Dr. Judy Garber, Chief of the Division for Cancer Genetics and Prevention at Dana-Farber Cancer Institute

Somatic NGS has proven utility to assess the genomic drivers of tumors. In addition, germline (inherited) drivers may produce a different treatment scenario. By understanding both sets of these drivers through comparing DNA alterations between tumor and normal tissue testing, clinicians can gain a deeper understanding of the disease and potential clinical pathways for treatment.

 is an analysis of the Tempus database for incidental germline findings across diverse cancer types, which currently lack universal germline guidelines. Importantly, the research highlights that a portion of patients with actionable incidental germline findings do not meet traditional frontline germline testing indications.

Q. What are your thoughts on NCCN guidelines for germline testing in cancer patients?

Increasingly every oncologist should be aware of germline testing, how to arrange it for patients and what the basic implications of any findings might be for the patient and family members. The guidelines go beyond just a few cancers, as the old idea that about 5% of all cancers are attributable to germline mutations seems to be generally true.There is a lot of information on genetic (germline) testing in breast, ovarian and colon cancers but there is more and more information as well for stomach, renal, uterine and even for hematologic malignancies. The NCCN guidelines help people think about those in context.

Q. Is it fair to say that when you perform NGS testing on tumor tissue, incidental germline findings detected through tumor normal match testing provide important benefits?

Definitely! It makes the tumor testing more accurate. It helps you know which genetic changes are targetable because they were acquired in the development of the tumor, and which ones were there all along.Comprehensive and validated germline testing is also important to assess potential increased risk of developing cancer for the patient's family members, which is important for early diagnosis and for appropriate surveillance and risk reduction.

Q. What is the germline testing protocol for you and your team?

At Dana Farber, we try to make germline testing available to most patients with those cancers for which we expect to find a high prevalence of mutations: breast, ovarian, colon, prostate, pancreas. We have systems in the hospital that make it easy for those patients to get tested. We try to ask the patient, “have you had genetic testing? Have you thought about genetic testing as a part of your care?”. This is true whether the patient has a new diagnosis or metastatic disease. We also see relatives and other individuals who don’t have cancer but are concerned about risk.

Beyond the common cancers, we have been working to educate our oncologists on the potential value of germline testing. Cancer patients already have to deal with their diagnosis, the complexities and side effects of treatment and therefore, genetics may not be top of mind. Generally, if we were to test germline in all patients, the rate of finding a mutation would be ~15-20%. At Dana Farber, we are trying to make genetic care part of what people think about overall, and particularly for people that have had their tumor tested and may not have realized that something in their results could be germline affiliated. Our goal is to make it easier for the oncologists to follow up on those surprises and unanticipated findings as well as those they should be looking for.

Q. What cancer patients should receive germline testing?

If you look at the data from the Tempus ASCO Abstract, older people can have a germline mutation, although it will not be as common to find germline mutations as in younger cancer patients. Genetic testing can be expanded but at this time, we believe we should at least test patients who have a reasonably high risk, including people under the age of 65 diagnosed with cancer, those who may have family history of cancer, and those that have had an abnormal finding on another test that could point to a genetic abnormality.

Clinical actionability for germline testing

Q. What clinical actions should be considered if they uncover incidental germline findings relevant to family history?

When you look for germline mutations you want to look only in genes that would affect patient care. It is not important yet to find mutations in genes that don’t affect decisions about managing risk or managing treatment. If you find a mutation in someone where you have reason to believe it could be germline - for example, if you have done a tumor analysis and find a mutation in BRCA1 or one of the Lynch Syndrome genes - then you would want to test germline, which often involves a second sample. However, paired tumor normal match testing does all of this up front and many oncologists are moving toward this type of testing.

It is also important to know that if you are doing blood testing to look for circulating tumor DNA (ctDNA), that is not the same as looking for germline even though it is a blood sample analysis, so you would still need a separate sample if a mutation were identified. If you find that mutation, you have information for your patient, and for their relatives. That is why it's critically important to prepare the patient before taking the sample, so that they know if something is found there may be implications for family members.

Q. What kind of risk levels are we talking about for family members that otherwise do not have a diagnosis?

There is quite a range. Knowing that risk is increased because you have a relative diagnosed with cancer with germline variants, it is also important to know how much the risk is increased. You don’t want people having preventive surgeries when their risk is not increased by very much. Mutations in some genes can give a lifetime risk of as much as ~70% - like the colon cancer risks in lynch syndrome. Once the risks are that high, you are talking about preventative interventions that certainly are more extreme than the general population should consider. The advantage of this kind of testing is finding people who did not realize their risks were increased based on family history alone. There is a lot of information available online and there are genetic counselors and oncologists specializing in cancer genetics to help provide the best information for oncologists and their patients.

Q. How does germline testing change the scope for practicing oncologists?

One of the most important things about oncology is that as a community of practice, we have said, we will take on the cancer care of patients from risk to death - we will manage it all.That means that oncologists have said that they will take responsibility for knowing something about the germline genetics, not just the tumor genetics. You can share that with specialists in genetics or those involved in surveillance or management of high-risk individuals, but your patients will expect you to know at least the basics of how to manage genetic risk information.

Research findings from Tempus’ publication at the 2021 ASCO Annual Meeting

Q. What were the key findings from Tempus’ publication at the 2021 ASCO Annual Meeting on somatic and incidental germline testing?

This was an interesting study that Tempus did very carefully using de-identified data from >21,000 patients - all had tumor sequencing and matched normal sequencing of blood or saliva. Tempus dug into the incidental normal DNA findings to understand germline mutations in tumors where people don’t generally think to look (bladder, head and neck cancers, cholangiocarcinoma’s) and then compared that to tumors where people did expect to find germline mutations (breast, ovarian).

Tempus found mutations in groups where you would not expect to find them. This has been found in other studies too - family history is not that precise. Tempus also found that there were mutations in genes that are not traditionally considered for germline testing. Considering that technology is now easily applicable (through paired analysis of tumor and normal saliva or blood), we have access to information to help us understand things that can be very important to a patient and their relatives.

The study does not speak to the use of tumor genetic testing repeatedly as a patient's disease progresses and changes, as it accrues new mutations. Every time you change treatment, you may have to look and see if there is a new target that you might exploit. However, the germline never changes. You can continue to use the germline information all along - that is where we are going in precision oncology - we will use sequential testing on the tumor and incorporate germline information along the way.

Q. In Tempus’ research, we also found patients that had a double hit or corresponding somatic alteration in addition to germline mutation, can you speak to that?

Many of the cancer susceptibility genes are tumor suppressor genes, and we assume that in tumor cells, they should have lost the second copy or inactivated it somehow with a mutation. Normal matched testing allowed us to assess this in the study. For many patients, the somatic and the incidental germline both had corresponding mutations that inactivated these suppressor genes. This gives us faith in the data and the study design.

Q. Might there be any kind of treatment implications for those double hit patients?

We have been thinking that knowing the germline status - BRCA genes for example - would help you identify patients who might benefit from PARP inhibitors, and that is true. However, in addition, it appears that somatic mutations can also render these tumors sensitive to treatment with those therapies that are indicated for those germline mutations.

Tumor and normal tissue testing is an efficient approach to generating complete information for cancer patients. The incidental germline findings need to be confirmed on a validated assay but as demonstrated in our ASCO presentation, offer some insight into the incidence of germline alterations in patients not normally sent for hereditary testing.This combined testing approach of tumor and germline testing is more complete, and also allows for removal of alterations that are hereditary, though it is not the only way, of course. It’s great that Tempus is offering this through the xT tumor + normal assay, and now the xG hereditary cancer panel can confirm any incidental findings found on the xT assay. Tempus’ database will allow continued thinking about how we can incorporate comprehensive sequencing in day-to-day practice.

Through Tempus’ comprehensive portfolio of genomic profiling panels: hereditary, tumor and liquid, clinicians get more information for treatment options at many points in their patient’s journey.

Dr. Calvin Chao, Sr. Vice President of Medical Affairs at Tempus

Articles

A Conversation about Somatic, Incidental Germline, and Standalone Germline Testing in Clinical Practice