PURPOSE: Tumor-only genomic profiling (TGP) is increasingly advocated for all patients with cancer given the possible therapeutic implications. It is critical to develop clinical algorithms to identify and address potentially actionable germline findings identified by TGP. METHODS: A multidisciplinary team analyzed publicly available data for genes in which mutations are implicated in germline cancer susceptibility and established a pipeline to automate clinical referral for evaluation of TGP findings. RESULTS: A total of 2,308 patients underwent TGP, with 81 patients (3.5%) identified by the automatic referral pipeline; 37 patients (1.6%) were referred outside the pipeline based on concerns by the molecular geneticist, pathologist, or oncologist regarding genotype-phenotype correlation. Thirty-one patients (38%) and 17 patients (46%) underwent germline testing from the automatic pipeline and other referrals, respectively, and of these patients, 23 (72%) and four (24%) had confirmed germline pathogenic variants (GPVs), respectively. The majority of confirmed GPVs were in automatic referral genes, with BRCA2 being most common (confirmed GPVs in 11 [85%] of 13 patients tested), followed by PALB2 (five [67%] of six patients), BRCA1 (two [40%] of five patients), MSH6 (two of three patients), and MLH1 (two of two patients). Forty-eight percent of confirmed GPVs were found in tumors known to be associated with germline mutations in the gene. Germline testing was not performed in 50 (62%) of 81 patients identified by automatic referral as a result of poor patient health or death (30%), lack of follow-up (30%), and patient refusal (30%). CONCLUSION: Of patients undergoing TGP, 5% had somatic findings triggering referral, and implementation of an automatic referral pipeline based solely on gene versus other clinical or molecular features resulted in a 74% germline confirmation. However, only 41% of referred patients underwent germline testing. Systems-based approaches are needed to identify carriers of actionable germline cancer susceptibility mutations identified by TGP.
PURPOSE:Tumor-only genomic profiling (TGP) is increasingly advocated for all patients with cancer given the possible therapeutic implications. It is critical to develop clinical algorithms to identify and address potentially actionable germline findings identified by TGP. METHODS: A multidisciplinary team analyzed publicly available data for genes in which mutations are implicated in germline cancer susceptibility and established a pipeline to automate clinical referral for evaluation of TGP findings. RESULTS: A total of 2,308 patients underwent TGP, with 81 patients (3.5%) identified by the automatic referral pipeline; 37 patients (1.6%) were referred outside the pipeline based on concerns by the molecular geneticist, pathologist, or oncologist regarding genotype-phenotype correlation. Thirty-one patients (38%) and 17 patients (46%) underwent germline testing from the automatic pipeline and other referrals, respectively, and of these patients, 23 (72%) and four (24%) had confirmed germline pathogenic variants (GPVs), respectively. The majority of confirmed GPVs were in automatic referral genes, with BRCA2 being most common (confirmed GPVs in 11 [85%] of 13 patients tested), followed by PALB2 (five [67%] of six patients), BRCA1 (two [40%] of five patients), MSH6 (two of three patients), and MLH1 (two of two patients). Forty-eight percent of confirmed GPVs were found in tumors known to be associated with germline mutations in the gene. Germline testing was not performed in 50 (62%) of 81 patients identified by automatic referral as a result of poor patient health or death (30%), lack of follow-up (30%), and patient refusal (30%). CONCLUSION: Of patients undergoing TGP, 5% had somatic findings triggering referral, and implementation of an automatic referral pipeline based solely on gene versus other clinical or molecular features resulted in a 74% germline confirmation. However, only 41% of referred patients underwent germline testing. Systems-based approaches are needed to identify carriers of actionable germline cancer susceptibility mutations identified by TGP.
Authors: Brittany L Bychkovsky; Tianyu Li; Jilliane Sotelo; Nabihah Tayob; Joanna Mercado; Israel Gomy; Anu Chittenden; Sarah Kane; Samantha Stokes; Melissa E Hughes; Ji Seok Kim; Renato Umeton; Mark M Awad; Panagiotis A Konstantinopoulos; Matthew B Yurgelun; Brian M Wolpin; Mary-Ellen Taplin; Randall E Newmark; Bruce E Johnson; Neal I Lindeman; Laura E MacConaill; Judy E Garber; Nancy U Lin Journal: Clin Cancer Res Date: 2022-06-01 Impact factor: 13.801
Authors: Ari VanderWalde; Axel Grothey; Daniel Vaena; Gregory Vidal; Adam ElNaggar; Gabriella Bufalino; Lee Schwartzberg Journal: J Pers Med Date: 2020-11-27
Authors: Stefan Klek; Brandie Heald; Alex Milinovich; Ying Ni; Jame Abraham; Haider Mahdi; Bassam Estfan; Alok A Khorana; Brian J Bolwell; Petros Grivas; Davendra P S Sohal; Pauline Funchain Journal: JNCI Cancer Spectr Date: 2020-03-05
Authors: Deepak B Poduval; Elisabet Ognedal; Zuzana Sichmanova; Eivind Valen; Gjertrud T Iversen; Laura Minsaas; Per E Lønning; Stian Knappskog Journal: Clin Epigenetics Date: 2020-08-28 Impact factor: 6.551
Authors: Stephen E Lincoln; Robert L Nussbaum; Allison W Kurian; Sarah M Nielsen; Kingshuk Das; Scott Michalski; Shan Yang; Nhu Ngo; Amie Blanco; Edward D Esplin Journal: JAMA Netw Open Date: 2020-10-01