Abstract BRCA-associated homologous recombination deficiency (HRD) is present in ~50% of high-grade serous carcinomas (HGSC) and predicts sensitivity to platinum-based therapy. However, there is little understanding of why some patients with BRCA-deficient tumors experience poor outcomes. In a large HGSC cohort (n = 1389) including 282 individuals with pathogenic germline BRCA variants (gBRCApv), residual disease after primary surgery has limited prognostic effect in gBRCApv-carriers compared to non-carriers, and prognostic outcomes differ based on the mutation location within functional domains of the BRCA genes. Multi-omic profiling is performed on 154 tumors, enriched for patients with BRCA-deficient tumors that experienced short overall survival ( ≤ 3 years, n = 42). Patients with BRCA2-deficient HGSC and loss of NF1 survive twice as long as those without NF1 loss, whereas PIK3CA, RAD21 and MYC amplification define BRCA2-deficient HGSC with exceptionally short survival. Patients with BRCA1-deficient HGSC and a more elevated HRD score survive significantly longer. BRCA1-deficient tumors in short survivors have evidence of immunosuppressive c-kit signaling and EMT. Our findings confirm that outcome is not determined by BRCA status alone, but rather a combination of co-occurring genomic alterations, the extent of DNA repair deficiency, and the tumor-immune microenvironment.

Background:The introduction of oral anticancer therapies has, at least partially, shifted treatment from clinician-supervised hospital care to patient-managed home regimens. However, patients with breast cancer receiving oral cyclin-dependent kinase 4/6 inhibitor therapy still require regular hospital visits to monitor side effects. Telemonitoring has the potential to reduce hospital visits while maintaining quality care. Objective:This study aims to develop a digital home-based health care center (DHHC) for acquiring electrocardiograms (ECGs), white blood cell (WBC) counts, side effect photo documentation, and patient-reported quality of life (QoL) data. Methods:The DHHC was set up using an Apple Watch Series 6 (ECG measurements), a HemoCue WBC DIFF Analyzer (WBC counts), an iPhone SE (QoL assessments and photo documentation), a TP-Link M7350-4G Wi-Fi router, and a Raspberry Pi 4 Model B. A custom-built app stored and synchronized remotely collected data with the clinic. The feasibility and acceptance of the DHHC among patients with breast cancer undergoing cyclin-dependent kinase 4/6 inhibitor therapy were evaluated in a prospective, single-arm, monocentric study. Patients (n=76) monitored side effects-ECGs, WBC counts, photo documentation, and QoL-at 3 predefined time points: study inclusion (on-site), day 14 (remote), and day 28 (remote). After the study completion, patients completed a comprehensive questionnaire on user perception and feasibility. Adherence to scheduled visits, the success rate of the data transfer, user perception and feasibility, and the clinical relevance of remote measurements were evaluated. Results:Mean adherence to the planned remote visits was 63% on day 14 and 37% on day 28. ECG measurements were performed most frequently (day 14: 57/76, 75%; day 28: 31/76, 41%). The primary patient-reported reason for nonadherence was device malfunction. The expected versus the received data transfer per patient was as follows: ECGs: 3 versus 3.04 (SD 1.9); WBC counts: 3 versus 2.14 (SD 1.14); QoL questionnaires: 3 versus 2.5 (SD 1.14); and photo documentation: 6 versus 4.4 (SD 3.36). Among patients, 81% (55/68) found ECG measurements easy, 82% (55/67) found photo documentation easy, and 48% (33/69) found WBC measurements easy. Additionally, 61% (40/66) of patients felt comfortable with self-monitoring and 79% (54/68) were willing to integrate remote monitoring into their future cancer care. Therapy-induced decreased neutrophil count was successfully detected (P<.001; mean baseline: 4.3, SD 2.2, ×109/L; on-treatment: 1.8, SD 0.8, ×109/L). All-grade neutropenia and corrected QT interval prolongations were detected in 80% (55/68) and 2% (1/42) of patients, respectively. Conclusions:Adherence to scheduled remote visits was moderate, with nonadherence primarily attributed to device-related complications, which may have also affected the success rate of data transfer. Overall, patients considered remote monitoring useful and feasible. The prevalence of reported adverse events was comparable to existing literature, suggesting clinical potential. This initial feasibility study highlights the potential of the DHHC.

Schema of study numbers for each analysis to describe different cohort numbers due to pathology review and missing data. MOC, mucinous ovarian carcinoma; MBOT, mucinous borderline ovarian tumor; LGI, lower gastrointestinal; UGI, upper gastrointestinal; SISH, silver in situ hybridization.

Associations between gene expression and stage group and OS in MOC.

Chemotherapies are still widely used in advanced breast cancer, specifically in patients with HER2-negative disease. This non-interventional real-world study assessed the utilization of nab-paclitaxel in a broad patient population with advanced breast cancer. SERAPHINA (NCT02642406) was a single arm, non-interventional study performed in Germany. Patients were eligible if they were treated with nab-paclitaxel according to the Summary of Product Characteristics (SmPC) as indicated by their physician. Progression-free survival (PFS), overall survival (OS), safety and quality of life were evaluated. Additionally, efficacy was assessed in patient subgroups based on age, metastasis pattern, performance status and therapy line. A total of 432 patients were treated with nab-paclitaxel. The majority of patients had HER2-negative disease (94.2

Patients with hormone receptor‐positive (HRpos), HER2‐negative (HER2neg) breast cancer (BC) benefit less from neoadjuvant chemotherapy (NACT) than patients with triple‐negative and HER2‐positive BC. In this retrospective analysis of the phase IV PreFace clinical trial (NCT01908556), where postmenopausal HRpos BC patients ( n = 3297) were treated with 5‐year upfront adjuvant letrozole therapy, we evaluated the prognosis of patients treated with adjuvant versus neoadjuvant chemotherapy in HRpos/HER2neg early‐stage BC. HRpos/HER2neg patients with information on (neo)adjuvant chemotherapy ( n = 2895) were retrospectively selected from all patients enrolled in the PreFace trial. Invasive disease‐free survival (iDFS) and overall survival (OS) were compared between patient groups that were treated with neoadjuvant or adjuvant chemotherapy. Chemotherapy was given to 1051 patients (36.3% of all patients), of which 874 (83.2%) received adjuvant chemotherapy and 177 (16.8%) NACT. Pathologic complete response (pCR) rate in the NACT group was 6.9%. Patients treated with NACT had a worse outcome than those treated with adjuvant chemotherapy (5‐year iDFS rate 81% vs. 88%; 5‐year OS rate 89% vs. 93%). This effect was maintained after adjusting for age, BMI, lymph node status, grading, tumor size, and histology (hazard ratio for iDFS: 1.95 (95%CI: 1.28–2.95); hazard ratio for OS: 2.13 (95%CI: 1.24–3.66)). Further adjustment for taxane‐based regimes did not alter results. In conclusion, in this retrospective analysis of patients with early‐stage HRpos/HER2neg BC, patients with NACT had a more unfavorable prognosis than patients treated adjuvantly, independent of patient and tumor characteristics. Prognosis of neoadjuvant patients might be affected by resistance mechanisms, warranting further investigation.

Kaplan–Meier curves of OS in (A) main tumor groups (n = 582)—MBOT, MOC, LGI, and UGI; (B) patients with MOC by FIGO stage (n = 184); (C) patients with MOC by pattern of invasion in all stages (n = 178); and (D) patients with stage I MOC (n = 134), by pattern of invasion.

The role of germline genetics in adjuvant aromatase inhibitor (AI) treatment efficacy in ER-positive breast cancer is poorly understood. We employed a two-stage candidate gene approach to examine associations between survival endpoints and common germline variants in 753 endocrine resistance-related genes. For a discovery cohort, we screened the Breast Cancer Association Consortium database (n ≥ 90,000 cases) and retrieved 2789 AI-treated patients. Cox model-based analysis revealed 125 variants associated with overall, distant relapse-free, and relapse-free survival (p-value ≤ 1E-04). In validation analysis using five independent cohorts (n = 8857), none of the six selected candidates representing major linkage blocks at CELA2B/CASP9, NR1I2/GSK3B, LRP1B, and MIR143HG (CARMN) were validated. We discuss potential reasons for the failed validation and replication of published findings, including study/treatment heterogeneity and other limitations inherent to genomic treatment outcome studies. For the future, we envision prospective longitudinal studies with sufficiently long follow-up and endpoints that reflect the dynamic nature of endocrine resistance.

Background Endometrial cancer is the most common gynaecological cancer in high-income countries. In addition to environmental risk factors, genetic predisposition contributes towards endometrial cancer development but is still incompletely defined. Methods Building on genome-wide association studies (GWASs) by the Endometrial Cancer Association Consortium, we conducted a GWAS meta-analysis of 17,278 endometrial cancer cases and 289,180 controls, incorporating biobank samples from the UK, Finland, Estonia and Japan. Findings GWAS analysis identified five additional risk loci (3p25.2, 3q25.2, 6q22.31, 12q21.2, and 17q24.2). Corresponding gene-based analyses supported findings for three of the five loci, at NAV3 (12q21.2), PPARG (3p25.2), and BPTF (17q24.2), as well as two additional candidate risk regions at ATF7IP2 (16p13.2-p13.13) and RPP21 (6p22.1). Validation genotyping in further independent case-control series replicated the most significant locus at 12q21.2 and corroborated risk variants located intronic to NAV3, the gene for Neuron Navigator 3. Downregulation of NAV3 in endometrial cell lines accelerated cell division and wound healing capacity whereas NAV3 overexpression reduced cell survival and increased cell death, indicating that NAV3 acts as a tumour suppressor in endometrial cells. Interpretation Our large study extends the number of genome-wide significant risk loci identified for endometrial carcinoma by about one-third and proposes a role of NAV3 as a tumour suppressor in this common cancer. Funding This study was mainly supported by funding from the Wilhelm Sander Foundation, Germany, and the National Health and Medical Research Council (NHMRC) of Australia. A complete list of funding organisations is provided in the acknowledgements.

Heat map of unsupervised clustering analysis. Contains all samples with a concordant pathology diagnosis (n = 497), with MOC grouped by FIGO stage. Labels show main clusters and diagnoses. Gene-expression values are normalized and logarithm base 2 transformed. dx, diagnosis.

Supplementary Figures S1-S13

Overall survival in MOC by pattern of invasion.

Supplementary Tables S1-S11

Patient characteristics and analytical cohorts.

Supplementary Table S5. Summary of cell lines used in this study.

Supplementary Table S10. Number of patients by study and histotype.

BACKGROUND:Prognostication has been used to identify patient populations that could potentially benefit from treatment de-escalation. In patients with hormone receptor-positive (HRpos), human epidermal growth factor receptor 2-negative (HER2neg) early breast cancer (eBC), treatment de-escalation classically involved omitting chemotherapy. With recently developed specialized therapies that require hands-on side-effect management, the therapeutic landscape is changing and therapy decisions are no longer based only on prognosis, but also consider potential side-effects. Therefore, identification of patient groups based on prognostication has gained importance. MATERIALS AND METHODS:In this retrospective analysis, a population of 2359 node-negative HRpos/HER2neg eBC patients was selected from all patients treated at the University Breast Center of Franconia, Germany between 2002 and 2021. The prognostic value of the IHC3 score (incorporating immunohistochemical measurements of the estrogen and progesterone receptor status and Ki-67) with clinical parameters (lymph node status, tumor stage, grading) regarding invasive disease-free survival (iDFS) and overall survival (OS) was assessed. RESULTS:IHC3 positively correlated with Ki-67 expression and inversely correlated with hormone receptor expression. IHC3 categorized into quartiles identified patients with a more unfavorable prognosis: 5-year and 10-year iDFS rates for patients in the highest versus the lowest quartile were 84% versus 95% and 70% versus 88%, respectively. A sensitivity analysis of distant disease-free survival showed similar results to those of iDFS. Five-year and 10-year OS rates for patients in the highest versus the lowest quartile were, respectively, 92% versus 97% and 81% versus 92%. CONCLUSIONS:IHC3 is able to define prognostic groups in patients with node-negative, HRpos/HER2neg eBC. Node-negative patients with a high IHC3 score had the worst prognosis, which was comparable to that of node-positive patients described in recent trials. This simple and cost-effective tool could thus potentially aid in identifying patient groups for innovative therapeutic approaches.