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Identification of stromal ColX?1 and tumor-infiltrating lymphocytes as putative predictive markers of neoadjuvant therapy in estrogen receptor-positive/HER2-positive breast cancer.

ABSTRACT: The influence of the tumor microenvironment and tumor-stromal interactions on the heterogeneity of response within breast cancer subtypes have just begun to be explored. This study focuses on patients with estrogen receptor-positive/human epidermal growth factor receptor 2-positive (ER+/HER2+) breast cancer receiving neoadjuvant chemotherapy and HER2-targeted therapy (NAC+H), and was designed to identify novel predictive biomarkers by combining gene expression analysis and immunohistochemistry with pathologic response.We performed gene expression profiling on pre-NAC+H tumor samples from responding (no or minimal residual disease at surgery) and non-responding patients. Gene set enrichment analysis identified potentially relevant pathways, and immunohistochemical staining of pre-treatment biopsies was used to measure protein levels of those pathways, which were correlated with pathologic response in both univariate and multivariate analysis.Increased expression of genes encoding for stromal collagens, including Col10A1, and reduced expression of immune-associated genes, reflecting lower levels of total tumor-infiltrating lymphocytes (TILs), were strongly associated with poor pathologic response. Lower TILs in tumor biopsies correlated with reduced likelihood of achieving an optimal pathologic response, but increased expression of the Col10A1 gene product, colX?1, had greater predictive value than stromal abundance for poor response (OR = 18.9, p = 0.003), and the combination of increased colX?1 expression and low TILs was significantly associated with poor response in multivariate analysis. ROC analysis suggests strong specificity and sensitivity for this combination in predicting treatment response.Increased expression of stromal colX?1 and low TILs correlate with poor pathologic response in ER+/HER2+ breast tumors. Further studies are needed to confirm their predictive value and impact on long-term outcomes, and to determine whether this collagen exerts a protective effect on the cancer cells or simply reflects other factors within the tumor microenvironment.

SUBMITTER: Brodsky AS

PROVIDER: S-EPMC4835834 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Identification of stromal ColXα1 and tumor-infiltrating lymphocytes as putative predictive markers of neoadjuvant therapy in estrogen receptor-positive/HER2-positive breast cancer.

Brodsky Alexander S AS Xiong Jinjun J Yang Dongfang D Schorl Christoph C Fenton Mary Anne MA Graves Theresa A TA Sikov William M WM Resnick Murray B MB Wang Yihong Y

BMC cancer 20160418

<h4>Background</h4>The influence of the tumor microenvironment and tumor-stromal interactions on the heterogeneity of response within breast cancer subtypes have just begun to be explored. This study focuses on patients with estrogen receptor-positive/human epidermal growth factor receptor 2-positive (ER+/HER2+) breast cancer receiving neoadjuvant chemotherapy and HER2-targeted therapy (NAC+H), and was designed to identify novel predictive biomarkers by combining gene expression analysis and imm ...[more]

PMID: 27090210

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Project description:ImportanceThe presence of tumor-infiltrating lymphocytes at diagnosis is reported to be prognostic in triple-negative breast cancer.ObjectiveTo evaluate the association of stromal tumor-infiltrating lymphocytes (STILs) with recurrence-free survival (RFS) in women with human epidermal growth factor receptor 2 (HER2)-positive breast cancer treated with chemotherapy or chemotherapy plus trastuzumab in the N9831 trial.Design, setting, and participantsHematoxylin-eosin-stained tumor slides from patients with early-stage HER2-positive breast cancer in 2 of the 3 arms of the N9831 trial were assessed for STILs at an academic medical center. The amounts of STILs were quantitated in deciles, and a level of at least 60% STILs was used for the prespecified categorical cutoff. The association between STILs and RFS was evaluated with Cox models.ExposureStandard chemotherapy consisting of doxorubicin-cyclophosphamide followed by weekly paclitaxel (arm A) or doxorubicin-cyclophosphamide followed by weekly paclitaxel plus trastuzumab followed by trastuzumab alone (arm C).Main outcomes and measuresStromal tumor-infiltrating lymphocytes and their association with RFS.ResultsA total of 489 patients from arm A and 456 patients from arm C were assessed with a median (range) follow-up of 4.4 (0-13.6) years. The 10-year Kaplan-Meier estimates for RFS in arm A were 90.9% and 64.5% for patients with high and low levels of STILs, respectively (hazard ratio [HR], 0.23 [95% CI, 0.07-0.73]; P = .01). The 10-year estimates for RFS in arm C were 80.0% and 80.1% for patients with high and low levels of STILs, respectively (HR, 1.26 [95% CI, 0.50-3.17]; P = .63). The test for interaction between trastuzumab treatment and STIL status was statistically significant (P = .03). In a multivariable analysis, STIL status remained significantly associated with RFS in arm A and not significantly associated in arm C (HR, 1.01 [95% CI, 0.89-1.15]; interaction P = .04).Conclusions and relevanceThis analysis of participants in the N9831 trial found that the presence of STILs was prognostically associated with RFS in patients treated with chemotherapy alone but not in patients treated with chemotherapy plus trastuzumab. High levels of STILs were associated with lack of trastuzumab therapy benefit, in contrast to a previously reported association between increased levels of STILs and increased trastuzumab benefit in HER2-positive patients.Trial registrationclinicaltrials.gov Identifier: NCT00005970.

Dataset Information

Identification of stromal ColX?1 and tumor-infiltrating lymphocytes as putative predictive markers of neoadjuvant therapy in estrogen receptor-positive/HER2-positive breast cancer.

Publications

Identification of stromal ColXα1 and tumor-infiltrating lymphocytes as putative predictive markers of neoadjuvant therapy in estrogen receptor-positive/HER2-positive breast cancer.

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