| 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. |
| Keywords: |
adult; controlled study; treatment outcome; aged; aged, 80 and over; disease-free survival; middle aged; retrospective studies; young adult; clinical trial; mortality; antineoplastic agents; comparative study; disease free survival; neoadjuvant therapy; cancer staging; antineoplastic agent; neoplasm staging; prospective study; prospective studies; tumor associated leukocyte; lymphocytes, tumor-infiltrating; metabolism; protein kinase inhibitor; randomized controlled trial; antineoplastic combined chemotherapy protocols; proportional hazards models; epidermal growth factor receptor 2; odds ratio; risk factors; enzymology; pathology; breast neoplasms; retrospective study; tumor marker; risk factor; time factors; protein kinase inhibitors; immunology; proportional hazards model; remission; remission induction; receptor, erbb-2; phase 3 clinical trial; trastuzumab; quinazolines; lapatinib; quinazoline derivative; erbb2 protein, human; time factor; drug effects; very elderly; humans; human; female; antagonists and inhibitors; biomarkers, tumor
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