Prognostic and predictive impacts of tumor-infiltrating lymphocytes differ between Triple-negative and HER2-positive breast cancers treated with standard systemic therapies

Abstract

Tumor-infiltrating lymphocytes (TILs) have potential value for stratifying the treatment of breast cancer (BC), though their precise use remains unclear. We aimed to investigate the utility of TILs using an alternative approach in different settings. We reviewed patients with triple-negative (TN) or human epithelial growth factor receptor 2 (HER2)-positive invasive ductal carcinomas from a single institutional cohort and classified archived hematoxylin-eosin-stained samples in terms of TIL score as low (<10 %), intermediate, and high (>50 %). The prognostic and predictive values of TILs were analyzed retrospectively in both adjuvant and neo-adjuvant settings. In the adjuvant setting, the presence of TILs at primary surgery was a significant favorable prognostic factor among 154 TNBCs [relapse-free survival (RFS): p = 0.015], but not among 183 HER2+ BCs (RFS: p = 0.097). The TNBC low-TIL group tended to relapse earlier. In the neo-adjuvant setting, detection of TILs on biopsy before primary systemic therapy was associated with the ratio of patients achieving pathological complete response among 48 TNBCs (p = 0.024), but not among 58 HER2+ BCs (p = 0.30). The presence of TILs in surgical specimens after systemic therapy had prognostic value in HER2+ BC (RFS: p = 0.007). The impact of TILs differs between patients with TN and HER2+ BC treated with standard therapies. Our three-grade scale for TILs may contribute to our understanding of the importance of the tumor microenvironment in routine practice. TILs after primary systemic therapy may be useful for the further stratification of treatment of HER2+ BC.

Keywords: Breast cancer; HER2-positive; Triple-negative; Tumor-infiltrating lymphocyte.

Fig. 1

Representative photomicrographs of HE-stained tissue sections illustrating the simple scoring method for tumor-infiltrating lymphocytes (TILs). The area proportion of TILs was defined as low (a <10 %), intermediate (b 10–50 %), or high (c >50 %) in a medium-power field (×100 a–c). This score was evaluated in a hot spot (d, red arrow) infiltrated by many lymphocytes within the border of an invasive tumor. An inflammatory reaction occurring distantly from the tumor (e, blue arrow) or around the intraductal component (f, blue arrow) was not taken into account. A necrotic area was also excluded from a subject

Fig. 2

Prognostic value of tumor-infiltrating lymphocytes (TILs) in the adjuvant setting. Relapse-free survival was analyzed in the adjuvant setting for 154 TNBCs (a) and 183 HER2+ BCs (b). Stored samples obtained from primary surgery were categorized into three groups of low, intermediate, and high TILs. All patients received standard chemotherapy after curative surgery. TN triple-negative, BC breast cancer, HER2 human epithelial growth factor receptor 2

Fig. 3

Association between tumor-infiltrating lymphocytes (TILs) and pathological complete response (pCR). Core needle biopsy samples taken before primary systemic therapy were evaluated for TILs using the simple three-grade scale, and its association with the proportion of cases achieving pCR was compared among 48 TNBCs (a) and 58 HER2+ BCs (b). TN triple-negative, BC breast cancer, HER2 human epithelial growth factor receptor 2

Fig. 4

Survival analysis after neo-adjuvant systemic therapy. Relapse-free survival was analyzed among 28 TNBCs (a) and 41 HER2+ BCs (b). About 42 % of each subtype achieved pathological complete response (pCR) after standard neo-adjuvant chemotherapy (NAC). For non-pCR cases, tumor-infiltrating lymphocytes (TILs) in the residual carcinoma were evaluated in the three groups of low, intermediate, and high TILs. TN triple-negative, BC breast cancer, HER2 human epithelial growth factor receptor 2

Fig. 5

Influence of change in tumor-infiltrating lymphocyte (TIL) score before and after neo-adjuvant chemotherapy (NAC) on the proportion of recurrent cases. We applied the three-grade scale for TILs to both pre-treatment biopsy samples and post-treatment surgical specimens. Matched pairs of 26 TNBCs (a) and 32 HER2+ BCs (b) were analyzed. TN triple-negative, BC breast cancer, HER2 human epithelial growth factor receptor 2