Dataset Information

Biomarker analysis of neoadjuvant Doxorubicin/Cyclophosphamide followed by Ixabepilone or Paclitaxel in early-stage breast cancer

ABSTRACT: A randomized, open-label, multicenter, phase II trial (NCT00455533) enrolled previously untreated women with histologically-confirmed primary invasive breast adenocarcinoma (T2–3, N0–3, M0, tumor size ≥2.0 cm), regardless of hormone receptor or HER2 expression status. Patients received sequential neoadjuvant therapy starting with 4 cycles of AC (doxorubicin 60 mg/m2 intravenously and cyclophosphamide 600 mg/m2 intravenously) given every 3 weeks, followed by 1:1 randomization to either ixabepilone (40 mg/m2 3-hour infusion) every 3 weeks for 4 cycles, or paclitaxel (80 mg/m2 1-hour infusion) weekly for 12 weeks. Fresh tumor biopsies at screening were a mandatory prerequisite for study entry for biomarker analyses. Gene expression profiling was performed by Affymetrix GeneChip to determine if pre-specified gene models could distinguish between the clinical activity of two microtubule stabilizing agents, ixabepilone and paclitaxel. Three core needle tumor tissue biopsies were obtained from all subjects before neoadjuvant therapy with AC and immediately combined in RNAlater® solution for subsequent RNA extraction, cRNA labeling and gene expression profiling. Pre-specified gene models were tested for their capacity to distinguish pathologic complete response rates between the AC followed by ixabepilone versus the AC followed by paclitaxel treatment regimens. All samples were collected prior to treatment. All subject received cyclophosphamide/doxorubicin (AC) prior to randomization to either Ixabepilone or Paclitaxel.

ORGANISM(S): Homo sapiens

SUBMITTER: Horak Christine

PROVIDER: S-ECPF-GEOD-41998 | biostudies-other |

REPOSITORIES: biostudies-other

ACCESS DATA

Similar Datasets

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

Biomarker analysis of neoadjuvant Doxorubicin/Cyclophosphamide followed by Ixabepilone or Paclitaxel in early-stage breast cancer

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets