Intratumoral CD8+ Cytotoxic Lymphocyte Is a Favorable Prognostic Marker in Node-Negative Breast Cancer

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Abstract

Background

The prognostic effect of tumor infiltrating CD8 ⁺ cytotoxic lymphocytes (CTLs) in breast cancer is controversial. We analyzed the association between CD8 ⁺ CTLs and survival of untreated node-negative breast cancer patients.

Material and Methods

CD8 ⁺ CTLs infiltrate was evaluated by immunostaining in a cohort of 332 node-negative breast cancer patients with a median follow-up of 152 months. The prognostic significance of CD8 ⁺ CTLs for disease-free survival (DFS) and breast cancer-specific overall survival (OS) was evaluated with Kaplan-Meier survival analysis as well as univariate analysis and multivariate Cox analysis adjusted for age at diagnosis, pT stage, histological grade, estrogen receptor (ER) status, progesterone receptor (PR) status, Ki-67 expression and human epidermal growth factor receptor 2 (HER-2) status.

Results

285 (85.8%) patients showed strong CD8 ⁺ CTLs infiltrate positive status. Univariate analysis showed that CD8 ⁺ CTLs had statistically significant association with DFS (P = 0.004, hazard ratio [HR] = 0.454, 95% confidence interval [CI] = 0.265–0.777) and OS (P = 0.014, HR = 0.430, 95% CI = 0.220–0.840) in the entire cohort. The significance of CD8 ⁺ CTLs was especially strong in ER negative, HER-2 negative and ER, PR, HER-2 triple-negative breast cancers. In Kaplan-Meier analysis, CD8 ⁺ CTLs had significant effect on prognosis of patients (Log-rank test: P = 0.003 for DFS and P = 0.011 for OS), independent of established clinical factors for DFS (P = 0.002, HR = 0.418, 95% CI = 0.242–0.724) as well as for OS (P = 0.009, HR = 0.401, 95% CI = 0.202–0.797).

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Most cited references 26

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Thresholds for therapies: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2009

Michael Gnant, A Goldhirsch, J. N. Ingle … (2009)

The 11th St Gallen (Switzerland) expert consensus meeting on the primary treatment of early breast cancer in March 2009 maintained an emphasis on targeting adjuvant systemic therapies according to subgroups defined by predictive markers. Any positive level of estrogen receptor (ER) expression is considered sufficient to justify the use of endocrine adjuvant therapy in almost all patients. Overexpression or amplification of HER2 by standard criteria is an indication for anti-HER2 therapy for all but the very lowest risk invasive tumours. The corollary is that ER and HER2 must be reliably and accurately measured. Indications for cytotoxic adjuvant therapy were refined, acknowledging the role of risk factors with the caveat that risk per se is not a target. Proliferation markers, including those identified in multigene array analyses, were recognised as important in this regard. The threshold for indication of each systemic treatment modality thus depends on different criteria which have been separately listed to clarify the therapeutic decision-making algorithm.

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REporting recommendations for tumor MARKer prognostic studies (REMARK).

Lisa McShane, Douglas G. Altman, Willi Sauerbrei … (2006)

Despite years of research and hundreds of reports on tumor markers in oncology, the number of markers that have emerged as clinically useful is pitifully small. Often initially reported studies of a marker show great promise, but subsequent studies on the same or related markers yield inconsistent conclusions or stand in direct contradiction to the promising results. It is imperative that we attempt to understand the reasons that multiple studies of the same marker lead to differing conclusions. A variety of methodologic problems have been cited to explain these discrepancies. Unfortunately, many tumor marker studies have not been reported in a rigorous fashion, and published articles often lack sufficient information to allow adequate assessment of the quality of the study or the generalizability of study results. The development of guidelines for the reporting of tumor marker studies was a major recommendation of the National Cancer Institute-European Organisation for Research and Treatment of Cancer (NCI-EORTC) First International Meeting on Cancer Diagnostics in 2000. As for the successful CONSORT initiative for randomized trials and for the STARD statement for diagnostic studies, we suggest guidelines to provide relevant information about the study design, pre-planned hypotheses, patient and specimen characteristics, assay methods, and statistical analysis methods. In addition, the guidelines suggest helpful presentations of data and important elements to include in discussions. The goal of these guidelines is to encourage transparent and complete reporting so that the relevant information will be available to others to help them to judge the usefulness of the data and understand the context in which the conclusions apply.

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T-cell metagene predicts a favorable prognosis in estrogen receptor-negative and HER2-positive breast cancers

Achim Rody, Uwe Holtrich, Laos Pusztai … (2009)

Introduction Lymphocyte infiltration (LI) is often seen in breast cancer but its importance remains controversial. A positive correlation of human epidermal growth factor receptor 2 (HER2) amplification and LI has been described, which was associated with a more favorable outcome. However, specific lymphocytes might also promote tumor progression by shifting the cytokine milieu in the tumor. Methods Affymetrix HG-U133A microarray data of 1,781 primary breast cancer samples from 12 datasets were included. The correlation of immune system-related metagenes with different immune cells, clinical parameters, and survival was analyzed. Results A large cluster of nearly 600 genes with functions in immune cells was consistently obtained in all datasets. Seven robust metagenes from this cluster can act as surrogate markers for the amount of different immune cell types in the breast cancer sample. An IgG metagene as a marker for B cells had no significant prognostic value. In contrast, a strong positive prognostic value for the T-cell surrogate marker (lymphocyte-specific kinase (LCK) metagene) was observed among all estrogen receptor (ER)-negative tumors and those ER-positive tumors with a HER2 overexpression. Moreover ER-negative tumors with high expression of both IgG and LCK metagenes seem to respond better to neoadjuvant chemotherapy. Conclusions Precise definitions of the specific subtypes of immune cells in the tumor can be accomplished from microarray data. These surrogate markers define subgroups of tumors with different prognosis. Importantly, all known prognostic gene signatures uniformly assign poor prognosis to all ER-negative tumors. In contrast, the LCK metagene actually separates the ER-negative group into better or worse prognosis.

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Author and article information

Contributors

Stephanie Filleur: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Electronic): 1932-6203

Publication date Collection: 2014

Publication date (Electronic): 17 April 2014

Volume: 9

Issue: 4

Electronic Location Identifier: e95475

Affiliations

[1 ]Department of General Surgery, the Second Xiangya Hospital, Central South University, Changsha, China

[2 ]Department of Pathology, the Second Xiangya Hospital, Central South University, Changsha, China

Texas Tech University Health Sciences Center, United States of America

Author notes

* E-mail: TZH18773150286@ 123456163.com

Competing Interests: The authors have declared that no competing interests exist.

Conceived and designed the experiments: ZC XM ZT. Performed the experiments: ZC XC EZ GC KQ XW. Analyzed the data: ZC XM ZT. Wrote the paper: ZC XM ZT.

Article

Publisher ID: PONE-D-13-48251

DOI: 10.1371/journal.pone.0095475

PMC ID: 3990637

PubMed ID: 24743335

SO-VID: 7cfe2870-5d2d-4d50-acbf-ba40f2148555

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 27 November 2013

Date accepted : 27 March 2014

Page count

Pages: 12

Funding

The work was funded by the department of general surgery of the Second Xiangya Hospital of Central South University. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.