Tumor-Infiltrating Lymphocytes and Associations With Pathological Complete Response and Event-Free Survival in HER2-Positive Early-Stage Breast Cancer Treated With Lapatinib and Trastuzumab: A Secondary Analysis of the NeoALTTO Trial

Abstract

Importance: The presence of tumor-infiltrating lymphocytes (TILs) is associated with improved outcomes in human epidermal growth factor receptor 2 (HER2)-positive early breast cancer treated with adjuvant trastuzumab and chemotherapy. The prognostic associations in the neoadjuvant setting of other anti-HER2 agents and combinations are unknown.

Objective: To determine associations between presence of TILs, pathological complete response (pCR), and event-free survival (EFS) end points in patients with early breast cancer treated with trastuzumab, lapatinib, or the combination.

Design, setting, and participants: The NeoALTTO trial (Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimization) randomly assigned 455 women with HER2-positive early-stage breast cancer between January 5, 2008, and May 27, 2010, to 1 of 3 neoadjuvant treatment arms: trastuzumab, lapatinib, or the combination for 6 weeks followed by the addition of weekly paclitaxel for 12 weeks, followed by 3 cycles of fluorouracil, epirubicin, and cyclophosphamide after surgery. The primary end point used in this study was pCR in the breast and lymph nodes, with a secondary end point of EFS. We evaluated levels of percentage of TILs using hematoxylin-eosin-stained core biopsy sections taken at diagnosis (prior to treatment) in a prospectively defined retrospective analysis.

Main outcomes and measures: Levels of TILs were examined for their associations with efficacy end points adjusted for prognostic clinicopathological factors including PIK3CA genotype.

Results: Of the 455 patients, 387 (85.1%) tumor samples were used for the present analysis. The median (interquartile range [IQR]) level of TILs was 12.5% (5.0%-30.0%), with levels lower in hormone receptor-positive (10.0% [5.0%-22.5%]) vs hormone receptor-negative (12.5% [3.0%-35.0%]) samples (P = .02). For the pCR end point, levels of TILs greater than 5% were associated with higher pCR rates independent of treatment group (adjusted odds ratio, 2.60 [95% CI, 1.26-5.39]; P = .01). With a median (IQR) follow-up time of 3.77 (3.50-4.22) years, every 1% increase in TILs was associated with a 3% decrease in the rate of an event (adjusted hazard ratio, 0.97 [95% CI, 0.95-0.99]; P = .002) across all treatment groups.

Conclusions and relevance: The presence of TILs at diagnosis is an independent, positive, prognostic marker in HER2-positive early breast cancer treated with neoadjuvant anti-HER2 agents and chemotherapy for both pCR and EFS end points.

Trial registration: clinicaltrials.gov Identifier: NCT00553358.

Figure 1. Rates of Pathological Complete Response According to Levels of Tumor-Infiltrating Lymphocytes Binned by Quartile to Illustrate the Nonlinear Effect

Figure 2. Kaplan-Meier Event-Free Survival (EFS) Curves Showing That Higher Levels of Tumor-Infiltrating Lymphocytes (TILs) Result in Better Survival Outcomes and Provide Information Independently of Pathological Complete Response (pCR)

A, Three-year EFS was 88% (95% CI, 82%-92%) for patients whose tumors contained at least 12.5% TILs (the median level of TILs) and 71% (95% CI, 64%-78%) for patients with less than 12.5% TILs (log-rank P < .001). B, Three-year EFS was 97% (95% CI, 88%-99%) for patients whose tumors contained more than 40% TILs and 77% (95% CI, 72%-83%) for those with less than 40% TILs (log-rank P < .001). C, Three-year EFS was 67% (95% CI, 57%-74%) for patients with no pCR and less than 12.5% TILs; 85% (95% CI, 77%-90%) for patients with no pCR and at least 12.5% TILs; 81% (95% CI, 67%-90%) for patients with pCR and less than 12.5% TILs; and 92% (95% CI, 83%-97%) for patients with pCR and at least 12.5% TILs. D, Three-year EFS was 72% (95% CI, 65%-77%) for patients with no pCR and less than 40% TILs; 95% (95% CI, 80%-99%) for patients with no pCR and more than 40% TILs; 85% (95% CI, 76%-91%) for patients with pCR and less than 40% TILs; and 100% for patients with pCR and more than 40% TILs.