Michael Offin

Age at diagnosis among patients with cancer is a predictor of pathogenic germline variant prevalence, yet age thresholds often misclassify genetic risk. We performed germline sequencing of 39,184 unselected patients with solid malignancies spanning 32 tumor types, interrogating >90 cancer predisposition genes independent of clinical suspicion. Patients were stratified into early-, average-, and late-onset groups based on standard deviations from tumor-specific mean age at diagnosis. Pathogenic variant prevalence inversely correlated with age at diagnosis: 18.4% in early-onset tumors, 15.6% in average-onset tumors, and 12.3% in late-onset tumors (P < 0.001). Variants in high/moderate-penetrance genes accounted for the enrichment in early-onset cases (12.4%, early-onset; 8.9%, average-onset; 5.1%, late-onset; P < 0.001). Restricting hereditary cancer testing to patients diagnosed before age 50, as is typically done, would miss 4,601 pathogenic variant carriers, 72% of all variants detected. These findings support broad-based germline testing beyond conventional age-based criteria, reflecting the burden of hereditary risk even among late-onset cases. Significance: Across 32 solid tumor types in a pan-cancer cohort, we found enrichment of germline pathogenic variants among patients with subtype-specific early-onset cancer. Using age 50 as a testing cutoff misses most patients with inherited predisposition, supporting universal germline genetic testing for all individuals diagnosed with cancer.

CHORUS (NCT04905316) was an open-label, non-randomized, single-arm phase I/II trial of the anti-IL-1beta monoclonal antibody canakinumab given with concurrent chemoradiotherapy and continued with anti-PD-L1 durvalumab consolidation in unresectable stage III non-small cell lung cancer. The primary endpoint was 24-month progression-free survival (PFS) from radiotherapy initiation; secondary endpoints included overall survival, objective response rate, and safety. Forty-one patients were enrolled, 37 received canakinumab, and 32 comprised the prespecified efficacy population. At a median follow-up of 25 months, 24-month PFS was 67% (95% confidence interval, 52–88); the lower bound of the prespecified one-sided 90% confidence interval was 56.5%, exceeding the 46% historical benchmark, and the primary endpoint was met. Twelve- and 24-month overall survival were 93% and 73%, respectively, and the confirmed objective response rate was 81%. Canakinumab-related grade 3–4 events included neutropenia (n = 5), febrile neutropenia (n = 1), lymphopenia (n = 1), lung infection (n = 1), fatigue (n = 1), and hypertension (n = 1); no canakinumab-related deaths occurred. Pneumonitis of any attribution occurred in 9 of 37 patients (24%; grade 2, n = 7; grade 3, n = 2). Peripheral immune cell profiling showed attenuated expansion of myeloid-derived suppressor cells and CTLA-4-expressing CD8 + T-cell subsets among responders. Circulating tumor DNA cleared by week 6 in 20 of 30 evaluable patients (66%). These findings support randomized evaluation of interleukin-1β blockade in this setting.

PURPOSE: Although we typically consider diffuse pleural mesothelioma (DPM) as a disease of elderly males with a history of asbestos exposure, young individuals are also affected. Given the increasing incidence of cancer in young individuals, we investigated the characteristics and underlying biology of young patients with DPM. METHODS: We identified patients with DPM age ≤50 years from Memorial Sloan Kettering Cancer Center (1990-2023). Clinicopathologic and genetic characteristics were compared between very young (≤35 years) and young (36-50 years) patients. RESULTS: We identified 273 patients with DPM age ≤50 years; 39% were female, 40% had a history of self-reported occupational asbestos exposure (very young, 16% v young, 45%; P < .01), 16% had a personal history of cancer (very young, 7% v young, 18%; P = .07), and 70% had a family history of cancer (most commonly breast, lung, and colon). Most frequently altered somatic genes (51/273 tested; 46/51 positive) included BAP1 (22/47, 47%), NF2 (18/47, 38%), CDKN2A/B (12/48, 25%), and TP53 (10/48, 21%). Very young patients had less somatic alterations in BAP1 (13% v 63%, P < .01) and a lower tumor mutational burden (0.9 v 1.8 mut/mB, P < .01); they were less frequently carriers of germline alterations (0% [0/8] v 43% [6/14], P = .05). Somatic alterations in CDKN2B were more frequent among females (females 42% v males 12%, P = .03). CONCLUSION: Young patients with DPM have strong personal and family histories of cancer, and heterogeneous somatic and germline alterations, indicating divergent underlying biology. With the increasing prevalence of young adults with cancers, mesotheliomas, although uncommon, should be on the differential for patients even without asbestos exposure history in this age group.

The phase II PHAROS study previously showed that encorafenib plus binimetinib has antitumor activity in patients with BRAF V600E-mutant metastatic non–small cell lung cancer (mNSCLC). In PHAROS, 98 patients (59 treatment-naïve; 39 previously treated) received encorafenib 450 mg once daily and binimetinib 45 mg twice daily. We report updated results from data cutoff of March 14, 2025. The median duration of treatment with both encorafenib and binimetinib was 16.3 months in treatment-naïve and 5.5 months in previously treated patients. After median follow-up for overall survival (OS) of 52.3 months in treatment-naïve patients, mOS was 47.6 months (95% CI, 31.3 to not estimable); 4-year OS probability was 49% (95% CI, 35 to 62). After median follow-up for OS of 48.2 months in previously treated patients, mOS was 22.7 months (95% CI, 14.1 to 32.6); 4-year OS probability was 31% (95% CI, 16 to 47). In treatment-naïve and previously treated groups, 58% and 26% received ≥1 subsequent systemic anticancer treatment, respectively. Safety profile remained consistent with that in previous analyses. Although comparisons across trials should be done cautiously, to our knowledge, encorafenib plus binimetinib was associated with the longest mOS reported to date with targeted treatment in patients with treatment-naïve BRAF V600E-mutant mNSCLC.

Association of PTV and dosimetry with toxicities.

Correlation of planning target volume (PTV) with development of esophagitis/dysphagia.

Overall (possibly, probably or definitely related) treatment-related toxicities by use of prior immunotherapy.

Purpose:Patients with extensive-stage small cell lung cancer are commonly treated with induction systemic therapy and consolidative thoracic radiotherapy (TRT). PARP inhibitors have demonstrated radiosensitization in preclinical lung cancer models. We performed an investigator-initiated, multi-institutional, single-arm, open-label phase I study of concurrent olaparib with TRT.Patients and Methods:Patients without progression after induction platinum/etoposide ± atezolizumab were treated with oral olaparib for 3 weeks and concurrent low-dose TRT (30 Gy/10 fractions) in weeks 2 and 3. Olaparib dose started at 50 mg twice daily and escalated in 50 mg/dose increments in cohorts of three patients each. Primary objectives were the safety and maximum tolerated dose (MTD) of olaparib + TRT. Secondary objectives included in-field local recurrence rate, progression-free survival, and overall survival.Results:Between October 2018 and March 2022, 24 patients with a median age of 68 years were treated (median follow-up, 11.4 months) with platinum/etoposide and 30 Gy/10 fractions TRT; 10 patients also received atezolizumab. The MTD of olaparib with TRT was 200 mg twice daily. There were three grade 3 (G3) dose-limiting adverse events (AE), including pneumonitis/pneumonia, esophagitis, and abdominal pain. The most common G2 to G3 treatment-related AE were esophagitis (n = 12) and pneumonitis/pneumonia (n = 2). There were no G4 or G5 AE. The 12-month cumulative incidence of local recurrence was 27%, and the median progression-free survival and overall survival were 3.6 and 17.7 months, respectively.Conclusions:This study established the MTD and recommended a phase II dose of olaparib at 200 mg twice daily with concurrent low-dose TRT, and the combination seemed safe without unexpected toxicities.