IMPORTANCEThe cyclin-dependent kinase 4 and 6 inhibitor palbociclib in combination with letrozole has become a standard first-line treatment for patients with endocrine-sensitive, hormone receptor-positive, ERBB2-negative advanced breast cancer. Meanwhile, the antiestrogen fulvestrant was shown to be superior to anastrozole in the absence of cyclin-dependent kinase 4 and 6 inhibition for this patient population. OBJECTIVE To assess whether fulvestrant is superior to letrozole when combined with palbociclib in the first-line scenario. DESIGN, SETTING, AND PARTICIPANTSIn this international, randomized, open-label, phase 2 clinical study conducted from July 30, 2015, to January 8, 2018, patients with hormone receptor-positive, ERBB2-negative advanced breast cancer with no prior therapy in the metastatic setting and endocrine-sensitive criteria were recruited from 47 centers in 7 countries. Data were analyzed from February 11 to May 15, 2020.INTERVENTIONS Patients were randomly assigned (1:1 ratio) to receive palbociclib with either fulvestrant or letrozole. Stratification factors were type of disease presentation (de novo vs recurrent) and the presence of visceral involvement (yes vs no). MAIN OUTCOMES AND MEASURESThe primary end point was investigator-assessed progression-free survival determined by Response Evaluation Criteria in Solid Tumors, version 1.1.RESULTS A total of 486 women (median age, 63 years [range, 25-90 years]; 3 Asian women [0.6%]; 4 Black women [0.8%]; 461 White women [94.9%]; 18 women of unknown race [3.7%]) were randomized (243 to fulvestrant-palbociclib and 243 to letrozole-palbociclib). Median investigator-assessed progression-free survival was 27.9 months (95% CI, 24.2-33.1 months) in the fulvestrant-palbociclib group vs 32.8 months (95% CI, 25.8-35.9 months) in the letrozole-palbociclib group (hazard ratio, 1.13; 95% CI, 0.89-1.45; P = .32). This result was consistent across the stratification factors. No significant differences were observed in objective response rate (46.5% vs 50.2%) and 3-year overall survival rate (79.4% vs 77.1%) for fulvestrant-palbociclib and letrozole-palbociclib, respectively. Grade 3-4 adverse events were comparable among treatment groups, and no new safety signals were identified. No treatment-related deaths were reported. CONCLUSIONS AND RELEVANCEAlthough fulvestrant-palbociclib demonstrated significant antitumor activity, this randomized clinical trial failed to identify an improvement in progression-free survival with this regimen over letrozole-palbociclib in patients with endocrine-sensitive, hormone receptor-positive, ERBB2-negative advanced breast cancer.

For patients with high-risk node-negative BC, the adjuvant FAC-wP regimen was associated with a small but significant improvement in DFS compared with FAC therapy, in addition to manageable toxicity, especially regarding long-term cardiac effects.

The question of whether screen detection confers an additional survival benefit in breast cancer is unclear and subject to several biases. Our aim was to examine the role of the diagnostic method (screen-detected, symptom-detected, and true interval cancers) and the clinical-pathological features in relapse-free survival and overall survival in breast cancer patients. We included 228 invasive breast cancers diagnosed in Barcelona from 1996 to 2008 among women aged 50-69 years. Ninety-seven patients were screen detected within the screening, 34 truly arose between 2-year screening mammograms (true interval cancers), and 97 were symptom detected outside the screening. The clinical-pathological features at diagnosis were compared. The overall and disease-free survival probabilities were computed using the Kaplan-Meier method. Cox proportional hazard models were applied, with adjustment by clinical-pathological variables. At diagnosis, symptom-detected and true interval cancers were in more advanced stages and were less differentiated. The highest proportion of triple-negative cancers was detected among true interval cancers (P=0.002). At 5 years of follow-up, the disease-free survival rates for screen-detected, true interval, and symptom-detected cancers were 87.5% (95% confidence interval, 80.5-95.2%), 64.1% (46.4-88.5%), and 79.4% (71.0-88.8%), respectively, and the overall survival rates were 94.5% (89.3-99.9%), 65.5% (47.1-91.2%), and 85.6% (78.3-93.6%), respectively. True interval cancers had the highest hazard ratio for relapse prediction (1.89; 0.67-5.31) and a hazard ratio of death of 5.55 (1.61-19.15) after adjustment for tumor-node-metastasis stage and phenotype. Clinically detected tumors, especially true interval cancers, more frequently showed biological features related to worse prognosis and were associated with poorer survival even after adjustment for clinical-pathological characteristics.

The objective of this phase I/II study was to establish the recommended dose of biweekly vinorelbine and oxaliplatin in patients with metastatic breast cancer and to evaluate the efficacy and safety profile of this schedule as first-line treatment. Four different dose levels of vinorelbine and oxaliplatin were selected for the phase I study: (i) 25 and 80 mg/m²; (ii) 25 and 90 mg/m²; (iii) 25 and 100 mg/m²; and (iv) 30 and 90 mg/m²; respectively. At least three patients were treated at each dose level. Overall, 12 patients were included in the phase I trial. No dose-limiting toxicities occurred at any dose level. Therefore, the fourth dose level (30 mg/m² of vinorelbine and 90 mg/m² of oxaliplatin) every 2 weeks was selected for the phase II trial. In this part, 44 patients were included and 61% completed the eight 2-week cycles of study treatment. On an intention-to-treat basis, overall response rate was 59%, and median progression-free survival and overall survival were 9.2 months (95% confidence interval: 7.6-10.9) and 18.6 months (95% confidence interval: 14.4-22.9), respectively. The main severe toxicities were neutropenia (46%) and fatigue (14%). We conclude that the biweekly combination of vinorelbine and oxaliplatin at doses of 30 mg/m² and 90 mg/m², respectively, is highly active and well tolerated as first-line treatment for patients with metastatic breast cancer.

BACKGROUND: Currently available therapeutic armamentarium for locally advanced and/or metastatic breast cancer (LA/MBC) allows an increasing tailored approach for each of the major tumor immunophenotypes. Nevertheless, there is scarce information about how these subgroups fare and how the alternative therapeutic approaches are actually being used during the disease course. CASCADE is an epidemiological, retrospective, and multicenter study aimed to retrieve demographic and clinical information from a representative cohort of LA/MBC patients treated within the Spanish National Healthcare System. MATERIALS AND METHODS: Several strategies were used to identify patients diagnosed with LA/MBC for the first time between 01/2007 and 12/2008 in 13 Spanish public hospitals covering nearly 5'000'000 inhabitants (>10% of the national population) and followed throughout their metastatic lifetime until death, lost to follow-up, or until December 2013. Data collected included demographical and clinical information for each line of treatment. Descriptive statistics were applied to analyze the information. RESULTS: We identified 443 LA/MBC patients. Median age at diagnosis was 59 years (CI95%: 49.5 - 71.6). Significant differences in dropout rates per line of treatment were found according to the tumor intrinsic immunophenotype. Patients reaching a 4th line were: whole study population 38.4%, HER2-/HR+ 42.8%, HER2+/HR- 41.5%, HER2+/HR+ 39.5%, and Triple-negative 31.9%. Median Overall survival (OS) and per line Progression Free Survival (PFS) for each line of treatment by tumor subtype were: Median OS and per line PFS by tumor subtype Subtype (%)OS (months)PFS (months)PFS (months)PFS (months)PFS (months)PFS (months)Treatment line--1L2L3L4L5LWhole PopulationAll33.57.25.94.33.73.0HER2-/HR+43.838.68.85.84.43.33.0HER2+/HR-12.036.37.46.74.34.03.0HER2+/HR+17.234.411.27.94.95.83.5Triple-negative16.319.04.03.52.43.32.9 Percent use of the four major pharmacological families per line of LA/MBC treatment was: Pharmacological families used per line of LA/MBC treatmentTreatment line1L2L3L4L5L6L7LChemotherapy75.463.075.979.487.976.178.6Anti-HER219.721.919.420.618.720.921.4Hormone therapy37.939.225.318.811.217.916.7Other targeted therapy13.09.612.212.47.511.914.3 CONCLUSION: Our study identifies differences in OS and PFS among BC immunophenotypes, with Triple-negatives faring the poorest. Among therapeutic families, chemotherapy clearly prevails along the disease lifetime, with hormone therapy being primarily used during the initial lines of treatment. Citation Format: Zamora P, Servitja S, Santaballa A, García J, de Paz L, Plata Y, Garau I, Florian J, Chacón I, de la Haba J, García P, Artime E, Rodríguez-Villanueva J, Velasco A, Martínez E, Segui MA. CASCADE study: Treatment and clinical outcomes of metastatic breast cancer by tumor immunophenotypes. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-07-39.

Introduction. The incorporation of cyclin-dependent kinase inhibitors 4 and 6 (CDK4/6 inhibitors) with endocrine therapy in patients with advanced hormone receptor-positive (HR+) breast cancer and without overexpression of the HER2 (HER2-) oncogene has demonstrated its efficacy improving progression-free survival (PFS), overall response rate (ORR) and, more recently, overall survival (OS). However, patients eventually progress due to resistance to treatment. To date, no clinical or molecular markers defining the HR +/HER2- patient population that obtains the greatest benefit from these drugs have been found, apart from estrogen receptor positivity. However, there are data from multiple retrospective analysis suggesting that within HR+/ HER2- disease, the non-luminal intrinsic subtypes (20-30% of these patients) have a worse prognosis and may not benefit from CDK4/6 inhibitors. Furthermore, the prognostic impact of tumor infiltrating lymphocytes (TILs) and gene expression related to the immune response in the context of HR + / HER2- advanced breast cancer have not been deeply investigated. Design. CDK-PREDICT is an observational, non-interventional, multicenter study that will include 114 patients with advanced breast cancer who have received, are receiving or are going to receive endocrine therapy plus a CDK4/6 inhibitor for, at least, 8 weeks as first-line treatment. The primary objective is to correlate the intrinsic subtypes (defined by PAM50) with the efficacy (measured as PFS) of CDK4/6 inhibitors + hormone therapy. As secondary objectives, the correlation of the intrinsic subtypes with ORR and with the histopathological characteristics of the tumor will be analyzed. In addition, the expression of immune response and cell cycle genes, as well as the presence of TILs, will be correlated with the intrinsic subtypes and with PFS and ORR. Overall, we aim to develop a predictive score combining clinical, genomic and immune expression data integrating tumor biology and microenvironment. For inclusion in the study, a metastatic sample taken within 90 days prior to CDK4/6 inhibitors treatment will be required. Once this sample has been collected, registered and assessed for quality, patients will be followed up every 6 months until disease progression, death or withdrawal from the study. This project has received a research grant from “Instituto de Salud Carlos III (ISCIII), Ministerio de Economía y Competitividad” (Spain) awarded within the National Research Program with reference PI 18/01408, co-funded with European Union ERDF funds (European Regional Development Fund). This study is included within the Biomarker program of SOLTI. Recruitment of this study started in June 2020. Citation Format: Pablo Tolosa, Tomás Pascual, Cristina Hernando, Sonia Servitja, María Fernández Abad, Rafael Villanueva, Fernando Henao, Javier Benítez, Laura Lema, Mario Martínez, Yolanda Ruano, Lucía Parrilla, Alejandra Bernardini, Ana María Roncero, Laia Paré, Jordi Canes, Fernando Salvador, Patricia Villagrasa, Aleix Prat, Eva Ciruelos. Solti-1801. Analysis of the efficacy of CDK4/6 inhibitors in combination with hormonal treatment in luminal breast cancer in relation to the intrinsic subtype and markers of immunity (CDK-PREDICT) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-26-04.

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Introduction Gene fusions (GFs) are genomic alterations with oncogenic potential. This class of alterations is highly actionable with targeted therapies showing high rates of durable responses in agnostic settings such as tumors with NTRK fusions. Recurrent GFs are rare in metastatic breast cancer (mBC) and ESR1 fusions drive endocrine resistance. AURORA is a molecular screening program for patients with mBC early in the course of their disease, collecting primary tumors, metastatic samples, liquid samples and longitudinal clinical follow-up data. Experimental procedures Patients are enrolled at the diagnosis of metastatic disease or after 1 line of therapy. Targeted gene sequencing of 411 BC genes is performed on the primary tumor, a metastatic sample, whole blood for germline variants and, for a subset of these genes, on tumor DNA from a baseline plasma sample. RNA-seq is performed on primary and metastatic tumor tissue samples. GFs were identified by rnafusion, a pipeline implementing 5 widely-used tools. Only GFs detected by at least 3 tools or 2 tools and 1 GF database match were considered for downstream analysis. Selected GFs were validated in-silico by FusionInspector. GFs detected in independent human normal tissue datasets were filtered out. Findings were correlated to available genomics, transcriptomics and clinical data. Results GFs data were generated from 316 paired primary/metastatic samples from 158 patients with curated clinical and genomic data: 97 ER+/HER2- (61.4%), 37 triple-negative (23.4%) and 24 HER2+ (15.2%). A total of 538 fusions were called in the primary samples (mean = 3.4 per sample) and 707 in the metastatic samples (mean = 4.5) with a validation rate of 72%. The gene fusion burden in metastatic samples was higher than in the primary (p<1e-4), especially for ER+ patients. In metastatic samples, gene fusion burden by PAM50 subtype was higher for basal, HER2-E and LumB when compared to LumA (max p=2e-3). A total of 400 acquired GFs were identified (mean=2.5 per sample), involving relevant BC genes, such as ESR1, ERBB2, NF1 and FGFR1.The presence of fusions involving actionable genes was associated with a shorter progression-free survival (PFS) on therapies in the metastatic setting (median PFS=8 vs 17 months, p=0.001). Conclusions We report on the characterization of GFs in a large cohort of patients with mBC. Through the analysis of matched primary and metastatic tumor samples from 158 patients, we delineated the landscape of acquired gene fusions in BC. We observed a significant increase of gene fusion burden in metastatic compared to corresponding primary samples, involving key BC genes. Fusions involving actionable genes were associated with shorter PFS. Additional integrative analyses combining detected GFs and available genomics, gene expression and/or patients' treatments and outcomes are ongoing and will be presented during the meeting. Citation Format: Matteo Benelli, Chiara Biagioni, Danai Fimereli, Florentine S. Hilbers, Claudia De Angelis, Ana Vivancos, David Venet, Andrea Vingiani, Alexandre Irrthum, Veerle Van Dooren, Peter Willem Vuylsteke, Sonia Servitja, Jorge Reis-Filho, Giuseppe Curigliano, Mafalda Oliveira, Martine Piccart, Philippe Aftimos. Characterization of gene fusions in paired primary and metastatic samples of breast cancer in the AURORA molecular screening program [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2488.