Negative Relationship between Post-Treatment Stromal Tumor-Infiltrating Lymphocyte (TIL) and Survival in Triple-Negative Breast Cancer Patients Treated with Dose-Dense Dose-Intense NeoAdjuvant Chemotherapy

Abstract

Background: Patients with triple-negative breast cancers (TNBC) have a poor prognosis unless a pathological complete response (pCR) is achieved after neoadjuvant chemotherapy (NAC). Few studies have analyzed changes in TIL levels following dose-dense dose-intense (dd-di) NAC. Patients and methods: From 2009 to 2018, 117 patients with TNBC received dd-di NAC at our institution. We aimed to identify factors associated with pre- and post-NAC TIL levels, and oncological outcomes relapse-free survival (RFS), and overall survival (OS). Results: Median pre-NAC and post-NAC TIL levels were 15% and 3%, respectively. Change in TIL levels with treatment was significantly correlated with metabolic response (SUV) and pCR. High post-NAC TIL levels were associated with a weak metabolic response after two cycles of NAC, with the presence of residual disease and nodal involvement at NAC completion. In multivariate analyses, high post-NAC TIL levels independently predicted poor RFS and poor OS (HR = 1.4 per 10% increment, 95%CI (1.1; 1.9) p = 0.014 and HR = 1.8 per 10% increment 95%CI (1.3−2.3), p < 0.0001, respectively). Conclusion: Our results suggest that TNBC patients with TIL enrichment after NAC are at higher risk of relapse. These patients are potential candidates for adjuvant treatment, such as immunotherapy, in clinical trials.

Keywords: dose dense neoadjuvant chemotherapy; stromal tumor-infiltrating lymphocyte; triple negative breast cancers.

Figure 1

Study diagram. Orange arrows represent dose dense dose intense anthracycline and cyclophosphamide-based chemotherapy; blue arrows represent taxanes based chemotherapy; green arrows represent weekly paclitaxel chemotherapy.

Figure 2

Associations between pre-NAC TIL levels and clinical, pathological, and metabolic factors. (A) Distribution of pre-NAC TIL levels; (B) Distribution of pre-NAC TIL levels, by increments of 10%; (C–E) Association of pre-NAC TIL levels with clinical and pathological factors: tumor size (C), tumor grade (D), pre-NAC SUV (E).

Figure 3

Change after NAC in SUV levels, TIL levels, and the correlation between the relative change in SUV and the absolute change in TIL levels. (A) Change in SUV levels after two courses of NAC. The lines indicate the pre NAC and post NAC (after two courses of NAC) paired SUV results for a given patient and are colored according to the category of change in SUV (more than 70%; less than 70%); (B) Change in TIL levels after NAC; (C) Pearson correlation between the relative change in SUV and the absolute change in TIL levels. Points are colored according to the category of change in TIL levels (decrease; no change; increase in TIL levels); (D) Change in TIL levels according to pre-NAC TIL level, binned by increments of 10%. (B,D) Lines indicate the paired pre and post NAC paired TIL levels for a given patient and are colored according to the category of change in TIL levels (decrease; no change; increase in TIL levels); (E) Waterfall plot representing the change in TIL levels according to pCR status; each bar represents one patient, and patients are ranked in ascending order of change in TIL levels.

Figure 4

Post-NAC TIL levels and their association with post-NAC pathological factors. (A) Distribution of post-NAC TIL levels; (B) Distribution of post-NAC TIL levels, by increments of 10%; (C) Association of post-NAC TIL levels with SUV values after two cycles of NAC; (D–F) Association of post-NAC TIL levels with clinical and pathological factors: pCR status (D); post-NAC nodal involvement (E); and post-NAC LVI (F); (G,H) RFS (G) and OS (H) according to post-NAC TIL level, stratified into three classes: 0–10%; 10–20%; ≥20%. The reported p-values are those for post-NAC TIL levels in the corresponding multivariate Cox regression (i.e., the continuous TIL levels, after adjustment for post-NAC nodal involvement and post-NAC LVI for RFS (G) and for post-NAC LVI for OS (H)). The corresponding Cox regressions are reported in Table 3 and Table S5, respectively.