bims-ovdlit 2025-02-23 papers

Issue of 2025–02–23
six papers selected by
Lara Paracchini, Humanitas Research

Surg Oncol. 2025 Feb 06. pii: S0960-7404(25)00008-8. [Epub ahead of print]58 102193

Outcomes of risk-reducing surgeries in women at high risk for gynaecological cancers: A tertiary center experience.

Danielle Mor-Hadar, Orla McNally, Abby Grant, Niveditha Rajadevan, Rosemary McBain, Yael Naaman, Fiona Chan, Estefania Vicario, C David Wrede.

OBJECTIVE: Ovarian and endometrial carcinomas are the most common gynecologic malignancies, with general population risks of 1.4 % and 2.5 % respectively. Certain genetic factors can raise these risks to 44 % and 60 % respectively. The most effective risk-reduction (RR) method is the removal of the fallopian tubes, ovaries, and/or uterus. This study investigates surgical outcomes and occult cancer rates following RR surgery in high-risk women.
METHODS: This is a retrospective cohort study of all women identified as high-risk for gynaecologic cancer who were referred to a high-volume tertiary centre and underwent RR surgery. All pathology specimens were assessed by sectioning and extensively examining the fimbriated end (SEE-FIM) protocol. The analysis included patients' demographics, peri- and post-operative evaluation, and final histopathological reports.
RESULTS: Between 2008 and 2024, 576 women completed RR surgery in our centre. The rates of intra- and post-operative complications were 3.1 % and 4.5 %, respectively. The overall occult cancer rate was 3.4 % (n = 20). Of these, 11 (55 %) patients had high-grade serous carcinoma of the ovary/fallopian tube, and seven (35 %) patients were found to have endometrial cancer. Two cases had unexpected metastasis in the ovaries (10 %). Of the whole cohort, 12 (2.1 %) patients were found to have premalignant disease; eight serous tubal intraepithelial carcinoma; two atypical endometrial hyperplasia and two dysplasia of the cervix.
CONCLUSION: RR surgeries are safe with a low complication rate. The incidence of occult cancer at the time of RR surgery is low but significant. Endometrial sampling is to be considered, and all fallopian tubes should be examined with the SEE-FIM protocol.

Keywords: Occult cancer; Risk-reduction surgery

DOI: https://doi.org/10.1016/j.suronc.2025.102193

Int J Gynecol Cancer. 2025 Jan 23. pii: S1048-891X(25)00180-X. [Epub ahead of print] 101657

Estimating high-grade serous fallopian tubal carcinoma in the era of tubal hypothesis.

Koji Matsuo, Matthew W Lee, Katelyn B Furey, Jane L Yang, Lynda D Roman, Maximilian Klar, Anil K Sood, Jason D Wright.

In the era of the serous tubal intraepithelial carcinoma hypothesis, investigation continues as to what proportions of high-grade serous tubo-ovarian carcinomas originate in the distal fallopian tube versus in the ovary. In this retrospective cohort study of 118,619 patients with high-grade serous tubo-ovarian carcinoma identified in the Commission-on-Cancer's National Cancer Database from 2004 to 2021, a diagnosis shift from high-grade serous ovarian carcinoma to high-grade serous fallopian tubal carcinoma occurred from 2004 to 2018 that the proportional distribution of high-grade serous fallopian tubal carcinoma increased 6.1-fold from 4.5% in 2004 to 27.6% in 2018 (p-trend < .001). This rapid diagnosis shift from high-grade serous ovarian carcinoma to high-grade serous fallopian tubal carcinoma reached a plateau at 2018, followed by steady proportional distribution of high-grade serous fallopian tubal carcinoma among the high-grade serous tubo-ovarian carcinomas for 4 consecutive years (27.6% in 2018 to 28.0% in 2021, p-trend = .801). The average rate of tubal carcinomas during this post-plateau period was 27.7%. In conclusion, the diagnosis shift in the primary site of high-grade serous tubo-ovarian carcinoma from the ovary to the fallopian tube may have ended in the late 2010s. After the implementation of College of American Pathologists diagnosis criteria, 1 in 3 to 4 high-grade serous tubo-ovarian carcinomas were classified as of fallopian tube origin.

Keywords: Diagnosis Shift; High-Grade Serous Fallopian Tubal Carcinoma; High-Grade Serous Ovarian Carcinoma; Serous Tubal Intraepithelial Carcinoma

DOI: https://doi.org/10.1016/j.ijgc.2025.101657

Mol Biol Rep. 2025 Feb 21. 52(1): 261

Beyond the BRCA1/2 genes in ovarian cancer: the role of germline pathogenic variants in the ATM gene.

Daniele Guadagnolo, Angelo Minucci, Antonella Chiavassa, Gabriella Gentile, Francesca Salvatori, Nader Khaleghi Hashemian, Giulia Maneri, Maria Piane, Simona Grotta, Paola Grammatico, Antonio Pizzuti, Daniele Santini, Laura De Marchis.

BACKGROUND: Ovarian Cancer (OC) prevention and early-stage detection represents a challenge due to the lack of effective surveillance. The identification of high-risk women is crucial as it provides access to prophylactic oophorectomy and reduces disease burden. Next-Generation Sequencing approaches enable the investigation of several genes associated with monogenic hereditary cancer predisposition, including ovarian cancer. For family members of patients affected by ovarian cancer without identification of a germline pathogenic variant, despite the increased empirical risk (3 times) of ovarian cancer incidence, prophylactic surgery is not indicated but may be suggested as the only efficient strategy.
METHODS AND RESULTS: We hereby present 2 cases of OC in which a germline heterozygous pathogenic variant in the ATM gene was identified: the first in the contest of Hereditary Breast and Ovarian Cancer (HBOC) family history and, in the other one, a late onset of neoplasms, to underline the importance of defining guidelines and management of moderate penetrance genes variants also for ovarian cancer prevention.
CONCLUSIONS: Carriers of heterozygous pathogenic variants in the ATM gene have an increased risk of neoplasms incidence, mostly breast but also of OC with an absolute estimated risk of 2-3 times greater than the general population. For these patients there is not well-established evidence of benefit in risk reducing bilateral Salpingo-oophorectomy.

Keywords: ATM ; Cancer prevention; Hereditary Breast and Ovarian Cancer; Moderate penetrance genes; Ovarian cancer; Risk-Reducing Bilateral Salpingo-oophorectomy

DOI: https://doi.org/10.1007/s11033-025-10357-x

Nature. 2025 Feb 21.

Putting early cancer detection to the test.

Michael Eisenstein.

Keywords: Biotechnology; Cancer; Health care

DOI: https://doi.org/10.1038/d41586-025-00530-4

Eur J Cancer. 2025 Feb 11. pii: S0959-8049(25)00080-2. [Epub ahead of print]219 115299

Somatic BRCA1/2 mutations are associated with a similar survival advantage to their germline counterparts in tubo-ovarian high grade serous carcinoma.

BACKGROUND: Half of high grade serous tubo-ovarian carcinomas (HGSOC) demonstrate homologous recombination repair (HRR) deficiency, most commonly through germline or somatic pathogenic variants in BRCA1/2 (gBRCA1/2 or sBRCA1/2). gBRCA1/2 is associated with favourable survival, greater response rate to platinum-based chemotherapy, and marked sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors. sBRCA1/2 has been assumed to confer a similar clinical phenotype; however, few studies have specifically investigated sBRCA1/2 versus gBRCA1/2 to demonstrate their equivalence.
METHODS: We investigated the association of gBRCA1/2, sBRCA1/2 and non-BRCA HRR gene mutations with HGSOC patient survival using two patient cohorts (cohort 1, n = 174 matched FFPE tumour and normal with panel-based sequencing; cohort 2, n = 279 matched fresh tumour and normal with whole genome sequencing). TCGA-OV samples (n = 316) were used for external validation.
RESULTS: Patients with HRR-mutant tumours (BRCA1, BRCA2, non-BRCA HRR-mutant) demonstrated prolonged survival across both cohorts (cohort 1: multivariable hazard ratio [multiHR] 0.53 [0.32-0.87]; cohort 2: multiHR 0.36 [0.25-0.51]). gBRCA1/2 and sBRCA1/2 were associated with a similar survival benefit compared to the HRR-wildtype group in the combined cohort (cohort 1 +2) (gBRCA1/2: multiHR 0.50 [0.34-0.71]; sBRCA1/2: multiHR 0.41 [0.25-0.68]). These findings were recapitulated using the TCGA-OV dataset (gBRCA1/2: multiHR 0.56 [0.34-0.91]; sBRCA1/2: multiHR 0.48 [0.25-0.92]). Non-BRCA HRR mutations were associated with marked survival advantage (multiHR vs HRR-wildtype 0.22 [0.11-0.45]). The survival advantage in BRCA1-mutant cases (germline or somatic) was less marked (multiHR for non-BRCA HRR-mutant vs BRCA1-mutant 0.41 [0.19-0.90]). gBRCA1/2, sBRCA1/2 and non-BRCA HRR mutations were all associated with high HRDetect scores measuring HRR deficiency (median 1.00 versus 0.56 in HRR-wildtype, P < 0.01).
CONCLUSION: gBRCA1/2 and sBRCA1/2 are equivalent in their association with prolonged survival. Non-BRCA HRR gene mutations may be associated with markedly favourable survival in HGSOC.

Keywords: BRCA1; BRCA2; Germline; Ovarian cancer; Somatic mutation; Survival

DOI: https://doi.org/10.1016/j.ejca.2025.115299

Int J Cancer. 2025 Feb 14.

Acceptability and somatic mutations in cervicovaginal self-sampling for early endometrial cancer detection in women with Lynch syndrome.

New molecular approaches are being developed to detect endometrial cancer using minimally invasive sampling methods. This study aims to evaluate the acceptability of self-collected cervicovaginal samples among women with Lynch syndrome, a group at high risk for developing endometrial cancer. Participants collected cervicovaginal self-samples and answered an at-home acceptability questionnaire in a cross-sectional study. Self-samples from a subset of these women were analyzed for somatic mutations using next-generation sequencing (NGS), targeting a panel of 47 genes. A total of 61 (88.4%) out of 69 eligible women participated in the study. The overall self-sampling experience was rated good or very good (N = 55, 90.2%). Most of the women were confident about correctly sampling (N = 58, 95.1%), and most reported no or mild pain (N = 56, 91.8%). During self-sample collection, most women reported feeling calm and comfortable and experiencing safety, privacy, and normality. In a pilot study using a subset of 15 samples, five somatic variants were identified in four self-samples (4/15, 26.7%) in ACVR2A, ARID1A, APC, and KMT2D. During follow-up, three out of four women with variants detected in the self-sample underwent prophylactic hysterectomy at a median of 9.1 months, while one out of four developed endometrial cancer after 3.9 years since the collection of the sample. Self-sampling is well-accepted and well-tolerated in women with Lynch syndrome and could potentially reduce some barriers associated with gynaecological surveillance. Further research is needed to evaluate the feasibility of implementing cervicovaginal self-collection and the accuracy of molecular testing for gynaecological surveillance in women with Lynch syndrome.

Keywords: Lynch syndrome; acceptability; endometrial cancer; gynaecologic surveillance; self‐sampling

DOI: https://doi.org/10.1002/ijc.35368