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. 2024 Aug 1;10(8):1077-1086.
doi: 10.1001/jamaoncol.2024.1917.

Tumor-Infiltrating Lymphocytes in Patients With Stage I Triple-Negative Breast Cancer Untreated With Chemotherapy

Veerle C M Geurts  1 , Sara Balduzzi  2 , Tessa G Steenbruggen  3   4 , Sabine C Linn  3   5   6 , Sabine Siesling  7   8 , Sunil S Badve  9   10 , Angela DeMichele  11 , Michail Ignatiadis  12 , Roberto A Leon-Ferre  13 , Matthew P Goetz  13 , Antonio C Wolff  14 , Natalie Klar  15   16 , Stefan Michiels  17 , Sherene Loi  18   19 , Sylvia Adams  15   16 , Hugo M Horlings  5 , Gabe S Sonke  3 , Roberto Salgado  20   21 , Marleen Kok  1   3
Affiliations

Tumor-Infiltrating Lymphocytes in Patients With Stage I Triple-Negative Breast Cancer Untreated With Chemotherapy

Veerle C M Geurts et al. JAMA Oncol. .

Erratum in

  • Error in the Abstract.
    [No authors listed] [No authors listed] JAMA Oncol. 2024 Aug 1;10(8):1138. doi: 10.1001/jamaoncol.2024.3526. JAMA Oncol. 2024. PMID: 39145802 Free PMC article. No abstract available.

Abstract

Importance: The absolute benefit of chemotherapy for all patients with stage I triple-negative breast cancer (TNBC) is unclear, and biomarkers are not currently available for selecting patients with an excellent outcome for whom neoadjuvant or adjuvant chemotherapy may have negligible benefit. High levels of stromal tumor-infiltrating lymphocytes (sTILs) are associated with favorable survival in TNBC, but data solely in stage I TNBC are lacking.

Objective: To examine the outcomes of patients of all ages with stage I TNBC solely and who received neither neoadjuvant nor adjuvant chemotherapy, according to centrally reviewed sTIL levels at prespecified cutoffs.

Design, setting, and participants: This cohort study used the Netherlands Cancer Registry to identify patients diagnosed with stage I TNBC between January 1, 2005, and December 31, 2015, who were not treated with chemotherapy. Only patients who did not receive neoadjuvant and/or adjuvant chemotherapy were selected. The clinical data were matched with their corresponding pathology data provided by the Dutch Pathology Registry. Data analysis was performed between February and October 2023.

Main outcomes and measures: The primary end point was breast cancer-specific survival (BCSS) at 5, 10, and 15 years for the prespecified sTIL level cutoffs of 30%, 50%, and 75%. Hematoxylin and eosin-stained slides were used for central review of histologic subtype, grade, and lymphovascular invasion. The International Immuno-Oncology Biomarker Working Group guidelines were used to score the sTIL levels; these levels were determined for 1041 patients.

Results: Of a total of 4511 females with stage I TNBC, patients who were not treated with chemotherapy were selected and tissue blocks requested; sTILs were scored in 1041 patients (mean [SD] age at diagnosis, 64.4 [11.1] years, median follow-up 11.4 [95% CI, 10.9-11.9] years) who were included in the analyses.. Most tumors (952 [91.5%]) were invasive carcinomas of nonspecial histologic subtype. Most patients (548 [52.6%]) had pT1cN0 tumors. Median (range) sTIL level was 5% (1%-99%). A total of 775 patients (74.4%) had sTIL levels below 30%, 266 (25.6%) had 30% or greater, 203 (19.5%) had 50% or greater, and 141 (13.5%) had 75% or greater. Patients with pT1abN0 tumors had a more favorable outcome vs patients with pT1cN0 tumors, with a 10-year BCSS of 92% (95% CI, 89%-94%) vs 86% (95% CI, 82%-89%). In the overall cohort, sTIL levels of at least 30% were associated with better BCSS compared with sTIL levels less than 30% (96% and 87%, respectively; hazard ratio [HR], 0.45; 95% CI, 0.26-0.77). High sTIL levels of 50% or greater were associated with a better outcome than low sTIL levels of less than 50% (HR, 0.27; 95% CI, 0.10-0.74) in patients with pT1C tumors, with a 10-year BCSS of 95% increasing to 98% with sTIL levels of 75% or greater.

Conclusions and relevance: Results of this study showed that patients with stage I TNBC and high level of sTILs who did not receive neoadjuvant or adjuvant chemotherapy had excellent 10-year BCSS. The findings further support the role of sTILs as integral biomarkers in prospective clinical trials of therapy optimization for this patient population.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Steenbruggen reported receiving personal fees from Gilead outside the submitted work. Professor Linn reported receiving Investigator-Initiated Studies grants paid to the institution from AstraZeneca, Roche, Genentech, Tesaro (now GSK), Eurocept Pharmaceuticals, and Agendia; grants from Immunomedics (now Gilead); nonfinancial support from AstraZeneca, Immunomedics (now Gilead), Roche, Genentech, Novartis, Tesaro (now GSK); and other from Daiichi-Sankyo outside the submitted work as well as holding a patent for Methods for assessing homologous recombination deficiency in ovarian cancer cells. Dr Badve reported being Director, ICGA-Foundation, India Global Health; serving on advisory boards of Agilent, AstraZeneca, Daiichi Sanyo, Bristol Myers Squibb Personalis, Mindpeak (Gmbh), and Roche Diagnostics; and receiving grants from Agilent, AstraZeneca, Bristol Myers Squibb, Daiichi Sanyo, Eli Lilly, and Roche Diagnostics outside the submitted work. Dr Ignatiadis reported receiving grants paid to the institution from Roche and Inivata Inc and personal fees from Menarini/Stemline, Seattle Genetics, Rejuveron Therapeutics, and Novartis outside the submitted work. Dr Leon-Ferre reported receiving honoraria paid to the institution from AstraZeneca, Gilead Sciences, and Lyell Immunopharma outside the submitted work. Dr Goetz reported receiving honoraria paid to the institution from ARC Therapeutics, AstraZeneca, Biotheranostics, Biotheryx, Blueprint Medicines, Engage Health Media, Lilly, Novartis, RNA Diagnostics, Seattle Genetics, and Sermonix; grants paid to the institution from Lilly, Pfizer, Sermonix, Loxo, ATOSSA Therapeutics, and AstraZeneca; nonfinancial support from Lilly; and personal fees from Research to Practice, Clinical Education Alliance, Medscape, MJH Life Sciences, Total Health, and Curio outside the submitted work. Dr Michiels reported receiving personal fees from Amaris, Roche, IQVIA, Sensorion, Kedrion, Biophytis, Servier, and Yuhan outside the submitted work. Professor Loi reported receiving nonfinancial support from BMS, Novartis, and Merck and grants from SeaGen, Pfizer, and AstraZeneca outside the submitted work. Dr Adams reported receiving institutional support from Genentech, Merck, Amgen, Bristol Myers, Squibb, Novatirs, and Celgene outside the submitted work. Dr Sonke reported receiving grants from Dutch Cancer Society during the conduct of the study and grants from Agendia, AstraZeneca, Merck, Novartise, Roche, and Seagen outside the submitted work. Dr Salgado reported receiving personal fees from Roche, BMS, AstraZeneca, Exact Sciences, and Daichii Sankyo as well as providing unpaid consulting to Case 45 during the conduct of the study. Dr Kok reported receiving funding for laboratory research from the Netherlands Organization for Scientific Research and Victoria’s Secret Global Fund for Women’s Cancers Rising Innovator Research Grant, in Partnership with Pelotonia & American Association for Cancer Research; grants paid to the institution from AstraZeneca, BMS, and Roche; and personal fees from Gilead, MSD, and Domain Therapeutics outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Flowchart
Patients with stage I triple-negative breast cancer (TNBC) diagnosed between January 1, 2005, and December 31, 2015, were identified from the Netherlands Cancer Registry. TIL indicates tumor-infiltrating lymphocyte.
Figure 2.
Figure 2.. Breast Cancer–Specific Survival (BCSS) of Patients in the Overall Cohort
A, Ten-year BCSS was 96% for a stromal tumor-infiltrating lymphocyte (sTIL) level 30% or greater and 87% for a level less than 30% (hazard ratio [HR], 0.45; 95% CI, 0.26-0.77). B, Ten-year BCSS was 92% for an sTIL level 50% or greater and 88% for a level less than 50% (HR, 0.59; 95% CI, 0.33-1.04). C, Ten-year BCSS was 87% for an sTIL level less than 30%, 94% for a level between 30% and 74% (HR, 0.38; 95% CI, 0.17-0.87), and 93% for a level 75% or greater (HR, 0.50; 95% CI, 0.25-1.00). TIL indicates tumor-infiltrating lymphocyte.
Figure 3.
Figure 3.. Breast Cancer–Specific Survival (BCSS) of Patients With pT1ab Tumors
A, Ten-year BCSS was 92% for a stromal tumor-infiltrating lymphocyte (sTIL) level 30% or greater and 92% for a level less than 30% (hazard ratio [HR], 0.93; 95% CI, 0.44-1.94). B, Ten-year BCSS was 90% for an sTIL level 50% or greater and 92% for a level less than 50% (HR, 1.35; 95% CI, 0.65-2.82). C, Ten-year BCSS was 92% for an sTIL level less than 30%, 97% for a level between 30% and 74% (HR, 0.41; 95% CI, 0.10-1.73), and 89% for a level 75% or greater (HR, 1.37; 95% CI, 0.62-3.05). TIL indicates tumor-infiltrating lymphocyte.
Figure 4.
Figure 4.. Breast Cancer–Specific Survival (BCSS) of Patients With pT1c Tumors
A, Ten-year BCSS was 95% for a stromal tumor-infiltrating lymphocyte (sTIL) level 30% or greater and 83% for a level less than 30% (hazard ratio [HR], 0.24; 95% CI, 0.10-0.60). B, Ten-year BCSS was 95% for an sTIL level 50% or greater and 84% for a level less than 50% (HR, 0.27; 95% CI, 0.10-0.74). C, Ten-year BCSS was 83% for an sTIL level less than 30%, 91% for a level between 30% and 74% (HR, 0.40; 95% CI, 0.15-1.10), and 98% for a level 75% or greater (HR, 0.09; 95% CI, 0.01-0.68). TIL indicates tumor-infiltrating lymphocyte.
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