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Neoadjuvant doxorubicin/cyclophosphamide followed by ixabepilone or paclitaxel in early stage breast cancer and evaluation of ?III-tubulin expression as a predictive marker.

ABSTRACT: This randomized phase II trial was designed to compare the rate of pathologic complete response (pCR) induced by neoadjuvant cyclophosphamide plus doxorubicin (AC) followed by ixabepilone or paclitaxel in women with early stage breast cancer (BC). Expression of ?III-tubulin as a predictive marker was also evaluated.Women with untreated, histologically confirmed primary invasive breast adenocarcinoma received four cycles of AC followed by 1:1 randomization to either ixabepilone 40 mg/m2 (3-hour infusion) every 3 weeks for four cycles (n = 148) or weekly paclitaxel 80 mg/m2 (1-hour infusion) for 12 weeks (n = 147). All patients underwent a core needle biopsy of the primary cancer for molecular marker analysis prior to chemotherapy. ?III-Tubulin expression was assessed using immunohistochemistry.There was no significant difference in the rate of pCR in the ixabepilone treatment arm (24.3%; 90% confidence interval [CI], 18.6-30.8) and the paclitaxel treatment arm (25.2%; 90% CI, 19.4-31.7). ?III-Tubulin-positive patients obtained higher pCR rates compared with ?III-tubulin-negative patients in both treatment arms; however, ?III-tubulin expression was not significantly associated with a differential response to ixabepilone or paclitaxel. The safety profiles of both regimens were generally similar, although neutropenia occurred more frequently in the ixabepilone arm (grade 3/4: 41.3% vs. 8.4%). The most common nonhematologic toxicity was peripheral neuropathy.Neoadjuvant treatment of early stage BC with AC followed by ixabepilone every 3 weeks or weekly paclitaxel was well tolerated with no significant difference in efficacy. Higher response rates were observed among ?III-tubulin-positive patients.

SUBMITTER: Saura C

PROVIDER: S-EPMC3720631 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Neoadjuvant doxorubicin/cyclophosphamide followed by ixabepilone or paclitaxel in early stage breast cancer and evaluation of βIII-tubulin expression as a predictive marker.

Saura Cristina C Tseng Ling-Ming LM Chan Stephen S Chacko Raju T RT Campone Mario M Manikhas Alexy A Nag Shona M SM Leichman Cynthia G CG Dasappa Lokanatha L Fasching Peter A PA Hurtado de Mendoza Fernando F Symmans W Fraser WF Liu David D Mukhopadhyay Pralay P Horak Christine C Xing Guan G Pusztai Lajos L

The oncologist 20130712 7

<h4>Background</h4>This randomized phase II trial was designed to compare the rate of pathologic complete response (pCR) induced by neoadjuvant cyclophosphamide plus doxorubicin (AC) followed by ixabepilone or paclitaxel in women with early stage breast cancer (BC). Expression of βIII-tubulin as a predictive marker was also evaluated.<h4>Patients and methods</h4>Women with untreated, histologically confirmed primary invasive breast adenocarcinoma received four cycles of AC followed by 1:1 random ...[more]

PMID: 23853246

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Project description:ObjectivesTrastuzumab (H) and pertuzumab (P) with standard chemotherapy is approved for use in the neoadjuvant setting for human epidermal growth receptor 2 -positive patients. A retrospective analysis was performed of patients treated with dose-dense (dd) doxorubicin and cyclophosphamide (AC) followed by paclitaxel (T), trastuzumab, and pertuzumab (THP) in the neoadjuvant setting. Here, the pathologic complete response (pCR) rates are reported.MethodsAn electronic medical record review was conducted of patients treated with HP-based therapy in the neoadjuvant setting from September 1, 2013, to March 1, 2015. Data on patient demographics, stage of breast cancer, pathology reports, surgical data, and information on systemic therapy were collected. The pCR was defined as total (tpCR, ypT0/is ypN0), German Breast Group (GBG) pCR (ypT0 ypN0), breast pCR (bpCR) with in situ disease (ypT0/is) and without in situ disease (ypT0), and explored axillary pCR (ypN0).ResultsCharts from 66 patients were reviewed, and 57 patients were evaluable for pCR. Median age was 46 years (range 26-68 years). Median tumor size was 4 cm. Of 57 patients, 53 (93%) had operable breast cancer (T1-3, N0-1, M0). Three patients (5.3%) had locally advanced disease (T2-3, N2-3, M0 or T4a-c, any N, M0), and 1 (1.7%) had inflammatory breast cancer (T4d, any N, M0). Overall, 44 (77%) and 13 (23%) had hormone receptor (HR)-positive and negative diseases, respectively. Median numbers of cycles of neoadjuvant treatment were as follows: AC (4, range 1-4), T (4, range 1-4), trastuzumab (6, range 3-8), and pertuzumab (6, range 2-8). In these 57 patients, the rates of tpCR and bpCR with in situ disease were demonstrated in 41/57 (72%) patients, and the rates of GBG pCR and bpCR without in situ disease were found in 30/57 (53%) patients. Of 26 patients with biopsy-proven lymph nodal involvement, axillary pCR occurred in 22 (85%) patients.ConclusionAt a single center, the tpCR and GBG pCR rates of dd AC followed by THP are high at 72% and 53%, respectively. The Oncologist 2017;22:139-143Implications for Practice: This is the first study describing the role of doxorubicin and cyclophosphamide followed by paclitaxel and dual anti-HER2 therapy with trastuzumab and pertuzumab (ACTHP) in patients with early stage HER2-positive breast cancer. Total (breast + lymph node) pathological complete remission (pCR) remission (ypT0/is ypN0) and German Breast Group pCR rates (ypT0/ ypN0) were high at 72% and 53%, respectively, with the ACTHP regimen. Rate of axillary clearance in patients with known axillary involvement was high at 85%, which may translate into less extensive axillary surgeries in this subset in the future.

Project description:For estrogen receptor (ER)-negative breast cancer patients, paclitaxel (P), doxorubicin (A) and cyclophosphamide (C) neoadjuvant chemotherapy (NAC) is the standard therapeutic regimen. Pathologic complete response (pCR) and residual disease (RD) are common surrogate measures of chemosensitivity. After NAC, most patients still have RD; of these, some partially respond to NAC, whereas others show extreme resistance and cannot benefit from NAC but only suffer complications resulting from drug toxicity. Here we developed a qualitative transcriptional signature, based on the within-sample relative expression ordering (REO) of gene pairs, to identify extremely resistant samples to PAC NAC. Using gene expression data for ER-negative breast cancer patients including 113 pCR samples and 137 RD samples from four datasets, we selected 61 gene pairs with reversal REO patterns between the two groups as the resistance signature, denoted as NR61. Samples with more than 37 signature gene pairs that had the same REO patterns within the extremely resistant group were defined as having extreme resistance; otherwise, they were considered responders. In the GSE25055 and GSE25065 dataset, the NR61 signature could correctly identify 44 (97.8%) of the 45 pCR samples and 22 (95.7%) of the 23 pCR samples as responder samples, respectively; it also identified 13 (16.9%) of 77 RD samples and 8 (21.1%) of 38 RD samples as extremely resistant samples, respectively. Survival analysis showed that the distant relapse-free survival (DRFS) time of the 14 extremely resistant cases was significantly shorter than that of the 108 responders (P < 0.01; HR = 3.84; 95% CI = 1.91-7.70) in GSE25055. Similar results were obtained in GSE25065. Moreover, in the integrated data of the two datasets with 94 responders and 21 extremely resistant samples identified from RD patients, the former had significantly longer DRFS than the latter (P < 0.01; HR = 2.22; 95% CI = 1.26-3.90). In summary, our signature could effectively identify patients who completely respond to PAC NAC, as well as cases of extreme resistance, which can assist decision-making on the clinical therapy for these patients.

Dataset Information

Neoadjuvant doxorubicin/cyclophosphamide followed by ixabepilone or paclitaxel in early stage breast cancer and evaluation of ?III-tubulin expression as a predictive marker.

Publications

Neoadjuvant doxorubicin/cyclophosphamide followed by ixabepilone or paclitaxel in early stage breast cancer and evaluation of βIII-tubulin expression as a predictive marker.

Similar Datasets

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