Adam H. Buchanan

Multiyear Clinical Outcomes of Cancers Diagnosed Following Detection by a Blood-Based Multicancer Early Detection Test

Abstract In the US, <20% of cancers are diagnosed by standard-of-care (SoC) screening. Multicancer early detection (MCED) tests offer the opportunity to expand cancer screening. Understanding the characteristics and clinical outcomes of MCED-detected cancers is critical to clarifying MCED tests’ potential impact. DETECT-A is the first prospective interventional trial of an MCED blood test (CancerSEEK). CancerSEEK, coupled with diagnostic PET-CT, identified cancers including those not detected by SoC screening, the majority of which were localized or regional. We report multiyear outcomes in patients with cancers diagnosed following a positive CancerSEEK test. Nine cancer types were diagnosed in 26 participants whose cancers were first detected by CancerSEEK. Information on cancer diagnoses, treatments, and clinical outcomes was extracted from medical records through November 2022. Data collection occurred at a median of 4.4 years (IQR: 4.1–4.6) following study enrollment. Thirteen of 26 (50%) participants were alive and cancer-free [ovarian (4), thyroid (1), uterine (2), breast (1), colorectal (2), and lung (3)]; 7/13 (54%) had cancers without recommended SoC screening modalities. All eight treated stage I or II participants (8/8, 100%) and 12/14 (86%) surgically treated participants were alive and cancer-free. Eligibility for surgical treatment was associated with favorable multiyear outcomes (P = 0.0002). Half of participants with MCED-detected cancers were alive and cancer-free after 4.4 years median follow-up. Most were diagnosed with early-stage cancers and were treated surgically. These results suggest that early cancer detection by CancerSEEK may have facilitated curative-intent treatments and associated positive clinical outcomes in some DETECT-A participants. Prevention Relevance: This study provides preliminary evidence of the potential of multicancer early detection testing as an effective screening tool for detecting cancers without standard-of-care (SoC) screening modalities and complementing SoC cancer screening.

Clinical outcomes of a genomic screening program for actionable genetic conditions

Three genetic conditions-hereditary breast and ovarian cancer syndrome, Lynch syndrome, and familial hypercholesterolemia-have tier 1 evidence for interventions that reduce morbidity and mortality, prompting proposals to screen unselected populations for these conditions. We examined the impact of genomic screening on risk management and early detection in an unselected population. Observational study of electronic health records (EHR) among individuals in whom a pathogenic/likely pathogenic variant in a tier 1 gene was discovered through Geisinger's MyCode project. EHR of all eligible participants was evaluated for a prior genetic diagnosis and, among participants without such a diagnosis, relevant personal/family history, postdisclosure clinical diagnoses, and postdisclosure risk management. Eighty-seven percent of participants (305/351) did not have a prior genetic diagnosis of their tier 1 result. Of these, 65% had EHR evidence of relevant personal and/or family history of disease. Of 255 individuals eligible to have risk management, 70% (n = 179) had a recommended risk management procedure after results disclosure. Thirteen percent of participants (41/305) received a relevant clinical diagnosis after results disclosure. Genomic screening programs can identify previously unrecognized individuals at increased risk of cancer and heart disease and facilitate risk management and early cancer detection.

Increased colorectal and endometrial cancer rates in a genomically ascertained Lynch syndrome cohort

Abstract Background Lynch syndrome (LS) is a hereditary cancer predisposition that increases risk for colorectal, endometrial, and other cancers. Although population-based genomic screening programs identify individuals with LS, clinical presentation in such genomically ascertained populations is unknown. Methods MyCode is a healthcare system-based biobank that returns clinically actionable genomic screening results to participants, including pathogenic/likely pathogenic (P/LP) variants in LS genes (MLH1, MSH2, MSH6, PMS2). Adult cases (participants with an LS result) and controls (participants without a cancer predisposition variant matched to cases) reported their personal and family cancer histories. Rates of meeting National Comprehensive Cancer Network (NCCN) genetic testing guidelines and rates of colorectal and endometrial cancers in cases, controls, and their family members were calculated and compared. Results A total of 175 cases (10 MLH1, 7 MSH2, 83 MSH6, and 75 PMS2) and 169 controls were included. Of case pedigrees, 62/175 (35.4%) met NCCN criteria for LS evaluation. Case pedigrees were more likely (P < .001) to meet criteria than control pedigrees (4/169, 8.35%). Case probands had significantly higher rates of colorectal and endometrial cancer than controls (7.7% vs 2.4%, P = .03 colorectal; 11.5% vs 0%, P < .001 endometrial), as did their relatives (3.1% vs 0.9%, P < .001 colorectal; 2.2% vs 0.5%, P < .001 endometrial). Conclusions NCCN guidelines missed 65% of cases with P/LP LS variants despite families having higher colorectal and endometrial cancer rates compared with controls. Genomic screening can assist in identifying individuals at risk for LS-related cancers, providing an opportunity to tailor risk management for cancer prevention and early detection.