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JAMA Oncol. 2015 Jul;1(4):448-54. doi: 10.1001/jamaoncol.2015.0830.

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.

Author information

1
Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium2Department of Pathology, Gasthuis Zusters Antwerpen Hospitals, Antwerp, Belgium.
2
Institute of Pathology, Charité-Universitätsmedizin, Berlin, Germany4German Cancer Consortium, Berlin, Germany.
3
Frontier Science (Scotland) Ltd, Grampian View, Kincraig, Kingussie, United Kingdom.
4
Division of Clinical Medicine and Research, Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, Victoria, Australia.
5
Val d'Hebron Institute of Oncology, Barcelona, Spain.
6
Breast European Adjuvant Study Team, Institut Jules Bordet, Brussels, Belgium.
7
Department of Obstetrics and Gynecology, Campus Kiel, University Hospital Kiel, Kiel, Germany.
8
GlaxoSmithKline Oncology, Collegeville, Pennsylvania.
9
Memorial Sloan-Kettering Cancer Center, New York, New York.
10
Department of Medicine, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
11
Centre de Recherche en Epidémiologie et Santé des Populations, INSERM U1018, Service de Biostatistique et d'Epidémiologie, Gustave Roussy, Université Paris-Sud, Villejuif, France.
12
Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.

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.

PMID:
26181252
PMCID:
PMC5551492
DOI:
10.1001/jamaoncol.2015.0830
[Indexed for MEDLINE]
Free PMC Article

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