Clinical utility of germline genetic testing after tumor genomic testing in colorectal cancer patients.

Abstract

e16089 Background: Practice guidelines support genomic and biomarker testing of colorectal cancer (CRC) to inform treatment options in advanced disease and to screen for MMR deficiency/MSI/Lynch syndrome. As yet, guidelines for follow-up germline testing are not well established. In 2019 ESMO recommended reflex germline testing when pathogenic variants (PV) were found in any of 27 cancer susceptibility genes (CSG) in tumor samples (PMID 31050713). The CSGs were chosen because PV in these genes were clinically actionable and had “germline conversion rates” (GCR) of > 10% (proportion of tumor-detected PV that were germline). We examined the utility of germline testing in a cohort of CRC patients who had prior tumor sequencing. Methods: We reviewed somatic & germline PV in an unselected consecutive series of CRC patients who were referred for germline testing and had prior tumor testing. We determined the GCR for genes with pathogenic germline variants (PGV) and compared our results to ESMO data. Results: 66 of 238 (27%) patients harbored PGV. 15% of PGV were not reported in the tumor assay. High GCR for BRCA1/2 (30%), MMR genes (40%), PALB2 (57%), and BRIP1 (67%) were in keeping with ESMO. Low GCR for APC (1.4%) and TP53 (3%) were similar to ESMO, and reflective of high somatic mutation rates in these genes. We noted high GCR for CHEK2 (75%) and ATM (24%), two genes not included in ESMO guidelines due to their intermediate penetrance. Conclusions: ESMO guidelines provide a key starting point for when reflex germline testing should be pursued after tumor testing. In our study 27% (65/238) of patients had PGV that conferred potential eligibility for targeted therapy or clinical trials. For CRC, finding PV in MMR genes, BRCA1/2, and other relevant CSGs should prompt follow-up germline testing. In cases with APC PV in tumor, ESMO recommended reflex germline testing only in patients < 30 yo, where the GCR was > 10%. Our study suggests that reflex germline testing after tumor sequencing yields clinically actionable results. [Table: see text]