bims-ovdlit 2025-08-17 papers

Issue of 2025–08–17
five papers selected by
Lara Paracchini, Humanitas Research

Gynecol Oncol. 2025 Aug 09. pii: S0090-8258(25)00948-5. [Epub ahead of print]201 44-52

Ovarian cancer after breast cancer in women with a BRCA1 or BRCA2 pathogenic variant.

Hereditary Breast Cancer Clinical Study Group

OBJECTIVE: Inherited BRCA1/2 pathogenic variants (mutations) confer high lifetime risks of breast and ovarian cancers. Estimating the cumulative ovarian cancer risk following a breast cancer diagnosis in these women will help guide decisions regarding preventive salpingo-oophorectomy.
METHODS: Women carrying a BRCA1 or BRCA2 mutation were followed after breast cancer and completed follow-up questionnaires every two years. The 15-year cumulative risk of ovarian cancer was estimated for women with a prior history of breast cancer and for matched control women without breast cancer.
RESULTS: A total of 2084 BRCA carriers with breast cancer (1515 BRCA1, 569 BRCA2) were included. During a mean follow-up of 3.9 years, 71 ovarian/fallopian carcinomas were diagnosed (66 BRCA1, 5 BRCA2). The 15-year cumulative ovarian cancer risk was 14.9 % in BRCA1 and 5.1 % in BRCA2 carriers. Women with breast cancer were compared to those without; 1378 matched pairs were included. The 15-year cumulative risk of ovarian/fallopian cancer was 10.8 % in women with a history of breast cancer versus 25.9 % in those without. Among BRCA1 carriers, the risk was 12.2 % in women with breast cancer and 32.0 % in those without. Among BRCA2 carriers, the 15-year ovarian cancer risk was 2.0 % in both groups.
CONCLUSIONS: Ovarian cancer risk remains high in BRCA1/2 carriers following breast cancer diagnosis. For BRCA1 mutation carriers, the risk is lower than in women without breast cancer. However, for both BRCA1 and BRCA2 the ovarian cancer risk is elevated, and considering the poor prognosis associated with ovarian cancer, risk-reducing salpingo-oophorectomy is strongly recommended for women with BRCA-associated breast cancer.

Keywords: BRCA mutation; Breast cancer; Ovarian after breast cancer; Ovarian cancer

DOI: https://doi.org/10.1016/j.ygyno.2025.07.030

JAMA Surg. 2025 Aug 13.

Gauging the Magnitude of Missed Opportunity for Ovarian Cancer Prevention.

Sara Moufarrij, Dana Hazimeh, Tori Rockwell, Victoria Ettorre, Christian Dagher, Nadeem R Abu-Rustum, Dennis S Chi, Kara C Long, Rebecca L Stone.

Importance: The impact of salpingectomy on the prevention of high-grade serous cancer (HGSC) at the population level is currently under investigation.
Objective: To determine the frequency of missed opportunity for salpingectomy with/without oophorectomy among patients diagnosed with HGSC.
Design, Setting, and Participants: This mixed-methods, multi-institutional retrospective study included patients diagnosed with HGSC at 2 academic medical centers between 2015 and 2021. Clinicopathologic data were abstracted from medical records. An electronic survey was also administered to members of a national ovarian cancer organization who self-identified as having had an HGSC diagnosis. The retrospective cohort included 1877 patients with HGSC and the survey included 917 respondents, of which 348 were diagnosed with HGSC. These data were analyzed from May 2023 and August 2023.
Exposure: Missed opportunity was defined as a history of either a surgical procedure resulting in permanent contraception (bilateral tubal ligation or hysterectomy without concurrent salpingectomy) at any age or another abdomino-pelvic surgery at 45 years or older when salpingectomy could have been performed 1 year or more preceding a diagnosis of HGSC.
Main Outcome and Measure: The proportion of HGSCs that could have been prevented with salpingectomy.
Results: Of the 445 patients (23.7%) with missed opportunities for salpingectomy in the retrospective cohort, 241 had a tubal ligation/hysterectomy (54.2%) and 204 had other abdomino-pelvic surgeries (45.8%). Cholecystectomy, hernia repair, and bowel surgeries were more commonly performed for patients 45 years or older than for younger patients. Among the 348 survey respondents, missed opportunity was reported by 54 (15.5%). The study team uncovered a 43.2% missed opportunity rate for germline genetic testing and reflex risk-reducing surgery among patients with an affected first-degree relative in the retrospective cohort.
Conclusions and Relevance: A considerable proportion of patients with HGSC missed opportunities for risk assessment with genetic testing and for surgical prevention. Given the lack of effective screening and limited treatment options for HGSC, eradicating it requires addressing the full spectrum of missed opportunities.

DOI: https://doi.org/10.1001/jamasurg.2025.2810

J Natl Cancer Inst. 2025 Aug 09. pii: djaf218. [Epub ahead of print]

The National Health Service-Galleri multi-cancer screening trial: explanation and justification of unique and important design issues.

Peter Sasieni, Charles Swanton, Richard D Neal.

Despite there being a plethora of multi-cancer early-detection tests, NHS-Galleri (ISRCTN91431511) is the only randomized controlled trial (RCT) of a multi-cancer liquid biopsy in a screening setting thus far. The NHS-Galleri trial has generated much debate, and it has been criticized in the medical press. Some of these criticisms stem from differing opinions over the choice of primary endpoint, others from poor reporting in statements to journalists from those not directly involved in the trial. Some of the debate is positive, and relates to the speed of enrolment, and the equity in participation, which have shown what is possible in large population-based RCTs. Here we explain our reasoning for undertaking the trial and designing it in the way we did. We focus on the reason to consider multi-cancer screening and why we felt that the results from non-randomized clinical studies of GRAIL's Galleri test justified a large RCT. We also consider the very slow progress in adopting effective cancer screening historically and in reducing cancer mortality through early detection. There is a need to plan now for future research and implementation depending on the results of the trial. NHS-Galleri is the first double-blind cancer screening RCT. It also, unusually, uses late-stage cancer incidence (rather than cancer mortality) as its primary outcome.

Keywords: Advanced stage; cell-free DNA; circulating tumor DNA; health inequalities; late-stage; multi-cancer early detection; nested analyses; pilot implementation; randomized controlled trial; sensitivity; surrogate endpoint; trial design

DOI: https://doi.org/10.1093/jnci/djaf218

Gynecol Oncol. 2025 Aug 13. pii: S0090-8258(25)00965-5. [Epub ahead of print]201 60-68

Germline landscape of high grade serous ovarian cancer across age groups: Is age just a number?

OBJECTIVE: To characterize age-related variations in germline pathogenic variants (gPVs) in patients with high-grade serous ovarian cancer (HGSOC).
METHODS: Patients with HGSOC who underwent clinical tumor-normal sequencing of ≥76 genes from 1/1/2015-11/15/2022, were included. Clinical variables including age at diagnosis were collected. Logistic regression models were built to examine associations between gPV, age, and clinical variables.
RESULTS: Of 1231 patients, median age at diagnosis was 63 years (range, 33-93); 163 patients (13 %) were diagnosed at age ≤ 49, 739 (60 %) between ages 50-69, and 329 (27 %) at age ≥ 70 years. gPVs were observed in 68 (42 %), 200 (27 %), and 52 patients (16 %) respectively, p < 0.001. Compared to patients diagnosed between ages 50-69, those diagnosed at age ≥ 70 were less likely to have a gPV (OR: 0.58; 95 % CI: 0.38-0.86) and those diagnosed at age ≤ 49 were more likely to have a gPV (OR: 1.78; 95 % CI: 1.18-2.68), after adjustment for genetic ancestry and NCI Comorbidity Index. Seven of 67 patients (10 %) diagnosed at age ≥ 80 years had a gPV, including 2 in OC-related genes (BRCA2, PALB2). Twelve of 21 patients (57 %) diagnosed at age ≤ 39 years had a gPV, all in OC-related genes. No differences in genetics follow-up or poly (ADP-ribose) polymerase inhibitor use were observed by age (p > 0.05).
CONCLUSION: Although gPV rates varied by age with the highest rates observed in patients with early-onset OC, rates were high (≥10 %) in all age groups, with similar genetics follow-up and implementation of targeted therapies. Universal genetic testing is important for all patients with OC regardless of age.

Keywords: Age; Genetic testing; Germline; High grade serous ovarian cancer; Ovarian cancer; Pathogenic variants; Rates

DOI: https://doi.org/10.1016/j.ygyno.2025.08.016

ESMO Open. 2025 Aug 13. pii: S2059-7029(25)01200-1. [Epub ahead of print]10(8): 105331

Addressing screening failures in early-phase clinical trials in oncology: impact on patient outcomes and strategies for improvement.

I Korakis, K Ouali, B Hanvic, L Verlingue, B Allignet, A Lusque, S Clementei, E Magne, C Massard, J-P Delord, P Cassier, C Baldini, B Segier, C Gomez-Roca.

BACKGROUND: Early-phase trials (EPT) assess efficacy/safety of new drugs that may represent therapeutic opportunities. Considering the stringent eligibility criteria, the screening process can result in high rate of screen failure (SF). We aimed to identify reasons for SF in patients who were initially deemed eligible and their prognostic factors.
PATIENTS AND METHODS: Patients with solid tumors who consented to participate in EPT yet screen failed between 2020 and 2022 across three French cancer centers were retrospectively included. We collected demographic data, Eastern Cooperative Oncology Group (ECOG) performance status (PS), Royal Marsden Hospital (RMH) score upon signature, reason for SF and survival data.
RESULTS: A total of 202 patients failed to enroll in EPT, representing an SF rate of 21.7% (Gustave Roussy Cancer Campus Villejuif), 21.4% (Oncopole Claudius Regaud, Toulouse) and 26.4% (Centre Léon Bérard, Lyon). Median age was 60 years (range 20-86 years); patients were mainly PS1 (n = 136, 67.3%). SF reasons were radiological (n = 59, 29.2%), biological (n = 48, 23.8%; n = 34 due to vital organ dysfunction), clinical (n = 45, 22.3%), administrative (n = 22, 10.9%), and PS deterioration (n = 24, 11.9%), and two patients died. Radiological reasons included brain metastases (n = 27), nonmeasurable disease (n = 17) and absence of target for mandatory biopsy (n = 8). Three-month mortality rate after SF was 30.2%, significantly related to biological (26.2%), clinical (26.2%) and PS deterioration (21.3%) (P = 0.012). Two-thirds of patients with newly discovered brain metastases were alive at 3 months (n = 18/27, 66.7%). Median follow-up was 24.6 months (19.6-26.9 months), 6-month overall survival was 47.5% (4.0-7.1 months). In the multivariable analysis adjusted for PS, location of metastatic sites and number of lines, RMH score remained significantly associated with OS (HR 2.20, P < 0.001). SF patients with RMH score of 0-1 presented an OS close to enrolled patients.
CONCLUSIONS: Main reasons for SF were radiological, biological and clinical. Therefore, referring patients with brain scan and laboratory results may help reduce SF rates. Current criteria deem ineligible 47.5% of patients who are alive at 6 months, questioning their accuracy for patient selection in EPT whose aim is to evaluate drug tolerance/activity.

Keywords: developmental drugs; patient selection; phase I trials; screen failure; survival analysis

DOI: https://doi.org/10.1016/j.esmoop.2025.105331