Development of a Cell-Free DNA Multicancer Screening Test
A noninvasive blood test based on cell-free DNA (cfDNA) can detect numerous types of cancer at different stages with high specificity, according to a preplanned substudy of the Circulating Cell-free Genome Atlas (CCGA) trial, a prospective, multicenter observational study.
The substudy included 878 patients with newly diagnosed cancer who had not received treatment. Twenty different tumor types and all disease stages were represented. The study also included 749 control individuals who did not have cancer, but who had similar characteristics as the patient group in terms of age, gender, and smoking status.
The substudy tested three cfDNA assay prototypes and developed a detection model for each. An assay that probed methylation levels based on whole-genome bisulfite sequencing (WGBS) had higher sensitivity than assays that compared paired cfDNA and white blood cell samples by either whole-genome sequencing or targeted sequencing of 507 genes for single nucleotide variants and insertion/deletion mutations.
The WGBS-based cfDNA assay detected 28 colorectal cancers with 66% sensitivity (95% CI [48%, 84%]), 19 esophageal cancers with 63% sensitivity (95% CI [38%, 84%]), five head and neck cancers with 56% sensitivity (95% CI [21%, 86%]), five hepatobiliary cancers with 80% sensitivity (95% CI [28%, 99%]), 73 lung cancers with 59% sensitivity (95% CI [47%, 70%]), 17 lymphomas with 77% sensitivity (95% CI [50%, 93%]), 11 multiple myelomas with 73% sensitivity (95% CI [39%, 94%]), 10 ovarian cancers with 90% sensitivity (95% CI [56%, 99%]), and 10 pancreatic cancers with 80% sensitivity (95% CI [44%, 98%]). The assay had low sensitivity for several cancers, including melanoma, renal, and uterine.
The ability of the WGBS-based cfDNA assay to detect a range of cancer types at various disease stages suggests it could become a screening test for multiple cancers. Current research is focused on developing the assay in an asymptomatic population.
Long-Term IMPACT Study Follow-Up Reveals Superior Outcomes With Matched Targeted Therapy
Matched targeted therapy (MTT) resulted in improved survival outcomes and tumor responses compared with nonmatched therapy (NMT) for patients with multiple cancer types in phase I trials, based on the long-term follow-up results of the IMPACT study. Targeted therapy with MEK/RAF and RET inhibitors was associated with longer overall survival (OS) and progression-free survival (PFS).
In the IMPACT study, 3,743 patients with refractory cancers were analyzed for molecular alterations using Clinical Laboratory Improvement Amendments (CLIA) testing. The most common types of tumors in the study were gastrointestinal (24.2%), gynecologic (19.4%), breast (13.5%), melanoma (11.9%), and lung (8.7%). The median number of prior therapies was four, although some patients received as many as 16 prior therapies. Among the 3,743 patients tested, 1,307 had at least one molecular aberration and were referred to phase I trials in which they received MTT (711 patients) or NMT (596 patients).
Of the 711 patients in the MTT group, 74 (10.4%) had an OS of 38 months or more, compared with 24 (4%) of the 596 patients in the NMT group (p < 0.0001). Therapies targeting the MEK/RAF and RET pathways were associated with longer OS and PFS as well as higher rates of complete or partial response and stable disease for at least 6 months compared with other targeted therapies.
Several factors predicted longer OS in the MTT group: non-PI3K pathway–targeted therapy, lack of liver metastases, ECOG performance status of less than 2, normal lactate dehydrogenase (LDH) and albumin levels, and normal platelet counts. Similarly, factors associated with longer PFS in the MTT group were non-PI3K MTT, lack of liver metastases, performance status of less than 2, normal LDH and albumin levels, and multi-agent therapy.
–Carina Storrs, PhD