Tumor infiltrating lymphocytes in patients receiving trastuzumab/pertuzumab-based chemotherapy: A TRYPHAENA substudy
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PROVIDER: PRJNA431776 | ENA |
REPOSITORIES: ENA
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Project description:Background: It is critical to identify biomarkers for treatment tailoring in HER2-amplified early breast cancer treated with trastuzumab/pertuzumab-based chemotherapy. Patients and methods: Among the 225 patients randomized to trastuzumab/pertuzumab concurrently or sequentially with an anthracycline-containing regimen or concurrently with an anthracycline-free regimen in the Tryphaena trial, we evaluated TILs at baseline in 213 patients of whom 126 with pathological complete response, pCR (ypT0/is ypN0) and 28 with Event Free Survival, EFS events. We computed associations between baseline TILs and either pCR or EFS after adjusting for clinicopathological characteristics using logistic and Cox regression models, respectively. To understand TILs biology, we evaluated associations between baseline TILs and baseline tumor gene expression data (800 gene set by NanoString) in a subset of 173 patients. Results: Among the 213 patients with evaluable TILs at baseline, the median level of TILs was 14% (interquartile range, IQR, 7-32%). After adjusting for clinicopathological characteristics, baseline TILs were not associated with pCR (adjusted odds ratio for every 10% increase in TILs aOR 1.12, 95%CI 0.95-1.31, p=0.17). At a median follow-up of 4.7 years, for every increase in baseline TILs of 10 percentage units there was a 25% reduction in the hazard of the EFS event (adjusted hazard ratio 0.75, 95%CI 0.56-1.00, p=0.05) after adjusting for baseline clinicopathological characteristics and pCR. Genes associated with Epithelial-Mesenchymal Transition (EMT) such as SNAIL1, TWIST1, ZEB1, B7-H3 and NOTCH3 were significantly anti-correlated with TILs. Conclusions: Baseline TILs provide independent prognostic information in patients treated with trastuzumab/pertuzumab-based neoadjuvant chemotherapy. Further validation is needed.
2018-04-01 | GSE109710 | GEO
Project description:We sequenced untreated BT474 cells, BT474 cells treated for three days with trastuzumab or trastuzumab + pertuzumab, as well as two BT474-derived trastuzumab-resistant pools and two BT474-derived trastuzumab + pertuzumab resistant pools. Resistant pools were generated by culturing BT474 cells in gradually increasing doses of trastuzumab and trastuzumab + pertuzumab over the course of several months and continually maintained in drug.
2020-01-26 | GSE121105 | GEO
Project description:Background:There is an urgent requirement to identify biomarkers to tailor treatment in human epidermal growth factor receptor 2 (HER2)-amplified early breast cancer treated with trastuzumab/pertuzumab-based chemotherapy. Methods:Among the 225 patients randomly assigned to trastuzumab/pertuzumab concurrently or sequentially with an anthracycline-containing regimen or concurrently with an anthracycline-free regimen in the Tryphaena trial, we determined the percentage of tumor-infiltrating lymphocytes (TILs) at baseline in 213 patients, of which 126 demonstrated a pathological complete response (pCR; ypT0/is ypN0), with 28 demonstrating event-free survival (EFS) events. We investigated associations between baseline TIL percentage and either pCR or EFS after adjusting for clinicopathological characteristics using logistic and Cox regression models, respectively. To understand TIL biology, we evaluated associations between baseline TILs and baseline tumor gene expression data (800 gene set by NanoString) in a subset of 173 patients. All statistical tests were two-sided. Results:Among the patients with measurable TILs at baseline, the median level was 14.1% (interquartile range = 7.1%-32.4%). After adjusting for clinicopathological characteristics, baseline percentage TIL was not associated with pCR (adjusted odds ratio [aOR] for every 10-percentage unit increase in TILs = 1.12, 95% confidence interval [CI] = 0.95 to 1.31, P = .17). At a median follow-up of 4.7 years, for every increase in baseline TILs of 10%, there was a 25% reduction in the hazard for an EFS event (aOR = 0.75, 95% CI = 0.56 to 1.00, P = .05) after adjusting for baseline clinicopathological characteristics and pCR. Additionally, genes associated with epithelial-mesenchymal transition, angiogenesis, and T-cell inhibition such as SNAIL1, ZEB1, NOTCH3, and B7-H3 were statistically significantly inversely correlated with percentage TIL. Conclusions:Baseline TIL percentage provides independent prognostic information in patients treated with trastuzumab/pertuzumab-based neoadjuvant chemotherapy. However, further validation is required.
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Project description:Ado-trastuzumab emtansine plus pertuzumab (T-DM1/P) and paclitaxel plus trastuzumab and pertuzumab (THP) are two of the experimental regiments evaluated in I-SPY 2, a neoadjuvant platform trial for high risk, early stage breast cancer. In pre-defined analyses we assessed 10 biomarkers at the pre-treatment timepoint in the HER2, ER/PR, and proliferation pathways to test their association with pCR (complete pathologic response).
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Project description:We report RNA sequencing data of trastuzumab plus pertuzumab-refractory tumor in a mouse xenograft model.
2020-03-05 | GSE146380 | GEO
Project description:The purpose of this study was to characterise the effects of trastuzumab and pertuzumab, either as single agents or as combination therapy on gene and protein expression in human ovarian cancer in vivo. Illumina BeadChips were used to profile the transcriptome after four days treatment of SKOV3 tumor xenografts. Although genes involved with HER2, MAP-kinase and p53 signaling pathways were commonly induced by all treatments, a greater number and variety of genes were differentially expressed by the complementary combination therapies compared to either drug on its own. The protein level of the CDK-inhibitors p21 and p27 were increased in response to both agents alone and further by the combination; pERK signaling was inhibited by all treatments; but only pertuzumab alone inhibited pAkt signaling. The expression of proliferation, apoptosis, cell division and cell cycle markers was distinct in a panel of primary ovarian cancer xenografts, suggesting heterogeneity of response in ovarian cancer and the need to establish biomarkers of response. This first comprehensive study of the molecular response to trastuzumab, pertuzumab and combination therapy in vivo highlights that there are both common and distinct downstream effects to different HER2 antibodies and that pathways may be invoked more strongly or in a different manner by a combination of agents. Some of the in vivo results for ovarian tumors differ from previous in vitro studies in breast cancer cells, emphasizing that the molecular response to anti-cancer agents involves variable and complex disease-specific interactions of signaling mechanisms. SCOV3 Ovarian cell line xenografts treated with Trastuzumab, pertuzumab or combination after 4 days
2012-05-02 | E-GEOD-31432 | biostudies-arrayexpress
Project description:RNA sequencing of BT474 cells treated with trastuzumab or trastuzumab + pertuzumab and BT474-derived cells resistant to trastuzumab or trastuzumab + pertuzumab
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Project description:Serum microRNAs profiles of HER2 positive advanced breast cancer patients and their treatment response after the trastuzumab/pertuzumab/taxane therapy
2022-11-04 | GSE122426 | GEO
Project description:The purpose of this study was to characterise the effects of trastuzumab and pertuzumab, either as single agents or as combination therapy on gene and protein expression in human ovarian cancer in vivo. Illumina BeadChips were used to profile the transcriptome after four days treatment of SKOV3 tumor xenografts. Although genes involved with HER2, MAP-kinase and p53 signaling pathways were commonly induced by all treatments, a greater number and variety of genes were differentially expressed by the complementary combination therapies compared to either drug on its own. The protein level of the CDK-inhibitors p21 and p27 were increased in response to both agents alone and further by the combination; pERK signaling was inhibited by all treatments; but only pertuzumab alone inhibited pAkt signaling. The expression of proliferation, apoptosis, cell division and cell cycle markers was distinct in a panel of primary ovarian cancer xenografts, suggesting heterogeneity of response in ovarian cancer and the need to establish biomarkers of response. This first comprehensive study of the molecular response to trastuzumab, pertuzumab and combination therapy in vivo highlights that there are both common and distinct downstream effects to different HER2 antibodies and that pathways may be invoked more strongly or in a different manner by a combination of agents. Some of the in vivo results for ovarian tumors differ from previous in vitro studies in breast cancer cells, emphasizing that the molecular response to anti-cancer agents involves variable and complex disease-specific interactions of signaling mechanisms.
2012-05-03 | GSE31432 | GEO
Project description:The clinical relevance of tumor infiltrating lymphocytes (TILs) in breast cancer (BC) is not firmly established. We aimed to validate previous prognostic findings in triple negative breast cancer (TNBC) and investigate predictive associations with trastuzumab benefit in HER2 overexpressing disease (HER2+).
2022-07-16 | GSE47994 | GEO