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

Abstract

IntroductionInfiltration 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.MethodsThe 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.ResultsIn 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.ConclusionsER-negative 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-based treatments are warranted.

Predictive and prognostic significance of CD8+ tumor-infiltrating lymphocytes in patients with luminal B/HER 2 negative breast cancer treated with neoadjuvant chemotherapy

“…The results of the present study revealed that the intratumoral expression of CD8 + TIL may be predictive of pCR in this patient population. Similar to previous studies (17,21,22,(40)(41)(42), 56% of patients with high intratumoral expression of CD8 + TIL achieved a pCR, in contrast with 13.3% for patients with low intratumoral CD8 + TIL. Denkert et al (17) investigated intratumoral and stromal lymphocytes in a total of 1,058 pre-therapeutic BC core biopsies from two neoadjuvant anthracycline/taxane-based studies.…”

Biological network-driven gene selection identifies a stromal immune module as a key determinant of triple-negative breast carcinoma prognosis

“…High-intratumoral levels of CD8 C T cells 43 or TILs 36,44 are associated with better clinical responses to anthracycline-based chemotherapy. West et al 45 reported that highlevels of lymphocyte GE were associated with a high rate (74%) of complete pathological responses to neoadjuvant anthracyclinebased chemotherapy. In 2011, Sabatier et al 20 showed, by geneexpression profiling, that "Immune High" patients (59%) were more likely to present pCR than "Immune Low" patients (43%), but this difference was not significant (p D 0.29).…”

Predictive biomarkers for triple negative breast cancer treated with platinum-based chemotherapy

“…TIL has been confirmed to be highly present in TNBC and related to increased pCR rate and improved disease-free survival (DFS) and OS after chemotherapy. [58][59][60] In neoadjuvant GeparSixto and PrECOG0105 trials, TIL levels are positively associated with pCR rate among TNBC patients. LPBC is defined as breast cancer with lymphocytes in 50% or more of tumor or stroma, which was also proved to be associated with pathologic response in GeparSixto trial.…”