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Among persons with breast cancer previously treated with hormonal therapy, the AKT pathway inhibitor capivasertib when added to fulvestrant significantly prolonged progression-free survival as compared with fulvestrant alone.

When a genetic test was used to assess prognosis, women with midrange scores were found to have similar outcomes after adjuvant treatment with either endocrine therapy alone or chemotherapy plus endocrine therapy.

Triple negative breast cancer (TNBC) is the most aggressive form of breast cancer with limited options of targeted therapy. Recent findings suggest that the clinical course of TNBC may be modified by the presence of tumor-infiltrating lymphocytes (TILs) and chemokine’s expression, such as CCL5 . Diverse studies have shown that CCL5 suppresses anti-tumor immunity and it has been related to poor outcome in different types of cancer while in other studies, this gene has been related with a better outcome. We sought to determine the association of CCL5 with the recruitment of TILs and other immune cells. With this aim we evaluated a retrospective cohort of 72 TNBC patients as well as publicly available datasets. TILs were correlated with residual tumor size after neoadjuvant chemotherapy (NAC) and CCL5 expression. In univariate analysis, TILs and CCL5 were both associated to the distant recurrence free survival; however, in a multivariate analysis, TILs was the only significant marker (HR = 0.336; 95%IC: 0.150–0.753; P = 0.008). CIBERSORT analysis suggested that a high CCL5 expression was associated with recruitment of CD8 T cells, CD4 activated T cells, NK activated cells and macrophages M1. The CD8A gene (encoding for CD8) was associated with an improved outcome in several public breast cancer datasets.

TAILORx established the role of the 21-gene predictor of genetic risk in ascertaining treatment for women with hormone-receptor–positive, human epidermal growth factor receptor 2–negative breast cancer. Clinical risk factors provided additional prognostic information for women with intermediate genetic risk.

CAPItello-291 is an ongoing phase 3 trial in which capivasertib–fulvestrant significantly improved progression-free survival versus placebo–fulvestrant in patients with hormone receptor-positive, HER2-negative advanced breast cancer who had relapse or disease progression during or after aromatase inhibitor treatment, in both the overall population and in patients with PIK3CA, AKT1, or PTEN-altered tumours. This study further explored patient-reported health-related quality of life (HRQOL), functioning, symptoms, and symptom tolerability in CAPItello-291. This phase 3, randomised, double-blind, placebo-controlled trial, which was conducted across 193 hospitals and cancer centres in 19 countries, enrolled women with any menopausal status or men, aged ≥18 years (≥20 years in Japan), with hormone receptor-positive, HER2-negative locally advanced or metastatic breast cancer who had relapse or disease progression during or after treatment with an aromatase inhibitor, with or without previous cyclin-dependent kinase (CDK) 4 or 6 inhibitor therapy. Patients had an Eastern Cooperative Oncology Group/WHO performance score of 0 or 1 and could have received up to two previous lines of endocrine therapy and up to one previous line of chemotherapy for advanced disease. Patients were randomly assigned (1:1) using block randomisation (stratified according to the presence or absence of liver metastases, previous use of a CDK4/6 inhibitor [yes vs no], and geographical region) to receive oral capivasertib 400 mg (twice daily for 4 days, followed by 3 days off) plus intramuscular fulvestrant 500 mg (every 14 days for the first three injections, then every 28 days) or placebo with matching fulvestrant dosing. The dual primary endpoint of the trial was investigator-assessed progression-free survival assessed both in the overall population and among patients with PIK3CA, AKT1, or PTEN-altered tumours. The EORTC Quality of Life Questionnaire 30-item core module (QLQ-C30) and breast module (QLQ-BR23), Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE), and Patient Global Impression of Treatment Tolerability (PGI-TT) questionnaires were used to assess patient-reported outcomes. Evaluation of EORTC QLQ-C30 and EORTC QLQ-BR23 were secondary endpoints and evaluation of PRO-CTCAE and PGI-TT were pre-defined exploratory endpoints, and these endpoints are the subject of analysis in this Article. Data were collected at baseline and prespecified timepoints. Patient-reported outcomes were analysed in all randomly assigned patients with an evaluable baseline assessment and at least one evaluable post-baseline assessment. Change from baseline was assessed using mixed model with repeated measures for EORTC QLQ-C30 and summarised for QLQ-BR23. Time to deterioration was described using the Kaplan–Meier method. PGI-TT and PRO-CTCAE responses were summarised at each treatment cycle. Patient-reported outcomes were not prospectively powered for statistical comparison. The trial is registered with ClinicalTrials.gov, NCT04305496. Between June 2, 2020, and Oct 13, 2021, 901 patients were enrolled, of whom 708 patients were randomly assigned to receive capivasertib–fulvestrant (n=355) or placebo–fulvestrant (n=353). The median age of the patients was 59 years (IQR 51–67) in the capivasertib–fulvestrant group and 58 years (IQR 49–66) in the placebo–fulvestrant group. At data cutoff (Aug 15, 2022), the median duration of follow-up for progression-free survival in censored patients was 13·0 months (IQR 9·1–16·7) for capivasertib–fulvestrant and 12·7 months (IQR 2·0–16·4) for placebo–fulvestrant in the overall population. EORTC QLQ-C30 global health status/quality of life (GHS/QOL) scores were maintained from baseline and were similar between treatment groups throughout the study period (difference in mean change from baseline of −2·5 [95% CI −4·5 to −0·6] with capivasertib–fulvestrant vs −5·6 [−7·9 to −3·4] with placebo–fulvestrant; treatment difference 3·1 [95% CI 0·2 to 6·0]). Median time to deterioration in EORTC QLQ-C30 GHS/QOL was 24·9 months (95% CI 13·8 to not reached) in the capivasertib–fulvestrant group and 12·0 months (10·2 to 15·7) in the placebo–fulvestrant group (hazard ratio [HR] 0·70, 95% CI 0·53 to 0·92). Time to deterioration HRs for all EORTC QLQ-C30 and QLQ-BR23 subscale scores showed little difference between the treatment groups, except for diarrhoea, which was worse in the capivasertib–fulvestrant group than in the placebo–fulvestrant group (HR 2·75, 95% CI 2·01–3·81). In PRO-CTCAE symptom assessment, the proportion of patients reporting loose and watery stools “frequently” or “almost constantly” was 29% higher at cycle 1, day 15 in the capivasertib–fulvestrant group than in the placebo–fulvestrant group, decreasing at subsequent cycles. Other PRO-CTCAE-reported symptoms (rash, mouth or throat sores, itchy skin, and numbness or tingling in hands or feet) were absent or mild in most patients in both groups throughout treatment. According to the PGI-TT, most patients in both groups reported “not at all” or “a little bit” of bother from treatment side-effects. Patient-reported outcomes from CAPItello-291 demonstrated that capivasertib–fulvestrant delayed time to deterioration of GHS/QOL and maintained other dimensions of HRQOL (except symptoms of diarrhoea) similarly to fulvestrant. With the clinical efficacy and manageable safety profile, these exploratory results further support the positive benefit–risk profile of capivasertib–fulvestrant in this population. AstraZeneca.

Epidemiological studies commonly identify the clinical characteristics and survival outcomes of patients with breast cancer at five years. Our study aims to describe the sociodemographic, clinicopathological characteristics and determine the long-term event-free survival (EFS) and overall survival (OS) of a Peruvian population with triple-negative breast cancer. We reviewed the medical records of new cases treated at a single institution in the period 2000-2014. The survival analysis included patients with stages I-IV. Survival estimates at 10 years were calculated with the Kaplan-Meier method and compared with the Log-rank test. We further used multivariate Cox regression analysis to calculate prognostic factors of recurrence and mortality. Among the 2007 patients included, the median age at diagnosis was 49 years (19-95 years). Most patients presented histologic grade III (68.7%), tumor stage II (34.2%), and III (51.0%) at diagnosis. Local and distant relapse was present in 31.9 and 51.4% of the patients, respectively. The most frequent sites of metastasis were the lungs (14.5%), followed by bone (9.7%), brain (9.6%), and liver (7.9%). The median follow-up was 153 months. At 3, 5, and 10 years, the EFS of the population was 55%, 49%, and 41%, respectively, while the OS was 64%, 56%, and 47%, respectively. Moreover, an N3 lymph node status was the most important prognostic factor for both disease relapse (HR: 2.54, 95% CI: 2.05-3.15) and mortality (HR: 2.51, 95% CI: 2.01-3.14) at ten years. An older age and higher T staging were associated with a worse OS, while patients who received radiotherapy and adjuvant chemotherapy had better survival rates. The sociodemographic features of Peruvian patients with TNBC are similar to those of other populations. However, our population was diagnosed at more advanced clinical stages, and thus, EFS and OS were lower than international reports while prognostic factors were similar to previous studies.

The phosphatidyl inositol 3-kinase (PI3K)/Akt pathway mediates the effects of a variety of extracellular signals in a number of cellular processes including cell growth, proliferation, and survival. The alteration of integrants of this pathway through mutation of its coding genes increases the activation status of the signaling and can thus lead to cellular transformation. The frequent dysregulation of the PI3K/Akt pathway in breast cancer (BC) and the mediation of this pathway in different processes characteristically implicated in tumorigenesis have attracted the interest of this pathway in BC; however, a more comprehensive understanding of the signaling intricacies is necessary to develop clinical applications of the modulation of this pathway in this pathology. We review a series of experiments examining the contribution of alteration of integrants of this signaling network to human BC and we make an update of the information about the effect of the modulation of this pathway in this cancer.

DDIT4 gene encodes a protein whose main action is to inhibit mTOR under stress conditions whilst several in vitro studies indicate that its expression favors cancer progression. We have previously described that DDIT4 expression is an independent prognostic factor for tripe negative breast cancer resistant to neoadjuvant chemotherapy. We herein report that high DDIT4 expression is related to the outcome (recurrence-free survival, time to progression and overall survival) in several cancer types. We performed in silico analysis in online platforms, in pooled datasets from KM Plotter and meta-analysis of individual datasets from SurvExpress. High levels of DDIT4 were significantly associated with a worse prognosis in acute myeloid leukemia, breast cancer, glioblastoma multiforme, colon, skin and lung cancer. Conversely, a high DDIT4 expression was associated with an improved prognostic in gastric cancer. DDIT4 was not associated with the outcome of ovarian cancers. Analysis with data from the Cell Miner Tool in 60 cancer cell lines indicated that although rapamycin activity was correlated with levels of MTOR , it is not influenced by DDIT4 expression. In summary, DDIT4 might serve as a novel prognostic biomarker in several malignancies. DDIT4 activity could be responsible for resistance to mTOR inhibitors and is a potential candidate for the development of targeted therapy.

Background Breast cancer remains a leading cause of cancer-related morbidity and mortality globally, with BRCA1/2 mutation carriers facing distinct challenges due to aggressive tumor biology and heightened risks of contralateral and secondary cancers. Purpose This review synthesizes evidence on managing early-stage breast cancer in BRCA mutation carriers, emphasizing Latin America’s heterogeneous BRCA prevalence (ranging from 5% to 25.7% across countries), which underscores the need for region-specific genetic screening. BRCA-associated tumors exhibit homologous recombination deficiency, informing therapeutic strategies such as PARP inhibitors, which exploit synthetic lethality, as demonstrated by the OlympiA trial showing Olaparib’s sustained survival benefits (28% reduction in mortality risk). Imaging strategies must adapt to BRCA-related tumor phenotypes: BRCA1 carriers often present mammography-elusive tumors, favoring MRI, while abbreviated MRI protocols offer cost-effective alternatives without compromising sensitivity. Surgical decision-making balances breast-conserving surgery (BCS) and mastectomy, with studies showing comparable survival outcomes but elevated contralateral cancer risk post-BCS (10-year risk: 14%), necessitating vigilant surveillance. Contralateral prophylactic mastectomy reduces contralateral cancer risk but requires personalized risk-benefit discussions. Neoadjuvant platinum-based chemotherapy shows higher pathologic complete response rates in BRCA carriers, particularly in triple-negative subtypes, though adjuvant platinum benefits remain under investigation. Emerging immunotherapies, such as pembrolizumab in KEYNOTE-522, show promise but lack BRCA-specific efficacy data. Special considerations for transgender BRCA carriers highlight evolving screening guidelines, including mammography for hormonally treated transgender women and multimodal imaging for non-mastectomized transgender men. Conclusions Optimizing outcomes for BRCA mutation carriers demands multidisciplinary, personalized approaches integrating genetic, regional, and clinical factors. Advances in targeted therapies, refined imaging, and risk-adapted surgery emphasize the importance of shared decision-making and ongoing research to address knowledge gaps in survivorship and equitable care.

Respiratory infections are one of the most common causes of illness and morbidity in neonates worldwide. In the acute phase infections are known to cause wide-spread peripheral inflammation. However, the inflammatory consequences to the critical neural control centres for respiration have not been explored. Utilising a well characterised model of neonatal respiratory infection, we investigated acute responses within the medulla oblongata which contains key respiratory regions. Neonatal mice were intranasally inoculated within 24 h of birth, with either Chlamydia muridarum or sham-infected, and tissue collected on postnatal day 15, the peak of peripheral inflammation. A key finding of this study is that, while the periphery appeared to show no sex-specific effects of a neonatal respiratory infection, sex had a significant impact on the inflammatory response of the medulla oblongata. There was a distinct sex-specific response in the medulla coincident with peak of peripheral inflammation, with females demonstrating an upregulation of anti-inflammatory cytokines and males showing very few changes. Microglia also demonstrated sex-specificity with the morphology of females and males differing based upon the nuclei. Astrocytes showed limited changes during the acute response to neonatal infection. These data highlight the strong sex-specific impact of a respiratory infection can have on the medulla in the acute inflammatory phase.