Durable clinical benefit to trastuzumab and chemotherapy in a patient with metastatic colon adenocarcinoma harboring ERBB2 amplification.
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ABSTRACT:
SUBMITTER: Disel U
PROVIDER: S-EPMC4506361 | biostudies-literature | 2015
REPOSITORIES: biostudies-literature
Publications
Durable clinical benefit to trastuzumab and chemotherapy in a patient with metastatic colon adenocarcinoma harboring ERBB2 amplification.
Disel Umut U Germain Alexis A Yilmazel Bahar B Abali Huseyin H Bolat Filiz Aka FA Yelensky Roman R Elvin Julia A JA Lipson Doron D Chmielecki Juliann J Wang Kai K Stephens Philip J PJ Ross Jeffrey S JS Miller Vincent A VA Ali Siraj M SM George Thomas J TJ
Oncoscience 20150701 6
Somatic ERBB2 amplification or activating mutations occur in approximately 2-5% of metastatic colorectal adenocarcinomas and are presumed to be oncogenic drivers, but limited evidence exists to suggest these lesions are sensitive to targeted monotherapy in patients. Here we present the case of a patient with advanced CRC with pulmonary metastases, who had progressed on both standard of care cytotoxic chemotherapy and anti-EGFR targeted therapy. Comprehensive genomic profiling (FoundationOne(®)) ...[more]
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Project description:ObjectivesSurvival benefit of combination over single-agent chemotherapy for metastatic pancreatic ductal adenocarcinoma (PDAC) was demonstrated in younger patients in clinical trials. The authors aimed to evaluate whether this survival benefit of combination chemotherapy is present in elderly patients with metastatic PDAC.Materials and methodsThe authors identified elderly patients (age 65 y or older) with stage IV PDAC and extracted available clinical information from a prospectively maintained institutional pancreatic cancer registry from 2007 to 2016. The primary endpoint was overall survival. Cox proportional hazards regression was used for multivariable survival analyses. Survival outcomes for the entire cohort and by age group I (elderly, 65 to 75 y) and age group II (very elderly, older than 75 y) were assessed.ResultsA total of 606 patients were included with a median age of 73.8 years. Among them, 239 patients (39%) received combination chemotherapy and 152 patients (25.1%) received single-agent chemotherapy as first-line treatment. Combination chemotherapy was associated with significantly longer median overall survival compared with single-agent chemotherapy (10.9 vs. 7.5 mo, P<0.001) with hazard ratio 0.62 (95% confidence interval, 0.47-0.81; P=0.001) after adjusting for age, sex, comorbidity, Eastern Cooperative Oncology Group (ECOG) performance status, and carbohydrate antigen 19-9 level. Analyses by age groups indicated that very elderly patients (age group II) benefited from combination chemotherapy compared with single-agent chemotherapy with hazard ratio 0.56 (95% confidence interval, 0.31-1; P=0.049), comparable with the age group I (Page-treatment interaction=0.81).ConclusionElderly patients, even those older than 75 years, with metastatic PDAC benefited from combination chemotherapy.
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Project description:Patients with gastric and esophageal (GE) adenocarcinoma tumors in which the oncogene ERBB2 has been amplified are routinely treated with a combination of cytotoxic chemotherapy and the ERBB2-directed antibody trastuzumab; however, the addition of trastuzumab, even when tested in a selected biomarker-positive patient population, provides only modest survival gains. To investigate the potential reasons for the modest impact of ERBB2-directed therapies, we explored the hypothesis that secondary molecular features of ERBB2-amplified GE adenocarcinomas attenuate the impact of ERBB2 blockade. We analyzed genomic profiles of ERBB2-amplified GE adenocarcinomas and determined that the majority of ERBB2-amplified tumors harbor secondary oncogenic alterations that have the potential to be therapeutically targeted. These secondary events spanned genes involved in cell-cycle regulation as well as phosphatidylinositol-3 kinase and receptor tyrosine kinase signaling. Using ERBB2-amplified cell lines, we demonstrated that secondary oncogenic events could confer resistance to ERBB2-directed therapies. Moreover, this resistance could be overcome by targeting the secondary oncogene in conjunction with ERBB2-directed therapy. EGFR is commonly coamplified with ERBB2, and in the setting of ERBB2 amplification, higher EGFR expression appears to mark tumors with greater sensitivity to dual EGFR/ERBB2 kinase inhibitors. These data suggest that combination inhibitor strategies, guided by secondary events in ERBB2-amplified GE adenocarcinomas, should be evaluated in clinical trials.
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Project description:Studies have shown that antibodies targeting the intracellular (ICD) or extracellular domains (ECD) of human epidermal growth factor receptor 2 (HER2) are equivalent when traditional methods are used. We describe a new method to quantify ICD and ECD expression separately and assess the prognostic value of domain-specific HER2 results in patients who received adjuvant trastuzumab therapy. We measured HER2 protein expression with quantitative immunofluorescence (QIF) in tissue microarrays (TMA) using two different antibodies targeting the ICD (CB11 and A0485) and ECD (SP3 and D8F12). We assessed the prognostic value of ICD and ECD expression in 180 patients from a clinical trial of adjuvant chemotherapy followed by trastuzumab (HeCOG 10/05). We performed an exploratory univariate domain-specific, disease-free survival (DFS) analysis and compared DFS functions with Kaplan-Meier estimates. All statistical tests were two-sided. HER2 ICD expression by QIF showed slightly higher sensitivity to predict ERBB2 (HER2) gene amplification than ECD expression, which was more specific and had higher positive predictive value. In the HeCOG 10/05 trial specimens, 15% of cases showed discordant results for ICD and ECD expression. High ECD was statistically associated with longer DFS (log-rank P = .049, HR = 0.31, 95% CI = 0.144 to 0.997), while ICD status was not. Among patients with low ECD, there was no difference in DFS by ICD status. However, when ICD was high, high ECD was statistically associated with longer DFS (log-rank P = .027, HR = 0.23, 95% CI = 0.037 to 0.82) compared with low ECD. Quantitative measurements of HER2 ICD and ECD expression in breast cancer suggest a subclassification of HER2-positive tumors. Trastuzumab-treated patients with high ECD showed better DFS than patients with low ECD. This suggests differential benefit from trastuzumab therapy based on HER2 ECD expression.
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Project description:BackgroundWe sought to determine the predictive value of in situ mRNA measurement compared to traditional methods on a cohort of trastuzumab-treated metastatic breast cancer patients.MethodsA tissue microarray composed of 149, classified as HER2-positive, metastatic breast cancers treated with various trastuzumab-containing chemotherapy regimens was constructed. HER2 intracellular domain(ICD), HER2 extracellular domain(ECD) and HER2 mRNA were assessed using AQUA. For HER2 protein evaluation, CB11 was used to measure ICD and SP3 to measure ECD of the HER2 receptor. In addition, HER2 mRNA status was assessed using RNAscope assay ERRB2 probe. Kaplan - Meier estimates were used for depicting time-to-event endpoints. Multivariate Cox regression models with backward elimination were used to assess the performance of markers as predictors of TTP and OS, after adjusting for important covariates.ResultsHER2 mRNA was correlated with ICD HER2, as measured by CB11 HER2, with ECD HER2 as measured by SP3 (Pearson's Correlation Coefficient, r = 0.66 and 0.51 respectively) and with FISH HER2 (Spearman's Correlation Coefficient, r = 0.75). All markers, HER2 mRNA, ICD HER2 and ECD HER2, along with FISH HER2, were found prognostic for OS (Log-rank p = 0.007, 0.005, 0.009 and 0.043 respectively), and except for FISH HER2, they were also prognostic for TTP Log-rank p = 0.036, 0.068 and 0.066 respectively) in this trastuzumab- treated cohort. Multivariate analysis showed that in the presence of pre-specified set of prognostic factors, among all biomarkers only ECD HER2, as measured by SP3, is strong prognostic factor for both TTP (HR = 0.54, 95% CI: 0.31-0.93, p = 0.027) and OS (HR = 0.39, 95%CI: 0.22-0.70, p = 0.002).ConclusionsThe expression of HER2 ICD and ECD as well as HER2 mRNA levels was significantly associated with TTP and OS in this trastuzumab-treated metastatic cohort. In situ assessment of HER2 mRNA has the potential to identify breast cancer patients who derive benefit from Trastuzumab treatment.
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Project description:Patients with advanced stage or recurrent mucinous ovarian carcinoma exhibit poor response to standard platinum- and taxane-based chemotherapy and poor prognosis. We report a 29-year-old patient with recurrent ERBB2-amplified mucinous ovarian carcinoma (with expansile growth pattern at initial diagnosis and previously treated with adjuvant capecitabine/oxaliplatin) who underwent optimal secondary cytoreduction followed by 6 cycles of carboplatin/paclitaxel/trastuzumab and 1-year maintenance trastuzumab. This patient remains without radiologic or biochemical evidence of disease for more than 3 years after secondary cytoreduction. This case supports routine assessment of HER2 status in patients with advanced or recurrent mucinous ovarian carcinoma and highlights the potential of HER2-targeted therapy with trastuzumab in combination with standard carboplatin and paclitaxel in this disease. This case also raises the possibility that expansile mucinous ovarian carcinomas with ERBB2 amplification and p53 mutant immunohistochemical staining pattern (as this patient had) may be associated with a more aggressive behavior and higher risk of relapse.
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Project description:ImportanceTo date, limited studies have examined the comparative outcomes of pertuzumab treatment in the real-world setting. End-of-study analyses of the CLEOPATRA trial found median overall survival (OS) of 57.1 months in patients receiving pertuzumab compared with 40.8 months in control patients, a benefit of 16.3 months. However, studies examining the real-world use of pertuzumab have found conflicting results.ObjectiveTo assess the real-world comparative effectiveness and safety of pertuzumab, trastuzumab, and chemotherapy for patients with metastatic breast cancer in Ontario, Canada.Design, setting, and participantsA population-based retrospective comparative effectiveness research study was conducted. Patients receiving first-line treatments for metastatic breast cancer from January 1, 2008, to March 31, 2018, in Ontario were identified. Data analysis was performed from November 13, 2019, to August 1, 2021. Thirteen patients had received treatment before diagnosis or were not Ontario residents and were excluded from the analysis. Of the remaining 1823 patients identified, 912 received pertuzumab and 911 were control patients. Using propensity-score methods, 579 pairs of patients receiving pertuzumab were matched to those in the control group, resulting in a total of 1158 patients in the final cohort.ExposuresPatients in the case group received pertuzumab with trastuzumab and chemotherapy and those in the control group received trastuzumab and chemotherapy.Main outcomes and measuresOverall survival (the primary outcome) and hazard ratios (HRs) were calculated using Kaplan-Meier and Cox proportional hazards regression methods. Secondary outcomes included cumulative incidence of safety end points including resource use and adverse events. Follow-up duration was up to 5 years from the start of therapy, with maximum follow-up to March 31, 2019.ResultsOf the 1158 matched patients (579 pairs) receiving pertuzumab and controls, 1151 (99%) were women (mean [SD] age, 58.2 [12.97] years). The median OS was higher in patients receiving pertuzumab (40.2; 95% CI, 35.6-47.8 months) than in the control patients (25.3; 95% CI, 22.8-27.6 months), a median OS improvement of 14.9 months. Pertuzumab was associated with reduced mortality (HR, 0.66; 95% CI, 0.57-0.79). The cumulative incidence of direct hospitalization at 1 year was lower among patients receiving pertuzumab (11.7%) compared with the control patients (19.0%) (P < .001).Conclusions and relevanceAlthough the median OS in both the pertuzumab and control groups were shorter in this study than those observed in the CLEOPATRA trial, there appears to be a similar significant OS benefit with pertuzumab in the real-world setting.
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