Skip to main content
Premium Trial:

Request an Annual Quote

Despite Barriers, Labs Starting to Report Suspected Cancer Risk Mutations Seen in Tumor Testing

NEW YORK – Paired tumor/germline testing is far from standard practice in cancer care, but some experts in the field are advocating that when patients have their tumors genomically profiled to determine precision medicine options, that is an opportunity to also evaluate them for their inherited risks for cancers.

Despite barriers, such as reimbursement, some labs in the field are recognizing this, and are starting to inform physicians of suspected incidental germline findings in tumor analysis.

As more precision therapies come to market, oncologists are increasingly offering advanced cancer patients the chance to have their tumors genomically profiled for identifying potential driver mutations that may be targeted with treatment. However, oncologists, depending on their specialty, may not be as aware of the need for germline testing or the impact an inherited cancer risk mutation could have on their patients' care and that of their relatives.

While genetic mutations detected in the tumor may be important for patients' cancer prognosis and guiding treatment decisions, identification of germline mutations is not only useful for precision medicine, but such findings can also indicate a heightened predisposition for cancers among patients and their family members. Knowing this can impact screening and help prevent future cancers.

However, current estimates suggest that the majority of patients, who according to guidelines should receive germline testing to gauge their inherited risk for cancers, aren't getting tested. For example, less than 10 percent of adults in the US with BRCA1/2 pathogenic or likely pathogenic variants (associated with a heightened risk for breast, ovarian, and pancreatic cancers) have been identified.

Studies also show that around 10 percent of cancer patients who undergo tumor testing have germline findings that increase their risk for hereditary cancers. Invitae, a leading provider of inherited cancer risk testing, recently conducted a retrospective analysis involving around 1,000 patients and reported an even higher proportion of patients — more than 30 percent — with a somatic test result also had a germline finding, and a majority of this information could be useful for precision therapy. 

"There is still confusion out there that somatic [testing] can substitute for germline and vice versa," Ed Esplin, a clinical geneticist at Invitae, said in a recent interview. "We're of the opinion that they don't substitute for each other."

Recognizing that tumor/germline testing is not standard practice currently, Invitae is conducting a large, prospective observational study with the Mayo Clinic to demonstrate to oncologists and payors the importance of testing patients for inherited cancer risk mutations alongside genomically profiling their tumors for targetable mutations.

The company's retrospective analysis has already identified gaps in care due to limited germline testing. For example, a subset of patients with germline findings — around 14 percent of those with prostate cancer and as many as 21 percent of those with ovarian cancer — had a previous primary cancer and at that time had not gotten germline testing. These patients received germline testing only after they got a second cancer and had tumor sequencing done.

While presenting this data at the Precision Medicine World Conference in California last month, Esplin gave the example of a breast cancer patient who is successfully treated but is never offered germline testing. Some years later, this patient develops another primary cancer, but this time in her ovaries. If she had received germline testing when she had breast cancer and it had identified an inherited BRCA1 or BRCA2 mutation, Esplin wondered whether that could have put her on a path to get more frequent screenings or prophylactic surgeries and kept her from developing ovarian cancer. "It kind of begs the question, 'Was this a missed opportunity?'"

Divergent practices

There are experts in the field who say it's unethical not to inform patients of suspected germline findings in tumor testing, given the impact this information could have on patients and families. Ellen Matloff, a leading voice in the genetic counseling community, believes that germline testing should be offered alongside tumor profiling, but short of that, labs should at a minimum make an effort to inform and educate physicians and patients of suspected germline findings.

However, based on her experience in the field, she sees there is a long way to go before paired somatic/germline analysis becomes routine. "From the conversations I've had, there seem to be some major holes in current lab processes to help clinicians understand if their patients might have an underlying germline finding," she said in an interview.

Current next-generation sequencing panels that test tumor samples can identify both somatic (acquired) mutations that occur only in mutated cancer cells and inherited (germline) genetic mutations that occur in all cells of the body. Although it's not possible to differentiate with certainty between the two without comparing the DNA of a tumor and normal sample, some gene mutations are more likely to show up in cancer cells than others. BRCA1 and BRCA2 gene mutations, for example, tend to be relatively uncommon in tumors. Therefore, if tumor testing detects mutations in these genes, there’s a fair chance that these are germline mutations.

In the commercial testing space, however, there is a wide variance in how labs are dealing with this issue. According to Matloff, many labs aren't conducting assessments of tumor and normal samples to confirm a suspected germline finding. And without naming any companies, she added that some labs known for tumor profiling may have been filtering out findings that can be indicative of a germline mutation.

At the PMWC, Matloff moderated a panel discussion on the challenges of addressing germline findings in the context of tumor testing with executives from four leading genetic testing companies — Tempus, Foundation Medicine, NeoGenomics Laboratories, and Guardant Health — and asked them how they currently handle this issue. All the experts acknowledged germline testing was important for cancer patients but described different policies.

Tempus performs DNA sequencing on tumor and matched normal samples from cancer patients, and performs RNA sequencing when sample quantity and quality permits. Germline analysis is done for every case where the physician orders such analysis, and the patient consents and sends a blood sample, according to Mark Oldroyd, senior VP of commercial markets at Tempus.

The company currently reports incidental germline findings for cancer-linked genes according to ACMG guidelines and other medical groups. Detected variants are listed in the test report under a section dedicated to germline findings with a comment recommending the patient follow up with a genetic counselor. If the patient does not consent to germline testing, but sends in a normal sample, germline findings are not included on the report. However, in such situations, Tempus still uses its tumor/normal pipeline to refine assessment of other somatic biomarkers, such as tumor mutational burden, that can be informative for guiding treatment.

Foundation Medicine is very much focused on tumor testing and has an FDA-approved tumor profiling NGS panel, FoundationOne CDx. The test's label cautions: "Alterations reported may include somatic (not inherited) or germline (inherited) alterations; however, the test does not distinguish between germline and somatic alterations. The test does not provide information about susceptibility." At the PMWC meeting, Foundation Medicine CEO Cindy Perettie said the company informs physicians of potential germline findings and noted that patients can also request access to all the detected mutations from the company.

A company spokesperson elaborated in a statement that the firm's position is that this type of testing is best done by experts that specialize in it. So, when testing suggests that a patient has a mutation that may have germline implications, Foundation recommends the provider follow up with confirmatory testing done by a germline testing lab, the spokesperson clarified.

"While we agree that germline testing is important, we’re focused on helping late-stage cancer patients understand what's driving their cancer now and how that can be addressed with targeted therapies or clinical trials," the spokesperson said. "Understanding whether a specific mutation is inherited can be helpful for informing family members, but it often doesn’t change the course of treatment in the near term. When you’re dealing with late-stage cancer, time is precious. Our goal is to help inform very sick patients of treatment options as quickly as possible."

In the short time oncologists have with patients to discuss imminent issues related to their cancer diagnosis, germline findings may not be at the top of the list of issues to discuss, Matloff acknowledged at the meeting. "Let's face it, when the patient in front of you has a lung cancer or has a pancreas cancer or a cancer of the ovary, you may be thinking there are bigger hurdles to jump and [discussing germline findings] is not our number one priority," she said. "However, the field is changing, and it will no longer be acceptable going forward to ignore these findings."

For example, there are now drugs on the market, such as PARP inhibitors, that are approved for patients with germline and somatic mutations in BRCA1/2. If more drugs are approved for subpopulations of patients with germline mutations in other genes, it will naturally move the field to considering germline testing not just for cancer risk assessments but also as a therapy selection tool.

"Germline [testing] is crossing into therapy selection," said Rebecca Nagy, senior director of medical affairs at Guardant Health, at the meeting, highlighting BRCA1/2 mutations as examples.

Guardant Health's Guardant360 is designed to detect somatic circulating tumor DNA in patients with advanced cancer and is intended to be used in therapy selection. The test is not validated for the detection of germline variants that are associated with hereditary cancer risk, but the liquid biopsy firm currently does report out germline incidental findings in BRCA1, BRCA2, EGFR T790M, and ATM, and also when patients have microsatellite instability (MSI).

Because Guardant360 is a test for guiding therapy, the company is focused on reporting those alterations that inform treatment selection in advanced cancers. Germline findings in these cases are added to the test report, and an email is sent within 24 hours to the treating physician to ensure that he or she is aware of the finding and that confirmatory testing with genetic counseling should be performed.

NeoGenomics does NGS tumor profiling and has a comprehensive hereditary cancer risk panel, but the company conducts tumor/normal NGS analysis only when specifically ordered by the physician. However, the company's molecular pathologists interpret results from tumor testing and flag variants that are likely to occur in the germline, according to Shari Brown, director of molecular pathology services at NeoGenomics. In such cases, the test report that's sent to physicians will note that the detected variant has been seen as a germline mutation in other patients and that this patient should receive genetic counseling.

The lab's pathologists also reach out to physicians if there are specific questions or concerns about a report. Brown added that in cases where a physician has questions about germline testing, but has ordered a somatic test, NeoGenomics discusses test limitations with the doctor and the best options for their patient's clinical scenario.

Barriers to adoption

At the meeting, the experts from these labs all said that while germline/tumor testing isn’t standard of care now, it is poised to become more routine in the future. Along the way, several barriers will have to be overcome, including reimbursement and physician education, as well as changes to patient care and lab workflows that ensure that appropriate consent is given for such testing and there is sufficient sample for analysis.

The added cost of germline and tumor analysis and payor reluctance to cover such testing is likely the biggest difficulty, the panelists agreed. Currently insurers have restrictive policies around when they cover NGS tumor profiling, and don't routinely cover tumor/germline analysis. Moreover, expert guidelines around what incidental findings labs should be reporting aren't in line with what payors are willing to cover at this point.

"I have [the American College of Medical Genetics and Genomics] on one side that says I should report these incidental findings, and I have the insurance company that says that if I report something beyond what was ordered, [I'm] basically doing an additional test the client didn't order," Brown said. "We have to balance that and work around that. Generally, it's easily handled with a phone call."

From a cost and reimbursement standpoint, Brown reflected that it may make more sense to take an algorithmic approach to implementing germline testing, focusing first on settings where inherited mutations are more common. In sarcomas, lymphomas, and leukemias, for example, the vast majority of mutations tend to be somatic. As such, Brown noted, payors may be more open to broadening coverage policies for germline testing in carcinomas and melanomas first where the chance of a mutation is higher.

Even in a difficult reimbursement environment, the use of NGS panels has soared in cancer care in recent years. And these large panels that gauge hundreds of genes are uncovering results that providers aren't expecting. "We're uncovering lots of different information, some of which the patient didn't come in to learn and some of which the doctor doesn't want to have to explain," said Nagy, "and one of those things is germline findings."

In Brown's experience, some community oncologists may not always know the difference between a germline and somatic mutation. In other cases, oncologists may not fully appreciate the importance of germline findings in patient care.

Labs are also finding that physicians may not be aware of the limits of tests they've ordered, and are having to educate them in this regard. For example, Nagy noted that some oncologists think that when they send a blood sample to Guardant, they're getting a comprehensive assessment of germline findings.

"[It's] pretty good but it's not perfect," she said, explaining that there are technical limitations when analyzing cell-free DNA that may end up missing certain types of mutations. "We need to be able to educate physicians on the differences between what they might get from a germline CLIA lab versus a somatic lab, [or] … a somatic lab that's providing full germline services as well."

All the experts agreed that for broader implementation of germline findings alongside tumor profiling, labs will have to figure out how to best consent patients so they understand upfront that the results they get back may impact their cancer care, but also their blood relatives. Moreover, currently, suspected germline findings identified within tumor testing should be confirmed in a second test, requiring an additional sample and more visits to the doctor. In the future, sample requisition processes will have to be streamlined to more easily facilitate germline analysis, the experts said.

A preemptive position

For Invitae's Esplin, reimbursement, physician awareness, and workflow issues are surmountable challenges. "These should not be persisting obstacles to patients getting access to their tumor and their germline [test results] that are really critical to their treatment," he said. "If you have cancer, you want to have all the information that impacts your treatment course up front."

Unlike the four testing companies discussed above, Invitae currently only conducts germline genetic analysis. In recent years, Invitae has employed a competitive pricing strategy and managed to take a leading position in the germline testing space alongside other established players, such as Myriad Genetics, Ambry Genetics, and GeneDx.

However, the company is developing and will soon launch a somatic NGS panel. Even before it enters the highly competitive tumor profiling space, currently dominated by the likes of Foundation Medicine and Guardant, it has taken the preemptive position that cancer patients who have their tumors genetically profiled would also benefit from being evaluated for their inherited risks for cancers, either simultaneously or as a follow-on test.

Recognizing that decision makers in the provider community, and in particular, payors, will need convincing, the company is conducting a large prospective observational trial to demonstrate the value of broadening germline testing access to cancer patients. The study, called INTERCEPT, will be done in partnership with the Mayo Clinic and test 3,200 cancer patients for germline mutations using Invitae's 83-gene next-generation sequencing panel and offer cascade testing to their relatives.

Germline testing will be performed regardless of patients' family history or other medical criteria at the time patients are diagnosed so that the results can be used to inform follow-up interventions and treatment. Some patients in the study will have had their tumors genomically profiled, while others not. Researchers will track the clinical utility and costs associated with broadly providing germline testing to cancer patients.

Invitae is hoping that the data from this study, which it plans to present at the American Society of Clinical Oncology's annual meeting in June, will nudge the field toward more readily integrating germline testing in cancer care. The company is also conducting the study with an eye toward affecting changes in guidelines.

Esplin highlighted that the INTERCEPT trial will enroll patients with 14 different kinds of malignancies, many of which currently don't have guidelines recommending germline testing, such as sarcomas, and renal, lung, and bladder cancers. Even when there are guidelines in this regard, lack of physician knowledge has limited adoption of germline/somatic analysis.

For example, the National Comprehensive Cancer Network recommends germline testing cancer patients when testing detects mutations in BRCA1 or BRCA2 in tumors. However, researchers from Stanford University published data last year showing that around 31 percent of 164 patients with detected BRCA1/2 mutations from tumor testing were not recommended for germline analysis. Moreover, researchers concluded that patients with sarcomas, lung, genitourinary, and skin cancers were less likely to be offered germline testing compared to patients with breast and gynecological cancers, where oncologists are more aware of the importance of germline BRCA1/2 testing.

When Invitae launches its tumor testing service sometime this year or in 2021, the company plans to make it easy for doctors to simultaneously order paired germline and somatic analysis. The offering will include a dedicated germline report, where the DNA is extracted by an independent process and interpreted using a germline-specific knowledgebase. Similarly, for somatic testing, DNA will be extracted from the tumor and interpretation will be done using a specific somatic database.  

"Somatic doesn't equal germline. Germline doesn't equal somatic. They are not interchangeable," Esplin said. "They are both good at what they're supposed to be good for, but they need to be working in combination with each other for the maximum benefit of the patient."