Background: Triple negative breast cancers (TNBC) have a greater risk of relapse than non-TNBC. New therapeutic approaches are needed for these patients (pts). CIBOMA/2004-01_GEICAM/2003-11 is a multinational, randomized phase III trial exploring adjuvant capecitabine (X) after completion of standard treatment in early TNBC pts. Materials and Methods: Patients with operable, node-positive (or node-negative with tumor size ≥ 1 cm), centrally confirmed hormone receptor-negative, HER2-negative early BC, who had received 6–8 cycles (cy) of standard anthracycline and/or taxane-containing chemotherapy or 4 cy of doxorubicin-cyclophosphamide (for node-negative disease) in the (neo)adjuvant setting, were eligible. Patients were randomized to either 8 cy of X (1,000 mg/m2 bid, days 1–14, every 3 weeks) or observation. Stratification factors included center, prior taxane-based therapy, number of involved axillary lymph nodes and phenotype (basal vs non-basal, according to cytokeratins 5/6 and/or EGFR positivity). The primary objective was to compare the disease-free survival (DFS) between both treatment arms, and secondary objectives included the comparison in terms of 5-year DFS, overall survival (OS) and safety. Assuming a 30% risk reduction in DFS rate at 5 years (from 64.7% to 73.7%, hazard ratio 0.70) with 80% power and a two-tailed log-rank test at 0.05, 834 evaluable pts were needed. 876 pts had to be finally enrolled considering a drop-out rate of 5%. Results: Recruitment of 876 pts from 8 countries was completed in September 2011. Median age was 49 years; 68.5% of pts were postmenopausal, 55.5% were lymph node negative, 71.7% had a basal phenotype, 67.5% received chemotherapy based on anthracyclines and taxanes. Median follow-up was 7.3 years (range 0.0 to 11.1). DFS was not significantly prolonged with X vs observation (hazard ratio (HR) 0.82; 95% confidence interval (CI), 0.63 to 1.06; P=0.1353). Five-year DFS was 79.6% (95% CI, 75.8% to 83.4%) with X and 76.8% (95% CI, 72.7% to 80.9%) with observation. OS was not statistically different between treatment arms (HR 0.92; 95% CI, 0.66 to 1.28; P=0.6228). In subgroup analysis for DFS, we found no statistically significant interaction between X treatment and different subgroups, with the exception of basal vs non-basal phenotypes (basal HR 0.97, 95% CI 0.72 to 1.32, P=0.8620; non-basal HR 0.51, 95% CI, 0.31 to 0.86, P=0.0101; interaction P=0.0357). Similar results were found for OS (basal HR 1.20, 95% CI 0.81 to 1.77, P=0.3684; non-basal HR 0.48, 95% CI, 0.26 to 0.91, P=0.0205; interaction P=0.0155). 75.2% of pts completed 8 cy of X, with a median relative dose intensity of 86.3%. Grade (G) 3 or higher adverse events (AEs) were observed in 40.4% of pts in X arm. In 9.6% of pts the AEs were related with X. Hand-foot syndrome was the most common AE in X arm (G3 on 18.8% of pts). Conclusions: In our study, the addition of adjuvant X after standard (neo) adjuvant anthracycline and/or taxane-containing chemotherapy was not associated with a statistically significant improvement of DFS or OS compared to observation in pts with early TNBC. However, in a subgroup analysis a significant DFS and OS improvement was observed with X in pts with non-basal phenotype. Sponsor: CIBOMA. Citation Format: Martín M, Barrios CH, Torrecillas L, Ruiz-Borrego M, Bines J, Segalla J, Ruiz A, García-Sáenz JA, Torres R, de la Haba J, García E, Gómez HL, Llombart A, Rodríguez de la Borbolla M, Baena JM, Barnadas A, Calvo L, Pérez-Michel L, Ramos M, Castellanos J, Rodríguez-Lescure A, Cárdenas J, Vinholes J, Martínez de Dueñas E, Godes MJ, Seguí MA, Antón A, López-Álvarez P, Moncayo J, Amorim G, Villar E, Reyes S, Sampaio C, Cardemil B, Escudero MJ, Bezares S, Carrasco E, Lluch A. Efficacy results from CIBOMA/2004-01_GEICAM/2003-11 study: A randomized phase III trial assessing adjuvant capecitabine after standard chemotherapy for patients with early triple negative breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr GS2-04.
Background: Preclinical data (de la Haba J, AACR 2011) and retrospective clinical data (Mander P, Cancer 2003; Linderhol B, JCO 2000) suggest that high vascular endothelial growth factor (VEGF) levels in breast tumors are associated with a decreased response to endocrine therapy. We designed the randomized phase III LEA study of first-line bevacizumab in combination with hormone therapy in endocrine responsive advanced breast cancer patients to address the hypothesis that anti-VEGF treatment can prevent resistance to hormone therapy in these patients. Methods: A multicenter, bi-national, randomized, open label, phase III study investigated the addition of Bevacizumab (B) 15mg/kg every 3 weeks to an endocrine therapy (ET) with letrozole (2.5 mg/day) or fulvestrant (250mg/4 weeks) as first-line therapy in advanced breast cancer. Postmenopausal patients with HER2-negative and hormone-receptor-positive breast cancer were eligible and randomized in a 1:1 ratio after being stratified for prior adjuvant therapy with an aromatase inhibitor (AI); number of involved sites (one/multiple); measurable lesions (yes/no) and participating country (Spain/Germany). The primary objective was to compare progression-free survival (PFS) between treatment arms. Secondary objectives were overall survival, time to treatment failure, overall response rate, response duration, clinical benefit rate, and safety. In total, 344 patients (172 in each treatment arm) were needed to detect a hazard ratio of 0.69 (corresponding to a median PFS of 9 months in the ET arm and 13 months in the ET+B arm) with α=0.05 and β=0.2. With an expected drop-out rate of 10%, 378 patients were to be included. The efficacy analysis is pre-planned after 270 events. Results: From 11/2007 to 8/2011, 380 patients were randomized in Spain and Germany to ET (n = 189) or ET+B (n = 191), 342 patients received letrozole and 38 fulvestrant. Baseline characteristics were well balanced. Median age was 65 years (38–86) and 72% of patients had ECOG PS 0. Twelve patients (4%) entered the trial with locally advanced disease, 65% had measurable lesions, 63% had bone and 45% visceral metastasis. 76% of patients had both hormone receptor positive. 44% had adjuvant chemotherapy and 51% adjuvant endocrine therapy from which 36% of patients received adjuvant AI. Full safety data will be presented at ESMO this year. The main side effects (any grade, per patient, ET+B vs ET) were anemia 76% vs 44%, p < 0.001; fatigue 50% vs 31%, p = 0.001; hemorrhage 19% vs 2%, p < 0.001; hypertension 55% vs 12%, p < 0.001; proteinuria 21%vs 3%, p < 0.001; and thrombosis grade 3–4, 2.3% vs 0%, p = 0.057. Until June 2012, 226 PFS events have been observed. The current event rate holds out the expectation to have the 270 necessary events by August-2012. Conclusions: LEA is the first phase III study to explore the use of an anti-angiogenic drug in combination with endocrine therapy. The efficacy results will be presented at the meeting. First and second authors have contributed equally to this study Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr S1-7.
Background: The addition of trastuzumab (T) to neoadjuvant chemotherapy increases pCR rate in patients with HER2 + breast cancer. Lapatinib (L) in combination with chemotherapy is also an active drug in breast cancer patients. This study investigates the efficacy of trastuzumab or lapatinib added to chemotherapy in the neoadjuvant setting. Methods: Patients (Pt) with tumors greater than 2 cm (or less with positive axilla) and HER2+ (Herceptest 3+ or 2+ with FISH+) that have not received any prior treatment for breast cancer were recruited. Pts were randomized to receive epirubicin 90 mg/m2 plus cyclophosphamide 600 mg/m2 × 4 cycles (cy) followed by docetaxel 100 mg/m2 (with growth colony stimulating factor support) plus either T 8 mg/kg loading dose and then 6 mg/Kg intravenous (EC-DT) or L 1250 mg orally (EC-DL). Patients were stratified according to tumor size (T1-2 vs T3-4), and estrogen receptor status (positive vs negative). The primary end-point was pathological complete response (pCR) in the breast measured by Miller and Payne criteria. Secondary end-points were clinical response (by imaging test), toxicity and correlation between pCR and tumor biomarkers. Results: From February-09 to October-10, 102 pts were randomized (50 EC-DT, 52 EC-DL). Pts characteristics were well balanced between arms. Median age was 48 years (30-79), 56% of pts were premenopausal, 7% grade I, 45% grade III. 14/59/12/15% were T1/T2/T3/T4 and 69% N+. 58% were estrogen receptor positive and 44% progesterone receptor positive. Three patients were FISH negative after central assessment and were not considered evaluable for efficacy. pCR rate in the breast was 52% (95% CI: 38–66) for EC-DT and 25% (95% CI: 13.5−37.5) for EC-DL (p-value=0.0065). pCR—pN0 was 48% (95% CI: 34–62) for EC-DT and 24% (95% CI: 12 - 35) for EC-DL (p-value=0.01). Clinical response was 77% with EC-DT and 65% with EC-DL (p-value=0.176). Grade III-IV toxicity was similar between arms except for diarrhea that was more frequent in EC-DL 14% than in EC-DT 2% (p-value=0.03); more patients discontinue treatment due to toxicity with EC-DL (1 vs 6; p-value=0.055). Conclusions: Our study shows that EC-DT was more efficacious and less toxic than EC-DL in the neoadjuvant treatment of HER2+ pts. Biomarker profiling in the tumors, including activation levels of tyrosine-kinase receptors, signaling pathways and surrogate markers (proliferation and apoptosis) is ongoing; their correlation with pCR will be presented at the meeting. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD07-04.
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.
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