bims-ovdlit 2024-09-22 papers

Sci Rep. 2024 09 16. 14(1): 21602

Human papillomavirus infection of the fallopian tube as a potential risk factor for epithelial ovarian cancer.

Edyta Paradowska, Daria A Haręża, Katarzyna D Kania, Dariusz Jarych, Miłosz Wilczyński, Andrzej Malinowski, Monika Kawecka, Mateusz Nowak, Jacek R Wilczyński.

Human papillomaviruses (HPVs) and herpesviruses are detected in patients with epithelial ovarian cancer (EOC). We sought to analyze the prevalence of HPV's 16 and 18, cytomegalovirus (CMV), and Epstein-Barr virus (EBV) DNA in peripheral blood, ovarian, and fallopian tube (FT) tissue samples collected from 97 EOC patients, including 71 cases of high-grade serous ovarian carcinoma (HGSOC), and from 60 women with other tumors or non-neoplastic gynecological diseases. DNA isolates were analyzed by PCR methods, including droplet digital PCR. The results demonstrate that (1) HPV16 DNA has been detected in one-third of the FT and tumor samples from EOCs; (2) the prevalence and quantity of HPV16 DNA were significantly higher in FT samples from HGSOCs, non-HGSOCs, and ovarian metastases than in those from non-neoplastic diseases; (3) CMV and EBV have been detected in approximately one-seventh of EOC samples. The results suggest that HPV16 might be a potential risk factor for EOC development.

Keywords: Epithelial ovarian cancer; Fallopian tube; Herpesvirus; High-grade serous ovarian carcinoma; Papillomavirus

DOI: https://doi.org/10.1038/s41598-024-72814-0

Ann Oncol. 2024 Sep 14. pii: S0923-7534(24)03762-1. [Epub ahead of print]

Niraparib first-line maintenance therapy in patients with newly diagnosed advanced ovarian cancer: final overall survival results from the PRIMA/ENGOT-OV26/GOG-3012 trial.

BACKGROUND: The phase III PRIMA/ENGOT-OV26/GOG-3012 trial met its primary endpoint. Niraparib first-line maintenance significantly prolonged progression-free survival (PFS) among patients with newly diagnosed advanced ovarian cancer that responded to first-line platinum-based chemotherapy, regardless of homologous recombination deficiency (HRD) status. Final overall survival (OS) results are reported.
PATIENTS AND METHODS: Patients were randomized 2:1 to niraparib or placebo, stratified by response to first-line treatment, receipt of neoadjuvant chemotherapy, and tumor HRD status. After reaching 60% target maturity, OS was evaluated via a stratified log-rank test using randomization stratification factors and summarized using Kaplan-Meier methodology. OS testing was hierarchical [overall population first, then the homologous recombination-deficient (HRd) population]. Other secondary outcomes and long-term safety were assessed; an updated, ad hoc analysis of investigator-assessed PFS was also conducted (cut-off date, 8 April 2024).
RESULTS: The median follow-up was 73.9 months. In the overall population, the OS hazard ratio was 1.01 [95% confidence interval (CI) 0.84-1.23; P = 0.8834] for niraparib (n = 487) versus placebo (n = 246). In the HRd (n = 373) and homologous recombination-proficient (n = 249) populations, the OS hazard ratios were 0.95 (95% CI 0.70-1.29) and 0.93 (95% CI 0.69-1.26), respectively. Subsequent poly(ADP-ribose) polymerase inhibitor therapy was received by 11.7% and 15.8% of niraparib patients and 37.8% and 48.4% of placebo patients in the overall and HRd populations, respectively. The 5-year PFS rate numerically favored niraparib in the overall (niraparib, 22%; placebo, 12%) and HRd populations (niraparib, 35%; placebo, 16%). Myelodysplastic syndromes/acute myeloid leukemia incidence was <2.5% (niraparib, 2.3%; placebo, 1.6%). No new safety signals were observed.
CONCLUSIONS: In patients with newly diagnosed advanced ovarian cancer at high risk of recurrence, there was no difference in OS between treatment arms. In the HRd population, patients alive at 5 years were two times as likely to be progression free with niraparib treatment than placebo. Long-term safety remained consistent with the established niraparib safety profile.

Keywords: PARP inhibitor; maintenance; niraparib; ovarian cancer; overall survival

DOI: https://doi.org/10.1016/j.annonc.2024.08.2241

medRxiv. 2024 Sep 04. pii: 2024.09.04.24313051. [Epub ahead of print]

Analysis of more than 400,000 women provides case-control evidence for BRCA1 and BRCA2 variant classification.

NBCS Collaborators

Clinical genetic testing identifies variants causal for hereditary cancer, information that is used for risk assessment and clinical management. Unfortunately, some variants identified are of uncertain clinical significance (VUS), complicating patient management. Case-control data is one evidence type used to classify VUS, and previous findings indicate that case-control likelihood ratios (LRs) outperform odds ratios for variant classification. As an initiative of the Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) Analytical Working Group we analyzed germline sequencing data of BRCA1 and BRCA2 from 96,691 female breast cancer cases and 303,925 unaffected controls from three studies: the BRIDGES study of the Breast Cancer Association Consortium, the Cancer Risk Estimates Related to Susceptibility consortium, and the UK Biobank. We observed 11,227 BRCA1 and BRCA2 variants, with 6,921 being coding, covering 23.4% of BRCA1 and BRCA2 VUS in ClinVar and 19.2% of ClinVar curated (likely) benign or pathogenic variants. Case-control LR evidence was highly consistent with ClinVar assertions for (likely) benign or pathogenic variants; exhibiting 99.1% sensitivity and 95.4% specificity for BRCA1 and 92.2% sensitivity and 86.6% specificity for BRCA2. This approach provides case-control evidence for 785 unclassified variants, that can serve as a valuable element for clinical classification.

Keywords: BRCA1; BRCA2; VUS; case-control; likelihood ratio; odds ratio; rare variant

DOI: https://doi.org/10.1101/2024.09.04.24313051

ESMO Open. 2024 Sep 16. pii: S2059-7029(24)01484-4. [Epub ahead of print]9(10): 103714

Characteristics and clinical outcomes of breast cancer in young BRCA carriers according to tumor histology.

BACKGROUND: Young women with breast cancer (BC) have an increased chance of carrying germline BRCA pathogenic variants (PVs). Limited data exist on the prognostic impact of tumor histology (i.e. ductal versus lobular) in hereditary breast cancer.
METHODS: This multicenter retrospective cohort study included women aged ≤40 years with early-stage breast cancer diagnosed between January 2000 and December 2020 and known to carry germline PVs in BRCA1/2. Histology was locally assessed in each center. The Kaplan-Meier method and Cox regression analysis were used to assess disease-free survival and overall survival.
RESULTS: Of 4628 patients included from 78 centers worldwide, 3969 (86%) had pure ductal, 135 (3%) pure lobular, and 524 (11%) other histologies. Compared with ductal tumors, lobular tumors were more often grade 1/2 (57.7% versus 22.1%), stage III (29.6% versus 18.5%), and luminal A-like (42.2% versus 12.2%). Lobular tumors were more often associated with BRCA2 PVs (71.1% BRCA2), while ductal tumors were more often associated with BRCA1 PVs (65.7% BRCA1). Patients with lobular tumors more often had mastectomy (68.9% versus 58.3%), and less often received chemotherapy (83.7% versus 92.9%). With a median follow-up of 7.8 years, no significant differences were observed in disease-free survival (adjusted hazard ratio 1.01, 95% confidence interval 0.74-1.37) or overall survival (hazard ratio 0.96, 95% confidence interval 0.62-1.50) between patients with ductal versus lobular tumors. No significant survival differences were observed according to specific BRCA gene, breast cancer subtype, or body mass index.
CONCLUSIONS: In this large global cohort of young BRCA carriers with breast cancer, the incidence of pure lobular histology was low and associated with higher disease stage at diagnosis, luminal-like disease and BRCA2 PVs. Histology did not appear to impact prognosis.

Keywords: BRCA; breast cancer; histology; lobular

DOI: https://doi.org/10.1016/j.esmoop.2024.103714

Mol Cancer Ther. 2024 Sep 16.

Emerging Tumor-Agnostic Molecular Targets.

Dedipya Bhamidipati, Alison M Schram.

Advances in tumor molecular profiling have uncovered shared genomic and proteomic alterations across tumor types that can be exploited therapeutically. A biomarker-driven, disease-agnostic approach to oncology drug development can maximize the reach of novel therapeutics. To date, eight drug-biomarker pairs have been approved for the treatment of patients with advanced solid tumors with specific molecular profiles. Emerging biomarkers with the potential for clinical actionability across tumor types include gene fusions involving NRG1, FGFR1/2/3, BRAF, and ALK, mutations in TP53 Y220C, KRAS G12C, FGFR2/3, and BRAF non-V600 (Class II). We explore the growing evidence for clinical actionability of these biomarkers in patients with advanced solid tumors.

DOI: https://doi.org/10.1158/1535-7163.MCT-23-0725