Clinically actionable results

To demonstrate the value of multi-gene panels in hereditary cancer risk assessment, Our partner laboratory has collaborated with several preeminent research hospitals on studies comparing the clinical actionability of multi-gene panels to traditional single-gene testing.

Clinical evaluation of multi-gene panel testing in more than 1000 patients (2015)

Overview

To determine the clinical actionability of multi-gene testing for hereditary breast and ovarian cancer (HBOC) risk, Invitae collaborated with researchers at Massachusetts General Hospital, Harvard Medical School, Stanford University, and Beth Israel Deaconess Medical Center. The results of this research, recently published in JAMA Oncology, show that positive panel test results warrant consideration of a change in management for the patient more often than is true for BRCA1 and BRCA2 testing alone.

Reference

Desmond, A, et al., Clinical actionability of multigene panel testing for hereditary breast and ovarian cancer risk assessment. JAMA Oncology. 2015. 10.1001/jamaoncol.2015.2690.

Background

Genetic testing for hereditary breast and ovarian cancer (HBOC) is evolving rapidly, owing to the recent introduction of multigene panels. Compared with testing for BRCA1/BRCA2 alone, these tests identify a greater number of individuals with genetic mutations. This study addresses how often and in which ways the identification of non-BRCA1/2 mutations would alter clinical management under current practice guidelines.

Methods

More than 1000 patients from three large medical centers (Stanford University School of Medicine, Massachusetts General Hospital, and Beth Israel Deaconess Medical Center) were prospectively enrolled. All patients met clinical criteria for HBOC evaluation and all were tested for BRCA1/2 and at least 23 other cancer risk genes. For the 63 patients found to have non-BRCA1/2 mutations, detailed clinical records and family histories were reviewed. We determined whether the positive test result would warrant consideration of a change in management in comparison with management recommendations based on personal and family history alone. These analyses were based on the most recent update (1.2015) to the National Comprehensive Cancer Network® (NCCN) guidelines for HBOC and other applicable current guidelines.

Results

Consistent with other studies of comparable populations, 9.0% of all patients were positive for BRCA1 or BRCA2, and 3.8% of the BRCA1/2-negative patients had a mutation uncovered in another cancer risk gene.

Most (92%) of the non-BRCA1/2 mutations were consistent with the spectrum of cancer(s) observed in the patient/family, suggesting that these results are clinically relevant and not incidental.

Additional screening or prevention measures—over and above any recommendations based on personal and family history alone—would be considered for the majority (52%) of the non-BRCA1/2-positive patients (Table 1).

Testing of most (72%) first-degree relatives of the non-BRCA1/2-positive patients would also be indicated based on the potential management changes for those individuals (Table 1).

Clinical impact was not restricted to a few of the tested genes: most genes with positive results had the potential to change management for at least some patients in this study.

Discussion

In a clinically representative cohort, we found that multigene panel testing for HBOC yields clinically actionable findings across a broad spectrum of cancer risk genes. Compared with the results of BRCA1/2 testing alone, these findings are likely to change risk assessment and management for substantially more patients and their family members under current practice guidelines.

Clinical evaluation of multi-gene panel testing in 198 patients (2014)

Overview

To demonstrate the value of multi-gene panels in hereditary cancer risk assessment, Invitae collaborated with Stanford University researchers, James Ford, M.D., and Allison W. Kurian, MD, MSc. The results of this research, recently published in the Journal of Clinical Oncology, show that that multi-gene hereditary cancer panels can offer comparable performance to traditional BRCA1/2 genetic testing and can provide additional clinical benefit to doctors and patients seeking cancer risk assessment.

Reference

Kurian, A.W., et al. Clinical Evaluation of a Multiple-Gene Sequencing Panel. JCO published online on April 14, 2014; DOI:10.1200/JCO.2013.53.2630.

Study Design

The study utilized a panel of 42 cancer risk genes selected for clinical and research relevance that were tested by Invitae on biobanked germline DNA from 198 women who had been referred for hereditary breast and ovarian cancer testing to the Stanford University Medical Center. These individuals had been previously tested for BRCA1/2 by an independent laboratory. Of the patients who participated in this study, 174 had breast cancer and 57 carried pathogenic germline variants in BRCA1/2.

Results summary

High concordance with previous BRCA test results

The study found that BRCA1/2 results from Invitae’s panel were highly concordant with previous clinical BRCA1/2 test results on these individuals. In addition to the study described here, Invitae has also embarked on a large rigorous clinical study to validate our analytic results and clinical interpretations, for more information about this research, please visit our Validation page.

Identification of additional cancer risk genes

Among the 141 BRCA-negative women, Invitae’s panel identified additional risk variants in the MLH1, CDH1, NBN, ATM, MUTYH, CDKN2A, SLX4, BLM, and PRSS1 genes.

Informing medical management

Based on the identification of new risk variants in genes beyond BRCA1/2, Stanford’s clinical staff determined that about 9% (13 of 141) participants warranted re-contact and additional counseling based on this new information. Stanford provided personalized recommendations for additional screening and other potential changes in care were provided as appropriate. The Stanford team found that this counseling was both feasible and was appreciated by the patients.

A case study of better patient care

Background: One of the patients described above is a woman who had been diagnosed with unilateral breast cancer in her mid-40s. At the time of her original diagnosis, the patient received a negative BRCA1/2 test report from an independent laboratory, and consented to have her DNA biobanked.

New Results

In this study, the patient was found to have a pathogenic variation in the gene MLH1 associated with Lynch syndrome. Following IRB-approved protocol, the patient was re-contacted and the MLH1 results independently confirmed and communicated to her.

Outcome

In the time between the BRCA1/2 and gene panel tests, the patient had been diagnosed with endometrial cancer. Additionally, a baseline colonoscopy had been performed at age 50 with negative results, and she had been told to come back at age 60. Following communication of her MLH1 status, she underwent an early second colonoscopy and a polyp was found and removed. She is currently 53 years old, so this tubular adenoma was caught 7 years earlier than if no broad genetic test had been performed.

Assessing Variant of Uncertain Significance (VUS) rates

This research study reported an average of 2.1 VUSs per patient across the complete panel of 42 genes selected for clinical and research relevance.

Following this research study, Our partner laboratory developed our commercial test for hereditary cancer focusing on 29 of the most clinically relevant cancer risk genes. The 29-gene test reduces the panel-wide VUS rate to about 0.7 VUS per patient and about 40% of patients receive an uncertain test result in any of these 29 genes (because some patients carry more than one VUS).