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 associati...
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2022-09-01
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| Series: | Breast Cancer Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13058-022-01552-w |
| _version_ | 1798004444529426432 |
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| author | Cornelia Kolberg-Liedtke Friedrich Feuerhake Madlen Garke Matthias Christgen Ronald Kates Eva Maria Grischke Helmut Forstbauer Michael Braun Mathias Warm John Hackmann Christoph Uleer Bahriye Aktas Claudia Schumacher Sherko Kuemmel Rachel Wuerstlein Monika Graeser Ulrike Nitz Hans Kreipe Oleg Gluz Nadia Harbeck |
| author_facet | Cornelia Kolberg-Liedtke Friedrich Feuerhake Madlen Garke Matthias Christgen Ronald Kates Eva Maria Grischke Helmut Forstbauer Michael Braun Mathias Warm John Hackmann Christoph Uleer Bahriye Aktas Claudia Schumacher Sherko Kuemmel Rachel Wuerstlein Monika Graeser Ulrike Nitz Hans Kreipe Oleg Gluz Nadia Harbeck |
| author_sort | Cornelia Kolberg-Liedtke |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-11T12:24:56Z |
| format | Article |
| id | doaj.art-8e767ca38fb44eb2b85c5566cfa49c03 |
| institution | Directory Open Access Journal |
| issn | 1465-542X |
| language | English |
| last_indexed | 2024-04-11T12:24:56Z |
| publishDate | 2022-09-01 |
| publisher | BMC |
| record_format | Article |
| series | Breast Cancer Research |
| spelling | doaj.art-8e767ca38fb44eb2b85c5566cfa49c032022-12-22T04:24:00ZengBMCBreast Cancer Research1465-542X2022-09-0124111310.1186/s13058-022-01552-wImpact of stromal tumor-infiltrating lymphocytes (sTILs) on response to neoadjuvant chemotherapy in triple-negative early breast cancer in the WSG-ADAPT TN trialCornelia Kolberg-Liedtke0Friedrich Feuerhake1Madlen Garke2Matthias Christgen3Ronald Kates4Eva Maria Grischke5Helmut Forstbauer6Michael Braun7Mathias Warm8John Hackmann9Christoph Uleer10Bahriye Aktas11Claudia Schumacher12Sherko Kuemmel13Rachel Wuerstlein14Monika Graeser15Ulrike Nitz16Hans Kreipe17Oleg Gluz18Nadia Harbeck19Department of Gynecology and Obstetrics, University Hospital EssenInstitute of Pathology, Medical School HannoverUniversity Hospital LuebeckInstitute of Pathology, Medical School HannoverWest German Study GroupWomen’s Clinic, University Clinics TuebingenPractice Network TroisdorfBreast Center, Rotkreuz Clinics MunichBreast Center, City Hospital HolweideBreast Center, Marien-HospitalPractice of Gynecology and OncologyDepartment of Gynecology, University Hospital LeipzigBreast Center, St. Elisabeth HospitalWest German Study GroupWest German Study GroupWest German Study GroupWest German Study GroupInstitute of Pathology, Medical School HannoverWest German Study GroupWest German Study GroupAbstract 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.https://doi.org/10.1186/s13058-022-01552-wTriple-negative breast cancersTilsNeoadjuvant chemotherapyPathologic complete response3-Week biopsy |
| spellingShingle | Cornelia Kolberg-Liedtke Friedrich Feuerhake Madlen Garke Matthias Christgen Ronald Kates Eva Maria Grischke Helmut Forstbauer Michael Braun Mathias Warm John Hackmann Christoph Uleer Bahriye Aktas Claudia Schumacher Sherko Kuemmel Rachel Wuerstlein Monika Graeser Ulrike Nitz Hans Kreipe Oleg Gluz Nadia Harbeck Impact of stromal tumor-infiltrating lymphocytes (sTILs) on response to neoadjuvant chemotherapy in triple-negative early breast cancer in the WSG-ADAPT TN trial Breast Cancer Research Triple-negative breast cancer sTils Neoadjuvant chemotherapy Pathologic complete response 3-Week biopsy |
| title | Impact of stromal tumor-infiltrating lymphocytes (sTILs) on response to neoadjuvant chemotherapy in triple-negative early breast cancer in the WSG-ADAPT TN trial |
| title_full | Impact of stromal tumor-infiltrating lymphocytes (sTILs) on response to neoadjuvant chemotherapy in triple-negative early breast cancer in the WSG-ADAPT TN trial |
| title_fullStr | Impact of stromal tumor-infiltrating lymphocytes (sTILs) on response to neoadjuvant chemotherapy in triple-negative early breast cancer in the WSG-ADAPT TN trial |
| title_full_unstemmed | Impact of stromal tumor-infiltrating lymphocytes (sTILs) on response to neoadjuvant chemotherapy in triple-negative early breast cancer in the WSG-ADAPT TN trial |
| title_short | Impact of stromal tumor-infiltrating lymphocytes (sTILs) on response to neoadjuvant chemotherapy in triple-negative early breast cancer in the WSG-ADAPT TN trial |
| title_sort | impact of stromal tumor infiltrating lymphocytes stils on response to neoadjuvant chemotherapy in triple negative early breast cancer in the wsg adapt tn trial |
| topic | Triple-negative breast cancer sTils Neoadjuvant chemotherapy Pathologic complete response 3-Week biopsy |
| url | https://doi.org/10.1186/s13058-022-01552-w |
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