TILs Positively Prognostic of HER2-Positive Breast Cancer Treatment Response

Pretherapeutic levels of tumour-infiltrating lymphocytes are associated with good response to treatment in human epidermal growth factor 2–positive breast cancer patients

medwireNews: In women with human epidermal growth factor 2 (HER2)-positive breast cancer, the presence of tumour-infiltrating lymphocytes (TILs) at diagnosis serves as a positive biomarker of response to treatment with HER2 inhibitors and chemotherapy, research suggests.

This association was “independent of the anti-HER2 agent given”, say Sherene Loi, from the Peter MacCallum Cancer Centre, Victoria, Australia, and co-authors in JAMA Oncology.

A total of 387 breast cancer patients with sufficient pretreatment tumour tissue for TIL assessment were included in this secondary analysis of the NeoALTTO phase III trial. The women had received one of three neoadjuvant therapies – trastuzumab and/or lapatinib – followed by paclitaxel and subsequently fluorouracil , epirubicin and cyclophosphamide after surgery.

Pathological complete response (pCR) rates “increased sharply” in women with stromal TIL levels of 5% or more irrespective of the treatment they received, with an adjusted odds ratio of 2.60 compared with lower levels, report the researchers.

However, commentator Sibylle Loibl, from the German Breast Group in Neu-Isenburg, points out that “the steep increase in pCR at 5% TILs seems to be confined to the 2 groups with single [anti-HER2] therapy”, suggesting that this nonlinear association could be a “chance finding”.

Noting that other factors could also have influenced the results, she adds: “It would have been interesting to see the change in TIL levels within the first 6 weeks when patients only received the anti-HER2 treatment without chemotherapy.”

Sherene Loi et al also report a linear correlation between the pretherapeutic levels of TILs and event-free survival (EFS) across all treatment arms, with each 1% increase in TIL levels associated with a 3% decrease in the rate of an event, with a significant hazard ratio of 0.97.

Interestingly, the 3-year EFS rate was comparable between women with greater than median levels (≥12.5%) of TILs at diagnosis who did not and did achieve pCR, at 85% and 92%, respectively. Women with TIL levels below the median who did not achieve pCR had the poorest response in terms of EFS, at 67%.

“Hence, as we move forward into an era of dual anti-HER2 therapy, it is possible that we can identify a subgroup of patients defined by their TIL level at diagnosis who may not require more than the current adjuvant standard of trastuzumab and chemotherapy”, say the researchers.

Recognising the difficulty of proposing such cutoffs for clinical use, they conclude: “If a TIL cutoff can be identified and robustly validated using the large adjuvant HER2-positive data sets, future clinical trials of anti-HER2 therapy may be better placed to test the efficacy of new therapies in the poor prognostic group.”


Salgado R, Denkert C, Campbell C, et al. 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.JAMA Oncol 2015; Advance online publication 30 April. doi:10.1001/jamaoncol.2015.0830

Loibl S. The Dual Role of Tumor-Infiltrating Lymphocytes in HER2-Positive Primary Breast Cancer. Two Sides of the Same Coin?JAMA Oncol 2015; Advance online publication 30 April. doi:10.1001/jamaoncol.2015.0851

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