5009 - Tumor infiltrating lymphocytes predict benefit from TAC but not from ddAC in triple negative breast cancer in the randomized MATADOR trial (BOOG 2004-04)

Background

Increased tumor infiltrating lymphocytes (TILs) predict response to neoadjuvant chemotherapy and is also associated with favorable survival in triple negative breast cancer (TNBC). However, it is unknown whether the presence of TILs can be used as a biomarker to select patients for a specific type of chemotherapy, such as the addition of a taxane to anthracycline-based adjuvant chemotherapy. The primary objective of the MATADOR trial (ISRCTN61893718) was to test whether gene expression profiling can be used to select patients who will benefit from the addition of docetaxel.

Methods

Patients were randomized between 6 cycles adjuvant docetaxel-doxorubicin-cyclophosphamide (T₇₅A₅₀C₅₀₀) and 6 cycles dose-dense AC (ddA₆₀C₆₀₀). The primary endpoint was recurrence free survival (RFS). RNA-sequencing data were obtained from 591 (482 ER-positive, 91 TNBC and 18 HER2-positive) of the 664 patients enrolled in this multicenter trial. Gene set enrichment analysis (GSEA) was done using the median expression of the 50 hallmark gene sets. Additionally, TILs were scored according to the guidelines of the International TILs working group.

Results

With 7 years follow up, we observed 102 RFS events. Due to the overall low number of events our analyses did not reveal a robust predictive gene expression profile. However, GSEA of the hallmark gene sets showed significant interaction between immune-related pathways (such as interferon-alpha, regulatory T cells, T cells) and the addition of docetaxel in the exploratory subgroup analysis with TNBC. In subsequent analysis of TILs, TNBC patients were classified as TIL high (≥20%) or TIL low (<20%) according to the median. A significant interaction between TILs and treatment was observed for RFS (adjusted p = 0.022) with a better RFS of TIL high patients versus TIL low patients after TAC treatment (hazard ratio 0.15, confidence interval 0.03-0.69), and not after ddAC.

Conclusions

In our prospective randomized clinical trial we observed a significant benefit from adding docetaxel to AC in patients with high TIL tumours, while this benefit was not observed in patients with low TIL tumours.

Clinical trial identification

ISRCTN61893718 - date assigned: 20/12/2005.

Legal entity responsible for the study

Netherlands Cancer Institute.

Funding

Unrestricted research grants from Sanofi and Amgen.

Editorial Acknowledgement

Disclosure

H.M. Oosterkamp: Unrestricted institutional research grant: Sanofi and Amgen to conduct the MATADOR study (ISRCTN61893718); Advisory board member: Roche, Pfizer and Novartis; Research support funding: Roche. M. Kok: Advisory board member: BMS; Institutional research support funding: Roche and BMS. S.C. Linn: Unrestricted institutional research grant: Sanofi and Amgen to conduct the MATADOR study (ISRCTN61893718); Advisory board member: AstraZeneca, Cergentis, Novartis, Pfizer, Roche, and Sanofi; Institutional research support funding: Amgen, AstraZeneca, Genentech, Roche, Sanofi and Tesaro. All other authors have declared no conflicts of interest.