Background: Eribulin is the only cancer agent that has demonstrated a significant prolongation in overall survival on previously treated breast cancer patients. To date, no biomarker exists to prospectively select patients who will derive the maximum benefit from this chemotherapeutic. In the SOLTI1007-NeoEribulin study, we explored, in a prospective clinical trial, the efficacy and the association of pre-treatment expression of RNA in patients with HER2-negative breast cancer treated with neoadjuvant eribulin. Methods: SOLTI1007 is a phase II, open-label, single-arm, exploratory pharmacogenomic study of single agent eribulin as neoadjuvant treatment for stage I-II HER2-negative breast cancer (planned n=100 hormonal receptor-positive [HR+] and n=100 HR-negative). Patients received 1.4 mg/m2 of eribulin intravenously on Days 1 and 8 every 21-day cycle, for 4 cycles. Baseline and post-treatment (surgical) formalin-fixed, paraffin-embedded tissue samples were collected and gene expression profiled. PAM50 intrinsic subtype and the Risk of Relapse based on subtype and proliferation (ROR-P) were evaluated in each time-point. The association of each PAM50 signature and pathological complete response in the breast (pCRB) was evaluated using univariate logistic regression models. Results: Between September 2012 and October 2015, one hundred and seventy-four patients (TNBC n=73 and HR+ n=101) were recruited. Mean age (55.5), stage II (90%), negative axilla (78% and 67%), grade 3 (62% and 26%), mean tumor size (3 cm and 3.6 cm) and mean Ki-67 (61% and 31%). Completion of 4 cycles of eribulin was achieved by 85% of the patients. Grade 3-4 toxicities were observed in 19.54%, mostly due to neutropenia (5.1%) and alopecia (4.02%). The overall pCRB was 5.4%. No significant differences were observed between HR+ and TNBC disease. Distribution of the PAM50 intrinsic subtypes was as follows: Luminal A (n=43, 27.7%), Luminal B (n=42, 27.1%), Basal-like (n=63, 40.6%) and HER2-enriched (n=7, 4.5%). pCRB rates by subtype were the following: HER2-enriched (28.6%, 2/7), Luminal B (7.1%, 3/42), Basal-like (4.8%, 3/63), Luminal A (2.3%, 1/43). pCRB rates significantly (p=0.047) differed when HER2-enriched was compared to the other subtypes (odds ratio = 8.06, 95% CI 1.32-49.1). pCRB rate differed significantly by ROR-P (p=0.006): ROR-P high (17.1%, 6/35), ROR-P med (2.7%, 2/75), ROR-P low (2.2%, 1/45). Ki67 % by IHC did not predict pCRB (p=0.918). Subtype change at surgery occurred in 60% (3/5) HER2-enriched, 44.1% (15/34) of Luminal Bs, 10.3% (4/39) of Luminal A and 5.4% (2/37) of Basal-like tumors. 100% of subtype changes in Luminal B disease were to Luminal A. Conclusions: From a response and biological perspective, patients with HER2-enriched and Luminal B disease may benefit the most from eribulin therapy. Mechanistically, our gene expression data further supports previous preclinical evidence suggesting that eribulin triggers a phenotypic conversion. Citation Format: Prat A, Ortega V, Villagrasa P, Paré L, Galván P, Oliveira M, Nucíforo P, Lluch A, Morales S, Amillano K, Lopez R, Gonzalez R, Manso L, Martinez J, Llombart A, De la Peña L, Di Cosimo S, Rubio IT, Harbeck N, Baselga J, Cortés J. Efficacy and gene expression results from SOLTI1007 NEOERIBULIN phase II clinical trial in HER2-negative early breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-09-09.
Purpose : Molecular classification of breast cancer (BC) through immunohistochemistry classifies patients globally in 4 subtypes with similar features and prognosis. The present study was designed to compare features of BC subtypes in early versus locally advanced clinical stages. A secondary objective was compare molecular subtypes of the primary vs recurrences. Methods : The study included 1621 patients with non-metastatic invasive BC that were consecutively diagnosed at Hospital Universitario 12 de Octubre, Madrid, between 1997 and 2007. Luminal A was defined as ER+ and PR+, HER2−negative and Ki67 < 14%. Luminal B was defined as PR-negative, HER2−positive or ki67≥14%. HER2 was defined as ER and PR-negative, and HER2−positive.Triple negative (TN) were tumors with ER, PR and HER2 -negativity. Clinicopathological characteristics and outcomes were retrospectively reviewed. Variables were compared with the X2 test, and survival curves were evaluated with Kaplan-Meier method. Results : Most patients were diagnosed as T1 (48%) and T2 (39.7%) clinical stages, and classified as Luminal B (49%) and Luminal A (29%). GIII frequency increased from T1 to T3-4 in Luminal A (p=0.002), and Luminal B (p=0.051) subtypes, but not in HER2 (p=0.867) or TN (p=0.53). Molecular subtypes carry significant different prognosis (DFS and OS) in all T stages except for T1a cases. When T3-4 and T1 stages of the same molecular subtype were compared, a significant shorter DFS were found for more advanced stages in the Luminal A (p=0.0002), Luminal B (0.0001) and TN (0.0017), but not for HER2 (p=0.54) subtype. And, similar results were found for OS. We compared molecular subtypes in the primary tumor and in the metastatic site in 83 cases (excluding contralateral recurrences) and found change of phenotype in 54% of the cases. Changes from Luminal A to a more aggressive phenotype were more frequent than in the opposite situation (14 vs 2 cases). Conclusion : Despite the molecular classification of early-stage BC that classifies patients in well-defined prognostic subgroups, tumors are continuously changing and tumor behavior becomes more aggressive through progression. Therefore, even tumors with favorable phenotype could loss their good prognosis in locally advanced stages. Obtention of tumor tissue at metastatic sites is also mandatory to a better selection of systemic therapies in relapsed patients. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-05-06.
Background: Circulating epithelial tumor cells (CTCs) in peripheral blood are an ideal source for the detection of disseminated tumor cells of an easy sampling procedure. Their prognosis significance has been demonstrated in metastasic breast carcinoma and have potencial to influence the clinical management for pts. with breast cancer (Cristofanilli, NEJM 2004). The antiangiogenic agent bevacizumab (Bev.), in combination with CT, improves progression free survival (PFS) of first line treatments, may modify tumor cell intravasation and CTC count, and may change CEC levels. Aims of this study are the evaluation of the prevalence and kinetics of CTCs and CECs before and after antiangiogenic treatment with Bev in pts with metastatic breast cancer. Methods: Eligible pts. received Bev (10mg/kg q2w) combined with paclitaxel 150 mg/m2 and gemcitabine 2000mg/m2 d 1 y 15 q28d as first line therapy, until disease progression, unacceptable toxicity or withdrawal. For pts. participating in the sub-study, CTC and CEC were measured in 7.5ml of blood at baseline and after the first cycle of treatment. Samples were subjected to imnumomagnetic enrichment with an anti-EpCAM antibody and fluorescence labelled. CTCs were defined as nucleated cells (DAPI+) expressing cytokeratin 8, 18 and 19 but CD45 negative phenotype. CECs were defined as nuclear cells (DAPI+) expressing CD105 PE and CD45 negative phenotype. A sample was considered positive when 1 or more cells were detected. Results: Data are available for 37 pts. We found ≥1 CTCs before first cycle of treatment with bev in 73% of the patients (N=27). After first treatment, reduction of CTCs was found in 57% of the patients (N=16). The median number of CTCs was 34 cells/7.5 ml (min 0-max 845) of blood in the first determination and 4.79 cells/7.5 ml (min 0-max 99) in the second determination, p=0.0075. In 38% of the pts (N=14) we found ≥5 baseline CTCs and after treatment <5 CTCs were found in 89% of the pts (N=25). In 70% of pts with baseline ≥5 CTCs count, a reduction to < 5CTCs was observed in the second determination (N=10), p=0.20 (IC 34.15-93.33). In 10 pts we found CTCs=0 baseline value (35%) and in the second determination after treatment CTCs=0 cells/7.5 ml was observed in 53%, p=0.058. Baseline CECs ≥1 was observed in 100% of the pts (N=31). After first cycle of treatment with bev plus CT CECs=0 was found in 1 patient (3.4%). In 70% of pts (N=14) there was a reduction of baseline CECs count, p=0.3. The median value of baseline CECs was 123 cells/7.5 ml (min 4- max 1407) and the median value in second determination was 54 cells/7.5 ml (min 0-max 349). The median of reduction of CECs after treatment was 70 CECs, p=0.02. Conclusions: The addiction of bev to 1st line CT was related with high reduction of the value of baseline CTCs and CECs count, statistically significant correlation. Reduction to < 5 CTCs of patients with baseline ≥5 CTCs (unfavourable prognosis) was observed in 70% of patients. The results of this explorative study are preliminary and a large number of pts and follow-up is required. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-02-11.
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