Association of TILs with clinical parameters, Recurrence Score® results, and prognosis in patients with early HER2-negative breast cancer (BC)-a translational analysis of the prospective WSG PlanB trial

Abstract

Background: The presence of tumor-infiltrating lymphocytes has been associated with prognosis and chemotherapy response, particularly in high-risk breast cancer subtypes. There is limited data so far as to (i) how tumor-infiltrating lymphocyte (TIL) measurements correlate with genomic measurements such as the Oncotype DX Recurrence Score® and (ii) whether the survival impact of TIL measurements varies according to different adjuvant systemic therapies.

Methods: The WSG PlanB trial compared an anthracycline-free chemotherapy regimen (6x docetaxel/cyclophosphamide, TC) to an anthracycline-taxane sequence (4xEC followed by 4x docetaxel) in patients with intermediate-risk, HER2-negative early breast cancer (EBC). Patients with HR-positive HER2-negative EBC were further stratified to receive endocrine therapy alone vs. chemotherapy followed by endocrine therapy based on Recurrence Score results and nodal status. In this analysis, three independent observers quantified and categorized the presence of TILs among tumor samples from patients in PlanB. TIL measurements were correlated with clinical/pathological parameters and treatment outcome overall and according to the treatment arm.

Results: Disease-free survival (DFS) rates were significantly better (p = .04) in HR-negative patients with high vs. intermediate TIL levels and were higher in low vs. intermediate TIL patients, however with borderline significance only (p = .06). There were no significant differences among TIL categories in HR+ patients. High RS categories, HR-negative status, and high KI67 were independently and significantly associated with high TIL categories. There was no significant impact of TIL category on DFS in patients treated by endocrine therapy only; however, in patients receiving chemotherapy, DFS in the intermediate TIL category was lower than that in the other categories.

Conclusion: Although the presence of high TILs is associated with negative prognostic parameters such as high KI67 and HR-negative status among patients with HR-positive HER2-negative EBC, patients with high TILs show a favorable 5-year DFS in both HR-positive/HER2-negative and triple-negative breast cancer.

Trial registration: ClinicalTrials.gov NCT01049425.

Keywords: Adjuvant chemotherapy; Breast cancer; Disease-free survival; Hormone receptor status; Tumor-infiltrating lymphocytes (TILs).

Conflict of interest statement

Fred Heinisch, Matthias Christgen, Toralf Reimer, Friedrich Feuerhake, Michael Clemens Monika Graeser, and Ronald Kates have reported no potential conflict of interest.

Cornelia Kolberg-Liedtke has received honoraria/travel support by Phaon Scientific, Novartis, Pfizer, Celgene, Roche, AstraZeneca, Lilly, HEXAL, Amgen, Eisai, and SonoScape and has received research funding by Roche, Novartis, and Pfizer (CKL). Rachel Würstlein has reported financial support by Agendia, Amgen, Aristo, Astra Zeneca, Boeringer Ingelheim, Carl Zeiss, Celgene, Daiichi-Sankyo, Esai, Genomic Health, Glaxo Smith Kline, Hexal, Lilly, Medstrom Medical, MSD, Mundipharma, Nanostring, Novartis, Odonate, Paxman, Palleos, Pfizer, Pierre Fabre, PumaBiotechnolgogy, Riemser, Roche, Seattle Genetics, Tesaro Bio, and Teva. Hans Kreipe has received honoraria from AstraZeneca, Genomic Health, Roche Pharma, Novartis, Amgen, and Pfizer. Wolfram Malter has received honoraria from Genomic Health, Pfizer, Novartis, NanoString, Celgene, and Roche. Oleg Gluz has reported personal fees/travel support from Genomic Health, NanoString Technologies, Roche, Celgene, and Teva.

Benno Nuding has served in a consulting or advisory role for Roche, Novartis, and Pfizer. Steven Shak is an employee and stock owner for Genomic Health. Ulrike Nitz has received personal fees from Genomic Health and Roche. Nadia Harbeck has received honoraria for lectures and consulting from Daiichi-Sankyo, Novartis, and Roche.

Figures

Fig. 1

a Kaplan-Meier analysis of DFS according to sTIL categories (HR negative). b Kaplan-Meier analysis of DFS according to sTIL categories (HR positive)

Fig. 2

Kaplan-Meier analysis of DFS according to sTILs. a Among patients with RS ≤ 11 and endocrine therapy alone (no Kaplan-Meier analysis was performed to low number of patients/events). b Among patients treated with chemotherapy (irrespective of HR status). c Among patients with HR-negative tumors treated with chemotherapy. d Among patients with HR-positive tumors (and RS values of 12–99 treated with chemotherapy)