Impact of stromal tumor-infiltrating lymphocytes (sTILs) on response to neoadjuvant chemotherapy in triple-negative early breast cancer in the WSG-ADAPT TN trial

Abstract

Background: Higher density of stromal tumor-infiltrating lymphocytes (sTILs) at baseline has been associated with increased rates of pathological complete response (pCR) after neoadjuvant chemotherapy (NACT) in triple-negative breast cancer (TNBC). While evidence supports favorable association of pCR with survival in TNBC, an independent impact of sTILs (after adjustment for pCR) on survival is not yet established. Moreover, the impact of sTIL dynamics during NACT on pCR and survival in TNBC is unknown.

Methods: The randomized WSG-ADAPT TN phase II trial compared efficacy of 12-week nab-paclitaxel with gemcitabine versus carboplatin. This preplanned translational analysis assessed impacts of sTIL measurements at baseline (sTIL-0) and after 3 weeks of chemotherapy (sTIL-3) on pCR and invasive disease-free survival (iDFS). Predictive performance of sTIL-0 and sTIL-3 for pCR was quantified by ROC analysis and logistic regression; Kaplan-Meier estimation and Cox regression (with mediation analysis) were used to determine their impact on iDFS.

Results: For prediction of pCR, the AUC statistics for sTIL-0 and sTIL-3 were 0.60 and 0.63, respectively, in all patients; AUC for sTIL-3 was higher in NP/G. The positive predictive value (PPV) of "lymphocyte-predominant" status (sTIL-0 ≥ 60%) at baseline was 59.3%, though only 13.0% of patients had this status. To predict non-pCR, the cut point sTIL-0 ≤ 10% yielded PPV = 69.5% while addressing 33.8% of patients. Higher sTIL levels (particularly at 3 weeks) were independently and favorably associated with better iDFS, even after adjusting for pCR. For example, the adjusted hazard ratio for 3-week sTILs ≥ 60% (vs. < 60%) was 0.48 [0.23-0.99]. Low cellularity in 3-week biopsies was the strongest individual predictor for pCR (in both therapy arms), but not for iDFS.

Conclusion: The independent impact of sTILs on iDFS suggests that favorable immune response can influence key tumor biological processes for long-term survival. The results suggest that the reliability of pCR following neoadjuvant therapy as a surrogate for survival could vary among subgroups in TNBC defined by immune response or other factors. Dynamic measurements of sTILs under NACT could support immune response-guided patient selection for individualized therapy approaches for both very low levels (more effective therapies) and very high levels (de-escalation concepts).

Trial registration: Clinical trials No: NCT01815242, retrospectively registered January 25, 2013.

Keywords: 3-Week biopsy; Neoadjuvant chemotherapy; Pathologic complete response; Triple-negative breast cancer; sTils.

Conflict of interest statement

CKL reports stock by Theraklion and Phaon Scientific (self and family), honoraria by Roche, AstraZeneca, Celgene, Novartis, Pfizer, Lilly, Hexal, Amgen, SonoScape (self) and Genomic Health, Amgen, AstraZeneca, Riemser, Carl Zeiss MediTec, TEVA Pharmaceuticals Industries, Theraklion, Janssen-Cilag, GlaxoSmithKline, LIV Pharma (family), Consulting to Roche, Novartis, Pfizer, Celgene, Phaon Scientific (self) and Pfizer, Novartis, SurgVision, CarlZeissMeditec, Amgen, Onkowissen (family); research funding by Roche, Novartis, Pfizer (self) as well as Travel and Accomodation by Roche, Daiichi Sankyo, Novartis (self) and Carl Zeiss Meditec, LIV Pharma, Novartis, Amgen, Pfizer, Daiichi Sankyo (family). FF reports research funding by IOMX Therapeutics AG (Research Collaboration). MG none. MC none. RK reports honoraria by Amgen, Celgene, Genomic Health, NanoString Technologies, Novartis pharma, Pfizer Pharmaceuticals and Roche (family); consulting/advisory role by Agendia, AstraZeneca, Celgene, Daiichi Sankyo, Lilly, Merck Sharp & Dohme, Novartis pharma, Odonate Therapeutics, Pfizer Pharmaceuticals, Roche/Genentech, Sandoz (family); Research funding by the West German Study Group (self) and Genentech, Novartis, Boehringer Ingelheim and Pfizer (self). EG none. HF none. MB reports honoraria by AstraZeneca, Exact Sciences, Novartis, Pfizer, Roche, Teva; Consulting/Advisory Role by AstraZeneca, Exact Sciences, Novartis, Puma, Roche and Travel/Accomodation by AstraZeneca, Celgene, Medac, Novartis, Roche. MW none. JH none. CU reports Consulting/Advisory Role by Tesaro, Novartis, Roche, Research Funding by West German Study Group, German Breast Group, Novartis, AstraZeneca, Tesaro, Palleos Healthcare Services Gmbh, Pierre Fabre, AGO-Studiengrouppe; Travel/Accomodation by German Breast Group, West German Study Group, AGO-Studiengruppe; Speakers’ Bureau by Pfizer, Novartis, Roche, PharmaMar, AstraZeneca. BA reports Consulting/Advisory Role by Pfizer, Roche Pharma, Merck Sharp & Dohme, onkowissen.de, Novartis Pharma, AstraZeneca, PharmaMar, Lilly, promedicis; Travel /Accomodation by astraZeneca, Roche, Novartis, Pfizer. CS none. SK reports Consulting/Advisory Role by Roche, Genomic Health, Novartis, AstraZeneca, Amgen, Celgene, SOMATEX Medical Technologies, Daiichi Sankyo, PFM medical, Pfizer, MSD, Puma Biotechnology; Travel/accommodation by Roche, Daiichi Sankyo; other relationship as Co-Director West German Study Group. RW report Served as advisor, consultant, speaker and travel grants by Agendia, Amgen, Aristo, Astra Zeneca, Boeringer Ingelheim, Carl Zeiss, Celgene, Clinsol, Daiichi Sankyo, Eisai, Exact Sciences, Genomic Health, Gilead, Glaxo Smith Kline, Hexal, Lilly, Medstrom Medical, MSD, Mundipharma, Nanostring, Novartis, Odonate, Paxman, Palleos, Pfizer, Pierre Fabre, PumaBiotechnolgogy, Riemser, Roche, Sandoz/Hexal, Seattle Genetics /Seagen, Tesaro Bio, Teva, Veracyte, Viatris. MG none. UN reports honoraria by Agendia, Amgen, Celgene, Genomic Health, NanoString Technologies, Novartis pharma, Pfizer Pharmaceuticals, Roche/Genentech, Teva; Consulting/Advisory Role by Genomic Health, Roche; Research Funding by Agendia, Amgen, Celgene, Genomic Health, NanoString Technologies, Roche, Sanofi; Expert Testimony by Genomic Health; Travel/Accommodation by Genomic Health, Pfizer Pharmaceuticals, Roche; other relationship as Co-Director West German Study Group. HK none. OG reports honoraria by Genomic Health/Exact Sciences, Roche, Celgene, Pfizer, Novartis, NanoString Technologies, AstraZeneca; Consulting/Advisory Rola by Celgene, Genomic Health/Exact Sciences, Lilly, MSD, Novartis, Pfizer, Roche; Travel/Accomodation by Roche; other relationship as Co-Director West German Study Group. NH reports honoraria by Amgen, AstraZeneca, Genomic Health, Novartis, Pfizer, Pierre Fabre, Roche, Zodiac Pharma; Consulting/Advisory Role by Agendia, AstraZeneca, Celgene, Daiichi Sankyo, Lilly, Merck Sharp & Dohme, Novartis, Odonate Therapeutics, Pfizer, Pierre Fabre, Roche/Genentech, Sandoz, Seattle Genetics, West German Study Group (family); Research Funding by Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Roche/Genentech; other relationship as Co-Director West German Study Group.

© 2022. The Author(s).

Figures

Fig. 1

Sensitivity (long-dashed curves), specificity (short-dashed curves), PPV (dotted curves) and % addressed (solid curve) as a function of cut point in ROC analysis for A sTIL-0 and B sTIL-3 (lower panel). Vertical lines indicate particular cut points discussed in the text. The rightmost cut point corresponds to “lymphocyte-predominant” status

Fig. 2

iDFS in Kaplan–Meier analysis for TIL+ (baseline lymphocyte-predominant status) versus TIL− in A all patients, B patients with non-pCR and C patients with pCR

Fig. 3

iDFS in Kaplan–Meier analysis for 3-week measurements, i.e., 3wTIL+ versus 3wTIL− versus 3wLC (low cellularity), in A all patients, B patients with non-pCR and C patients with pCR and D iDFS in Kaplan–Meier analysis for subgroups defined (see text) by sTIL transitions from baseline to 3 weeks