Benefit From Adjuvant Trastuzumab in NSABP Trial B-31
Benefit From Adjuvant Trastuzumab in NSABP Trial B-31
Background National Surgical Adjuvant Breast and Bowel Project (NSABP) trial B-31 suggested the efficacy of adjuvant trastuzumab, even in HER2-negative breast cancer. This finding prompted us to develop a predictive model for degree of benefit from trastuzumab using archived tumor blocks from B-31.
Methods Case subjects with tumor blocks were randomly divided into discovery (n = 588) and confirmation cohorts (n = 991). A predictive model was built from the discovery cohort through gene expression profiling of 462 genes with nCounter assay. A predefined cut point for the predictive model was tested in the confirmation cohort. Gene-by-treatment interaction was tested with Cox models, and correlations between variables were assessed with Spearman correlation. Principal component analysis was performed on the final set of selected genes. All statistical tests were two-sided.
Results Eight predictive genes associated with HER2 (ERBB2, c17orf37, GRB7) or ER (ESR1, NAT1, GATA3, CA12, IGF1R) were selected for model building. Three-dimensional subset treatment effect pattern plot using two principal components of these genes was used to identify a subset with no benefit from trastuzumab, characterized by intermediate-level ERBB2 and high-level ESR1 mRNA expression. In the confirmation set, the predefined cut points for this model classified patients into three subsets with differential benefit from trastuzumab with hazard ratios of 1.58 (95% confidence interval [CI] = 0.67 to 3.69; P = .29; n = 100), 0.60 (95% CI = 0.41 to 0.89; P = .01; n = 449), and 0.28 (95% CI = 0.20 to 0.41; P < .001; n = 442; Pinteraction between the model and trastuzumab < .001).
Conclusions We developed a gene expression–based predictive model for degree of benefit from trastuzumab and demonstrated that HER2-negative tumors belong to the moderate benefit group, thus providing justification for testing trastuzumab in HER2-negative patients (NSABP B-47).
Trastuzumab is a monoclonal antibody that is directed against HER2 protein overexpressed in approximately 20% of breast cancer patients with proven efficacy for both macro disease (metastatic and neoadjuvant setting) and micrometastatic disease (adjuvant setting).
The mechanisms responsible for trastuzumab response and resistance in adjuvant settings are not completely understood. National Surgical Adjuvant Breast and Bowel Project (NSABP) trial B-31 demonstrated the efficacy of adjuvant trastuzumab added to chemo-endocrine therapy not only for HER2-positive breast cancer but also, surprisingly, for HER2-negative breast cancer. Because HER2-positive tumors showed a high rate of pathologic complete response to neoadjuvant chemotherapy and complete responders tend to have favorable prognosis even without trastuzumab, in the adjuvant setting, where many patients may have already derived benefit from surgery and chemo-endocrine therapy, benefit from addition of trastuzumab could be determined through a complex interaction between HER2 and other confounding variables. In addition, more robust tumor cell response to trastuzumab could be expected in adjuvant vs advanced disease setting based on easier trastuzumab access to micrometastatic tumor cells, less compromised immune system favoring antibody-dependent cell-mediated cytotoxicity through trastuzumab, dependency of cancer stem cells on HER2 signaling pathway in the absence of HER2 overexpression, and overexpression of HER2 in bone metastasis in the absence of gene amplification.
Current clinical guidelines recommend that only HER2-positive patients be treated with trastuzumab. Because HER2 itself failed to show predictive interaction with trastuzmab in B-31, it is conceivable that not all HER2-positive patients receive benefit from trastuzumab while some HER2-negative patients may benefit. We attempted to use gene expression profiling of archived formalin-fixed paraffin-embedded tumor blocks from B-31 using the nCounter platform (NanoString Technologies, Seattle WA) to develop a predictive model for the degree of benefit from adjuvant trastuzumab that would improve upon the current clinical guideline for trastuzumab treatment.
Abstract and Introduction
Abstract
Background National Surgical Adjuvant Breast and Bowel Project (NSABP) trial B-31 suggested the efficacy of adjuvant trastuzumab, even in HER2-negative breast cancer. This finding prompted us to develop a predictive model for degree of benefit from trastuzumab using archived tumor blocks from B-31.
Methods Case subjects with tumor blocks were randomly divided into discovery (n = 588) and confirmation cohorts (n = 991). A predictive model was built from the discovery cohort through gene expression profiling of 462 genes with nCounter assay. A predefined cut point for the predictive model was tested in the confirmation cohort. Gene-by-treatment interaction was tested with Cox models, and correlations between variables were assessed with Spearman correlation. Principal component analysis was performed on the final set of selected genes. All statistical tests were two-sided.
Results Eight predictive genes associated with HER2 (ERBB2, c17orf37, GRB7) or ER (ESR1, NAT1, GATA3, CA12, IGF1R) were selected for model building. Three-dimensional subset treatment effect pattern plot using two principal components of these genes was used to identify a subset with no benefit from trastuzumab, characterized by intermediate-level ERBB2 and high-level ESR1 mRNA expression. In the confirmation set, the predefined cut points for this model classified patients into three subsets with differential benefit from trastuzumab with hazard ratios of 1.58 (95% confidence interval [CI] = 0.67 to 3.69; P = .29; n = 100), 0.60 (95% CI = 0.41 to 0.89; P = .01; n = 449), and 0.28 (95% CI = 0.20 to 0.41; P < .001; n = 442; Pinteraction between the model and trastuzumab < .001).
Conclusions We developed a gene expression–based predictive model for degree of benefit from trastuzumab and demonstrated that HER2-negative tumors belong to the moderate benefit group, thus providing justification for testing trastuzumab in HER2-negative patients (NSABP B-47).
Introduction
Trastuzumab is a monoclonal antibody that is directed against HER2 protein overexpressed in approximately 20% of breast cancer patients with proven efficacy for both macro disease (metastatic and neoadjuvant setting) and micrometastatic disease (adjuvant setting).
The mechanisms responsible for trastuzumab response and resistance in adjuvant settings are not completely understood. National Surgical Adjuvant Breast and Bowel Project (NSABP) trial B-31 demonstrated the efficacy of adjuvant trastuzumab added to chemo-endocrine therapy not only for HER2-positive breast cancer but also, surprisingly, for HER2-negative breast cancer. Because HER2-positive tumors showed a high rate of pathologic complete response to neoadjuvant chemotherapy and complete responders tend to have favorable prognosis even without trastuzumab, in the adjuvant setting, where many patients may have already derived benefit from surgery and chemo-endocrine therapy, benefit from addition of trastuzumab could be determined through a complex interaction between HER2 and other confounding variables. In addition, more robust tumor cell response to trastuzumab could be expected in adjuvant vs advanced disease setting based on easier trastuzumab access to micrometastatic tumor cells, less compromised immune system favoring antibody-dependent cell-mediated cytotoxicity through trastuzumab, dependency of cancer stem cells on HER2 signaling pathway in the absence of HER2 overexpression, and overexpression of HER2 in bone metastasis in the absence of gene amplification.
Current clinical guidelines recommend that only HER2-positive patients be treated with trastuzumab. Because HER2 itself failed to show predictive interaction with trastuzmab in B-31, it is conceivable that not all HER2-positive patients receive benefit from trastuzumab while some HER2-negative patients may benefit. We attempted to use gene expression profiling of archived formalin-fixed paraffin-embedded tumor blocks from B-31 using the nCounter platform (NanoString Technologies, Seattle WA) to develop a predictive model for the degree of benefit from adjuvant trastuzumab that would improve upon the current clinical guideline for trastuzumab treatment.
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