Tumor infiltrating lymphocytes predict response to anthracycline-based chemotherapy in estrogen receptor-negative breast cancer
Menée sur 2 cohortes indépendantes incluant 368 patientes atteintes d'un cancer du sein ER- (durée médiane de suivi : supérieure à 6 ans), cette étude évalue l'association entre le niveau des lymphocytes inflitrant les tumeurs et la réponse à une chimiothérapie à base d'anthracycline
INTRODUCTION:Infiltration of breast tumors by lymphocytes (TIL) has been linked to sensitivity to anthracycline-based chemotherapy. However, it is unclear if this is true within the estrogen receptor alpha negative (ER-) subset of breast tumors that manifest relatively high inherent 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- breast cancer cohorts in which patients were categorized as TIL-high or TIL-low. We defined an 8-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- tumors (n=113). We also examined the association between TIL and long-term chemotherapeutic efficacy in a second cohort of ER- tumors (n=255) with greater than 6 years of median follow-up using tissue microarrays and immunohistochemistry (IHC) for CD3, CD8, CD4, CD20, and TIA-1.RESULTS:In patients with ER- tumors treated with neoadjuvant anthracycline-based chemotherapy, pathological complete responses (pCR) were achieved by 23 of 31 (74%) TIL-high patients and 25 of 80 (31%) TIL-low patients (OR 6.33, 95% CI 2.49-16.08; 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 following CMF treatment 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+ and triple negative tumor phenotypes.CONCLUSIONS:ER- breast cancers with high levels of TIL have heightened sensitivity to anthracycline-based chemotherapy as assessed by the immediate response to neoadjuvant therapy and long-term outcome following adjuvant therapy. Investigations of TIL-based predictive tests to identify patients likely to benefit from anthracycline treatment are warranted.
Breast Cancer Research , résumé, 2010