May 12, 2014
By Shira Klapper, Senior Writer/Editor
In the past five years, a revolution has come to the field of genetics in the form of multiple-gene sequencing. The technology, also called “massively parallel sequencing,” has the ability to code and screen huge amounts of DNA with a high level of accuracy and at a substantially lower cost than before.
But patients should pause before rushing headlong into getting printouts of every mutation in their DNA. After all, certain questions related to the clinical value of multiple-gene sequencing still need to be answered. For example, which mutations are actually “actionable,” that is, known to cause hereditary cancer or double the risk of developing cancer among high-risk populations? And which of these mutations are present at rates high enough to warrant testing among high-risk patients?
The second question—assessing the prevalence of actionable mutations—is the focus of a study out of Stanford University in collaboration with InVitae Corporation, a genetic information company. The study utilized the new technology to assess the clinical value of a panel that honed in on 42 potentially actionable genes among women at high risk for breast cancer who were BRCA negative. The study, “Clinical Evaluation of a Multiple-Gene Sequencing Panel for Hereditary Cancer Risk Assessment,” is one among the first to focus specifically on patients one would see in a genetics clinic and to assess how testing affects those patients’ decisions about treatment.
According to lead author Dr. Allison Kurian, MD, MSc, the study, published in the Journal of Clinical Oncology (JCO) online ahead of print (April 14, 2014), looked at two main measures to assess whether the gene panel offered clinical value.
“First, we tested how likely it is that we find a mutation in a typical clinical population,” said Dr. Kurian. “Second, we looked at the immediate impact testing had on patients’ decisions about changes in their care.”
The gene panels determined that of the 141 BRCA-negative women studied, approximately 10% were found to carry pathogenic mutations that warranted a change in screening or treatment. All participants were invited to the Stanford Medical Center to meet with an oncologist and a genetics counselor. Twelve participants were advised to consider more frequent screening. After meeting with the counselor, one patient diagnosed with Lynch syndrome decided on prophylactic surgery to remove her fallopian tubes and ovaries, and had a screening colonoscopy that identified—and led to the decision to remove—a tubular adenoma.
Gene panel design and testing
In designing the gene panel, Dr. Kurian and her colleagues, including the study’s senior author, James Ford, MD, searched through the literature to identify 42 cancer-associated genes, including those identified with Lynch Syndrome, Hereditary Diffuse Gastric Cancer Syndrome, and other genes associated with a moderate risk of developing breast and other cancers.
The investigators tested the DNA of 198 women who had been referred to the clinic for BRCA testing from 2002-2012. Of those women, 174 had breast cancer, and 141 were BRCA negative. It was in this group of 141 women that approximately 10% were found to have actionable mutations.
That figure of 10% carries weight; insurance providers and the National Comprehensive Cancer Network state that once a person’s probability of carrying a high-risk gene mutation is estimated to reach 10%, he or she should have genetic counseling and testing.
“It’s a clinically significant finding,” said Dr. Kurian.
Setting the bar for future studies
In the current study, women found to have actionable mutations had the chance to meet with a genetic counselor and a medical oncologist (the study investigators Drs. Ford and Kurian) before making decisions about their treatment. But outside of a research setting, there are no set guidelines for those who test positive for many of the 42 mutations that were studied.
“I think we need prospective studies that will watch these patients and see what happens to them down the line in terms of their ability to understand results and their choices of prevention strategies,” said Dr. Kurian. “I think we also need large population-based studies to see how these mutations affect risk.”
Until those data come in, Drs. Ford and Kurian urge caution in applying gene panels to patients outside of clinical trials. But they stress that there is reason to be excited about the potential of multiple-gene sequencing to change and hopefully improve, cancer treatment.
“It turns out that when the technology and the cost allowed us to throw a wide net on patients’ DNA, we actually found many more actionable mutations that we never would have looked for before and didn’t really know were there,” said Dr. Ford. “The fact is—it’s a whole new world.”
Allison Kurian, MD, MSc, is an Assistant Professor of Medicine and of Health Research and Policy at Stanford University School of Medicine. She has been an ASCO member since 2003. James Ford, MD, is an Associate Professor of Medicine, Pediatrics and Genetics at Stanford University School of Medicine, the Director of the Stanford Cancer Genetics Clinic and Program Director of the Oncology Fellowship Training Program. He has been an ASCO member since 1994.
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Kurian, AW, Hare, EE, Mills, MA, et al. Clinical evaluation of a multiple-gene sequencing panel for hereditary cancer risk assessment. J Clin Oncol. 2014; Published online ahead of print 3.14.2014.
The Exclusive Coverage series on ASCO.org highlights selected research from JCO with additional perspective provided by the lead or corresponding author.
@ 2014 American Society of Clinical Oncology