RC48-ADC Combined With Bevacizumab in HER2-positive Advanced Colorectal Cancer
Ontology highlight
ABSTRACT:
DISEASE(S): Colorectal Cancer,Colorectal Neoplasms
PROVIDER: 12742 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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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.
2018-10-16 | GSE116335 | GEO
Project description:Gene expression data of HER2+ breast tumor samples Increasing evidence indicates that a subset of patients with HER2-positive breast cancer may achieve significant clinical benefit with anti-HER2 targeted therapy without chemotherapy. Thus, identification of biomarkers of long-term benefit from anti-HER2 agents is needed, especially in the metastatic setting. In the HERLAP study (NCT00842998), patients with HER2-positive metastatic breast cancer were randomized to trastuzumab or lapatinib as first-line therapy. Patients showing radiological signs of tumor regression after 8 weeks of treatment were allowed to continue on single agent anti-HER2 therapy until disease progression. Chemotherapy was added to anti-HER-2 therapy in patients failing to achieve tumor regression at the 8-week evaluation and those progressing at any time. Expression analysis of 105 selected genes was performed from formalin-fixed paraffin-embedded in 17 primary tumor samples. The research-based PAM50 intrinsic subtypes were also identified. The association of the expression of each biomarker with clinical outcome endpoints was evaluated. Nineteen patients were enrolled. In 4 patients (21.1%) we observed disease control lasting longer than 12 months with single agent anti-HER2 therapy (range 14.9-38.8 months). High expression of 17q12-21 amplicon genes HER2 and GRB7, and the PAM50 HER2-enriched intrinsic profile, were found significantly associated with 8-week overall response rate and with the duration of disease control during single agent anti-HER2 therapy. Conversely, high expression of luminal-related genes such as PGR, MDM2 or PIK3CA, or the PAM50 luminal intrinsic profile, was found associated with reduced benefit from single agent anti-HER2 therapy. Conclusions: Our data indicate that gene expression-based biomarkers can identify patients with HER2-positive metastatic breast cancer that benefit substantially from single agent chemo-free anti-HER2 targeted therapy. In the study presented here, a well-defined cohort of 21 breast cancer cases from the HERLAP trial, was used to acquire expression profiles of a total of 105 unique genes
2013-10-25 | E-GEOD-46350 | biostudies-arrayexpress
Project description:We have assayed differential miRNA expression between late stage (stage IV) metastatic Her2+ and Her2- breast cancer. 4 late stage metastatic Her2- samples were compared to 3 late stage metastatic Her2+ samples. There are 4 within array replicates for each sample.
2010-04-29 | E-GEOD-20066 | biostudies-arrayexpress
Project description:The goal of our study is to build an integrated transcriptome landscape model for HER2 positive breast tumors and identify the crucial signaling pathways associated with HER2 tumors. Genomic features include, 685 genes that were differentially expressed only in HER2-positive tumors, 102 genes that were alternatively spliced in a pattern that is unique to HER2-positive tumors, and 303 genes that expressed single nucleotide sequence variants (eSNVs) that were unique to HER2-positive tumors. Network analysis was performed to integrate the genomic features into a transcriptome landscape model that identified 12 highly interconnected cellular processes that appear to be critical to the establishment and maintenance of HER2-positive tumors. We observed that integrin signaling was linked to lapatinib sensitivity in vitro and strongly associated with risk of relapse in the NCCTG N9831 adjuvant trastuzumab clinical trial dataset. We analyzed RNA-seq data from a survey panel consisting of 8 benign breast lesions, 8 ER+, 8 triple negative, and 8 HER2-positive primary breast tumors to identify genomic features that were uniquely associated with HER2-positive tumors
2013-12-06 | E-GEOD-45419 | biostudies-arrayexpress
Project description:Array-CGH experiments of HER2+ breast cancer cell lines grown under standard conditions. All hybridizations performed using pooled normal female DNA as reference. 11 cell lines profiled in total, 10 HER2+, 1 HER2-. Each was hybridized once on an Agilent 244k aCGH microarray.
2013-06-01 | E-GEOD-34236 | biostudies-arrayexpress
Project description:Trastuzumab, a humanized monoclonal antibody directed to the HER2 protein, is the standard-of-care treatment for patients with HER2 positive breast cancer, reducing the risk of relapse and death in patients. Nonetheless, some patients relapse after treatment, underscoring the need to identify patients for whom chemotherapy + trastuzumab is adequate versus patients requiring additional drugs. To search for genes predictive of relapse in HER2-positive breast carcinoma patients treated with adjuvant trastuzumab, we conducted gene expression profiling analysis in 53 cases treated in the clinic with doxorubicin/paclitaxel (AT) followed by cyclophosphamide/methotrexate/fluorouracil (CMF) and trastuzumab. Gene expression profiling was performed using RNA from formalin-fixed paraffin-embedded tissues from 53 patients with primary HER2-positive (HER2+) tumors. The series consists in 23 relapsed and 30 non-relapsed cases with similar clinical-pathological characteristics (size, pathological lymph node involvement and estrogen receptor positivity) (3-year median follow up).
2015-10-19 | E-GEOD-55348 | biostudies-arrayexpress
Project description:The goal of our study is to build an integrated transcriptome landscape model for HER2 positive breast tumors and identify the crucial signaling pathways associated with HER2 tumors. Genomic features include, 685 genes that were differentially expressed only in HER2-positive tumors, 102 genes that were alternatively spliced in a pattern that is unique to HER2-positive tumors, and 303 genes that expressed single nucleotide sequence variants (eSNVs) that were unique to HER2-positive tumors. Network analysis was performed to integrate the genomic features into a transcriptome landscape model that identified 12 highly interconnected cellular processes that appear to be critical to the establishment and maintenance of HER2-positive tumors. We observed that integrin signaling was linked to lapatinib sensitivity in vitro and strongly associated with risk of relapse in the NCCTG N9831 adjuvant trastuzumab clinical trial dataset.
2013-12-06 | GSE45419 | GEO
Project description:We have assayed differential miRNA expression between late stage (stage IV) metastatic Her2+ and Her2- breast cancer.
2010-04-29 | GSE20066 | GEO
Project description:The CHER-LOB randomized phase II study showed that the combination of lapatinib and trastuzumab plus chemotherapy increases the pathologic complete remission (pCR) rate as compared to chemotherapy plus either trastuzumab or lapatinib. An extensive biomarker programme was prospectively planned to identify potential predictors of sensitivity to different treatments and evaluate treatment effect on tumor biomarkers. A mutation in PIK3CA exon 20 or 9 was documented in 20% of the cases. Overall, the pCR rates were similar in PIK3CA wild type and PIK3CA mutated patients (33.3% vs 22.7%; p=0.323). However, for patients receiving trastuzumab plus lapatinib, the probability of pCR was higher in PIK3CA wild type tumors (48.4% vs 12.5%; p=0.06). Ki67, pAKT and apoptosis measured on the residual disease were significantly reduced from baseline. The degree of Ki67 inhibition was significantly higher in patients receiving the dual anti-HER2 blockade. In conclusion, PIK3CA mutations seem to identify patients less likely to benefit from dual anti-HER2 inhibition. p95-HER2 and markers of PI3K pathway deregulation are not confirmed as markers of different sensitivity to trastuzumab or lapatinib.
2015-10-06 | GSE66305 | GEO
Project description:Chimeric antigen receptor T cells (CAR-T) therapy has not yet been fully explored in solid tumors. Human epidermal growth factor receptor-2(HER2) is widely expressed in cancers. Investigators have developed anti-HER2 CAR-modified T cells and validated the efficiency targeting HER2-positive cancer in preclinical studies. This study is aimed to confirm its adverse effects including cytokine storm response and any other adverse effects. In addition, CAR-T cells persistence, tumor elimination and disease status after treatment will be evaluated.
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