Combination therapies are widely used in oncology due to their potential to improve therapeutic efficacy and overcome drug resistance. However, these potential advantages must be weighed against added toxicity, treatment burden, and costs. In this commentary, we examine some recent examples of divergent opinions by the US Food and Drug Administration and the European Medicines Agency across three indications. In neuroendocrine tumours, NETTER-2 demonstrated that early treatment intensification may improve progression-free survival. However, the higher toxicity, the absence of a demonstrated overall survival or quality of life benefit, and several important design limitations, including the open-label design and a potentially suboptimal control arm, complicate the interpretation of the results. In pleural mesothelioma, CheckMate-743 and KEYNOTE-483 did not prospectively evaluate biologically distinct histological or biomarker-defined subgroups, contributing to uncertainty regarding the populations most likely to benefit. In prostate cancer, the MAGNITUDE trial illustrates how prospectively defined adjacent cohorts, hierarchical testing, and subgroup-specific futility rules can more efficiently identify patients deriving meaningful benefit. Although it is often assumed that adjacent subgroup designs require larger sample sizes, MAGNITUDE challenges this misconception, having enrolled fewer patients than PROpel or TALAPRO-2. These cases illustrate how trial design influences the interpretation of benefit-risk outcomes, particularly when studies rely on broad trial populations, open-label designs, suboptimal control arms, or insufficiently powered subgroup analyses. Future trials of combination therapies should move beyond demonstrating regimen-level efficacy. Efforts must focus on identifying which patients benefit, whether each component is needed, and whether the added toxicity, treatment burden, and costs are justified.

Epidemiologic studies of PFAS and liver cancer risk have produced conflicting results with no strong or clear associations for pre-diagnostic perfluorooctanesulfonate (PFOS), perfluorooctanoate (PFOA), and perfluorohexanesulfonate (PFHxS). We now report analyses of nine additional PFAS in a nested case-control study within 12 prospective cohorts (853 cases, 853 matched controls) in the United States. Using multivariable-adjusted conditional logistic regression, we estimated odds ratios per 90th vs. 10th percentile increase in PFAS levels. Perfluoroheptanoic acid (PFHpA) was positively associated with liver cancer risk (OR: 1.78, 95% CI: 1.26-2.52); no associations were observed for other PFAS. Significant heterogeneity was observed by sex, cancer subtype, and time from blood collection. Associations were stronger among males (OR: 3.72, 95% CI: 2.10-6.59), for hepatocellular carcinoma (4.53, 2.59-7.94), and for those diagnosed ≤10 years after blood collection (3.17, 1.80-5.57). Given continued use of short-chain PFAS in consumer products, further research on their effects on liver health is warranted.

Global incidence and mortality rates for endometrial and cervical cancers have been steadily rising, while these rates for ovarian cancer have decreased. Although these cancers represent unique diseases and challenges, overlapping biology and responses to targeted and immunotherapies create opportunities to advance research through shared knowledge and resources. In 2025, investigators funded by National Cancer Institute (NCI) Specialized Programs of Research Excellence (SPORE) and other NCI-supported grants convened a hybrid meeting to identify challenges and knowledge gaps in translational research, highlight advances, define shareable resources and technologies, and foster collaboration among the Gynecologic Cancer SPORE sites, patient advocates, and NCI staff. Special sessions were arranged for presentations by Patient Advocates, Early-stage Investigators, Investigators Transitioning to Gynecologic Cancer Research. Meeting-wide workshops on Sharing Resources and Reducing Time to Activation of Clinical Trials and networking events were included. Collectively, the presentations converged on three overarching themes: (i) interception and early disease biology, (ii) development of innovative targeted and immune-based therapies, (iii) critical role of shared resources and collaborative infrastructure in accelerating translational progress. The unifying theme across disease sites was molecular advances to improve early detection/prevention and to drive therapeutic advancements. Novel findings discussed included: candidate precursor cells and mechanisms of high grade serous ovarian cancer development; therapeutic vaccines and their delivery methods for cervical dysplasia; identification of immune-targetable ovarian cancer antigens; various novel molecularly targeted drugs and immune-based agents for endometrial and ovarian cancers; and approaches to bypass drug resistance. Workshops delineated actionable strategies to further advance gynecologic cancer translational research.