Translating potential germline findings from tumour profiling into routine clinical care.
Authors: Zaheed Milita , Grady John P. , Murrow Beverley , Douglas Bridget , Carpenter Ellie , Mckay Skye , Liang Shuang , Taylor Natalie , Lin Frank Po-Yen , Goldstein David , Tucker Kathy , Thomas David Morgan , Ballinger Mandy L. 
Published: August 2024

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Background: Tumor molecular profiling (TMP) provides an opportunity to identify heritable cancer predisposition. Molecular Screening and Therapeutics Study (MoST) (8000 patients, 2016-23) and Cancer Screening Program (CaSP) (23000 patients, 2023-25) are Australian research programs providing TMP for therapy matching in advanced cancer. Matched germline testing is resource-inefficient and is not performed . An integrated approach between TMP and cancer genetics is needed to improve familial cancer outcomes through prevention and early detection. Methods: In MoST, potential germline variants (PGV) in actionable cancer genes were investigated in blood DNA in a research setting. Positive cases were informed, and a genetics review for clinical testing recommended. In CaSP, germline follow-up recommendations are included in the Molecular Oncology Board (MOB) Report based on decision algorithms to inform clinicians of PGV needing clinical assessment. Cancer genetics clinics in Australia were surveyed regarding preferences for the return of genetic information from tumor profiling. A centralised precision care clinic was launched in March 2024 to investigate the implementation of returning PGV information from tumor-only profiling. Results: In MoST, 38% (140/367) of PGVs tested were positive in blood DNA. Of these, 44% were identified in the highest actionability genes: BRCA1, BRCA2, PALB2, Lynch Syndrome. The validation and return of results process was unsatisfactory; it was resource-heavy, timeframes were extended, DNA was sometimes unavailable, and communicating information to non-participating relatives of deceased participants was challenging due to a lack of established pathways. The systems design in CaSP has allowed the study to manage higher volume without a net increase in germline workforce. To date, 2372 patients have completed profiling with 173 MOB recommendations for PGV validations. Fifty-four cancer genetics staff nationally responded to the survey. Many (61%) were concerned about the increased uptake of TMP without a workforce to match germline testing demand (97%) and lack of funding assigned in a universal healthcare system (70%) being main concerns. Most (82%) supported a centralised service anticipating improved efficiency gain (71%), equity of access (77%) and streamlining of processes (71%). The stakeholders voiced a consistently high (>50%) demand for information regarding PGV in lower actionability genes. MOB recommendations were adapted to reflect 3 tiers of actionability The centralised clinic has reviewed 21 patients nationally to test 23 highest actionability variants. The average referral to review time is 2 weeks. Conclusions: Precision oncology can play a role in familial cancer prevention. Deliberate collaboration and integration between precision research and relevant specialised care can lead to resource-optimised, equitable delivery of quality care.