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ASCO Publishes Guidelines for Germline Testing in Solid Tumors

NEW YORK – The American Society of Clinical Oncology on Friday released guidelines to help guide use of multigene germline genetic testing panels for cancer patients.

The guidelines, published in the Journal of Clinical Oncology on Friday, aimed to address which patients should be offered multigene panel germline testing, when the testing should take place in the diagnostic process, which genes should be assessed within these test panels, and how patients' family history of cancer should be collected. An expert panel reviewed 52 guidelines and consensus statements from a range of professional organizations that contained information on genetic testing for gauging hereditary risk of solid tumors to develop this set of recommendations.

The first recommendation was that all patients should have their family history of cancer recorded. Clinicians should ask about cancers in first-degree and second-degree relatives along with the type of cancer, age at diagnosis, and any known results if a relative has previously had germline testing for cancer predisposition. The panel concluded that even if patients' information is incomplete, that family history and the process of asking patients about their relatives' experience with cancer is valuable.

The question about when and how multigene germline testing should be ordered can vary by cancer type. The panel reviewed guidelines and documents from many organizations on various cancer types, including recommendations for patients with colorectal, gastrointestinal, breast, ovarian, prostate, neuroendocrine, and other tumor types. The panel concluded that when germline testing is indicated for patients, a multigene panel should be offered if they could potentially harbor clinically meaningful variants in more than one gene.

The germline panel should include at least the genes that the panel strongly recommends patients be tested for based on their personal and family history of cancer. For example, the ASCO panel determined, after conducting their evidence review, that breast cancer patients should be tested to see if they have cancer-associated germline variants in BRCA1, BRCA2, PALB2, CDH1, PTEN, STK11, and TP53. The expert panel similarly compiled a "strongly recommended" list of genes to test in patients with colorectal, endometrial, gastric, gastrointestinal stromal, medullary thyroid, non-small cell lung, adrenocortical, melanoma, ovarian, pancreatic, pheochromocytomas, paragangliomas, prostate, renal cell, and sarcoma tumors.

The strongly recommended genes for a particular tumor type are those associated with a higher relative risk — greater than fourfold increase in risk — for that specific cancer, or they are genes with a lower relative risk for a particular tumor type but are highly actionable.

Physicians can also order a panel that gauges genes beyond those on the "strongly recommended" list, but the benefits of a broader panel test should be clearly identified because larger panels without clear clinical significance can cause patients anxiety if results are inconclusive or can be misinterpreted by physicians with limited understanding of genetics, according to the ASCO panel.

The experts also compiled a list of genes that they recommend patients be tested for less strongly because they are associated with a lower relative risk for that cancer — less than fourfold increase in risk — or because pathogenic variants in these genes are less actionable. Providers can choose to test patients for both the strongly recommended genes and the less strongly recommended genes, but "testing all genes relevant to the patient's personal and family cancer history is reasonable," the panel concluded.

The experts further said providers should notify patients if or when a variant of uncertain significance detected via germline testing is reclassified as benign or pathogenic.

According to the ASCO panel, patients who meet the criteria for germline genetic testing should be offered it regardless of prior results from somatic tumor genetic testing. However, the experts also noted that results from somatic genetic testing can sometimes suggest that patients have an inherited genetic risk for cancer though they may not otherwise qualify for germline testing based on family history or clinical factors. The panel compiled a list of genes that patients should be offered germline testing for if somatic testing identifies a variant in them.

The expert panel emphasized the importance of discussing germline testing with cancer patients when appropriate, which may improve adoption. They also highlighted that the cost of testing or insurance coverage along with patient factors like race, ethnicity, geographic location, and socioeconomic status may affect germline genetic testing access. The type of testing ordered may need to change based on these factors, the panel acknowledged, such as ordering one large multigene germline panel for a patient whose insurance will only cover one instance of genetic testing.

Tumor genomic profiling is considered part of standard care in certain settings like non-small cell lung cancer, for which many treatments are approved according to the somatic mutations driving the tumor. However, the expert panel noted that oncologists are increasingly recognizing the clinical significance of germline genetic testing as more treatments targeting germline mutations are approved, such as PARP inhibitors in certain cancers harboring BRCA1/2 pathogenic variants or immunotherapy in tumors with microsatellite instability or mismatch repair deficiency.