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

TY - JOUR

T1 - Impact of stromal tumor-infiltrating lymphocytes (sTILs) on response to neoadjuvant chemotherapy in triple-negative early breast cancer in the WSG-ADAPT TN trial

AU - Kolberg-Liedtke, Cornelia

AU - Feuerhake, Friedrich

AU - Garke, Madlen

AU - Christgen, Matthias

AU - Kates, Ronald

AU - Grischke, Eva Maria

AU - Forstbauer, Helmut

AU - Braun, Michael

AU - Warm, Mathias

AU - Hackmann, John

AU - Uleer, Christoph

AU - Aktas, Bahriye

AU - Schumacher, Claudia

AU - Kuemmel, Sherko

AU - Wuerstlein, Rachel

AU - Graeser, Monika

AU - Nitz, Ulrike

AU - Kreipe, Hans

AU - Gluz, Oleg

AU - Harbeck, Nadia

N1 - © 2022. The Author(s).

PY - 2022/9/2

Y1 - 2022/9/2

N2 - 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.

AB - 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.

KW - Antineoplastic Combined Chemotherapy Protocols/therapeutic use

KW - Biomarkers, Tumor/analysis

KW - Breast Neoplasms/pathology

KW - Female

KW - Humans

KW - Intracellular Signaling Peptides and Proteins

KW - Lymphocytes, Tumor-Infiltrating

KW - Neoadjuvant Therapy/methods

KW - Reproducibility of Results

KW - Triple Negative Breast Neoplasms/drug therapy

U2 - 10.1186/s13058-022-01552-w

DO - 10.1186/s13058-022-01552-w

M3 - SCORING: Journal article

C2 - 36056374

VL - 24

JO - BREAST CANCER RES

JF - BREAST CANCER RES

SN - 1465-5411

IS - 1

M1 - 58

ER -