Skip to main content

Intermountain to Roll Out Germline Testing for All Newly Diagnosed Cancer Patients in 2019

Premium

NEW YORK (GenomeWeb) – Intermountain Healthcare is planning to test all newly diagnosed cancer patients for mutations in genes that increase their and their families' risks for the disease.

As an early adopter of precision oncology, the Salt Lake City-headquartered healthcare system began genomically profiling the tumors of all stage IV cancer patients in 2013, first with a 96-gene NGS panel and more recently with a 165-gene panel. The results of this somatic testing are used to inform treatment decisions for advanced cancer patients.

Intermountain also offers testing for cancer predisposition genes to assess individuals' inherited disease risk. The health system started off with an 18-gene panel for gauging germline mutations associated with inherited breast and ovarian cancer, but has now expanded that panel, called Heredigene, to 104 genes associated with many other cancers. "We want to run [this] on all newly diagnosed cancer patients of all tumor types and all stages and do germline testing on them," said Lincoln Nadauld, executive director of precision medicine and precision genomics at Intermountain.

Nadauld noted there is increasing evidence to suggest that broadly testing cancer patients for risk mutations could have benefits beyond standard screening approaches based on an individual’s personal and family history of cancer. "Current guidelines for germline genetic testing results in about 50 percent of pathogenic variants being missed in cancer patients," Nadauld said. "We want to expand the panel of genes we're using to test these patients in order to identify more patients affected by inherited variants, which could be passed on to other family members and put them at risk for cancer as well."

Researchers from Memorial Sloan Kettering Cancer Center published data in JAMA last year on around 1,000 patients, mostly with advanced cancer, who had consented to tumor DNA sequencing, but whose doctors had referred them for germline analysis of 76 cancer predisposition genes.

The analysis showed that out of 1,040 patients who received germline testing, 182 had clinically actionable cancer risk mutations, meaning if patients had these mutations, then there was evidence showing they could benefit from prevention strategies or certain therapeutic interventions. Among those with actionable mutations, 149 patients had moderate- to high-penetrance gene mutations, and 101 patients (or 55 percent) would not have had their mutations detected using standard screening criteria based on their family, personal history of cancer, and the features of their tumor.

Researchers led by Diana Mandelker from MSKCC concluded that their strategy of sequencing all advanced cancer patients for somatic and germline mutations identifies more individuals with "potentially clinically significant" inherited mutations compared to if they were tested according to traditional guidelines. "Knowledge of these additional mutations can help guide therapeutic and preventive interventions," they wrote. "But whether all of these interventions would improve outcomes for patients with cancer or their family members requires further study."

This research is part of the growing evidence base guiding the deployment of MSK-IMPACT, a 468-gene panel, which includes 88 genes associated with hereditary cancer predisposition. All advanced cancer patients at MSKCC are eligible for testing on the full panel.

"We have many cases where the germline finding resulted in a change of treatment and clinical response in the individual," said Mandelker. "Additionally, we have multiple cases where we determined that a relative of the patient we diagnosed with a hereditary cancer predisposition was also found to be at risk, and screening protocols detected curable, early-stage cancers." She added that MSKCC is continuing to collect this data on how testing is impacting patient outcomes.

Right now, MSK is offering germline testing primarily as part of MSK-IMPACT to advanced cancer patients. "This is the case simply because our protocols involve concurrent somatic and germline testing, and it's largely patients who need systemic therapy who may benefit from somatic testing," Mandelker said. But she noted that MSK has plans to deploy universal germline testing to earlier stage patients, especially in settings where a pathogenic finding could impact treatment.

Based on the experience of MSK and others, Intermountain is hoping to move forward with its plan to implement germline testing in all newly diagnosed patients with early-stage and advanced cancer, with the expectation that such testing will impact their surveillance, how they are treated for their current diagnoses, as well as how their families with pathogenic variants are screened. "A patient with a BRCA1/2 mutation and breast cancer might have a different kind of [preventive] surgery if they know that up front," Nadauld noted.

Another example he offered is of a patient identified to have Lynch syndrome with germline testing who would be surveilled differently after getting treated for their cancer, and their relatives would receive cascade testing.

Intermountain’s plan to deploy germline testing in all newly diagnosed patients, regardless of stage, means that while advanced patients will receive tumor and germline testing, earlier-stage patients will now be routinely evaluated for their inherited cancer risks. Intermountain is not doing somatic testing for early-stage patients, Nadauld explained, because there's not enough molecularly informed treatment options in this setting.

Before going live with the germline testing program, however, Intermountain will initiate a 500-patient pilot program to test the feasibility of doing this on a bigger scale and to collect data on the impact of the strategy. Similar to the MSK study, researchers will track patients treated within the Intermountain system to see how often germline testing identifies a pathogenic variant and how often those variants would have been missed by standard screening guidelines. Researchers will also estimate how many cancers might be prevented or detected at an earlier stage with this screening strategy, as well as the impact of cascade testing on relatives, and the costs.

Nadauld expects the data from the pilot phase will support a broad roll out of the screening strategy, but he also recognized the importance of demonstrating that the testing program won't harm patients. Importantly, the pilot phase will be a chance to identify potential gaps in the delivery system, before it is operationalized across Intermountain's 22 hospitals and 180 physician clinics.

"Leading up to this, we've spent a lot of time getting genetic counseling support in place and defining our follow-up algorithms," Nadauld said, explaining that during the limited roll out his team will stress test the level of genetic counseling support being provided to patients and the mechanisms in place for facilitating cascade testing for families.

Outside the cancer setting, there have been calls for screening healthy individuals for high-penetrance cancer risk genes, such as BRCA1 and BRCA2 associated with breast and ovarian cancer syndromes, and MLH1, MSH2, MSH6, and PMS2 associated with Lynch syndrome. The Centers for Disease Control and Prevention have recognized that screening for mutations in these genes could improve health through early cancer detection and prevention, and this is being increasingly recognized within large healthcare systems around the country. For example, Geisinger Health System in Pennsylvania is reporting results to study participants when they have clinically actionable findings in certain genes, including BRCA1/2, and the Healthy Nevada Project has similar plans.

The cost impact of a universal screening strategy remains a matter of debate, but as more companies offer germline testing for a panel of cancer-linked genes for a few hundred dollars, the cost-benefit analysis may start to look more favorable.

Historically, the cost of genetic testing, the lack of understanding about genetic variants associated with cancer, and limited knowhow as to how to manage patients who harbored those variants, hindered health systems from investing in screening programs like the one Intermountain is looking to implement. "Our belief is that germline testing [of newly diagnosed cancer patients] is now financially feasible … and enough patients are affected by inherited pathogenic variants that it warrants testing for those," Nadauld said. "Essentially, it's cheap enough, fast enough, and we know enough about it, that we can do this in a responsible way."