Explore the vast range of titles available.

This study aims to identify signatures of miR associated with hereditary, BRCA1 or BRCA2 mutation positive breast cancer (BC), and non-hereditary BC, either sporadic (SBC) or non-informative (BRCAX). Moreover, we search for signatures associated with tumor stage, immunohistochemistry and tumor molecular profile. Twenty formalin fixed paraffin embedded (FFPE) BCs, BRCA1, BRCA2, BRCAX and SBC, five per group were studied. Affymetrix platform miRNA v.3.0 was used to perform miR expression analysis. ER, PR, HER2 and Ki67 protein expression was analyzed by immunohistochemistry. BRCA1 , BRCA2 and RASSF1 methylation analysis, AURKA copy number variations, and BRCA1 and BRCA2 deletions, were studied by MLPA. We validated eight of the miR selected by the arrays in 77 BCs by qRT-PCR. The miR profiles associated with tumor features were studied applying the Sparse Partial Least Squares Discriminant Analysis . MiR discrimination capability to distinguish hereditary and non-hereditary BC was analyzed by the discriminant function. With 15 out of 1,733 hsa-miRs, it was possible to differentiate the four groups. BRCA1, BRCA2 and SBC were associated with clusters of hyper-expressed miRs, and BRCAX with hypo-expressed miRs. Hsa-miR-4417 and hsa-miR-423-3p expressions (included among the eight validated miRs) differentiated 70.1 % of hereditary and non-hereditary BCs. We found miR profiles associated with tumor features like node involvement, histological grade, ER, PR and HER2 expression. Regarding molecular parameters, we only found a weak association of miRs in BC harboring losses in AURKA . We conclude that array miR expression profiles can differentiate the four study groups using FFPE BC. However, miRs expression estimated by qRT-PCR differentiates only hereditary and non-inherited BCs. The miR expression array is a simple and rapid approach that could be useful to facilitate the identification of those SBC carrying genetic or epigenetic changes in BRCA genes responsible of BRCA-like phenotype. These patients could benefit from the treatment with PARP inhibitors.

Introduction Mammographic density (MD) is one of the strongest determinants of sporadic breast cancer (BC). In this study, we compared MD in BRCA1/2 mutation carriers and non-carriers from BRCA1/2 mutation-positive families and investigated the association between MD and BC among BRCA1/2 mutation carriers per type of mutation and tumor subtype. Methods The study was carried out in 1039 female members of BRCA1 and BRCA2 mutation-positive families followed at 16 Spanish Genetic Counseling Units. Participants’ density was scored retrospectively from available mammograms by a single blinded radiologist using a 5-category scale (<10 %, 10-25 %, 25-50 %, 50-75 %, >75 %). In BC cases, we selected mammograms taken prior to diagnosis or from the contralateral breast, whereas, in non-cases, the last screening mammogram was evaluated. MD distribution in carriers and non-carriers was compared using ordinal logistic models, and the association between MD and BC in BRCA1/2 mutation carriers was studied using logistic regression. Huber-White robust estimators of variance were used to take into account correlations between family members. A similar multinomial model was used to explore this association by BC subtype. Results We identified and scored mammograms from 341 BRCA1 , 350 BRCA2 mutation carriers and 229 non-carriers. Compared to non-carriers, MD was significantly lower among BRCA2 mutation carriers (odds ratio (OR) =0.71; P- value=0.04), but not among BRCA1 carriers (OR=0.84; P- value=0.33). MD was associated with subsequent development BC (OR per category of MD=1.45; 95 % confidence interval=1.18-1.78, P- value<0.001), with no significant differences between BRCA1 and BRCA2 mutation carriers ( P- value=0.48). Finally, no statistically significant differences were observed in the association of MD with specific BC subtypes. Conclusions Our study, the largest to date on this issue, confirms that MD is an independent risk factor for all BC subtypes in either BRCA1 and BRCA2 mutation carriers, and should be considered a phenotype risk marker in this context.

Immune-based combination therapies have become the standard first-line treatment for metastatic renal cell carcinoma (mRCC) and have positively impacted survival outcomes in phase III clinical trials. However, these trials are conducted in highly selected populations and controlled settings, which may limit the generalizability of toxicity profiles to routine clinical practice. Real-world data are therefore essential to better characterize the incidence and determinants of severe adverse events (AEs) associated with immune-based combinations. We conducted a multinational, retrospective analysis of the ARON-1 registry, of patients with mRCC who received first-line immune-based combination therapy across 17 countries. The primary endpoint was to evaluate the real-world incidence of grade 3-4 (G3-G4) AEs. Logistic regression analyses were performed to identify clinical factors associated with toxicity. Overall survival (OS) was assessed using Kaplan-Meier methods, with landmark analyses to explore the association between G3-G4 AEs and survival outcomes. Among 2, 401 patients receiving immune-based combinations, 1, 921 (80%) had complete data on grade 3-4 AEs and were included in the analysis. G3-G4 AEs occurred in 34% (n=653). Pembrolizumab plus lenvatinib was associated with the highest incidence of high-grade AEs, whereas nivolumab plus ipilimumab showed the lowest. Older age and female sex were independently associated with an increased risk of G3-G4 toxicity. Although the occurrence of severe AEs was associated with improved OS in unadjusted analyses, this association was non-significant in the 6-month landmark analyses. In this large, multinational real-world cohort, the incidence of G3-G4 adverse events in patients with mRCC treated with immune-based combinations was lower than that reported in pivotal clinical trials, underscoring meaningful differences between trial and routine practice settings. Patient- and regimen-specific factors significantly influenced toxicity risk. These findings highlight the complementary role of real-world evidence in informing toxicity management and support individualized treatment strategies to optimize outcomes in everyday clinical practice.

Background/Objectives: Androgen receptor-targeted agents have significantly improved the prognosis of metastatic hormone-sensitive prostate cancer (mHSPC). Prostate-specific antigen (PSA) levels are key prognostic markers, with rapid and deep reductions associated with better outcomes. This study aims to assess the association between the new PSA cut-offs and survival in mHSPC patients treated with Apalutamide. Methods: We conducted a multicentre, retrospective analysis of mHSPC patients treated with Apalutamide between March 2021 and January 2023. Overall survival (OS) and radiographic progression-free survival (rFPS) were analyzed and stratified by the following PSA ranges: <0.02 ng/mL (ultralow), 0.02–0.2 ng/mL, and >0.2 ng/mL. Cox regression was applied to identify variables associated with OS and rPFS. Results: Among 193 patients, 34.2% had de novo mHSPC, with the majority classified as M1b. A total of 58.2% (110) of our cohort achieved ultralow PSA levels, with 20.6% between 0.02 and 0.2 ng/mL, and 21.2% of PSA levels > 0.2 ng/mL. Most patients reached ultralow PSA within six months. Low-volume, metachronous, and M1a subgroups displayed a higher prevalence of patients reaching ultralow PSA levels. At 18 months, OS was 100% in the ultralow PSA group, 94.4% for the 0.02–0.2 ng/mL group, and 67.7% in the >0.2 ng/mL group. Similarly, rPFS at 18 months was 100%, 93.5%, and 50.7%, respectively. Cox regression revealed that both ultralow PSA levels and ISUP grade had a significant impact on OS (HR of 8.256 and 0.164, respectively). For rPFS, only ultralow PSA levels had a significant impact (HR = 0.085). Conclusions: This real-world study of mHSPC patients treated with Apalutamide plus ADT revealed that achieving ultralow PSA levels is strongly associated with better oncological outcomes.

PD-1 and PD-L1 inhibitors are active in metastatic urothelial carcinoma, but positive randomised data supporting their use as a first-line treatment are lacking. In this study we assessed outcomes with first-line pembrolizumab alone or combined with chemotherapy versus chemotherapy for patients with previously untreated advanced urothelial carcinoma. KEYNOTE-361 is a randomised, open-label, phase 3 trial of patients aged at least 18 years, with untreated, locally advanced, unresectable, or metastatic urothelial carcinoma, with an Eastern Cooperative Oncology Group performance status of up to 2. Eligible patients were enrolled from 201 medical centres in 21 countries and randomly allocated (1:1:1) via an interactive voice-web response system to intravenous pembrolizumab 200 mg every 3 weeks for a maximum of 35 cycles plus intravenous chemotherapy (gemcitabine [1000 mg/m2] on days 1 and 8 and investigator's choice of cisplatin [70 mg/m2] or carboplatin [area under the curve 5] on day 1 of every 3-week cycle) for a maximum of six cycles, pembrolizumab alone, or chemotherapy alone, stratified by choice of platinum therapy and PD-L1 combined positive score (CPS). Neither patients nor investigators were masked to the treatment assignment or CPS. At protocol-specified final analysis, sequential hypothesis testing began with superiority of pembrolizumab plus chemotherapy versus chemotherapy alone in the total population (all patients randomly allocated to a treatment) for the dual primary endpoints of progression-free survival (p value boundary 0·0019), assessed by masked, independent central review, and overall survival (p value boundary 0·0142), followed by non-inferiority and superiority of overall survival for pembrolizumab versus chemotherapy in the patient population with CPS of at least 10 and in the total population (also a primary endpoint). Safety was assessed in the as-treated population (all patients who received at least one dose of study treatment). This study is completed and is no longer enrolling patients, and is registered at ClinicalTrials.gov, number NCT02853305. Between Oct 19, 2016 and June 29, 2018, 1010 patients were enrolled and allocated to receive pembrolizumab plus chemotherapy (n=351), pembrolizumab monotherapy (n=307), or chemotherapy alone (n=352). Median follow-up was 31·7 months (IQR 27·7–36·0). Pembrolizumab plus chemotherapy versus chemotherapy did not significantly improve progression-free survival, with a median progression-free survival of 8·3 months (95% CI 7·5–8·5) in the pembrolizumab plus chemotherapy group versus 7·1 months (6·4–7·9) in the chemotherapy group (hazard ratio [HR] 0·78, 95% CI 0·65–0·93; p=0·0033), or overall survival, with a median overall survival of 17·0 months (14·5–19·5) in the pembrolizumab plus chemotherapy group versus 14·3 months (12·3–16·7) in the chemotherapy group (0·86, 0·72–1·02; p=0·0407). No further formal statistical hypothesis testing was done. In analyses of overall survival with pembrolizumab versus chemotherapy (now exploratory based on hierarchical statistical testing), overall survival was similar between these treatment groups, both in the total population (15·6 months [95% CI 12·1–17·9] with pembrolizumab vs 14·3 months [12·3–16·7] with chemotherapy; HR 0·92, 95% CI 0·77–1·11) and the population with CPS of at least 10 (16·1 months [13·6–19·9] with pembrolizumab vs 15·2 months [11·6–23·3] with chemotherapy; 1·01, 0·77–1·32). The most common grade 3 or 4 adverse event attributed to study treatment was anaemia with pembrolizumab plus chemotherapy (104 [30%] of 349 patients) or chemotherapy alone (112 [33%] of 342 patients), and diarrhoea, fatigue, and hyponatraemia (each affecting four [1%] of 302 patients) with pembrolizumab alone. Six (1%) of 1010 patients died due to an adverse event attributed to study treatment; two patients in each treatment group. One each occurred due to cardiac arrest and device-related sepsis in the pembrolizumab plus chemotherapy group, one each due to cardiac failure and malignant neoplasm progression in the pembrolizumab group, and one each due to myocardial infarction and ischaemic colitis in the chemotherapy group. The addition of pembrolizumab to first-line platinum-based chemotherapy did not significantly improve efficacy and should not be widely adopted for treatment of advanced urothelial carcinoma. Merck Sharp and Dohme, a subsidiary of Merck, Kenilworth, NJ, USA.

Background The efficacy of nivolumab for advanced renal cell carcinoma (aRCC) has been evaluated in real-world evidence (RWE) studies across several European countries, yet data from Spain have been lacking. Patients and methods We conducted a multicenter, retrospective study of 222 previously treated aRCC patients to assess the efficacy of nivolumab and the influence of pre-treatment factors on clinical outcomes across 13 Spanish centers. Eligible patients had received at least one dose of nivolumab in routine clinical practice. Demographic, clinical, and laboratory data were extracted from electronic records. Efficacy endpoints were overall survival (OS), progression-free survival (PFS), disease control rate (DCR), and overall response rate (ORR). Survival estimates were calculated by the Kaplan–Meier method, and groups were compared with the log-rank test. The Cox proportional hazards regression model was used to evaluate factors independently associated with OS. Factors associated with disease control (DC) and response were tested with logistic regression in univariable and multivariable analyses. Comparisons between patient and disease characteristics were carried out using Fisher’s exact test. All  P  values were two-sided, and those < 0.05 were considered statistically significant. Results were contextualized with key clinical experiences involving nivolumab monotherapy in aRCC. Results With a median follow-up of 14.6 months, median overall survival (OS) was 18.1 months (95% confidence interval [CI], 14.2–23.7 months), and median progression-free survival (PFS) was 4.96 months (95% CI, 3.98–7.13). The disease control rate was 51% (95% CI, 45–58%), and the objective response rate was 23% (95% CI, 18–30%). Poor International Metastatic RCC Database Consortium (IMDC) risk score was independently associated with shorter OS, while prior nephrectomy predicted improved OS. Poor IMDC risk and ≥ 3 metastatic sites were independently associated with shorter PFS; ≥ 3 metastatic sites also correlated with reduced disease control. Conclusion Consistent with previous clinical trials and RWE studies, our findings reinforce the efficacy of nivolumab in routine clinical practice for an unselected cohort of previously treated aRCC patients in Spain.

Secondary amyloidosis is a rare complex complication related to chronic inflammatory disease. This complication is sparsely associated to malignant neoplasms. Renal cell carcinoma (RCC) is the most common solid organ malignancy related with this paraneoplastic syndrome. Some case reports have described stabilisation or even remission of amyloidosis with cytoreductive nephrectomy. Majority of those reports were based on locally advanced RCC. We report the first case of early aggressive systemic secondary amyloidosis in high-volume metastatic RCC. The subject was diagnosed with metastatic RCC within 6 months of secondary amyloidosis; on month 5 of initiation of targeted therapy (pazopanib) developed nephrotic syndrome with a heavy proteinuria (>18 g/day), severe hypoalbuminaemia (1.53 g/dL), intense and progressive oedema, severe pancolitis and mild dyspnoea with hypotension. A colon biopsy and the immunohistochemistry confirmed the histological diagnosis of a secondary amyloidosis. The multidisciplinary tumour board decided to perform cytoreductive nephrectomy in order to reduce the pro-inflammatory status. Pathology report showed a complete resection of clear cell RCC plus renal amyloid deposits. The patient died within 4 days of surgery due to multiorgan failure.

The SOGUG-IMANOL trial was a phase 2, uncontrolled, Spanish multicenter study to assess the effect of maintenance treatment with olaparib on radiographic progression-free survival (PFS) in patients with metastatic castration-resistant prostate cancer (mCRPC) who achieved partial or complete response or disease stabilization on docetaxel treatment and had a documented germline/somatic mutation in any of the homologous recombination repair (HRR) genes. Patients received olaparib 300 mg orally twice daily. From the screened population (n = 134), 26 (19.4%) somatic mutations were found, and 14 patients were included in the study. The median radiographic PFS was 11.1 (95%CI, 5.7 to 16.5) months. The median PSA-PFS was 3.5 (95%CI, 1.0 to 6.0) months, and the median clinical PFS was 14.7 (95%CI, 1.8 to 27.5 months). Clinical benefit was observed in 12 patients (85.7%, 95%CI 67.4% to 100%), including two patients with partial response and 10 with stable disease. Six patients reported grade 3–5 adverse events: asthenia (n = 3), anemia (n = 2) and neutropenia (n = 1). In this setting, olaparib has been shown to be an efficacious maintenance treatment in terms of radiographic PFS and clinical benefit, becoming a therapeutic option for some patients harboring an HRR gene mutation and in scenarios where further investigation is needed.

PurposeThe aim of this multicenter study was to evaluate the clinical outcomes of patients with metastatic renal cell carcinoma (mRCC) who received sunitinib retreatment.MethodsClinical data from patients treated with sunitinib rechallenge in nine Spanish centers were retrospectively analyzed. All patients received first-line sunitinib until progression or intolerance, followed by one or more successive drugs and rechallenge with sunitinib thereafter.ResultsThirty-seven patients were included. At first-line treatment, objective response rate (ORR) was 69.4% and median progression-free survival (PFS) was 19.4 months. At rechallenge, ORR was 27.2% and 39.4% of patients obtained stabilization of disease. Median PFS was 6.2 months. Clinical benefit was obtained by 21 patients (75%) with > 6-month interval between sunitinib treatments and by 1 patient (20%) among those with ≤ 6-month interval (P = 0.016). Hemoglobin levels ≥ lower level of normal were associated with clinical benefit (P = 0.019) and with PFS (P = 0.004). Median overall survival from start of first-line sunitinib was 52.7 months. No new adverse events were observed at rechallenge.ConclusionsSunitinib rechallenge is a feasible treatment option for selected patients with mRCC.

The study aims to identify the relevance of immunohistochemistry (IHC), copy number aberrations (CNA) and epigenetic disorders in BRCAness breast cancers (BCs). We studied 95 paraffin included BCs, of which 41 carried BRCA1/BRCA2 germline mutations and 54 were non hereditary (BRCAX/Sporadic). Samples were assessed for BRCA1ness and CNAs by Multiplex Ligation-dependent Probe Amplification (MLPA); promoter methylation (PM) was assessed by methylation-specific-MLPA and the expression of miR-4417, miR-423-3p, miR-590-5p and miR-187-3p by quantitative RT-PCR. IHC markers Ki67, ER, PR, HER2, CK5/6, EGFR and CK18 were detected with specific primary antibodies (DAKO, Denmark). BRCAness association with covariates was performed using multivariate binary logistic regression (stepwise backwards Wald option). BRCA1/2 mutational status ( p  = 0.027), large tumor size ( p  = 0.041) and advanced histological grade ( p  = 0.017) among clinic-pathological variables; ER ( p  < 0.001) among IHC markers; MYC ( p  < 0.001) among CNA; APC ( p  = 0.065), ATM ( p  = 0.014) and RASSF1 ( p  = 0.044) among PM; and miR-590-5p ( p  = 0.001), miR-4417 ( p  = 0.019) and miR-423 ( p  = 0.013) among microRNA expression, were the selected parameters significantly related with the BRCAness status. The logistic regression performed with all these parameters selected ER+ as linked with the lack of BRCAness ( p  = 0.001) and MYC CNA, APC PM and miR-590-5p expression with BRCAness ( p  = 0.014, 0.045 and 0.007, respectively). In conclusion, the parameters ER expression, APC PM, MYC CNA and miR-590-5p expression, allowed detection of most BRCAness BCs. The identification of BRCAness can help establish a personalized medicine addressed to predict the response to specific treatments.