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“We Found a Change In Your DNA And We Don’t Know What it Means” – Questions and Challenges in the Era of Massively Parallel Gene Sequencing

Basser imageWomen who develop breast cancer while they’re young are often searching for answers about the cause for their disease or what they can do to improve their chances of being cured. While an increasing number of large genetic testing panels promise to scrutinize their DNA to uncover clues, a team of researchers from the Perelman School of Medicine and the Abramson Cancer Center has found that those powerful tests tend to produce more questions than they answer. The group presented their findings earlier this month during the American Association for Cancer Research Annual Meeting 2013 in Washington, D.C.

Sometimes, these tests reveal deleterious – clearly bad – mutations in genes that are associated with an increased risk in developing cancer. When women test positive for mutations of the BRCA 1 and BRCA 2 genes, they may opt for mastectomies and ovary removal surgery – which research shows slashes their risk of developing those cancers. However, there is not yet guidance for clinicians on how to care for patients who exhibit these other types of mutations. The new study also uncovered many of what are known as variants of unknown significance (VUS) – genetic wrinkles that experts don’t yet know how to interpret.

“We’re in a time where the testing technology has outpaced what we know from a clinical standpoint. There’s going to be a lot of unknown variants that we’re going to have to deal with as more patients undergo large genetic testing panels,” said the new study’s lead author Kara Maxwell, MD, PhD, a fellow in the division of Hematology-Oncology in Penn’s Abramson Cancer Center. “It’s crucial that we figure out the right way to counsel women on these issues, because it can really provoke a lot of anxiety for a patient when you tell them, ‘We found a change in your DNA and we don’t know what it means.’”

Researchers will gather to delve further into these topics tomorrow at the first Basser Research Center for BRCA Symposium.

In the study presented during the AACR meeting, the Penn Medicine team studied 250 patients who had been diagnosed with breast cancer under the age of 40, were not carriers of the BRCA1 or BRCA2 mutations, and had no family history of ovarian cancer. Sixty-five percent of the women studied had a family history of breast cancer. The researchers performed massively parallel gene sequencing to detect 28 known or proposed breast cancer susceptibility genes in each woman. In an analysis of the first 119 patients, 4,483 different genetic variants were found. Though the testing did reveal multiple variants of genes that are known to confer increased risk of breast cancer in patients who develop the disease young, only one percent of patients tested were found to have mutations that are actionable under current treatment guidelines.

“We know from studies in large populations that some of these mutations increase risk,” said the study’s senior author, Katherine Nathanson, MD, an associate professor in the division of Translational Medicine and Human Genetics who serves as co-leader of the Cancer Control Program in the Abramson Cancer Center. “However, we don’t know yet what to do with the information on an individual basis, and there certainly are no clinical standards.  Knowing there is a mutation may not help us any more than knowing that the person has a positive family history – which we already know.”

The research team says their findings highlight the need for further study to evaluate the importance of variants of unknown significance, as panels for testing a large number of genes are increasingly offered to patients, often without proper genetic counseling accompanying presentation of results.

This field of research is especially important when dealing with families who appear to have genetic predisposition to breast or other cancers but don’t carry BRCA1/2 mutations, Maxwell said.

“When you’re working with people who may not have cancer but want to understand what they could be facing in the future, the stakes are very high,” Maxwell says. “We need to be very careful with how we use this data. You could be taking someone who thinks they’re not at risk and making them at risk, or taking someone who is believed to be at risk and relieving them of that risk, but we don’t know enough yet to be confident in our assessments of these findings.”

During the AACR meeting, Maxwell was also awarded the 2013 AACR-Amgen Inc. Fellowship in Clinical/Translational Research, which will provide her with a $45,000 grant to support her research into the results of gene panel testing among women with triple-negative breast cancer.

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