Unraveling the role of stromal disruption in aggressive breast cancer etiology and outcomes DOI
Mustapha Abubakar, Máire A. Duggan, Shaoqi Fan

et al.

JNCI Journal of the National Cancer Institute, Journal Year: 2025, Volume and Issue: unknown

Published: May 14, 2025

Abstract Background Aggressive (typically high-grade) breast cancers (BCs) remain major contributors to BC-related mortality globally. The tissue changes underpinning their etiology and outcomes, however, poorly characterized. Methods Spatially resolved machine-learning algorithms were used characterize “stromal disruption” as a morphological metric of reduced/altered extracellular matrix increased immune, inflammatory, and/or wound response-related processes in normal, benign disease (BBD), invasive hematoxylin eosin (H&E)-stained tissues. Associations stromal disruption with BC etiologic factors assessed among 4023 healthy donors, its impact on incidence was 974 BBD patients nested case–control study, while prognostic associations 4 patient cohorts (n = 4223). Results Epidemiologic risk for aggressive BC, including younger age, multiparity, Black race, obesity, family history, demonstrated strong increasing H&E sections prior tumor development. Substantial associated ∼4-fold (high-grade) ∼3 years shorter latency from diagnosis, independently histology. Across cohorts, (mostly phenotypes markedly poor prognosis ER-positive patients, irrespective immunobiology reflected heightened innate (CD68+), adaptive (CD3+CD4+, CD3+CD8+), immunoregulatory (CD3+CD4+FOXP3+), immune escape (PD1+PDL1+), endothelial (CD31+), myofibroblast (α-SMA+) marker expression. Conclusion Our findings highlight the active role opening possibilities readily identifying high-risk women across continuum that may benefit stroma-centric preventative or therapeutic strategies.

Language: Английский

Overall survival in the OlympiA phase III trial of adjuvant olaparib in patients with germline pathogenic variants in BRCA1/2 and high-risk, early breast cancer DOI Creative Commons
Charles E. Geyer, Judy E. Garber, Richard D. Gelber

et al.

Annals of Oncology, Journal Year: 2022, Volume and Issue: 33(12), P. 1250 - 1268

Published: Oct. 10, 2022

Language: Английский

Citations

293
A phase II study of talazoparib monotherapy in patients with wild-type BRCA1 and BRCA2 with a mutation in other homologous recombination genes DOI Creative Commons
Joshua J. Gruber, Anosheh Afghahi, Kirsten M. Timms

et al.

Nature Cancer, Journal Year: 2022, Volume and Issue: 3(10), P. 1181 - 1191

Published: Oct. 17, 2022

Abstract Talazoparib, a PARP inhibitor, is active in germline BRCA1 and BRCA2 (g / 2 )-mutant advanced breast cancer, but its activity beyond g poorly understood. We conducted Talazoparib Beyond BRCA ( NCT02401347 ), an open-label phase II trial, to evaluate talazoparib patients with pretreated HER2-negative cancer n = 13) or other solid tumors 7) mutations homologous recombination (HR) pathway genes than . In four had Response Evaluation Criteria Solid Tumors (RECIST) partial response (overall rate, 31%), three additional stable disease of ≥6 months (clinical benefit 54%). All PALB2 ; encoding partner localizer BRCA2) treatment-associated tumor regression. Tumor plasma circulating DNA (ctDNA) HR deficiency (HRD) scores were correlated treatment outcomes increased all tumors. addition, -associated mutational signature was associated response. Thus, has been demonstrated have efficacy who mutations, showing the context gene

Language: Английский

Citations

86
Differences in Cancer Phenotypes Among Frequent CHEK2 Variants and Implications for Clinical Care—Checking CHEK2 DOI Creative Commons
Brittany L. Bychkovsky, Nihat Buğra Ağaoğlu, Carolyn Horton

et al.

JAMA Oncology, Journal Year: 2022, Volume and Issue: 8(11), P. 1598 - 1598

Published: Sept. 22, 2022

Germline CHEK2 pathogenic variants (PVs) are frequently detected by multigene cancer panel testing (MGPT), but our understanding of PVs beyond c.1100del has been limited.To compare phenotypes frequent individually and collectively variant type.This retrospective cohort study was carried out in a single diagnostic laboratory from 2012 to 2019. Overall, 3783 participants with identified via MGPT were included. Medical histories PVs, negative (wild type), loss-of-function (LOF), missense compared.Participants stratified PV type. Descriptive statistics summarized including median (IQR) for continuous variables proportions categorical characteristics. Differences age assessed Wilcoxon rank sum Fisher exact tests, respectively. Frequencies, odds ratios (ORs), 95% confidence intervals calculated, P values corrected multiple comparisons where appropriate.Of the 3473 (92%) female most reported White race. Breast less p.I157T (OR, 0.66; CI, 0.56-0.78; P<.001), p.S428F 0.59; CI. 0.46-0.76; p.T476M 0.74; 0.56-0.98; = .04) compared other an association nonbreast cancers not found. Following exclusion p.I157T, p.S428F, p.T476M, monoallelic had younger at first diagnosis (P < .001) more likely have breast 1.83; 1.66-2.02; .001), thyroid 1.63; 1.26-2.08; kidney 2.57; 1.75-3.68; than wild-type cohort. Participants colorectal 0.62; 0.51-0.76; those There no significant differences between LOF PVs.CHEK2 few exceptions (p.I157T, p.T476M), associated similar irrespective cancer, breast, kidney, cancers. Compared alleles attenuated These data may inform genetic counseling care individuals PVs.

Language: Английский

Citations

55
Enhancing the BOADICEA cancer risk prediction model to incorporate new data onRAD51C,RAD51D,BARD1updates to tumour pathology and cancer incidence DOI Creative Commons
Andrew Lee, Nasim Mavaddat, Alex Cunningham

et al.

Journal of Medical Genetics, Journal Year: 2022, Volume and Issue: 59(12), P. 1206 - 1218

Published: Sept. 26, 2022

Background BOADICEA (Breast and Ovarian Analysis of Disease Incidence Carrier Estimation Algorithm) for breast cancer the epithelial tubo-ovarian (EOC) models included in CanRisk tool ( www.canrisk.org ) provide future risks based on pathogenic variants cancer-susceptibility genes, polygenic risk scores, density, questionnaire-based factors family history. Here, we extend to include effects recently established EOC susceptibility up-to-date age-specific pathology distributions continuous factors. Methods was extended further incorporate associations BARD1 , RAD51C RAD51D with risk. The model association PALB2 Age-specific oestrogen-receptor-negative triple-negative status variant carriers these genes CHEK2 ATM were also incorporated. A novel method developed, exemplified by including adult height as continuous. Results explain 0.31% variance. When incorporated into multifactorial model, 34%–44% would be reclassified near-population 15%–22% high-risk categories UK National Institute Health Care Excellence guidelines. Under 62%, 35% 3% have lifetime <5%, 5%–10% >10%, respectively. Including continuous, increased relative variance from 0.002 0.010. Conclusions These extensions will allow better personalised more informed choices screening, prevention, factor modification or other risk-reducing options.

Language: Английский

Citations

47
Genetic Predisposition to Colorectal Cancer: How Many and Which Genes to Test? DOI Open Access
Francesca Rebuzzi, Paola Ulivi, Gianluca Tedaldi

et al.

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(3), P. 2137 - 2137

Published: Jan. 21, 2023

Colorectal cancer is one of the most common tumors, and genetic predisposition key risk factors in development this malignancy. Lynch syndrome familial adenomatous polyposis are best-known diseases associated with hereditary colorectal cancer. However, some other disorders confer an increased cancer, such as Li-Fraumeni (TP53 gene), MUTYH-associated (MUTYH Peutz-Jeghers (STK11 Cowden (PTEN juvenile (BMPR1A SMAD4 genes). Moreover, recent advances molecular techniques, particular Next-Generation Sequencing, have led to identification many new genes involved cancers, RPS20, POLE, POLD1, AXIN2, NTHL1, MSH3, RNF43 GREM1. In review, we summarized past more findings field genes, insights into role encoded proteins disorders. Furthermore, discussed possible clinical utility testing terms prevention protocols therapeutic approaches.

Language: Английский

Citations

41
Hereditary breast cancer: syndromes, tumour pathology and molecular testing DOI Creative Commons
Anna Sokolova, Kate Johnstone, Amy E. McCart Reed

et al.

Histopathology, Journal Year: 2022, Volume and Issue: 82(1), P. 70 - 82

Published: Dec. 5, 2022

Hereditary factors account for a significant proportion of breast cancer risk. Approximately 20% hereditary cancers are attributable to pathogenic variants in the highly penetrant BRCA1 and BRCA2 genes. A genetic risk is also explained by other susceptibility genes, including ATM , CHEK2 PALB2 RAD51C RAD51D BARD1 as well genes associated with predisposition syndromes – TP53 (Li–Fraumeni syndrome), PTEN (Cowden CDH1 (hereditary diffuse gastric cancer), STK11 (Peutz–Jeghers syndrome) NF1 (neurofibromatosis type 1). Polygenic risk, cumulative from carrying multiple low‐penetrance alleles, well‐recognised contributor This review provides an overview established syndromes, highlights distinct genotype–phenotype correlations germline mutation status discusses molecular testing therapeutic implications context cancer.

Language: Английский

Citations

39
Hereditary cancer syndromes DOI Open Access
Evgeny N. Imyanitov, Ekatherina Sh. Kuligina, Anna P. Sokolenko

et al.

World Journal of Clinical Oncology, Journal Year: 2023, Volume and Issue: 14(2), P. 40 - 68

Published: Feb. 20, 2023

Hereditary cancer syndromes (HCSs) are arguably the most frequent category of Mendelian genetic diseases, as at least 2% presumably healthy subjects carry highly-penetrant tumor-predisposing pathogenic variants (PVs). breast-ovarian and Lynch syndrome make highest contribution to morbidity; in addition, there several dozen less types familial tumors. The development majority albeit not all hereditary malignancies involves two-hit mechanism,

Language: Английский

Citations

30
Gender-Specific Genetic Predisposition to Breast Cancer: BRCA Genes and Beyond DOI Open Access
Virginia Valentini,

Agostino Bucalo,

Giulia Conti

et al.

Cancers, Journal Year: 2024, Volume and Issue: 16(3), P. 579 - 579

Published: Jan. 30, 2024

Among neoplastic diseases, breast cancer (BC) is one of the most influenced by gender. Despite common misconceptions associating BC as a women-only disease, can also occur in men. Additionally, transgender individuals may experience BC. Genetic risk factors play relevant role predisposition, with important implications precision prevention and treatment. The genetic architecture susceptibility similar women men, high-, moderate-, low-penetrance variants; however, some sex-specific features have emerged. Inherited high-penetrance pathogenic variants (PVs) BRCA1 BRCA2 genes are strongest factor. PVs more commonly associated increased female male BC, respectively. Notably, BRCA-associated BCs characterized pathologic features. Recently, next-generation sequencing technologies helped to provide insights on moderate-penetrance variants, particularly PALB2, CHEK2, ATM genes, while international collaborative genome-wide association studies contributed evidence their combined effect polygenic models, modulators BRCA1/2 PV carriers. Overall, all these suggested that basis although similar, differ from Evaluating component distinct entity first step improve both personalized assessment therapeutic choices patients sexes order reach gender equality care. In this review, we summarize latest research field predisposition particular focus similarities differences discuss implications, challenges, open issues surround establishment gender-oriented clinical management for

Language: Английский

Citations

16
Identification of aberrant luminal progenitors and mTORC1 as a potential breast cancer prevention target in BRCA2 mutation carriers DOI
Rachel Joyce, Rosa Pascual, Luuk Heitink

et al.

Nature Cell Biology, Journal Year: 2024, Volume and Issue: 26(1), P. 138 - 152

Published: Jan. 1, 2024

Language: Английский

Citations

11
Cost-Effectiveness of Gene-Specific Prevention Strategies for Ovarian and Breast Cancer DOI Creative Commons
Wei Xia, Li Sun, Eric Slade

et al.

JAMA Network Open, Journal Year: 2024, Volume and Issue: 7(2), P. e2355324 - e2355324

Published: Feb. 9, 2024

Importance Pathogenic variants (PVs) in BRCA1 , BRCA2 PALB2 RAD51C RAD51D and BRIP1 cancer susceptibility genes (CSGs) confer an increased ovarian (OC) risk, with PVs also conferring elevated breast (BC) risk. Risk-reducing surgery, medical prevention, BC surveillance offer the opportunity to prevent cancers deaths, but their cost-effectiveness for individual CSGs remains poorly addressed. Objective To estimate of prevention strategies OC among individuals carrying previously listed CSGs. Design, Setting, Participants In this economic evaluation, a decision-analytic Markov model evaluated risk-reducing salpingo-oophorectomy (RRSO) and, where relevant, mastectomy (RRM) compared nonsurgical interventions (including risk) from December 1, 2022, August 31, 2023. The analysis took UK payer perspective lifetime horizon. simulated cohort consisted women aged 30 years who carried or PVs. Appropriate sensitivity scenario analyses were performed. Exposures CSG-specific interventions, including RRSO at age 35 50 without (ie, tamoxifen anastrozole) 40 years, RRM both RRM, no intervention. Main Outcomes Measures incremental ratio (ICER) was calculated as cost per quality-adjusted life-year (QALY) gained. cases deaths estimated. Results cancer, undergoing most cost-effective (RRM years; years), 45 years) corresponding ICERs −£1942/QALY (−$2680/QALY), −£89/QALY (−$123/QALY), £2381/QALY ($3286/QALY), respectively. PV carriers strategies. £962/QALY ($1328/QALY), £771/QALY ($1064/QALY), £2355/QALY ($3250/QALY), preventive strategy 1000 could 923 302 those ; 686 170 464 130 102 64 118 76 55 37 . Probabilistic indicated 96.5%, 89.2%, 84.8% simulations PVs, respectively, while approximately 100% Conclusions Relevance study, varying optimal ages These findings support personalizing surgery guideline recommendations risk management.

Language: Английский

Citations

9