BRCA Pioneer Offit Shares Insights on Evolving Testing Landscape

Kenneth Offit, MD, MPH

For more than two decades, Kenneth Offit, MD, MPH, has been researching the molecular genetic factors that increase cancer risk, notably concerning germline BRCA mutations in breast and ovarian cancer, with a focus on potential preventive surgical remedies and screening programs for women at hereditary risk. In 2013, the American Society of Clinical Oncology (ASCO) recognized Offit’s contributions to the field with the ASCO-American Cancer Society Award and Lecture.

Offit is a medical oncologist who serves as chief of the Clinical Genetics Service and co-leader of the Program in Cancer Survivorship, Outcomes, and Risk at Memorial Sloan Kettering Cancer Center in New York City. He also is a professor of Medicine and Public Health at Weill Cornell College of Medicine.

In an interview with OncologyLive, Offit discussed developments in BRCA testing that have arisen as a result of continung research and an increase in commercially available assays in the wake of the US Supreme Court’s landmark 2013 ruling overturning patents on human genes.

1. Which cancers have BRCA mutations and how does identifying these mutations through genetic testing inform clinical decision making?

BRCA mutations are found primarily in cancers of the breast, ovary, pancreas, and prostate. These mutations occur as inherited events. Nonetheless, they make these tumors susceptible to targeted therapy with PARP inhibitors, a new class of drugs. However, BRCA testing informs not only therapy but also targeted prevention using such strategies as early screening and preventive surgery, as we summarized in a review in The New England Journal of Medicine relating to breast cancer some years ago.¹

2. How problematic are unclassified variants? Unclassified variants were initially a significant challenge in translating BRCA to clinical testing.

Shortly after the discovery of these genes, the rate of these variants was as high as 20% to 30%. It has now come down to lower than 5% with the assembling of large BRCA databases. For newly discovered genes, the rates of variants being reported using “commercial panels,” as revealed at a session that I chaired at ASCO last June, were in the range of 15% to 90%. Needless to say, this rate of unknown variants is an enormous, but surmountable, roadblock to the responsible translation of genetic risk information to families.

Table. Snapshot of New Genetic Testing Registry

Name: PROMPT (Prospective Registry of Multiplex Testing)

Cohort: Individuals and families who have consented to participate in studies examining cancer-causing genetic mutations

How to Register: Participants sign up themselves via website

Spreading the Word: Commercial testing companies agree to provide information about PROMPT to patients and providers. Participants include Ambry Diagnostics, Gene Dx, Myriad Genetics, and Quest Diagnostics.

Academic sponsors:

• Abramson Cancer Center Penn Medicine
• Memorial Sloan Kettering Cancer Center
• Dana-Farber Cancer Institute
• Mayo Clinic Cancer Center

Website: www.promptstudy.org

3. Why do the companies that have entered the genetic testing market since the US Supreme Court’s ruling have different rates for variant of unknown significance? Do they use different reference databases to classify variants?

With regard to the Supreme Court ruling, this essentially opened the floodgates for commercial companies to come in to the market and include BRCA testing as well as other genes that were previously thought to be under intellectual property protection. Rates of calling a particular variant of unknown significance vary from company to company depending on their preexisting and public databases as well as in-house expertise, for example, in performing functional studies.

4. What are the relative merits of stand-alone BRCA testing compared with screening panels that include BRCA?

There are enormous benefits to panel testing because of cost efficiency. However, in some circumstances, such as an individual affected by breast cancer at later age who happens to be of Ashkenazi background, the simplest test may be the most cost effective. That simplest test would include screening for three mutations which together account for the vast majority of BRCA mutations in that particular group.

I think one of the greatest challenges to the implementation of genomic testing that we now face in cancer medicine is how to sort out the enormous variation made visible to us by next-generation sequencing of panels of cancer susceptibility genes.

In an effort to address this challenge head on, a number of us at academic centers, including Harvard, Penn, Mayo, and Memorial Sloan-Kettering, reached out to the commercial companies to join with us in a prospective registry (Table). All of the major companies including Ambry, Myriad, Gene Dx, and Quest and others have agreed to include in their reports a website for a patient portal for individuals to join this prospective registry. The registry is called PROMPT.

The goal of this effort will be to catalog variation in cancer susceptibility genes as well as clinical parameters to provide an evidence base for determination of risk counseling to guide our preventive strategies. We are off to a great start and look forward to integrating this effort with those under way in Europe as well.

5. What are your thoughts on more universal BRCA screening versus testing only those with family or personal history, or who have had breast or ovarian cancer? Is now the time, as some have suggested, or should we hold off?

I do believe that the time has come for universal BRCA screening for individuals from ethnic or geographic subsets where “founder” mutation rates are particularly high. This is not a new idea, as I proposed it back when my group first discovered the most common Ashkenazi BRCA2 mutation in the late 1990s.

At that time, and still present today, were concerns of «group stigmatization.” This is an issue that can be overcome, as many of us have tried to articulate that in fact this should represent “group empowerment” rather than stigmatization since the detection of these mutations can serve as a powerful strategy to decrease the inherited burden of breast and ovarian cancer that has accumulated over the centuries. We can then use targeted screening and prevention and, in some cases, assisted reproduction to actually decrease the prevalence of these mutations if so desired by a family.

Reference

1. Robson R, Offit K. Management of an inherited predisposition to breast cancer. N Engl J Med. 2007;357(2):154-162.