Tumor-infiltrating lymphocytes predict response to anthracycline-based chemotherapy in estrogen receptor-negative breast cancer

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dc.contributor.authorWest, Nathan R.
dc.contributor.authorMilne, Katy
dc.contributor.authorTruong, Pauline T.
dc.contributor.authorMacpherson, Nicol
dc.contributor.authorNelson, Brad H,
dc.contributor.authorWatson, Peter H.
dc.date.accessioned2014-06-04T22:00:56Z
dc.date.available2014-06-04T22:00:56Z
dc.date.copyright2011en_US
dc.date.issued2011-12-08
dc.descriptionBioMed Centralen_US
dc.description.abstractIntroduction Infiltration of breast tumors by tumor-infiltrating lymphocytes (TIL) has been associated with sensitivity to anthracycline-based chemotherapy. However, it is unclear whether this is true within the estrogen receptor-alpha (ER)-negative subset of breast tumors that frequently manifest high TIL levels. Methods The association of TIL with short-term and long-term clinical response to anthracycline-based therapy was assessed in two independent ER-negative breast cancer cohorts in which patients were categorized as TIL-high or TIL-low. We defined an eight-gene lymphocyte mRNA expression signature (including CD19, CD3D, CD48, GZMB, LCK, MS4A1, PRF1, and SELL) and used unsupervised hierarchical clustering to examine the association between TIL and short-term response to neoadjuvant chemotherapy in a previously published cohort of ER-negative tumors (n = 113). We also examined the association between TIL and long-term chemotherapeutic efficacy in a second cohort of ER-negative tumors (n = 255) with longer than 6 years of median follow-up by using tissue microarrays and immunohistochemistry (IHC) for detection of CD3, CD8, CD4, CD20, and TIA-1. Results In patients with ER-negative tumors treated with neoadjuvant anthracycline-based chemotherapy, pathologic complete responses (pCRs) were achieved by 23 (74%) of 31 TIL-high patients and 25 (31%) of 80 TIL-low patients (odds ratio (OR), 6.33; 95% confidence interval (CI), 2.49 to 16.08; P < 0.0001). Multivariate logistic regression with standard clinicopathologic features demonstrated that only tumor size (P = 0.037) and TIL status (P = 0.001) were independent predictors of anthracycline response. In the second cohort, adjuvant anthracycline-based therapy was associated with increased disease-free survival (DFS) only in patients with high levels of intraepithelial CD3+ TIL (P = 0.0023). In contrast, outcomes after CMF treatment (cyclophosphamide, methotrexate, and fluorouracil) showed no association with CD3 status. In both cohorts, cytotoxic T-cells were the primary TIL subtype associated with anthracycline sensitivity. Finally, TIL significantly predicted anthracycline sensitivity for both the Her2-positive and triple-negative tumor phenotypes.en_US
dc.description.reviewstatusRevieweden_US
dc.description.scholarlevelFacultyen_US
dc.description.sponsorshipThis study was supported by funding from the Canadian Institutes of Health Research (CIHR, grant MOP-64349) and the BC Cancer Foundation. The Manitoba Breast Tumor Bank, a member of the Canadian Tumor Repository Network, is supported by CIHR grant PRG80155. NRW is supported by a US DOD Breast Cancer Research Program predoctoral traineeship award (W81XWH-08-1-0781).en_US
dc.identifier.citationWest et al.: Tumor-infiltrating lymphocytes predict response to anthracycline-based chemotherapy in estrogen receptor-negative breast cancer. Breast Cancer Research 2011 13:R126.en_US
dc.identifier.urihttp://breast-cancer-research.com/content/13/6/R126
dc.identifier.urihttp://dx.doi.org/10.1186/bcr3072
dc.identifier.urihttp://hdl.handle.net/1828/5427
dc.language.isoenen_US
dc.publisherBioMed Centralen_US
dc.subject.departmentDepartment of Biochemistry and Microbiology
dc.subject.departmentDepartment of Biology
dc.titleTumor-infiltrating lymphocytes predict response to anthracycline-based chemotherapy in estrogen receptor-negative breast canceren_US
dc.typeArticleen_US

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