Nearly 35 years ago, in 1990, noted geneticist Mary-Claire King was the first person to show that a germline mutation—in this case in the BRCA1 gene—can cause a person to inherit a much higher risk of developing cancer. This first discovery in breast cancer opened the doors to the identification of many germline mutations that pass on increased risk of cancer types like ovarian, colorectal, pancreatic, prostate, endometrial, and gastric cancers, among others.
While new BRCA1 and BRCA2 germline variants are thought to confer roughly 20% of all hereditary cancers, other frequently mutated germline genes like ATM, TP53, CHEK2, PALB2, APC, NF1, PMS2, and RB1 may play a part depending on the type of cancer.
But how should the increasing amounts of data on the cancer risks conferred by germline variants be used by clinicians?
“I would like people to get germline testing before they get cancer,” said Tuya Pal, MD, a professor of genetic medicine at Vanderbilt University Medical Center and vice chair of the National Comprehensive Cancer Network (NCCN) Genetic/Familial High-Risk Assessment: Breast, Ovarian and Pancreatic Cancer Panel. “The purpose of these tests is to be able to detect cancer early or prevent it altogether. So, by the time someone has developed cancer, and they don’t know they have a germline mutation, we’re already behind the game.”
That said, Pal acknowledges that treatments and known prevention strategies, if they exist at all, are scarce for most of the identified germline cancer risk variants. The notable exception is BRCA, for which options may include estrogen blockers such as tamoxifen. “But the only treatment, I would argue, is the double mastectomy for BRCA for prevention,” she said.
Role of germline testing guidelines
The NCCN currently publishes and updates their Genetic/Familial High-Risk Assessment for a range of cancers and published their first guideline in 1999, which only included breast and ovarian cancer at the time.
The American Society for Clinical Oncology has their own set of guidelines and this year, released germline genetic testing panel guidelines to help guide clinician decision making. The guideline addresses issues such as the collection of family history to determine eligibility for testing, when multigene panel germline testing should be used, which genes are recommended for which cancers, and which patients should be referred for germline testing based on earlier somatic testing results.
President and Chief Clinical Officer of Oncology, Myriad Genetics
“We believe these guidelines play a valuable role in advancing germline testing by addressing gaps in understanding and education among oncology practitioners about the impact of this testing on patient care,” said George Daneker Jr., MD, president and chief clinical officer of oncology of the molecular diagnostics company Myriad Genetics. “Importantly, if a patient meets germline criteria, testing should be ordered regardless of genomic (somatic) results, as approximately 10% of germline pathogenic variants are missed on tumor testing.”
According to Elizabeth Chao, MD, chief medical officer of hereditary genetic testing company Ambry Genetics, the company largely bases the hereditary tests they offer on NCCN guidelines. “We’ve seen a tremendous impact over the last five to ten years with NCCN helping the field align on who needs testing, what the benefits are of testing, and which populations benefit the most from getting germline genetic testing,” she said. “I feel like that has been a big win clinically.”
Chief Medical Officer
Ambry Genetics
Further, Chao added, the guidelines have helped insurance payers better determine which germline tests to cover, for which cancer, and under what circumstances. While the payer landscape remains spotty, with different payers setting different criteria for who gets covered, published guidelines have helped make the tests more readily accessible to patients and their doctors.
The NCCN guidelines are also constantly changing, Pal said, as new information becomes available.
Cancer germline testing in the clinic
Today, germline testing for cancer-causing variants is most commonly used after a person has been diagnosed with cancer. Even then, the tests are often employed as a reflex test only after completing tumor testing for somatic mutations and if the results suggest that the disease is linked to a germline variant.
Daneker, however, thinks waiting could cause patients to miss their chance to get the most effective treatment for their form of cancer. “Once that patient does receive a cancer diagnosis, germline testing should then be paired with genomic or somatic testing to … answer whether the patient has an inherited mutation that will impact not only their management, but also their family members,” Daneker said. “Having information from both somatic and germline testing can inform therapeutic options and the sequencing of therapies for that patient.”
Unfortunately, germline testing rates remain alarmingly low among patients with forms of cancer potentially caused by germline mutations, as opposed to those caused by somatic mutations. Research published last year in JAMA, led by Allison Kurian, MD, from the Stanford School of Medicine and colleagues from research institutions across the U.S. found that germline testing rates are desperately low. The observational study of 1.3 million people diagnosed with cancer between 2013 and 2019 in Georgia and California showed that only 93,000 people, or 6.8% of those diagnosed with cancer, received germline genetic testing.
But testing rates varied widely based on the form of cancer. Of those who had germline testing, male breast cancer patients were tested at the highest rate—50%—followed by other cancers: ovarian (38.6%), female breast (26%), endometrial (6.4%), pancreatic (5.6%), and colorectal (5.6%). Prevalence of germline testing was particularly dismal for prostate cancer (1.1%) and lung cancer (0.3%).
Despite these low rates, “of all pathogenic results, 67.5% to 94.9% of variants were identified in genes for which practice guidelines recommend testing and 68.3% to 83.8% of variants were identified in genes associated with the diagnosed cancer type,” the researchers wrote, highlighting the potential utility of germline testing after diagnosis—if clinicians would order the tests.
The news is not all bad, however, as the researchers noted that the testing rates represented the average over a six-year study period. They noted that testing increased steadily between 2013 and 2019. For instance, in pancreatic cancer, only 1.2% of patients had germline testing in 2013, but this number rose to more than 18% by 2019.
Increasing uptake
Although germline testing rates are rising, the tests still are not widely used. This is a significant gap in cancer care, especially considering that women with a BRCA mutation have an increased risk—between 45% and 85%—of developing breast cancer. Increasing the adoption of germline testing will likely take a combination of educating both clinicians and patients about its benefits.
One area of opportunity is cascade testing, which is the testing of family members of a person either diagnosed with a cancer caused by a germline mutation or whose medical history shows a risk of inherited cancer. According to Pal, the barriers to cascade testing are complex.
“Even when someone is positive in the cancer setting, it’s up to them to share their information, but sometimes they’re not empowered to share the information,” Pal said. “It’s not easy to talk to family members, and even when they do talk to family members, many don’t want to do it. We see this all the time in our practice.”
In other instances, treating doctors do not see cascade testing as a priority in the immediate aftermath of a cancer diagnosis, said Chao. “I’ve talked to a lot of oncologists who, often for very good reasons, will say things like: ‘My patient just got their cancer diagnosis. We really want to focus right now on treating the current cancer.’ I don’t think there is much harm in starting with somatic testing and knowing that in a few months you’ll move to germline testing,” she said. “But germline testing can get lost sometimes in the melee of treating the cancer, and that is one of the downsides to not doing both [somatic and germline testing] up front.”
Testing rates could also increase if it were easier for non-geneticists to order them. “It’s not simple to order genetic testing and a lot of primary care doctors shy away from it,” said Chao. “We need to change that.”
Some of this reluctance is based on the model of providing genetic counseling for people who receive germline testing for familial risk. The counseling helps those who test positive for a known variant understand the implications—an area that is not a strong suit of oncologists. Further, due to the shortage of genetic counselors, wait times for germline testing can be long.
But Vanderbilt, Pal noted, is beginning to break this mold.
“Many centers, including our own, have started pushing out a point-of-care model where we’ll just support the oncologist to get the initial test done, and we’ll deal with the results on the back end,” she said. “So again, I think that really is an opportunity to increase throughput.”
Pal also added that the referral process for germline testing does not need to be complicated, noting that primary care physicians routinely take family histories of their patients, but may still need to be educated on flags that would suggest a germline test.
“The family history doesn’t need to be ‘strong’ or ‘multigenerational.’ You have a mother with breast cancer who died at 40? You are eligible for testing. That’s how simple it can be,” Pal noted, while acknowledging that the NCCN has made strides in clarifying what can often seem like complicated guidelines. She is optimistic that new clinicians are bringing a deeper understanding of genetics to their practices as school curricula are broadening their teaching of genetics.
Yet, many clinicians have developed an overreliance on somatic tumor testing to provide the information they need for a clear picture. Even if someone’s tumor “does not show a germline mutation, if they qualify for germline testing based on their personal cancer history, they should get germline testing. They should not be reassured,” Pal said. “I hear this from my oncology colleagues at my own institution: ‘The tumor testing was normal, so I don’t need to worry.’ Well, no, that’s actually not true, because a proportion of germline [variants] are going to be missed.”
An example of this could be a BRCA variant-driven cancer. Chao noted that a somatic test could identify the majority of BRCA1 and BRCA2 mutations that would steer a clinician toward prescribing a PARP inhibitor, “but there are groups and classes of germline alterations that are very difficult to identify in somatic testing. … There are unique or rare types of variants that we target in germline testing, like Alu or mobile element insertions that typically aren’t picked up on somatic testing.”
Further, Chao noted, somatic testing is done on the tumor tissue itself, and because tumors are continually mutating their DNA, the germline information can get lost in this heterogeneity.
Even in a patient with breast cancer whose somatic testing has revealed a BRCA positive mutation and who was correctly prescribed a PARP inhibitor that eliminated the cancer, germline testing remains appropriate. “I hear this from patients again and again: ‘I’ve already had a breast cancer diagnosis. Why does it matter to me?’” Pal said. “Well, it matters for you because if you are a BRCA mutation carrier, your risk for a second breast cancer is much higher than the general population. You’re at risk for ovarian cancer, you’re at risk for pancreatic cancer. For men, you’re at risk for prostate cancer. So there are other cancers to be thinking about, even if you’ve already had a cancer diagnosis.”
Looking to the future
One untapped area for germline testing is better understanding dual diagnoses, where the person has more than one cancer-causing variant in more than one gene. “At least 5% of our diagnoses are dual diagnoses,” Chao said. “The majority of these we found are usually one positive in a high penetrance gene and one positive in a moderate penetrance gene. Some of them overlap in terms of the cancer spectrum and some of them don’t. It is a challenging area and the interplay is complicated to tease out.”
These findings naturally lead germline testing advocates to consider genome-wide associations studies (GWAS) to understand which genes play a role in hereditary cancer. Importantly, GWAS can help assess which combinations of known oncogenes are additive and confer even higher risk and which combinations may lower the risk despite the presence of a high-penetrance gene variant.
The way Daneker sees it, as more germline variants involved in cancer development are discovered, the increase in knowledge will sway how testing for these variants is employed in clinical care.
“We envision that germline and genomic testing will become increasingly important earlier in the treatment planning and patient journey,” Daneker concluded. “The challenge of recalling multiple cancer syndromes, coupled with the recognition that patients do not know their family history, has made multigene panels attractive to many oncologists. We hope to see the expansion of gene panels, earlier testing, and targeted cancer type-specific testing to inform better treatment selection, and better risk assessment and prevention for patients and their families.”
Read more:
Nadine Tung et al., Selection of Germline Genetic Testing Panels in Patients with Cancer: ASCO Guideline. Journal of Clinical Oncology, May 2024.
Allison W Kurian, Steven J Katz et al., Germline Genetic Testing After Cancer Diagnosis, JAMA, July 2023.
