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.

Conflict of interest statement

Conflict of Interest Disclosures: Dr de Azambuja has received grants from GlaxoSmithKline and Roche and personal fees from Roche outside this work. Dr Ellis is an employee of GlaxoSmithKline, the funder of the NeoALTTO study. Drs Baselga and Piccart-Gebhart have received personal fees from Roche. No other disclosures are reported.

Figures

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.