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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 whodevelop breast cancer while they’re young are often searching for answers aboutthe cause for their disease or what they can do to improve their chances ofbeing cured. While an increasing number of large genetic testing panels promiseto scrutinize their DNA to uncover clues, a team of researchers from thePerelman School of Medicine and the Abramson Cancer Center has found that thosepowerful tests tend to produce more questions than they answer. The group presentedtheir findings earlier this month during the American Association for CancerResearch Annual Meeting 2013 in Washington, D.C.

Sometimes, thesetests reveal deleterious – clearly bad – mutations in genes that areassociated with an increased risk in developing cancer. When women testpositive for mutations of the BRCA 1 and BRCA 2 genes, they may opt formastectomies and ovary removal surgery – whichresearch shows slashes their risk of developing those cancers. However, thereis not yet guidance for clinicians on how to care for patients who exhibitthese other types of mutations. The newstudy 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 technologyhas outpaced what we know from a clinical standpoint. There’s going to be a lotof unknown variants that we’re going to have to deal with as more patientsundergo large genetic testing panels,” said the new study’s lead author KaraMaxwell, MD, PhD, a fellow in the division of Hematology-Oncology in Penn’sAbramson Cancer Center. “It’s crucial that we figure out the right way tocounsel women on these issues, because it can really provoke a lot of anxiety fora patient when you tell them, ‘We found a change in your DNA and we don’t knowwhat it means.’”

Researcherswill gather to delve further into these topics tomorrow at the first BasserResearch Center for BRCA Symposium.

In the studypresented during the AACR meeting, the Penn Medicine team studied 250 patientswho had been diagnosed with breast cancer under the age of 40, were notcarriers of the BRCA1 or BRCA2 mutations, and had no family history of ovariancancer. Sixty-five percent of the women studied had a family history of breastcancer. The researchers performed massively parallel gene sequencing to detect28 known or proposed breast cancer susceptibility genes in each woman. In ananalysis of the first 119 patients, 4,483 different genetic variants werefound. Though the testing did reveal multiple variants of genes that are knownto confer increased risk of breast cancer in patients who develop the diseaseyoung, only one percent of patients tested were found to have mutations thatare actionable under current treatment guidelines.

“Weknow from studies in large populations that some of these mutations increaserisk,” said the study’s senior author, KatherineNathanson, MD, anassociate professor in the division of Translational Medicine and Human Genetics who serves asco-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, andthere certainly are no clinical standards.  Knowing there is a mutationmay not help us any more than knowing that the person has a positive familyhistory – which we already know.”

The researchteam says their findings highlight the need for further study to evaluate the importanceof variants of unknown significance, as panels for testing a large number ofgenes are increasingly offered to patients, often without proper geneticcounseling accompanying presentation of results.

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

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

During the AACRmeeting, Maxwell was also awarded the 2013 AACR-Amgen Inc. Fellowship inClinical/Translational Research, which will provide her with a $45,000 grant tosupport her research into the results of gene panel testing among women withtriple-negative breast cancer.

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