCA2 mutations, but also other risk modifying mutations for which less is known.
This has brought about an exciting time for advancing science and knowledge in a field where we were once limited to investigating only a fraction of the potential causes of hereditary or familial breast cancer.
Familial breast cancer refers to families with a strong history of cancer and who have tested negative for BRCA1/2. That whole piece of the pie, about 20-25% of breast cancers, likely have a gene or several genes contributing to the cancer risk in the family. Those are the families we are now able to investigate further by using next generation sequencing panels.
With progress comes its own set of controversies. Questions abound, including:
- Who should be offered testing? (one recent study demonstrated that 50% of patients found to have a mutation in BRCA1/2 would not have met criteria for testing due to lack of family history)
- What types of panels should be offered?
- Should we be retesting everyone with panels who initially tested negative for BRCA1/2?
- What do we do with indeterminate results?
- What do we tell patients who are found to have a mutation in a lesser-known gene, especially when we have limited information about how that mutation may influence their cancer risk and cancer risk reduction?
If there is anything that is clear in all of this, it’s that the world of breast cancer genetics has become complicated. It is imperative that we moved forward in a systematic way so that the testing that is done now can be used to gain insight into gene mutations that we know very little about. These other genes, PALB2, CHEK2, TP53, ATM, PTEN, BRIP1 and others may not be so uncommon after all. We just weren’t looking for them.
In a very short period of time, in my own clinical practice, we have come across many of these so-called “rare” mutations. No doubt, it poses a clinical dilemma as I am often limited in what I can tell my patients about their cancer risk after testing positive for one of these mutations. I base screening guidelines on their family history and what little is known in the literature regarding their mutation. However, by testing and collecting information about their family’s cancer history and recording their known mutation, we are paving the way for a better understanding of breast cancer genetics BEYOND BRCA1/2.
In light of this Revolution, many institutions and laboratories have recognized the need to collect and share this data. Last month, Quest Laboratories and LabCorp announced their participation in BRCA Share, a database of de-identified BRCA testing results that will help clarify the significance of indeterminate BRCA test results called Variants of Uncertain Significance (VUS). Taking this concept a step further, the PROMPT Study (The Prospective Registry of Multiplex Testing), initiated by investigators at The University of Pennsylvania, Dana-Farber Cancer Institute, The Mayo Clinic Cancer Center and Memorial Sloan Kettering, requests that patients who are found to have a VUS or a gene mutation on panel testing enroll to provide information on their test results and cancer history for future research.
Due to the complexity of testing and the interpretation of genetics, it is incredibly important to have testing through a certified genetic counselor and/or clinical geneticist. Genetic counselors are not only trained to educate you about the different types of testing, but will guide you through the potential results of that testing to prepare you for positive, negative and indeterminate results. Keep in mind, most insurers are only paying for one round of genetic testing. Though testing is now more affordable, since the Supreme Court ruling against Myriad, testing is a one shot deal, so you want to get it right. If you are questioning your eligibility for genetic testing, you can try using the Assess Your Risk Tool through BrightPink.org. You can also find a certified genetic counselor in your area through the National Society of Genetic Counselors.
Since the identification of BRCA1 in 1990, we have come a long way in what we know about hereditary breast cancer, but we have a lot left to learn. The good news is, many of the barriers to genetic testing have now been eliminated and testing is much more affordable. Unfortunately, our ability to test for mutations exceeds our ability to apply these results to any evidenced-based management strategy, particularly for any genes outside of BRCA1/2. Therefore, it is critical to seek out a certified genetic counselor or high risk hereditary cancer clinic before embarking on this journey. Professionals can help you interpret the results of this complex testing and come up with a cancer prevention plan that can be modified as new information becomes available.
Genetic testing is a powerful tool for women at risk for breast cancer. If used correctly, it can often clarify risk in individuals and families, lead someone to a proactive approach to cancer prevention, and can even save lives.