Extracting Clinical Information from Cancer Genomics

by Sahana Shankar
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In an ASCO panel that discussed the importance of gleaning relevant and significant information from cancer genomic tests, practicing clinicians shared case studies of considering and interpreting mutations/variants and their effect on therapy, screening for disease, and risk assessment for the patient’s family. The panel consisted of 

  1. Dr. Larissa Korde from National Cancer Institute
  2. Dr. Matt Yurgelun from Dana Farber Cancer Center
  3. Dr. Courtney DiNardo, UT MD Anderson

Dr. Korde’s talk focused on the importance of classifying a variant from a genetic test as somatic or germline and the world of difference it makes to the patient’s therapy options and their families’ risk to the given disorder. She gave the example of a patient who was diagnosed with metastatic breast cancer and a family history of cancer. She had a direct-to-consumer (DTC) ancestry test, which did not show any pathogenic variants.

Dr. Larissa Korde, National Cancer Institute

However, clinical tests found a pathogenic variant in BRCA1, which changed the course of her treatment and screening for her daughters. This could be explained by the fact that some DTH panels focus only on important and deeply penetrant founder mutations on genes such as BRCA1/2 and HER. However, more than 1000 BRCA1/2 variants are associated with breast cancer, as are other genes such as ATM, CHEK2, PTEN, etc.

Identification of variants guide subsequent treatments. For example, PARP inhibitors perform better for germline BRCA1/2 variants, while there is not much available data on their efficacy in somatic variants.

Dr. Korde reviewed aspects of DTC tests such as consent, pre- and post-counselling, and disclosure of results without a healthcare professional. She argued that DTC tests should indicate that in case of identification of a germline variant, it needs to be validated and placed in context for the patient and their family regarding risk, additional screening, and prevention methods.


Lynch Syndrome and Cancer Predisposition

Dr. Yurgelun discussed the gene-specific risks in Lynch syndrome. Lynch syndrome is an autosomal dominant inherited syndrome for cancer predisposition in a wide spectrum of cancers. It is quite common and is defined by pathogenic germline mutations in the genes of the DNA repair pathway.

Dr. Matt Yurgelun, Dana Farber Cancer Center

Historically, lynch syndrome management included a wide spectrum of organ-specific screening to identify which cancer the patient is predisposed to. However, patient-specific factors such as age, sex, gene, family history may narrow down the search for organs that may be affected, as is evident from the Prospective Lynch Syndrome Database (PLSD) and ASK2ME repositories. For example, PSM2 has a lower penetrance, and its variants are not relevant in ovarian, GI, or urinary tract cancers, and MSH2 has high penetrance and has the widest spectrum of cancer risk.

Dr. Yurgelun demonstrated how several factors dictate risk in Lynch syndromes, and tools can enable personalized risk estimates based on patient-specific factors. For a 27 yo female with Lynch syndrome of MSH2 variant and family history of cancer, we can assess future risk. Based on risk calculators, she is at risk for colorectal cancer, endometrial cancer, and lower risk of the urinary tract and pancreatic cancers. If she had a PMS2 variant, her risk for cancers and management plan would differ. This information can immensely help management and cancer surveillance.


Mosaic Variants

Dr. DiNardo talked about how genetic variants may not always be reflective of germline mutations. They can come from somatic variants which need specialized molecular tests to be detected. She demonstrated the issue with the following case study of a 43 yo female with breast cancer who had a family history of cancer. In a genetic test, she was found to have a mosaic TP53 pathogenic variant which is associated with Li-Fraumeni Syndrome (LFS), a rare familial cancer syndrome with a high risk to a wide variety of cancers, usually breast cancer in women. A germline variant would mean extensive cancer surveillance.

Dr. Courtney DiNardo, UT MD Anderson

Mosaic variant meant that the variant had a sub-heterozygous frequency of 25%, suggesting that it could be a somatic variant from clonal hematopoiesis. Confirming that the variant was not germline with a bone marrow evaluation, she did not undergo the prescribed LFS treatment plan and responded well to radiation therapy, and is in surveillance for breast and blood cancers.

Clonal hematopoiesis is the formation of distinct subpopulations of blood cells during the course of multiple divisions. It can give rise to somatic variants, which can occur later in life and be tissue-specific. The variants are seen mostly in epigenetic regulation and DNA repair genes. It is more common in patients with cancer. Its frequency increases with age, ovarian cancer, and smoking. It causes an increased risk of blood cancer and cardiovascular disease.

Hence, Dr. DiNardo prescribed caution in confirming pathogenic variants at low frequency. 

In the Q&A session, the presenters addressed a few audience issues. 

When asked how they would evaluate variants of uncertain significance (VOS) for patients and their families, Dr.Korde said that clinical and family history need to be evaluated and also prevalence based on ethnicity. Any variant needs to be validated with functional tests.

Dr. Yurgelun emphasized that not all variants are equal. Certain clinical tests could provide additional evidence. Care needs to be exercised among classifications from different genetic tests. A variant categorized as likely pathogenic in one test may be VOS in another. Genetic counselors could add context to this. 

The panel discussed how valuable hereditary gene panels are when the results do not correlate with clinical evidence. Dr. Yurgelun argued that there is still some value of genomic data to understand gene penetrance and risk assessment. Dr.DiNardo said we should exercise caution in choosing the panel of genes while testing. 

When asked about their preferred follow-up of DTC test results, Dr.Korde said that a positive result is certainly informative, but no clinical decisions should be made on its basis. It needs to be validated in an FDA-approved clinical test. In case of a negative result, when the patient has a known malignancy and/or family history, clinical and certified tests should be done.

Dr. DiNardo was asked if a variant recognized from cell-free DNA always comes from a tumor, and she said it could be from normal cells and may be a germline variant or could be due to clonal hematopoiesis. A clue may be in their VAF (variable allelic frequency). She also said clonal hematopoiesis could explain secondary leukemia in some patients.

Related Article: New IO Targets and Resistance Mechanisms of Immune Checkpoint-Based Therapies


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