Minimal Harm Associated with Multiplex Gene Testing for Inherited Cancer Risk

Allison W. Kurian, MD, MSc

Interim analysis of a clinical trial of multiplex gene testing for inherited cancer risk suggests that fears of unnecessary surgery or adverse psychological effects associated with testing may be unwarranted.

According to data presented at the 2016 ASCO Annual Meeting, patients undergoing genetic testing for pathogenic mutations did not demonstrate increased rates of prophylactic surgeries, intrusive thoughts, or regrets. Patients who were positive for genetic mutations were also more likely to advise relatives to get tested, suggesting that they understood the implications of test results, the researchers reported.

“After multiplex testing of diverse patients, few reported preventive surgery at 3 months,” said Allison W. Kurian, MD, MSc, associate professor of Medicine and of Health Research and Policy at Stanford University School of Medicine, and director of the Stanford Women’s Cancer Genetics Clinic. “In addition, patients testing positive for a variant of uncertain significance (VUS) had no more distress, regret or uncertainty than negative patients.”

As Dr. Kurian explained, the use of multiplex gene panels, which can simultaneously test between 15 and 40 genes, is on the rise, leading to a significant increase in the pathogenic detection rate of mutations in selected patients. However, this heightened sensitivity comes with the added cost of complexity.

“Sequencing more genes increases the likelihood of finding VUS, which can be frustrating for both patients and clinicians,” said Dr. Kurian. “The key question here is, does multi-gene panel testing cause distress or inappropriate intervention?”

Study Design

Researchers in 3 cancer genetics clinics (LA County, University of South California, and Stanford University) conducted a prospective cohort study of a multi-gene panel, sequencing the following genes:APC, ATM, BARD1, BMPR1A, BRCA1, BRCA2, BRIP1, CDH1, CDK4, CDKN2A, CHEK2, EPCAM, MLH1, MSH2, MSH6, MUTYH, NBN, PALB2, PMS2, PTEN, RAD51C, RAD51D, SMAD4, STK11, TP53.

Patients were eligible for the study if they had no prior genetic testing, were 18 years or older, and had at least a 2.5% probability of carrying 1 of the mutations on the panel.

Participants were surveyed at entry, and then 3, 6, and 12 months after receiving their results. These surveys included a validated instrument, the Multidimensional Impact of Cancer Risk Assessment (MICRA) scale, to measure distress.

Dr. Kurian and colleagues aim to enroll 2000 patients, with a planned interim analysis after 1000.

Few Unwarranted Surgeries

Of the 1000 participants (818 female), 11.6% tested positive for a pathogenic mutation, 51.9% were negative, and 36.5% had a VUS in any of the genes. With 38% non-Hispanic whites, 4.1% non-Hispanic blacks, 40% Hispanic, and 12.9% Asian, the patient population was also ethnically diverse, Dr. Kurian reported.

Analysis of post-testing surgical procedures showed that the rate of bilateral mastectomy at median follow up of 3 months was low (3%). In general, these were treatment mastectomies, said Dr. Kurian, with only 1 in the VUS category being reported for cancer prevention.

Researchers also observed low rates of prophylactic hysterectomy (1.5%) and oophorectomy (0.8%), with the majority of both types of operations being for cancer treatment.

Minimal Adverse Psychological Effects

Patients were then asked to report their experience in relation to genetic testing, grouped by the categories of positive, VUS, and negative. According to survey results, adverse psychological effects were minimal.

“At least at this early stage, we don’t see much evidence of harm in terms of high prophylactic surgery rates or intrusive thoughts or regret,” said Dr. Kurian.

“Most patients never or rarely had thoughts of cancer affecting daily activities, never regretted testing, and wanted to know all results, even those that doctors do not fully understand,” she added.

Results of the validated MICRA questionnaire were divided into 3 components: distress, uncertainty, and positive experiences.

“As could be expected, patients who tested positive had slightly higher distress scores compared to the negative and VUS groups. However, uncertainty was not so different, and there were only slightly lower positive experiences of testing among patients who test positive for a mutation,” said Dr. Kurian.

In addition, scores of VUS patients did not differ significantly from those of negative patients for any MICRA components.

“It appears that the VUS patients were really behaving more like the negative patients and not like the positive patients in this setting,” Dr. Kurian reported.

Relatives Encouraged to Test

Finally, researchers asked patients whether they notified their relatives about their results and whether those relatives went on to have a genetic evaluation or testing.

Interim analysis showed that patients who had a positive pathogenic mutation encouraged relatives to have genetic testing (81.8%) significantly more than VUS (38.2%) or negative patients (37.8%,P< 0.001).

&ldquo;We think that notification and testing of relatives at this early stage appears relatively appropriate,&rdquo; said Dr. Kurian. &ldquo;Patients who have a pathogenic mutation were more likely to tell their relatives to test, which is what we&rsquo;d hope to see.&rdquo;

That being said, with a median of only 3.3 months, follow-up time remains short at this stage of the study.

&ldquo;It will be interesting to see if rates of prophylactic surgery, distress, or regret rise as the trial progresses,&rdquo; said Dr. Kurian. &ldquo;And what will happen if these VUS are reclassified?&rdquo;

Researchers expect enrollment of 2000 patients to be completed by the end of the year.

Kurian AW, Idos G, Culver J, et al. Safety of multiplex gene testing for inherited cancer risk: Interim analysis of a clinical trial.J Clin Oncol34, 2016 (suppl; abstr 1503).