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. 2024 Apr 2;331(13):1135-1144.
doi: 10.1001/jama.2024.3056.

Tumor-Infiltrating Lymphocytes in Triple-Negative Breast Cancer

Roberto A Leon-Ferre  1 , Sarah Flora Jonas  2 , Roberto Salgado  3   4 , Sherene Loi  4 , Vincent de Jong  5   6 , Jodi M Carter  7 , Torsten O Nielsen  8 , Samuel Leung  8 , Nazia Riaz  8 , Stephen Chia  8 , Gérôme Jules-Clément  9 , Giuseppe Curigliano  10   11 , Carmen Criscitiello  10   11 , Vincent Cockenpot  12 , Matteo Lambertini  13   14 , Vera J Suman  15 , Barbro Linderholm  16 , John W M Martens  17 , Carolien H M van Deurzen  17 , A Mieke Timmermans  17 , Tatsunori Shimoi  18 , Shu Yazaki  18 , Masayuki Yoshida  18 , Sung-Bae Kim  19 , Hee Jin Lee  19 , Maria Vittoria Dieci  20   21 , Guillaume Bataillon  22 , Anne Vincent-Salomon  22 , Fabrice André  2 , Marleen Kok  5   6 , Sabine C Linn  5   6 , Matthew P Goetz  1 , Stefan Michiels  2 ; International Immuno-Oncology Biomarker Working Group
Affiliations

Tumor-Infiltrating Lymphocytes in Triple-Negative Breast Cancer

Roberto A Leon-Ferre et al. JAMA. .

Abstract

Importance: The association of tumor-infiltrating lymphocyte (TIL) abundance in breast cancer tissue with cancer recurrence and death in patients with early-stage triple-negative breast cancer (TNBC) who are not treated with adjuvant or neoadjuvant chemotherapy is unclear.

Objective: To study the association of TIL abundance in breast cancer tissue with survival among patients with early-stage TNBC who were treated with locoregional therapy but no chemotherapy.

Design, setting, and participants: Retrospective pooled analysis of individual patient-level data from 13 participating centers in North America (Rochester, Minnesota; Vancouver, British Columbia, Canada), Europe (Paris, Lyon, and Villejuif, France; Amsterdam and Rotterdam, the Netherlands; Milan, Padova, and Genova, Italy; Gothenburg, Sweden), and Asia (Tokyo, Japan; Seoul, Korea), including 1966 participants diagnosed with TNBC between 1979 and 2017 (with follow-up until September 27, 2021) who received treatment with surgery with or without radiotherapy but no adjuvant or neoadjuvant chemotherapy.

Exposure: TIL abundance in breast tissue from resected primary tumors.

Main outcomes and measures: The primary outcome was invasive disease-free survival [iDFS]. Secondary outcomes were recurrence-free survival [RFS], survival free of distant recurrence [distant RFS, DRFS], and overall survival. Associations were assessed using a multivariable Cox model stratified by participating center.

Results: This study included 1966 patients with TNBC (median age, 56 years [IQR, 39-71]; 55% had stage I TNBC). The median TIL level was 15% (IQR, 5%-40%). Four-hundred seventeen (21%) had a TIL level of 50% or more (median age, 41 years [IQR, 36-63]), and 1300 (66%) had a TIL level of less than 30% (median age, 59 years [IQR, 41-72]). Five-year DRFS for stage I TNBC was 94% (95% CI, 91%-96%) for patients with a TIL level of 50% or more, compared with 78% (95% CI, 75%-80%) for those with a TIL level of less than 30%; 5-year overall survival was 95% (95% CI, 92%-97%) for patients with a TIL level of 50% or more, compared with 82% (95% CI, 79%-84%) for those with a TIL level of less than 30%. At a median follow-up of 18 years, and after adjusting for age, tumor size, nodal status, histological grade, and receipt of radiotherapy, each 10% higher TIL increment was associated independently with improved iDFS (hazard ratio [HR], 0.92 [0.89-0.94]), RFS (HR, 0.90 [0.87-0.92]), DRFS (HR, 0.87 [0.84-0.90]), and overall survival (0.88 [0.85-0.91]) (likelihood ratio test, P < 10e-6).

Conclusions and relevance: In patients with early-stage TNBC who did not undergo adjuvant or neoadjuvant chemotherapy, breast cancer tissue with a higher abundance of TIL levels was associated with significantly better survival. These results suggest that breast tissue TIL abundance is a prognostic factor for patients with early-stage TNBC.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Leon-Ferre reported other (consulting honoraria to institution for research activities) from AstraZeneca, Gilead Sciences, and Lyell Immunopharma. No personal fees outside the submitted work. Dr Salgado reported other (advisory board) from Roche, Bristol Myers Squibb, Exact Sciences, and AstraZeneca; other (research funding) from Merck; and other (consulting) from Owkin and Daichii-Sankyo during the conduct of the study. Dr Loi reported grants from Novartis, Roche Genentech, Merck, SeaGen, Bristol Myers Squibb, and AstraZeneca outside the submitted work. Dr Carter reported personal fees from AstraZeneca (consulting) outside the submitted work. Dr Nielsen reported grants from the Canadian Cancer Society during the conduct of the study; personal fees (PAM50 classifier) from Bioclassifier outside the submitted work; and royalties from Veracyte (holding a patent for the PAM50 classifier). Dr Curigliano reported personal fees (advisory board) from Roche, Daichii Sankyo, Lilly, Novartis, Pfizer, Menarini, and Gilead outside the submitted work. Dr Criscitiello reported grants from Gilead and Seagen; and personal fees from Pfizer, Roche, Lilly, Merck, Daiichi Sankyo, and AstraZeneca outside the submitted work. Dr Lambertini reported other (advisory role and speaker honoraria) from Roche, Lilly, Pfizer, and Novartis; other (advisory role) from Merck, Seagen, and Exact Sciences; other (advisory role and travel grant) from Gilead; research funding (to the institution) from Gilead; other (speaker honoraria and travel grant) from Daiichi Sankyo; other (speaker honoraria) from Takeda, Ipsen, Sandoz, Libbs, and Knight outside the submitted work. Dr Suman reported grants from the National Institutes of Health (NIH) during the conduct of the study. Dr Martens reported personal fees (consulting) from Novartis outside the submitted work. Dr Yoshida reported personal fees (honoraria for lectures) from Roche and Merck; and personal fees (honoraria for a presentation) from Agilent, Chugai, and Ono outside the submitted work. Dr Kim reported research funding from Novartis, Sanofi-Aventis, and DongKook Pharma; other (consultant on advisory boards) from Novartis, AstraZeneca, Lilly, Dae Hwa Pharmaceutical, ISU Abxis, and Daiichi-Sankyo; and ownership of stocks from Genopeaks. Dr Dieci reported personal fees (advisory and consultancy role) from Lilly, Novartis, Pfizer, Roche, Gilead, Seagen, Daiichi-Sankyo, AstraZeneca, Bristol Myers Squibb, and Exact Sciences outside the submitted work; and holding a patent (EP20382679.7) licensed to Università di Padova. Dr Vincent-Salomon reported grants from Ibex Medical Analytics outside the submitted work. Dr Andre reported grants to the institution from Roche, Guardant Health, Novartis, Owkin, AstraZeneca, Daiichi Sankyo, Pfizer, and Lilly; and personal fees from Lilly outside the submitted work. Dr Kok reported grants from AstraZeneca, Bristol Myers Squibb, and Roche; nonfinancial support from Natera; and other (advisory board) from Merck, AstraZeneca, and Domain Therapeutics outside the submitted work. Dr Linn reported grants to the institution from the Netherlands Organization for Health Research and Development, the Dutch Cancer Society, A Sister’s’ Hope Foundation, the [Z]aan de Wandel Foundation, De Vrienden van UMC Utrecht Foundation, AstraZeneca, Eurocept Pharmaceuticals, Roche/Genentech, Gilead, GSK, Merck, Novartis, and Agendia; nonfinancial support (study drug for investigator-sponsored study) from AstraZeneca, Merck, Roche/Genentech, GSK, and Novartis; nonfinancial support (study drug for the TROPICS02 study) from Gilead; other (travel grant and consultancy fees to the institution) from Daiichi Sankyo outside the submitted work; and holding a patent for methods for assessing homologous recombination deficiency in ovarian cancer cells (pending WO2023031121). Dr Goetz reported grants from National Cancer Institute (NCI) P50 CA116201 during the conduct of the study; personal fees (continuing medical education [CME]) from Research to Practice, Clinical Education Alliance, Medscape, and MJH Life Sciences; personal fees (breast cancer panelist) from Total Health Conferencing; personal fees (moderator for CME) from Curio Science; other (fees to the institution for consulting) from ARC Therapeutics, AstraZeneca, Biothernaostics, Blueprint Medicines, and Lilly; grants to the institution from AstraZeneca, Lilly, Pfizer, Sermonix, Loxo, and Atossa Therapeutics; other (fees to the institution for clinical advisory board) RNA Diagnostics and Sanofi Genzyme; other (fees to the institution for data and safety monitoring board [DSMB]) from Seattle Genetics; and personal fees (roundtable interview for expert perspective) from Engage Health Media. Dr Michiels reported personal fees (statistical advice) from Amaris; personal fees (scientific committee study membership) from Roche; and personal fees (DSMB membership of clinical trials) from IQVIA, Sensorion, Kedrion, Biophytis, Servier, and Yuhan outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Flow of Patients
aPatients were women with triple-negative breast cancer who received locoregional therapy but no chemotherapy from 13 participating institutions. Data were submitted from the 13 participating centers, which were located in North America (Rochester, Minnesota, USA; Vancouver, British Columbia, Canada), Europe (Paris, Lyon, and Villejuif, France; Amsterdam and Rotterdam, the Netherlands; Milan, Padova, and Genova, Italy; Gothenburg, Sweden), and Asia (Tokyo, Japan; Seoul, Korea). bNumber of cases included for each tumor-infiltrating lymphocyte (TIL) level: less than 30%, 1300 (66%); 30% to 49%, 249 (13%); 50% to 74%, 249 (13%); and 75% or greater, 168 (9%).
Figure 2.
Figure 2.. Clinical Outcomes According to TIL Thresholds in the Overall Study Population and According to Stage
aIndicates sample sizes after multilevel multiple imputation for missing variables, as described in Methods. Right panel illustrates point estimates for each survival end point in all patients, according to stage and tumor-infiltrating lymphocyte (TIL) level. Area of the circles is proportional to the sample size for each TIL subgroup. iDFS indicates invasive disease-free survival; RFS, recurrence-free survival; and DRFS, survival free of distant recurrence.
Figure 3.
Figure 3.. Cumulative Rates of Cancer and Mortality Events for the Entire Population According to Prespecified TIL Thresholds
The median was reached at 9.71 years (95% CI, 8.16-11.2) years. TIL indicates tumor-infiltrating leukocyte; DFS, disease-free survival; RFS, recurrence-free survival; and DRFS, survival free of distant recurrence.
Figure 4.
Figure 4.. Cumulative Rates of Cancer and Mortality Events for the Subset of Patients With Stage I Triple-Negative Breast Cancer According to Prespecified TIL Thresholds
TIL indicates tumor-infiltrating leukocyte; DFS, disease-free survival; RFS, recurrence-free survival; and DRFS, survival free of distant recurrence.
See this image and copyright information in PMC

Comment in

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