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Among patients with metastatic breast cancer and a germline BRCA mutation, daily treatment with the PARP inhibitor olaparib was associated with longer progression-free survival than standard single-agent chemotherapy.

PIK3CA mutations occur in approximately 40% of patients with hormone receptor–positive breast cancer. A PI3K inhibitor, alpelisib, combined with fulvestrant led to a median progression-free survival of 11 months, as compared with 5.7 months with placebo plus fulvestrant. Hyperglycemia, rash, and diarrhea were more common with alpelisib.

About a half of HER2-negative breast cancer (BC) show HER2-low expression that can be targeted by new antibody-drug conjugates. The main aim of this study is to describe the evolution of HER2 expression from primary BC to relapse by including HER2-low category in both primary and recurrent BC samples. Patients with matched primary and relapse BC samples were included. HER2 was evaluated according to ASCO/CAP recommendations in place at the time of diagnosis. A cutoff of >10% cells staining for HER2-positivity was applied. HER2-negative cases were sub-classified as HER2-low (IHC = 1 + /2+ and ISH not amplified), or HER2-0 (IHC-0). 547 patients were included. The proportion of HER2-low cases was 34.2% on the primary tumor and 37.3% on the relapse samples. Among HER2-negative cases, HER2-low status was more frequent in HR-positive vs triple-negative tumors (47.3% vs 35.4% on primary tumor samples, 53.8% vs 36.2% on relapse samples). The overall rate of HER2 discordance was 38.0%, mostly represented by HER2-0 switching to HER2-low (15%) and HER2-low switching to HER2-0 (14%). Among patients with a primary HER2-negative tumor, the rate of HER2 discordance was higher in HR-positive/HER2-negative vs triple-negative cases (45.5% vs 36.7% p  = 0.170). This difference was mostly driven by cases switching from HER2-0 to HER2-low. HER2-low expression is highly unstable during disease evolution. Relapse biopsy in case of a primary HER2-0 tumor may open new therapeutic opportunities in a relevant proportion of patients.

In a study involving patients with non–small-cell lung cancer with a MET exon 14 skipping mutation, the use of tepotinib (a selective MET inhibitor) was associated with a partial response in approximately half the patients. The main adverse event was peripheral edema.

Approximately a half of breast tumors classified as HER2-negative exhibit HER2-low-positive expression. We recently described a high instability of HER2-low-positive expression from primary breast cancer (BC) to relapse. Previous studies reporting discordance in HER2 status between baseline biopsy and residual disease (RD) in patients undergoing neoadjuvant treatment did not include the HER2-low-positive category. The aim of this study is to track the evolution of HER2-low-positive expression from primary BC to RD after neoadjuvant treatment. Patients undergoing neoadjuvant treatment with available baseline tumor tissue and matched samples of RD (in case of no pCR) were included. HER2-negative cases were sub-classified as HER2-0 or HER2-low-positive (IHC 1+ or 2+ and ISH negative). Four-hundred forty-six patients were included. Primary BC phenotype was: HR-positive/HER2-negative 23.5%, triple-negative (TN) 35%, HER2-positive 41.5%. HER2-low-positive cases were 55.6% of the HER2-negative cohort and were significantly enriched in the HR-positive/HER2-negative vs. TN subgroup (68.6% vs. 46.8%, p = 0.001 χ2 test). In all, 35.3% of non-pCR patients (n = 291) had a HER2-low-positive expression on RD. The overall rate of HER2 expression discordance was 26.4%, mostly driven by HER2-negative cases converting either from (14.8%) or to (8.9%) HER2-low-positive phenotype. Among HR-positive/HER2-negative patients with HER2-low-positive expression on RD, 32.0% and 57.1% had an estimated high risk of relapse according to the residual proliferative cancer burden and CPS-EG score, respectively. In conclusion, HER2-low-positive expression showed high instability from primary BC to RD after neoadjuvant treatment. HER2-low-positive expression on RD may guide personalized adjuvant treatment for high-risk patients in the context of clinical trials with novel anti-HER2 antibody-drug conjugates.

Although 1% is the recommended cut-off to define estrogen receptor (ER) positivity, a 10% cut-off is often used in clinical practice for therapeutic purposes. We here evaluate clinical outcomes according to ER levels in a monoinstitutional cohort of non-metastatic triple-negative breast cancer (BC) patients undergoing (neo)adjuvant chemotherapy. Clinicopathological data of 406 patients with ER < 10% HER2-negative BC treated with (neo)adjuvant chemotherapy between 01/2000 and 04/2019 were collected. Patients were categorized in ER-negative (ER < 1%; N  = 364) and ER-low positive (1–9%, N  = 42). At a median follow-up of 54 months, 88 patients had relapsed and 64 died. No significant difference was observed in invasive relapse-free survival (iRFS) and overall survival (OS) according to ER expression levels, both at univariate and multivariate analysis (5-years iRFS 74.0% versus 73.1% for ER-negative and ER-low positive BC, respectively, p  = 0.6; 5-years OS 82.3% versus 76.7% for ER-negative and ER-low positive BC, respectively, p  = 0.8). Among the 165 patients that received neoadjuvant chemotherapy, pathological complete response rate was similar in the two cohorts (38% in ER-negative, 44% in ER-low positive, p  = 0.498). In conclusion, primary BC with ER1–9% shows similar clinical behavior to ER 1% BC. Our results suggest the use of a 10% cut-off, rather than <1%, to define triple-negative BC.

In early-stage HER2-positive breast cancer, escalation or de-escalation of systemic therapy is a controversial topic. As an aid to treatment decisions, we aimed to develop a prognostic assay that integrates multiple data types for predicting survival outcome in patients with newly diagnosed HER2-positive breast cancer. We derived a combined prognostic model using retrospective clinical–pathological data on stromal tumour-infiltrating lymphocytes, PAM50 subtypes, and expression of 55 genes obtained from patients who participated in the Short-HER phase 3 trial. The trial enrolled patients with newly diagnosed, node-positive, HER2-positive breast cancer or, if node negative, with at least one risk factor (ie, tumour size >2 cm, histological grade 3, lymphovascular invasion, Ki67 >20%, age ≤35 years, or hormone receptor negativity), and randomly assigned them to adjuvant anthracycline plus taxane-based combinations with either 9 weeks or 1 year of trastuzumab. Trastuzumab was administered intravenously every 3 weeks (8 mg/kg loading dose at first cycle, and 6 mg/kg thereafter) for 18 doses or weekly (4 mg/kg loading dose in the first week, and 2 mg/kg thereafter) for 9 weeks, starting concomitantly with the first taxane dose. Median follow-up was 91·4 months (IQR 75·1–105·6). The primary objective of our study was to derive and evaluate a combined prognostic score associated with distant metastasis-free survival (the time between randomisation and distant recurrence or death before recurrence), an exploratory endpoint in Short-HER. Patient samples in the training dataset were split into a training set (n=290) and a testing set (n=145), balancing for event and treatment group. The training set was further stratified into 100 iterations of Monte-Carlo cross validation (MCCV). Cox proportional hazard models were fit to MCCV training samples using Elastic-Net. A maximum of 92 features were assessed. The final prognostic model was evaluated in an independent combined dataset of 267 patients with early-stage HER2-positive breast cancer treated with different neoadjuvant and adjuvant anti-HER2-based combinations and from four other studies (PAMELA, CHER-LOB, Hospital Clinic, and Padova) with disease-free survival outcome data. From Short-HER, data from 435 (35%) of 1254 patients for tumour size (T1 vs rest), nodal status (N0 vs rest), number of tumour-infiltrating lymphocytes (continuous variable), subtype (HER2-enriched and basal-like vs rest), and 13 genes composed the final model (named HER2DX). HER2DX was significantly associated with distant metastasis-free survival as a continuous variable (p<0·0001). HER2DX median score for quartiles 1–2 was identified as the cutoff to identify low-risk patients; and the score that distinguished quartile 3 from quartile 4 was the cutoff to distinguish medium-risk and high-risk populations. The 5-year distant metastasis-free survival of the low-risk, medium-risk, and high-risk populations were 98·1% (95% CI 96·3–99·9), 88·9% (83·2–95·0), and 73·9% (66·0–82·7), respectively (low-risk vs high-risk hazard ratio [HR] 0·04, 95% CI 0·0–0·1, p<0·0001). In the evaluation cohort, HER2DX was significantly associated with disease-free survival as a continuous variable (HR 2·77, 95% CI 1·4–5·6, p=0·0040) and as group categories (low-risk vs high-risk HR 0·27, 0·1–0·7, p=0·005). 5-year disease-free survival in the HER2DX low-risk group was 93·5% (89·0–98·3%) and in the high-risk group was 81·1% (71·5–92·1). The HER2DX combined prognostic score identifies patients with early-stage, HER2-positive breast cancer who might be candidates for escalated or de-escalated systemic treatment. Future clinical validation of HER2DX seems warranted to establish its use in different scenarios, especially in the neoadjuvant setting. Instituto Salud Carlos III, Save the Mama, Pas a Pas, Fundación Científica, Asociación Española Contra el Cáncer, Fundación SEOM, National Institutes of Health, Agenzia Italiana del Farmaco, International Agency for Research on Cancer, and the Veneto Institute of Oncology, and Italian Association for Cancer Research.

Background/Objectives: Cancer-related cognitive impairment (CRCI) is a frequent and clinically significant consequence of breast cancer (BC) and its treatments. With rapidly evolving therapeutics and a growing body of biomarker research, a BC-specific synthesis is needed. This review aimed to evaluate associations between blood- and saliva-based biomarkers and objective and patient-reported cognitive outcomes in adults with non-metastatic BC, while accounting for treatment modality and assessment timing. Methods: This systematic review followed the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines and was pre-registered in the International Prospective Register of Systematic Reviews (PROSPERO, ID: CRD420251079969). PubMed, Embase, and Web of Science were searched for articles published up until April 2025. Eligible studies included adults with BC that investigated associations between blood and/or saliva biomarkers and cognitive outcomes. Results: A total of 53 studies met inclusion criteria: 31 examined biochemical biomarkers; 17, genetic; and 5, both. Assessments were predominantly post-treatment. Baseline measures were more infrequent. Chemotherapy (ChT) predominated, while endocrine therapy (ET) and radiotherapy (RT) were variably examined. Targeted therapies and immunotherapies were rarely included. IL-6 and TNF-α were most consistently linked to poorer cognition, although results varied by timing and assessment type. CRP and derived indices showed intermittent associations. Stress-axis markers and BDNF were mainly related to subjective outcomes. Genetic findings implicated DNA repair and oxidative stress pathways, while APOE, COMT, and BDNF results were inconsistent. Conclusions: Evidence for biomarker correlates of CRCI in BC is highly heterogeneous. Longitudinal, harmonized, and treatment-specific studies are needed to establish reproducible biomarker panels for risk stratification and targeted intervention.

Background Liquid biopsy has the potential to monitor biological effects of treatment. KRAS represents the most commonly mutated oncogene in Caucasian non-small-cell lung cancer (NSCLC). The aim of this study was to explore association of dynamic plasma KRAS genotyping with outcome in advanced NSCLC patients. Methods Advanced NSCLC patients were prospectively enrolled. Plasma samples were collected at baseline (T1), after 3 or 4 weeks, according to treatment schedule (T2) and at first radiological restaging (T3). Patients carrying KRAS mutation in tissue were analysed in plasma with droplet digital PCR. Semi-quantitative index of fractional abundance of mutated allele (MAFA) was used. Results KRAS -mutated cohort included 58 patients, and overall 73 treatments ( N  = 39 chemotherapy and N  = 34 immune checkpoint inhibitors) were followed with longitudinal liquid biopsy. Sensitivity of KRAS detection in plasma at baseline was 48.3% (95% confidence interval (CI): 35.0–61.8). KRAS mutation at T2 was associated with increased probability of experiencing progressive disease as best radiological response (adjusted odds ratio: 7.3; 95% CI: 2.1–25.0, p  = 0.0016). Increased MAFA (T1–T2) predicted shorter progression-free survival (adjusted hazard ratio (HR): 2.1; 95% CI: 1.2–3.8, p  = 0.0142) and overall survival (adjusted HR: 3.2; 95% CI: 1.2–8.4, p  = 0.0168). Conclusions Longitudinal analysis of plasma KRAS mutations correlated with outcome: its early assessment during treatment has great potentialities for monitoring treatment outcome in NSCLC patients.

ObjectiveUnplanned hospital readmissions within 30 days of discharge measure the quality of healthcare. This study aims to identify the characteristics of patients at higher risk of readmission.DesignRetrospective cohort study.SettingNorth-east Italy (Marca Trevigiana Local Health Authority).Data sourceThe study examined a total of 39 467 index admissions from hospital discharges (SDO) in the 890 000-inhabitant area during 2022.Outcome measureReadmission rates and 95% CIs were computed by risk factor, age and type of admission (surgical or medical). A logistic mixed-effects model was used to estimate readmission OR, adjusting for potential confounders.ResultsA total of 2197 readmissions occurred within 30 days of the index admission, resulting in an overall rate of 30-day readmissions of 6.7% (CI 6.4% to 7.0%). The median time to readmission was 11 days (IQR 5 to 20). In the multivariate analysis, after adjusting for age and sex, the following clinical conditions were associated with a higher risk of readmission: alcohol-related disease (OR=2.06, CI 1.36 to 3.13), metastatic cancer (OR=1.98, CI 1.57 to 2.50), epilepsy (OR=1.93, CI 1.36 to 2.75), dialysis or end-stage kidney disease (OR=1.92, CI 1.39 to 2.66), chronic obstructive pulmonary disease (OR=1.88, CI 1.49 to 2.36), stoma (OR=1.72, CI 1.22 to 2.44), transplant (OR=1.62, CI 1.03 to 2.55), being bedridden (OR=1.57, CI 1.28 to 1.93), anaemia (OR=1.57, CI 1.35 to 1.83), urinary tract infection (OR=1.54, CI 1.30 to 1.83), pneumonia (OR=1.52, CI 1.31 to 1.75), dementia (OR=1.49, CI 1.24 to 1.79), diabetes (OR=1.37, CI 1.17 to 1.61) and transfusion (OR=1.34, CI 1.03 to 1.73).ConclusionSeveral chronic and acute conditions at index admission significantly increased the risk of readmission. Strengthening transitional care, outpatient services and palliative care could mitigate readmissions.