Clinical criteria/Family history-based BRCA testing misses a large proportion of BRCA carriers who can benefit from screening/prevention. We estimate the cost-effectiveness of population-based BRCA testing in general population women across different countries/health systems. A Markov model comparing the lifetime costs and effects of BRCA1/BRCA2 testing all general population women ≥30 years compared with clinical criteria/FH-based testing. Separate analyses are undertaken for the UK/USA/Netherlands (high-income countries/HIC), China/Brazil (upper–middle income countries/UMIC) and India (low–middle income countries/LMIC) using both health system/payer and societal perspectives. BRCA carriers undergo appropriate screening/prevention interventions to reduce breast cancer (BC) and ovarian cancer (OC) risk. Outcomes include OC, BC, and additional heart disease deaths and incremental cost-effectiveness ratio (ICER)/quality-adjusted life year (QALY). Probabilistic/one-way sensitivity analyses evaluate model uncertainty. For the base case, from a societal perspective, we found that population-based BRCA testing is cost-saving in HIC (UK-ICER = $−5639/QALY; USA-ICER = $−4018/QALY; Netherlands-ICER = $−11,433/QALY), and it appears cost-effective in UMIC (China-ICER = $18,066/QALY; Brazil-ICER = $13,579/QALY), but it is not cost-effective in LMIC (India-ICER = $23,031/QALY). From a payer perspective, population-based BRCA testing is highly cost-effective in HIC (UK-ICER = $21,191/QALY, USA-ICER = $16,552/QALY, Netherlands-ICER = $25,215/QALY), and it is cost-effective in UMIC (China-ICER = $23,485/QALY, Brazil−ICER = $20,995/QALY), but it is not cost-effective in LMIC (India-ICER = $32,217/QALY). BRCA testing costs below $172/test (ICER = $19,685/QALY), which makes it cost-effective (from a societal perspective) for LMIC/India. Population-based BRCA testing can prevent an additional 2319 to 2666 BC and 327 to 449 OC cases per million women than the current clinical strategy. Findings suggest that population-based BRCA testing for countries evaluated is extremely cost-effective across HIC/UMIC health systems, is cost-saving for HIC health systems from a societal perspective, and can prevent tens of thousands more BC/OC cases.

PD1 blockade therapy, harnessing the cytotoxic potential of CD8 ⁺ T cells, has yielded clinical success in treating malignancies. However, its efficacy is often limited due to the progressive differentiation of intratumoral CD8 ⁺ T cells into a hypofunctional state known as terminal exhaustion. Despite identifying CD8 ⁺ T cell subsets associated with immunotherapy resistance, the molecular pathway triggering the resistance remains elusive. Given the clear association of CD38 with CD8 ⁺ T cell subsets resistant to anti-PD1 therapy, we investigated its role in inducing resistance. Phenotypic and functional characterization, along with single-cell RNA sequencing analysis of both in vitro chronically stimulated and intratumoral CD8 ⁺ T cells, revealed that CD38-expressing CD8 ⁺ T cells are terminally exhausted. Exploring the molecular mechanism, we found that CD38 expression was crucial in promoting terminal differentiation of CD8 ⁺ T cells by suppressing TCF1 expression, thereby rendering them unresponsive to anti-PD1 therapy. Genetic ablation of CD38 in tumor-reactive CD8 ⁺ T cells restored TCF1 levels and improved the responsiveness to anti-PD1 therapy in mice. Mechanistically, CD38 expression on exhausted CD8 ⁺ T cells elevated intracellular Ca ²⁺ levels through RyR2 calcium channel activation. This, in turn, promoted chronic AKT activation, leading to TCF1 loss. Knockdown of RyR2 or inhibition of AKT in CD8 ⁺ T cells maintained TCF1 levels, induced a sustained anti-tumor response, and enhanced responsiveness to anti-PD1 therapy. Thus, targeting CD38 represents a potential strategy to improve the efficacy of anti-PD1 treatment in cancer.

Ovarian cancer poses a significant and growing burden, particularly in low- and middle-income countries (LMICs) where incidence and mortality are projected to increase by over 50 % by 2050. However, there is a critical lack of qualitative data on the challenges and opportunities for improvement in treatment and care for women with ovarian cancer in these regions. The aim of this research is to investigate clinicians' perspectives on the matter in 24 LMICs. As part of the multi-country observational Every Woman Study™ (EWS), semi-structured interviews were conducted with clinicians between June 2022 and June 2023. The interview guide was developed by the EWS LMIC Oversight Committee, including patients, clinicians and data specialists. Relational content and inductive thematic analyses were employed and categories synthesized using the World Health Organization's six building blocks of the Health Systems Framework. 24 clinicians (54 % female; 79 % gynaecologic oncologists, 8 % gynaecologists, 8 % clinical oncologists not specializing in gynaecological cancers, and 4 % clinical oncologists specializing in gynaecological cancers; 42 % from Africa, 29 % from Asia, 29 % from Latin America) participated. Six dominant themes were identified: "Poor Ovarian Cancer Data'', "Inequity in Access to Treatment", "In-Country Inequities in Access to Care", "Role of Cultural Norms on Women's Health", "Increased Engagement of Men in Ovarian Cancer Control", and "Advocacy and Education for Empowering Women". Content analysis revealed system-level challenges such as delayed drug payments, lack of population-based cancer data, and limited imaging facilities. Patient-level challenges included disparities in access to specialists, limited medication affordability, poor symptom recognition, and reliance on alternative treatments. This study reveals the complexity of ovarian cancer treatment and care in LMICs and the need to mitigate disparities in these regions, underscoring the need for patient-centred, context specific and intersectoral strategies to be considered in cancer planning to improve ovarian cancer care quality and equity in LMICs.

Dysfunctional homologous recombination DNA repair (HRR), frequently due to BRCA mutations, is a determinant of sensitivity to platinum chemotherapy and poly(ADP-ribose) polymerase inhibitors (PARPi). In cultures of ovarian cancer cells, we have previously shown that HRR function, based upon RAD51 foci quantification, correlated with growth inhibition ex vivo induced by rucaparib (a PARPi) and 12-month survival following platinum chemotherapy. The aim of this study was to determine the feasibility of measuring HRR dysfunction (HRD) in other tumours, in order to estimate the frequency and hence wider potential of PARPi. A total of 24 cultures were established from ascites sampled from 27 patients with colorectal, upper gastrointestinal, pancreatic, hepatobiliary, breast, mesothelioma, and non-epithelial ovarian cancers; 8 were HRD. Cell growth following continuous exposure to 10 μM of rucaparib was lower in HRD cultures compared to HRR-competent (HRC) cultures. Overall survival in the 10 patients who received platinum-based therapy was marginally higher in the 3 with HRD ascites (median overall survival of 17 months, range 10 to 90) compared to the 7 patients with HRC ascites (nine months, range 1 to 55). HRR functional assessment in primary cultures, from several tumour types, revealed that a third are HRD, justifying the further exploration of PARPi therapy in a broader range of tumours.