Project description:We studied the effect on tumour response to neoadjuvant therapy of the substitution of lapatinib for trastuzumab in combination with weekly paclitaxel after doxorubicin plus cyclophosphamide treatment, and of the addition of lapatinib and trastuzumab combined after doxorubicin plus cyclophosphamide treatment in patients with HER2-positive operable breast cancer to determine whether there would be a benefit of dual HER2 blockade in these patients.
Project description:This randomized phase II trial studies how well paclitaxel with or without carboplatin and/or bevacizumab followed by doxorubicin and cyclophosphamide works in treating patients with breast cancer that can be removed by surgery. Drugs used in chemotherapy, such as paclitaxel, carboplatin, doxorubicin, and cyclophosphamide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Bevacizumab may stop the growth of tumor cells by blocking blood flow to the tumor. Giving chemotherapy together with bevacizumab before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed.
Project description:The human breast cancer (BR) data set (endpoints D and E) was contributed by the University of Texas M. D. Anderson Cancer Center (MDACC, Houston, TX, USA). Gene expression data from 230 stage I-III breast cancers were generated from fine needle aspiration specimens of newly diagnosed breast cancers before any therapy. The biopsy specimens were collected sequentially during a prospective pharmacogenomic marker discovery study between 2000 and 2008. These specimens represent 70-90% pure neoplastic cells with minimal stromal contamination. Patients received 6 months of preoperative (neoadjuvant) chemotherapy including paclitaxel, 5-fluorouracil, cyclophosphamide and doxorubicin followed by surgical resection of the cancer. Response to preoperative chemotherapy was categorized as a pathological complete response (pCR = no residual invasive cancer in the breast or lymph nodes) or residual invasive cancer (RD), and used as endpoint D for prediction. Endpoint E is the clinical estrogen-receptor status as established by immunohistochemistry. RNA extraction and gene expression profiling were performed in multiple batches over time using Affymetrix U133A microarrays. Genomic analysis of a subset of this sequentially accrued patient population were reported previously. For each endpoint, the first 130 cases were used as a training set and the next 100 cases were used as an independent validation set. Gene expression data from 230 stage I-III breast cancers
Project description:CALGB 40601 was activated as a 3-arm study (paclitaxel + trastuzumab + lapatinib [THL], paclitaxel + trastuzumab [TH] and paclitaxel + lapatinib [TL]). In December 2010, twoneoadjuvant studies were presented at the Cancer Therapy and Research Center-American Association for Cancer Research (CTRC-AACR) San Antonio Breast Cancer Symposium that affected the scientific and practical enthusiasm for the TL arm. For this reason the CALGB 40601 has been amended to omit the TL treatment arm (arm 3). In the Geparquinto trial, patients with HER2-positive breast cancer received epirubicin/cyclophosphamide followed by docetaxel combined either with trastuzumab (EC-DOC-H) or lapatinib (EC-DOC-L) neoadjuvantly, then trastuzumab for a total of 12 months adjuvantly [34]. Pathologic complete response (pCR) in breast and axilla was the primary endpoint. Among 620 patients randomized, there was a higher pCR rate (31% vs 22%) and lower toxicity with fewer discontinuations (10% vs 16%) among patients on the trastuzumab arm than the lapatinib arm. The first results of the NeoALTTO trial were similar [35]. Approximately 450 women with HER2-positive breast cancer received a lead-in phase of 6 weeks of biologic therapy withlapatinib (L), trastuzumab (H), or both, then paclitaxel was added for an additional 12 weeks prior to surgery. All drugs were given at doses similar to CALGB 40601. Postoperative adjuvant therapy included additional chemotherapy and biologic therapy, however, the presentation focused solely on the primary endpoint of pCR in the breast at surgery; no longterm outcomes were presented. There were more grade > 3 adverse events in the lapatinib arm compared with the trastuzumab arm, including diarrhea (23% vs 2%), hepatic abnormalities (13% vs 1%), and neutropenia (16% vs 3%). The only death occurred in the combined biologic (LH) arm. Failure to complete treatment as planned was higher in the L (34%) and LH arms (39%) that in the H arm (u%). PCR was highest with LH-paclitaxel (51%), followed by H-paclitaxel (30%), and L-paclitaxel (25%). Based on the inferior results and higher toxicity of the investigational lapatinib arms of these studies and in discussion with CTEP, in January 2011 it was decided to amend CALGB 40601 to omit Arm 3 (TL). Those patients on this arm will complete protocol therapy as perthe original study design. In CALGB 40601, it is recommended that all patients receive trastuzumab adjuvantly for 1 year, hence all of the patients including those previously randomized to the TL neoadjuvant arm, will be able to receive the known benefit of trastuzumab. After local IRB approval of Update #5, the remainder of the patients will be enrolled and randomized to Arm 1 (THL) and Arm 2 (TH) in a 2:1 fashion. Given that TH isthe standard regimen, and is also clearly the best tolerated, we will continue that arm of thestudy as the comparator, with THL as the only investigational arm.
