Genomics in Clinical Practice, Part 1: The Rise of Multiplex Gene Testing for Cancer

Kate M. O'Rourke


July 20, 2016

In This Article

Single-Gene vs Multiplex Testing

When choosing between single/limited gene testing and multiplex gene testing, there are many pros and cons. On the positive side, multigene panels are more cost-effective and more time-efficient, and they detect more mutations. However, there is an increased prevalence of VUS and cancer risk, and management options are often not well defined, particularly for some moderate- and low-penetrance genes. Panels may also include genes that patients don't wish to test for. Single/limited gene testing is better for phenotype-directed testing, and there is a lower likelihood of detecting a VUS.

Although it's clear that sequencing more genes increases the chances of finding a pathogenic mutation or a VUS, little is known about whether this may cause harm, by causing distress or spurring unwarranted surgery. In another analysis of the ongoing California study, Dr Kurian reported that an analysis of the reasons for posttesting surgical procedures showed this was not the case (Table 2). At 3 months after testing, patients in whom a VUS was identified had low rates of preventive surgery overall, with a 1.0% mastectomy rate, a 0.4% hysterectomy rate, and a 0.4% oophorectomy rate. "Our concern was that a patient would be identified with a VUS in a gene that we don't understand very well, such as NBN, and run off and have a prophylactic mastectomy," said Dr Kurian.

Table 2. Posttesting Surgical Procedures for Patients With a VUS

Type of Surgery Reason for the Procedure Number of Patients (%) Number of Patients With a VUS
Mastectomy Cancer treatment 47 (97.9) 15
Cancer prevention 1 (2.1) 1
Benign breast disease 1(a) (2.1) 0
Hysterectomy Cancer treatment 3 (60) 0
Cancer prevention 1 (20) 0
Benign disease (fibroids) 1 (20) 1
Oophorectomy Cancer treatment 3 (60) 0
Cancer prevention 1 (20) 0
(a)One patient who underwent bilateral mastectomy had one breast removed for treatment and the other for benign breast disease. From Idos G, Kurian A, Ricker CN, et al. J Clin Oncol. 2016;34(Suppl). Abstract 1509.

At 3 months, the large majority of patients said they did not regret testing; this was true regardless of whether a patient was given a positive result, a negative result, or a VUS diagnosis (86.6%), and those with a VUS said they had rarely or never had thoughts of cancer affecting their activities. More than 80% of patients, regardless of their test result, said they wanted to know all results, even the ones that doctors do not fully understand. Results from the Multidimensional Impact of Cancer Risk Assessment (MICRA), a survey that measures the specific impact of result disclosure after genetic testing, showed that patients who were identified with a VUS score behaved similarly to those who tested negative, in terms of viewing the testing experience in a positive light and being bothered by the uncertainty of testing. "In this early look at 1000 patients, we don't see much evidence of harm in terms of high prophylactic surgery rates or intrusive thoughts or regret," said Dr Kurian.

Patients who had a positive pathogenic mutation were twice as likely to encourage relatives to have genetic testing than were patients with a VUS or negative panel (positive, 81.8%; VUS, 38.2%; negative 37.8%; P < .001). "That is what we had hoped to see, because that would be the group in which testing relatives is useful," said Dr Kurian. "Testing if a patient had a VUS or negative results isn't so useful, and we think patients understood this."

Patients seem to be playing a big role in the uptake of multiplex gene panels.

The results are good news, because patients seem to be playing a big role in the uptake of multiplex gene panels. In a recent study involving 41 women who presented for genetic counseling at Beth Israel Deaconess Medical Center, Boston, and 36 matched genetic counselors, 80% of patients chose panel testing, despite the genetic counselors' belief that panel testing would have limited benefit for patients.[14]

Experts at the ASCO meeting agreed that multigene panel testing can allow a more comprehensive and efficient approach to testing, but many of the genes included in the panels have not been fully characterized, either in terms of cancer risk or management strategies.[15] The decision to pursue single-gene or multigene panel testing is complex, and referral to clinicians with expertise in cancer genetics is critical.[9] Interpretation of gene panel results by multiple experts in the context of personal and family histories maximizes actionable results.[9]

"I think it is really important to think about an individual's preference and their tolerance for ambiguity," said Dr Isaacs. "In June 2016, there is still a reasonable chance if you send someone for multigene panel testing that you will find a mutation in a moderate penetrance gene or you will get a VUS, and you have to make sure the patient feels comfortable with that. I think the technology has outpaced our medical knowledge, but our medical knowledge will catch up."

Dr Kurian disclosed research funding from Ambry Genetics, GenDx, Genomic Health, Invitae, and Myriad Genetics. Dr Idos disclosed research funding from Myriad. Dr Isaacs disclosed honoraria from Genentech/Roche, Pfizer, Genentech, and Novartis. Dr Weitzel has disclosed no relevant financial relationships.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.
Post as: