Biopsy tissue-based genomic classifiers (GCs) for prostate cancer are commercially available tools to enhance prognostication. They may corroborate candidacy for active surveillance/watchful waiting (AS/WW) or identify men who are more likely to benefit from radiotherapy (RT) with androgen deprivation therapy (ADT). We analyze real-world use of GC and associations with clinical decision making. We examined US commercial (n = 134,561) and Medicare (n = 68,431) insurance claims of men with newly diagnosed, localized prostate cancer between 2013 and 2022. We evaluated utilization of GCs over time and compared use of AS/WW, RT with or without ADT, radical prostatectomy (RP), or focal ablative therapy (FT) based on the receipt and type of GC. GC utilization increased from <1% to 17% in 8 years with a median payment of $3,001 (IQR, $0-3,873). Younger age, higher median household income, and high-deductible health insurance were associated with higher odds of receiving a GC (all P < .001). Patients with GC were more likely to pursue AS/WW than treatment (odds ratio, 2.00 [95% CI, 1.85 to 2.1]; P < .001). Patients receiving OncotypeDX, Prolaris, and Decipher were most likely to pursue AS/WW, RP, and RT with ADT, respectively (all P < .001). Prolaris was ordered more than three times as often in Detroit as in any other city, whereas OncotypeDx was ordered more than twice as often in New York City as in any other city. We show contemporary, real-world GC utilization trends, costs, and associations with treatment patterns. Prospective trials are ongoing to validate GC-informed treatment, but US uptake has expanded and management is associated with the use and type of GC.

PURPOSEMaster protocols represent transformations, enabling multiple therapies or diseases under a single protocol. These designs streamline therapeutic development by reducing redundancies. Suited for evolving fields such as oncology and global emergencies such as the COVID-19 pandemic, master protocols have been exemplified by studies such as RECOVERY, Solidarity, and I-SPY 2, which accelerated effective treatment identification (with I-SPY 2 focused on molecular subtypes). Recent oncology examples, such as MORPHEUS, evaluate immunotherapy combinations with shared controls. Despite advantages, their application in early-phase oncology remains underutilized amid growing regulatory emphasis on randomization for robust evidence.METHODSUS Food and Drug Administration (FDA) Oncology Center of Excellence (OCE) initiatives, such as Project Optimus and Project FrontRunner, emphasize randomization in early-phase oncology trials. However, these initiatives pose challenges, including larger sample sizes, patient and physician reluctance to randomization, and high failure rates from poor accrual. To address these, this article adapts master protocol designs to consolidate early-phase trials for novel therapeutics sharing a common backbone therapy, integrating hybrid controls from published standard-of-care data to minimize randomization to the control arm.RESULTSBy consolidating trials under a shared standard-of-care control arm, the proposed master protocol design reduces total sample size by as much as 55% when compared with independent trials (with control arm sizes 2.4-2.9 times lower), lowers costs and duration, and enhances enrollment through reduced randomization to controls. Incorporating hybrid controls from prior studies and sharing information among arms with common background standard-of-care further improve efficiency, increasing power (reaching 90% overall) while controlling type I error rates acceptable levels.CONCLUSIONMaster protocol designs with hybrid controls and Bayesian information sharing enable the efficient integration of randomization into early-phase oncology trials, enhancing efficiency, cost-effectiveness, and patient-centricity while aligning with FDA OCE initiatives.

Individuals with thyroid cancer have the highest prevalence of clonal hematopoiesis (CH) among patients with cancer. We sought to determine whether individuals who later develop thyroid cancer more frequently have CH before diagnosis or germline cancer susceptibility than healthy controls. We conducted a retrospective case-control study using subjects enrolled between 2002 and 2015 in a population-based biobank. Cases were healthy at enrollment but subsequently developed an incident thyroid cancer. Controls were healthy age- and race-matched subjects who were never diagnosed with a cancer. To assess baseline CH, whole-exome sequencing (WES) was performed on peripheral blood (PB) DNAs collected at enrollment. To assess CH acquisition over time, we recontacted a subset of cases and controls approximately 20 years after initial sampling for repeat PB WES. At enrollment, on average 9 years before a thyroid cancer diagnosis for cases, we identified CH in three of 63 (5%) cases and four of 125 (3%) controls. Adjusting for age, sex, and race, those with CH had a 1.51 odds (0.31-7.33; P = .61) of a thyroid cancer diagnosis versus those without CH at baseline. We detected pathogenic germline cancer susceptibility variants in 11% of cases and 7% of controls (P = .44). Among seven cases and seven controls recontacted, we found incident CH development in three (43%) and two (29%), respectively. We found that individuals who later develop early-stage thyroid cancers do not have a significantly higher prevalence of CH years before their diagnosis nor carry germline cancer susceptibility variants more often than those who do not develop thyroid cancer. Larger longitudinal studies are needed to fully elucidate the impact of germline and exposures in CH etiology.

Up to 30% of patients with metastatic castration-resistant prostate cancer (mCRPC) have DNA damage repair (DDR) gene alterations, mainly in BRCA2. PARP inhibitors (PARPi) are standard treatments for BRCA1/2-altered patients with mCRPC, and evidence for platinum agents is limited. This study assesses single-agent platinum therapy in patients with mCRPC with and without DDR alterations. This multicenter, retrospective study included patients with mCRPC with known DDR status treated with platinum monotherapy. DDR-positive (DDR+) patients had deleterious germline or somatic alterations in DDR genes (BRCA1, BRCA2, CDK12, ATM, CHEK2, PALB2, or FANCA), whereas DDR-negative (DDR-) patients had no such alterations. Prostate-specific antigen (PSA) response, progression-free survival (PFS, PSA/clinical/radiographic), and overall survival (OS) were assessed in DDR+ and DDR- groups. Among 129 patients, 81 had DDR+ and 48 had DDR- cancers. A PSA decline of ≥50% was demonstrated in 48% in BRCA, 9% in DDR+ non-BRCA, and 13% in DDR- patients (P < .0001). Objective responses occurred in 37.5% in BRCA, 11% in DDR+ non-BRCA, and 13% in DDR- patients (P = .017). No response was reported in DDR+ patients who had received previous PARPi (n = 16). The median PSA response was 5 months for BRCA, 2 months for DDR+ non-BRCA, and 1.7 months for DDR- patients, respectively (P = .015), whereas the median clinical/radiographic PFS was 4.7 months, 2.8 months, and 2 months, respectively (P = .2). In PARPi-naïve patients, the median OS was 13.7 months for BRCA, 8.7 months for DDR+ non-BRCA, and 6.1 months for DDR- patients (P = .013). Single-agent platinum agents show significant anticancer activity in BRCA-mutated patients with mCRPC without previous PARPi exposure. With their low cost and broad availability, platinum agents offer a practical alternative, particularly in regions where PARPi are inaccessible.

Tumor next-generation sequencing (NGS) enables molecular profiling to identify actionable mutations and guide targeted therapy. Adolescent and young adults (AYAs) with advanced sarcoma often face poor prognosis and limited systemic options. This study evaluated the clinical utility of tumor NGS in this population. A retrospective cohort study was conducted at Chris O'Brien Lifehouse, Sydney, including consecutive AYA patients with sarcoma who underwent tumor NGS between 2015 and 2025. Sequencing was performed through four molecular screening programs: Molecular Screening and Therapeutics, Cancer Screening Program, Personalized Rare and Infrequent Solid Malignancies, Zero Childhood Cancer Program, and commercial platform Foundation Medicine (FoundationOne CDx). Platforms used whole-genome sequencing, whole-exome sequencing, or targeted panels, assessing between 324 and 523 genes. Analyzed biomarkers included somatic mutations, gene fusions, tumor mutational burden (TMB), and microsatellite instability. Key end points included frequency of actionable mutations, treatment changes, and outcomes from NGS-guided therapies. NGS was successfully performed in 108 of 115 patients (94%). Actionable mutations were identified in 28 patients (24.4%), with molecular confirmation of diagnosis in four (3.5%). TMB was reported in 93 cases: 88 (94.6%) had low TMB (<10 mut/MB) and five (5.4%) had high TMB (≥10 mut/MB). Sixteen patients (14.8%) received NGS-directed therapy, mostly through clinical trials. Of them, 12 (75%) experienced disease progression, and only five (4.4%) derived clinical benefit (stable disease, partial response, or complete response). Among high TMB patients accessing immune checkpoint inhibitors, all but one progressed. Although few AYA patients with sarcoma derived clinical benefit from NGS-directed therapy (<5%), NGS proved useful for diagnosis and trial access. The absence of routine RNA sequencing may have limited the detection of fusion-driven sarcomas. Future integration of broader molecular techniques and collaborative infrastructure is essential to fully realize the potential of NGS in rare and high-risk sarcomas.

PURPOSEThe Clinical Pharmacogenetics Implementation Consortium (CPIC) recommends screening for four common DPYD variants to prevent severe toxicity in patients with cancer treated with fluoropyrimidines. A 50% starting dose followed by toxicity-based dose titration is advised for patients heterozygous for these variants. In this study, the appropriateness of the CPIC-recommended 5-fluorouracil (5-FU) starting dose was evaluated. PATIENTS AND METHODSPatients were grouped into four variant categories (DPYD*2A [c.1905+1G>A], DPYD*13 [c.1679T>G], c.2846A>T [p.D949V], c.1236G>A/HapB3 [p.E412E]) and a DPYD wild-type control group. Uracil loading tests were used for phenotyping. Variant patients started on a 50% reduced 5-FU dose. On the basis of steady-state 5-FU plasma concentrations, dose adjustments were made during cycles 2-4 until an 5-FU target AUC0-46h of 20-30 mg × h/L was achieved, if tolerated. RESULTSTwenty-six wild-type controls and 34 DPYD variant patients were included: 16 with c.1236G>A/HapB3, eight with c.1905+1G>A, eight with p.D949V, and two with c.1679T>G. Heterozygous carriers of c.1905+1G>A (DPYD*2A) and c.1679T>G (DPYD*13) displayed significant reduced uracil metabolism. The impact on uracil clearance was highly variable in p.D949V but only minor in c.1236G>A/HapB3 variants. In all, 65% of wild-type controls had 5-FU exposure within target range on a 100% dose (mean, 23.2; IQR, 6.6). In 97% of all variant patients, the 50% reduced dose resulted in 5-FU underexposure, with a median AUC of 10.6 mg × h/L (IQR, 3.2). Dose escalation to 70% or higher was tolerated in most patients, reaching the target AUC in 68% of patients. CONCLUSIONThe current CPIC guidelines are overly conservative for c.1236G>A/HapB3 and most p.D949V variants. A 75% starting dose is more appropriate for most c.1236G>A/HapB3 carriers. We recommend 5-FU therapeutic drug monitoring in all patients with DPYD variants to achieve optimal 5-FU exposure.

Microsatellite instability (MSI) arises from mismatch repair-deficiency (MMR-d) and is a predictor of immune checkpoint blockade (ICB) therapy response. Although MSI diagnostics typically yield a binary classification (MSI or microsatellite stable), the molecular phenotype likely represents a continuum. We explored whether MSI follows a quantitative spectrum, reflecting the extent and severity of microsatellite alterations, and whether it holds clinical significance. To quantitatively assess MSI, we evaluated the length of MSI peak shifts from polymerase chain reaction-based fragment length data in two cohorts (combined N = 237) of hereditary (Lynch syndrome) and sporadic MMR-d colorectal carcinomas (CRCs). We examined whether MSI peak shift lengths in diagnostic markers BAT25, CAT25, BAT26, and BAT40 correlate with specific MMR defects, histologic and clinical features, and coding microsatellite (cMS) mutations, potentially reflecting antigen load. MSI peak shift lengths varied among MMR-d CRCs and were influenced by the specific underlying MMR defect, such as germline mutations in MLH1, MSH2, MSH6, or PMS2, or somatic MLH1 promotor hypermethylation. Hereditary MSH6-deficient CRCs exhibited shorter peak shifts compared with hereditary MLH1-deficient and MSH2-deficient CRCs. Longer MSI peak shifts were associated with larger tumor sizes (odds ratio of 1.3 for every 1-cm increase in tumor diameter) and number of cMS mutations per tumor (P = 8.73e-09). Our findings demonstrate that (1) MSI peak shift lengths differ among MMR-d CRCs, (2) this variation is influenced by the specific MMR defect, and (3) this variation correlates with tumor size and number of cMS mutations. These findings suggest that a quantitative MSI classification could enhance clinical utility, with potential, for instance, in predicting disease progression and ICB therapy response.