The Lynx Group

Impact of Elevated Tumor-Infiltrating Lymphocytes Differs Across Breast Cancer Subtypes

June 2017, Vol 8, No 3

San Antonio, TX—Concentrations of tumor-infiltrating lymphocytes (TILs) had significant but variable associations with survival in breast cancer, according to 2 large retrospective studies of pathology specimens reported at the 2016 San Antonio Breast Cancer Symposium.

In one study, every 10% increase in the concentration of stromal TILs was associated with an 11% reduction in the survival hazard for patients with metastatic breast cancer. The second study, which involved tumor samples from multiple randomized trials, confirmed previous evidence that higher levels of TILs predicted response to neoadjuvant chemotherapy and improved survival in patients with HER2-positive or triple-negative disease. In contrast, lower concentrations of TILs were associated with improved survival in luminal breast cancer.

Taken together, the 2 studies supported a role for immunotherapeutic strategies in the treatment of certain breast cancer subtypes, and provided insights into the effects of treatment on breast cancer biology.

“This is the first study investigating associations between TILs and survival in advanced HER2-positive breast cancer treated with first-line pertuzumab [Perjeta]. The positive influence of preexisting antitumor immunity persists in the advanced setting. Strategies to augment immunity may further improve survival,” said Stephen Luen, MBChB, Medical Oncology Fellow, Peter MacCallum Cancer Centre, University of Melbourne, Victoria, Australia.

Investigators in the second study concluded that elevated TIL levels are “a strong predictive marker” for pathologic complete response (pCR) to neoadjuvant chemotherapy in all breast cancer subtypes and most clinical subgroups.

“This pCR effect is translated into a survival benefit in HER2-positive and triple-negative breast cancer. In contrast, no survival benefit is observed in luminal tumors,” said Carsten Denkert, MD, Senior Pathologist, Institute of Pathology, Charité University, Berlin, Germany.

“The effects in luminal tumors may suggest a contribution of subsequent therapies, but should be interpreted with caution. The role of TILs in resistance to different types of endocrine therapy should be investigated in further studies,” Dr Denkert added.

TILs arise as a byproduct of an adaptive immune response that forms during tumor development. Previous studies showed that TILs predict response to neoadjuvant therapy in patients with HER2-positive and triple-negative breast cancer, but their role in luminal breast cancer and advanced disease remained unclear. The potential relevance of TILs increased with the emergence of immunotherapeutic agents.

CLEOPATRA: New Analysis

Dr Luen reported findings from a new analysis of the randomized phase 3 CLEOPATRA trial involving 808 patients with previously untreated HER2-positive breast cancer. All patients received trastuzumab and docetaxel and were randomized to pertuzumab or placebo. Topline results showed that the addition of pertuzumab was associated with a 6.3-month improvement in median progression-free survival and 15.7-month improvement in median overall survival (OS).

Dr Luen and colleagues examined associations between TILs and survival, using tumor specimens from 678 participants in the CLEOPATRA trial. In addition, investigators had 20 paired samples from primary tumors and metastases for comparison.

Tissue evaluation showed significantly higher levels of TILs in estrogen receptor (ER)-negative tumors (15% vs 10% for ER-positive tumors; P <.001) and in Asian versus white patients (15% vs 10%; P = .002). African-American patients had even lower levels (5%) of TILs, but accounted for only 4% of the study population. In addition, archival tissue samples (15%) had higher levels of TILs than did fresh tissue specimens (10%; P <.0004).

Analysis of the paired tissue specimens revealed numerically higher levels of TILs in primary tumors (10% vs 7.5%; P = .07).

In a multivariate analysis, TIL concentration did not have a significant association with progression-free survival, but higher levels of TILs did predict improved survival (hazard ratio, 0.89; 95% confidence interval, 0.83-0.96; P = .001).

The association between TILs and survival held up in both treatment arms (P <.0001 for trend). In the pertuzumab group, patients with >20% TILs had a 3-year OS of 78% compared with 64% for patients with ≤20% TILs. Among patients who received only trastuzumab, the 3-year survival was 55% with TILs >20% and 50% with lower levels.

Implications for Different Subtypes

Dr Denkert reported data from analyses of tumor specimens from 3771 patients from 6 prospective clinical trials of neoadjuvant therapy conducted by the German Breast Group. Using a cutoff of ≥60% to define high levels of TILs, Dr Denkert and colleagues found increased TIL concentrations in 30% of triple-negative tumors, 19% of HER2-­positive tumors, and 13% of hormone receptor–positive/HER2-negative (ie, luminal) tumors.

For all 3 breast cancer subtypes, increased TIL levels had a significant association with CR (P <.0005). Multivariate analysis showed that every 10% increase in TIL levels was associated with a 17% increase in the likelihood of achieving a CR (P <.0001). The association persisted in an extensive analysis of clinical subgroups that included tumor stage, nodal status, tumor grade, progesterone receptor status, Ki-67 activity, and ductal or lobular cancers.

TIL levels had different associations with disease-free survival (DFS) and OS, according to breast cancer subtype. By multivariate analysis, high levels of TILs were associated with better DFS and OS in patients with HER2-positive and triple-negative breast cancers but worse survival in luminal/HER2-negative breast cancer.

In contrast, low TIL levels had a significant association with improved DFS and OS in patients with luminal/HER2-negative breast cancer (P = .036 and P <.0005, respectively). Dr Denkert said the most favorable prognosis among patients with luminal disease occurred in association with low TILs and absence of pCR. One possible interpretation is that higher TIL levels are associated with reduced endocrine response.

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