Paclitaxel-based regimens are frequently associated with the development of peripheral neuropathy. The autonomous nervous system (ANS) effects, however, of this chemotherapeutic agent remain unexplored. We investigated a group of 31 female patients with ovarian cancer receiving treatment with paclitaxel and carboplatin, as well as a group of 16 healthy age- and gender-matched healthy volunteers. All study participants completed a questionnaire and were assessed neurophysiologically at three time points (baseline, 3–4 months and 6–8 months following the onset of chemotherapy). The evaluation of the ANS included assessment of the adrenergic cardiovascular function (orthostatic hypotension-OH), parasympathetic heart innervation (30/15 ratio) and sympathetic skin response (SSR). At the 3–4 months ANS assessment, 19.2 % of the patients had systolic OH and the same percentage had diastolic OH, but at the 6–8 months evaluation no patient had systolic OH and only 13.8 % had diastolic OH. The values of the 30/15 ratio were significantly reduced at both time points, whereas the SSR was not affected. Combined paclitaxel and carboplatin chemotherapy is associated with significant effects on the parasympathetic heart innervation and occasionally with effects on the adrenergic cardiovascular reaction. The SSR remained unaffected. Physicians should be alert to the possibility of these treatment-emergent side effects, so as to monitor ANS parameters and introduce treatment modifications accordingly. Our findings however, should be validated in larger cohorts.

Background: The shift towards an earlier diagnosis of breast cancer (BC) highlights the need for biomarkers that would identify patients at risk for relapse and metastatic spread and indicate the potential value of additional treatment strategies. Osteopontin (OPN) is a matricellular protein that has been suggested to be a potential biomarker in BC. In the present study, we used archived BC patient samples to assess the clinical utility of OPN. Methods: Formalin-fixed paraffin-embedded tumor tissue samples from 975 patients were collected from two large phase III randomized adjuvant chemotherapy trials (HE10/97 and HE10/00) that included patients with high risk BC. All tissue samples were assessed for ER, PgR, Ki67 and HER2 protein expression. OPN protein and mRNA expression was evaluated using immunohistochemistry and quantitative reverse transcription-polymerase chain reaction, respectively. Results: OPN mRNA expression data were available for 814 patients, whereas OPN protein expression data were available for 546 patients. The majority of patients were ER/PgR-positive (78.3%), HER2-negative (76.5%) and Ki67-positive (55.2%) and had received adjuvant radiation therapy (76.8%) and hormonal therapy (81.1%). OPN mRNA expression was significantly associated with age (60.9% in high OPN tumors vs. 54.1% in low OPN tumors, p = 0.047), ER/PgR-negative status (25.7 vs. 17.2%, p = 0.004) and BC subtypes (p = 0.021). In addition, high OPN mRNA expression was significantly associated with reduced DFS (HR 1.26, 95% CI 1.00–1.59, Wald’s p = 0.050) and OS (HR 1.37, 95% CI 1.05–1.78, p = 0.019), while it retained its prognostic significance for both DFS (HR 1.39, 95% CI 1.10–1.77, p = 0.007) and OS (HR 1.54, 95% CI 1.61–2.05, p = 0.003) in the multivariate analysis. Conclusions: We showed that high OPN mRNA expression is associated with decreased DFS and OS in a large cohort of BC patients treated with adjuvant chemotherapy in a clinical trial setting. Our results suggest that OPN may serve as a prognostic factor and a potential target for therapy. Trial registration Australian New Zealand Clinical Trials Registry; HE10/97 ACTRN12611000506998; HE10/00 ACTRN12609001036202

Background/Aim: PTEN-loss and PIK3CA mutations have been addressed as markers of PI3K activation in breast cancer. We evaluated these markers in early high-risk breast cancer (EBC) focusing on PTEN immunohistochemistry (IHC) issues, particularly in HER2-positive disease. Materials and Methods: We examined PTEN-loss and PIK3CA mutations in 1265 EBC patients treated with adjuvant chemotherapy within two clinical trials. Two different methods for the evaluation of PTEN IHC were used, one upfront binary (loss; no-loss) and the other initially multi-scale allowing for the classification of “grey zone” tumors with low and very low PTEN protein expression. Results: PTEN-loss (33.4% and 22.1%, depending on the IHC method) and PIK3CA mutations (29.6%) were associated with ER/PgR/HER2-negative and ER/PgR-positive disease, respectively. Concordance of the two IHC methods was moderate (Cohen's kappa 0.624). PTEN-loss discrepancy and intra-tumor heterogeneity concerned “grey zone” tumors that were prevalent among HER2-positive cancers. PTEN-loss independently conferred higher risk for relapse and death. Compared to single PIK3CA mutations,single PTEN-loss was independently associated with increased risk for relapse and death. Depending on the evaluation method, in HER2-positive cancer, PTEN-loss was without- or of marginal unfavorable prognostic significance. Conclusion: In EBC, PTEN-loss is an independent predictor of poor outcome. When occurring singly, PTEN-loss and PIK3CA mutations have opposite prognostic impact. In HER2-positive disease, assessment of PTEN-loss by IHC appears unreliable and the marker is without clear prognostic significance.

In breast cancer, current knowledge of the associations between clinicopathologic characteristics, genetic changes, and subtype-specific patterns remain unclear. This research investigated how pathological and clinical variables affect the actionability of NGS-based tumor molecular data. Materials and methods: 227 breast cancer patients referred to Genekor’s laboratory for tumor molecular profile analysis were included in the study. Pathology records, available in all cases, were used to assess critical clinicopathological features including HER2, ER, PR, Ki67, grade, metastatic site, and age. A 1021 gene NGS-based multigene panel was utilized to assess tumors’ biology alongside tumor mutational burden (TMB) and microsatellite instability (MSI) Results: Comprehensive genomic profiling revealed that 95.6% of the patients harbored at least one oncogenic or likely oncogenic alteration, highlighting the high diagnostic yield of NGS-based testing. Distinct subtype-specific patterns were observed: HR+/HER2-tumors were enriched for PIK3CA and ESR1 gene alterations, while Triple Negative Breast Cancer (TNBC) was dominated by TP53 alterations. Clinically actionable alterations were most common in HR+/HER2-tumors (~60% on-label), whereas TNBC more often harbored off-label or trial-associated targets. The inclusion of tumor-agnostic biomarkers (TMB/MSI) increased on-label actionability up to 64.5% in ER−/PR+ tumors. primarily driven by TMB-high cases. Median TMB values were low, and age was the only independent predictor. Furthermore, the presence of actionable alterations was significantly higher in metastatic tumors, and TP53 alterations were associated with aggressive tumor characteristics.Conclusions: Comprehensive NGS-based genomic profiling identifies clinically actionable alterations in over half of breast cancer patients, with substantial variability across molecular subtypes. The HR+/HER2-subtype demonstrates the highest prevalence of on-label actionable biomarkers. These findings support the routine implementation of comprehensive genomic profiling, especially in metastatic HER2-negative breast cancer, to guide precision oncology strategies and enable enrollment in biomarker-driven clinical trials.

Background/Objectives: Lynch syndrome is an inherited autosomal dominant disease that predisposes to a broad spectrum of malignancies. This condition is driven by a germline pathogenic variant in one or more of the mismatch repair (MMR) genes (MLH1, MSH2, MSH6, PMS2, EPCAM) that results in genomic microsatellite instability (MSI-high). However, microsatellite-stable (MSS) tumors in Lynch syndrome patients may occur, but the relevant literature is scant. Our aim is to systematically identify, organize, and characterize the comprehensive available literature for Lynch syndrome-associated gynecological cancers (vulvar, vaginal, cervical, ovarian, endometrial) exhibiting a dMMR/MSS phenotype. Methods: Systematic review of the literature. Three medical databases, major related conferences and relevant oncology journals were scrutinized for relative evidence. Results: Eleven reports were identified comprising 2351 patients, 774 had confirmed Lynch syndrome (LS), of whom MSI results were available for 299 patients. In total, 130 patients developed LS-associated gynecological cancers, for whom MSI results were available. Among them, 36 tumors (27.7%) exhibited a dMMR/MSS molecular phenotype (23 endometrial, 12 ovarian, one synchronous endometrial–ovarian). No data for vulvar, vaginal, or cervical cancers were found. For dMMR/MSS endometrial cancers, the mean age at diagnosis was 50.5 years (range 36–62). dMMR/MSS tumors arose predominantly in MSH6 and, to a lesser extent, PMS2 carriers. No data on selective response to immune checkpoint inhibitors treatment were available. Conclusions: Lynch syndrome-associated gynecological cancers with dMMR/MSS phenotype are strongly underrepresented in the literature. Endometrial and ovarian cancers with dMMR/MSS phenotype are early onset and arise in a small proportion of patients. Better characterization is demanding to unearth whether response to immunotherapy treatment vary across Lynch dMMR/MSS and dMMR/MSI-High phenotypes.