Prognostic relevance of tumor‑infiltrating lymphocytes in residual tumor tissue from patients with triple‑negative breast cancer following neoadjuvant chemotherapy: A systematic review and meta‑analysis

Cao,Bo; Zhang,Ziran; Wang,Chaoxian; Lv,Xiang

doi:10.3892/ol.2023.14028

Prognostic relevance of tumor‑infiltrating lymphocytes in residual tumor tissue from patients with triple‑negative breast cancer following neoadjuvant chemotherapy: A systematic review and meta‑analysis

Authors:
- Bo Cao
- Ziran Zhang
- Chaoxian Wang
- Xiang Lv
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Affiliations: Department of Breast Diseases, Jiaxing Maternity and Child Health Care Hospital, Affiliated Women and Children's Hospital of Jiaxing University, Jiaxing, Zhejiang 314000, P.R. China, Department of Breast Diseases, Jiaxing Maternity and Child Health Care Hospital, Affiliated Women and Children's Hospital of Jiaxing University, Jiaxing, Zhejiang 314000, P.R. China
Published online on: August 24, 2023 https://doi.org/10.3892/ol.2023.14028
Article Number: 441
Copyright: © Cao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Further adjuvant chemotherapy treatment can provide benefits to certain patients with triple‑negative breast cancer (TNBC) that fail to achieve pathological complete response (pCR) after the administration of a neoadjuvant chemotherapy (NAC) regimen. However, biomarkers suitable for identifying patients likely to experience poor prognostic outcomes after undergoing additional adjuvant chemotherapy are currently lacking. Accordingly, the present meta‑analysis was conducted to explore the relationship between tumor‑infiltrating lymphocytes (TILs) or TIL subtypes (CD4⁺ or CD8⁺) in residual tumor (RT) tissue following NAC and TNBC patient prognosis. Relevant studies published through March 2023 were identified in Pubmed, The Cochrane Library, Embase and Web of Science databases. After excluding irrelevant studies, data were extracted from the remaining reports, while study quality was analyzed with the Newcastle‑Ottawa Scale. Subsequent analyses were performed with Stata 14.0 and Review Manager 5.3. In total, seven relevant studies incorporating 1,202 patients were identified, all of which were retrospective cohort studies. Pooled analyses demonstrated that those patients exhibiting higher levels of RT TIL infiltration following NAC exhibited significantly improved recurrence‑free, metastasis‑free and event‑free survival (RFS/MFS/EFS) compared with patients with lower RT TIL infiltration levels, together with an improved distant recurrence‑free interval (DRFI) [hazard ratio (HR)=0.52; 95% confidence interval (CI)=0.39‑0.69; P<0.00001]. In addition, patients exhibiting high RT TIL infiltration exhibited improved overall survival (OS) and breast cancer‑specific survival (BCSS; HR=0.49; 95% CI=0.38‑0.65; P<0.00001). Additional subgroup analyses revealed that patients with higher TIL infiltration levels or TIL subtype (CD4⁺ or CD8⁺) infiltration exhibited improved RFS/MFS/EFS/DRFI as compared with patients with lower levels of overall TIL or TIL subtype (CD4⁺ or CD8⁺) infiltration in RT tissue (HR=0.35, 95% CI=0.20‑0.59, P<0.0001; HR=0.49, 95% CI=0.33‑0.71, P=0.0002). Consistently, the OS/BCSS of patients exhibiting high levels of overall TIL or TIL subtype (CD4⁺ or CD8⁺) infiltration was increased compared with patients with lower levels of such infiltration (HR=0.33, 95% CI=0.19‑0.59, P=0.0002; HR=0.55, 95% CI=0.41‑0.76, P=0.0002). These data thus demonstrate that levels of overall TIL infiltration or infiltration by CD4⁺ or CD8⁺ TILs in RT following NAC can be used as a biomarker to reliably predict prognostic outcomes in patients with TNBC, in addition to highlighting possible targets that may guide the further immunotherapeutic management of these patients.

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1	Garrido-Castro AC, Lin NU and Polyak K: Insights into molecular classifications of triple-negative breast cancer: Improving patient selection for treatment. Cancer Discov. 9:176–198. 2019. View Article : Google Scholar : PubMed/NCBI
2	Diana A, Carlino F, Franzese E, Oikonomidou O, Criscitiello C, De Vita F, Ciardiello F and Orditura M: Early triple negative breast cancer: Conventional treatment and emerging therapeutic landscapes. Cancers (Basel). 12:8192020. View Article : Google Scholar : PubMed/NCBI
3	Won KA and Spruck C: Triple-negative breast cancer therapy: Current and future perspectives (Review). Int J Oncol. 57:1245–1261. 2020. View Article : Google Scholar : PubMed/NCBI
4	Gupta GK, Collier AL, Lee D, Hoefer RA, Zheleva V, Siewertsz van Reesema LL, Tang-Tan AM, Guye ML, Chang DZ, Winston JS, et al: Perspectives on triple-negative breast cancer: Current treatment strategies, unmet needs, and potential targets for future therapies. Cancers (Basel). 12:23922020. View Article : Google Scholar : PubMed/NCBI
5	Masuda N, Lee SJ, Ohtani S, Im YH, Lee ES, Yokota I, Kuroi K, Im SA, Park BW, Kim SB, et al: Adjuvant capecitabine for breast cancer after preoperative chemotherapy. N Engl J Med. 376:2147–2159. 2017. View Article : Google Scholar : PubMed/NCBI
6	Cortazar P, Zhang L, Untch M, Mehta K, Costantino JP, Wolmark N, Bonnefoi H, Cameron D, Gianni L, Valagussa P, et al: Pathological complete response and long-term clinical benefit in breast cancer: The CTNeoBC pooled analysis. Lancet. 384:164–172. 2014. View Article : Google Scholar : PubMed/NCBI
7	Liedtke C, Mazouni C, Hess KR, André F, Tordai A, Mejia JA, Symmans WF, Gonzalez-Angulo AM, Hennessy B, Green M, et al: Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. J Clin Oncol. 26:1275–1281. 2008. View Article : Google Scholar : PubMed/NCBI
8	Isakoff SJ: Triple-negative breast cancer: Role of specific chemotherapy agents. Cancer J. 16:53–61. 2010. View Article : Google Scholar : PubMed/NCBI
9	Symmans WF, Wei C, Gould R, Yu X, Zhang Y, Liu M, Walls A, Bousamra A, Ramineni M, Sinn B, et al: Long-Term prognostic risk after neoadjuvant chemotherapy associated with residual cancer burden and breast cancer subtype. J Clin Oncol. 35:1049–1060. 2017. View Article : Google Scholar : PubMed/NCBI
10	Apetoh L, Ghiringhelli F, Tesniere A, Criollo A, Ortiz C, Lidereau R, Mariette C, Chaput N, Mira JP, Delaloge S, et al: The interaction between HMGB1 and TLR4 dictates the outcome of anticancer chemotherapy and radiotherapy. Immunol Rev. 220:47–59. 2007. View Article : Google Scholar : PubMed/NCBI
11	Zitvogel L and Kroemer G: The immune response against dying tumor cells: Avoid disaster, achieve cure. Cell Death Differ. 15:1–2. 2008. View Article : Google Scholar : PubMed/NCBI
12	García-Teijido P, Cabal ML, Fernández IP and Pérez YF: Tumor-Infiltrating lymphocytes in triple negative breast cancer: The future of immune targeting. Clin Med Insights Oncol. 10 (Suppl 1):S31–S39. 2016.PubMed/NCBI
13	Ravelli A, Roviello G, Cretella D, Cavazzoni A, Biondi A, Cappelletti MR, Zanotti L, Ferrero G, Ungari M, Zanconati F, et al: Tumor-infiltrating lymphocytes and breast cancer: Beyond the prognostic and predictive utility. Tumour Biol. 39:10104283176950232017. View Article : Google Scholar : PubMed/NCBI
14	Dieci MV, Radosevic-Robin N, Fineberg S, van den Eynden G, Ternes N, Penault-Llorca F, Pruneri G, D'Alfonso TM, Demaria S, Castaneda C, et al: Update on tumor-infiltrating lymphocytes (TILs) in breast cancer, including recommendations to assess TILs in residual disease after neoadjuvant therapy and in carcinoma in situ: A report of the International Immuno-Oncology Biomarker Working Group on breast cancer. Semin Cancer Biol. 52((Pt 2)): 16–25. 2018. View Article : Google Scholar : PubMed/NCBI
15	Gao G, Wang Z, Qu X and Zhang Z: Prognostic value of tumor-infiltrating lymphocytes in patients with triple-negative breast cancer: A systematic review and meta-analysis. BMC Cancer. 20:1792020. View Article : Google Scholar : PubMed/NCBI
16	Demaria S, Volm MD, Shapiro RL, Yee HT, Oratz R, Formenti SC, Muggia F and Symmans WF: Development of tumor-infiltrating lymphocytes in breast cancer after neoadjuvant paclitaxel chemotherapy. Clin Cancer Res. 7:3025–3030. 2001.PubMed/NCBI
17	Wells GA, Shea B, O'Connell D, Peterson J, Welch V, Losos M and Tugwell P: The Newcastle-Ottawa Scale (NOS) for Assessing the Quality of Non-Randomised Studies in Meta-Analyses. Symposium on Systematic Reviews: Beyond the Basics. 2014.
18	DerSimonian R and Laird N: Meta-analysis in clinical trials revisited. Contemp Clin Trials. 45((Pt A)): 139–145. 2015. View Article : Google Scholar : PubMed/NCBI
19	Luen SJ, Salgado R, Dieci MV, Vingiani A, Curigliano G, Gould RE, Castaneda C, D'Alfonso T, Sanchez J, Cheng E, et al: Prognostic implications of residual disease tumor-infiltrating lymphocytes and residual cancer burden in triple-negative breast cancer patients after neoadjuvant chemotherapy. Ann Oncol. 30:236–242. 2019. View Article : Google Scholar : PubMed/NCBI
20	Park JH, Ahn JH and Kim SB: How shall we treat early triple-negative breast cancer (TNBC): From the current standard to upcoming immuno-molecular strategies. ESMO Open. 3 (Suppl 1):e0003572018. View Article : Google Scholar : PubMed/NCBI
21	Andre F, Dieci MV, Dubsky P, Sotiriou C, Curigliano G, Denkert C and Loi S: Molecular pathways: Involvement of immune pathways in the therapeutic response and outcome in breast cancer. Clin Cancer Res. 19:28–33. 2013. View Article : Google Scholar : PubMed/NCBI
22	Ladoire S, Mignot G, Dabakuyo S, Arnould L, Apetoh L, Rébé C, Coudert B, Martin F, Bizollon MH, Vanoli A, et al: In situ immune response after neoadjuvant chemotherapy for breast cancer predicts survival. J Pathol. 224:389–400. 2011. View Article : Google Scholar : PubMed/NCBI
23	Lee H, Lee M, Seo JH, Gong G and Lee HJ: Changes in tumor-infiltrating lymphocytes after neoadjuvant chemotherapy and clinical significance in triple negative breast cancer. Anticancer Res. 40:1883–1890. 2020. View Article : Google Scholar : PubMed/NCBI
24	Denkert C, von Minckwitz G, Darb-Esfahani S, Lederer B, Heppner BI, Weber KE, Budczies J, Huober J, Klauschen F, Furlanetto J, et al: Tumour-infiltrating lymphocytes and prognosis in different subtypes of breast cancer: A pooled analysis of 3771 patients treated with neoadjuvant therapy. Lancet Oncol. 19:40–50. 2018. View Article : Google Scholar : PubMed/NCBI
25	Pruneri G, Gray KP, Vingiani A, Viale G, Curigliano G, Criscitiello C, Láng I, Ruhstaller T, Gianni L, Goldhirsch A, et al: Tumor-infiltrating lymphocytes (TILs) are a powerful prognostic marker in patients with triple-negative breast cancer enrolled in the IBCSG phase III randomized clinical trial 22–00. Breast Cancer Res Treat. 158:323–331. 2016. View Article : Google Scholar : PubMed/NCBI
26	Pruneri G, Vingiani A, Bagnardi V, Rotmensz N, De Rose A, Palazzo A, Colleoni AM, Goldhirsch A and Viale G: Clinical validity of tumor-infiltrating lymphocytes analysis in patients with triple-negative breast cancer. Ann Oncol. 27:249–256. 2016. View Article : Google Scholar : PubMed/NCBI
27	Dieci MV, Criscitiello C, Goubar A, Viale G, Conte P, Guarneri V, Ficarra G, Mathieu MC, Delaloge S, Curigliano G and Andre F: Prognostic value of tumor-infiltrating lymphocytes on residual disease after primary chemotherapy for triple-negative breast cancer: A retrospective multicenter study. Ann Oncol. 25:611–618. 2014. View Article : Google Scholar : PubMed/NCBI
28	Lejeune M, Reverté L, Sauras E, Gallardo N, Bosch R, Roso A, Petit A, Peg V, Riu F, García-Fontgivell J, et al: Prognostic implications of the residual tumor microenvironment after neoadjuvant chemotherapy in triple-negative breast cancer patients without pathological complete response. Cancers (Basel). 15:5972023. View Article : Google Scholar : PubMed/NCBI
29	Wang Y, Zong B, Yu Y, Wang Y, Tang Z, Chen R, Huang M and Liu S: Ki67 index changes and tumor-infiltrating lymphocyte levels impact the prognosis of triple-negative breast cancer patients with residual disease after neoadjuvant chemotherapy. Front Oncol. 11:6686102021. View Article : Google Scholar : PubMed/NCBI
30	Ghajar CM: On leukocytes in mammary development and cancer. Cold Spring Harb Perspect Biol. 4:a0132762012. View Article : Google Scholar : PubMed/NCBI
31	da Silva JL, de Albuquerque LZ, Rodrigues FR, de Mesquita GG, Fernandes PV, Thuler LCS and de Melo AC: Prognostic influence of residual tumor-infiltrating lymphocyte subtype after neoadjuvant chemotherapy in triple-negative breast cancer. Front Oncol. 11:6367162021. View Article : Google Scholar : PubMed/NCBI
32	Pinard C, Debled M, Ben Rejeb H, Velasco V, Tunon de Lara C, Hoppe S, Richard E, Brouste V, Bonnefoi H and MacGrogan G: Residual cancer burden index and tumor-infiltrating lymphocyte subtypes in triple-negative breast cancer after neoadjuvant chemotherapy. Breast Cancer Res Treat. 179:11–23. 2020. View Article : Google Scholar : PubMed/NCBI
33	Gu-Trantien C, Loi S, Garaud S, Equeter C, Libin M, de Wind A, Ravoet M, Le Buanec H, Sibille C, Manfouo-Foutsop G, et al: CD4⁺ follicular helper T cell infiltration predicts breast cancer survival. J Clin Invest. 123:2873–2892. 2013. View Article : Google Scholar : PubMed/NCBI
34	Lin KR, Pang DM, Jin YB, Hu Q, Pan YM, Cui JH, Chen XP, Lin YX, Mao XF, Duan HB and Luo W: Circulating CD8⁺ T-cell repertoires reveal the biological characteristics of tumors and clinical responses to chemotherapy in breast cancer patients. Cancer Immunol Immunother. 67:1743–1752. 2018. View Article : Google Scholar : PubMed/NCBI
35	Matsumoto H, Thike AA, Li H, Yeong J, Koo SL, Dent RA, Tan PH and Iqbal J: Increased CD4 and CD8-positive T cell infiltrate signifies good prognosis in a subset of triple-negative breast cancer. Breast Cancer Res Treat. 156:237–247. 2016. View Article : Google Scholar : PubMed/NCBI
36	Miyashita M, Sasano H, Tamaki K, Hirakawa H, Takahashi Y, Nakagawa S, Watanabe G, Tada H, Suzuki A, Ohuchi N and Ishida T: Prognostic significance of tumor-infiltrating CD8+ and FOXP3+ lymphocytes in residual tumors and alterations in these parameters after neoadjuvant chemotherapy in triple-negative breast cancer: A retrospective multicenter study. Breast Cancer Res. 17:1242015. View Article : Google Scholar : PubMed/NCBI
37	Sheri A, Smith IE, Johnston SR, A'Hern R, Nerurkar A, Jones RL, Hills M, Detre S, Pinder SE, Symmans WF and Dowsett M: Residual proliferative cancer burden to predict long-term outcome following neoadjuvant chemotherapy. Ann Oncol. 26:75–80. 2015. View Article : Google Scholar : PubMed/NCBI
38	Asano Y, Kashiwagi S, Goto W, Takada K, Takahashi K, Hatano T, Noda S, Takashima T, Onoda N, Tomita S, et al: Prediction of survival after neoadjuvant chemotherapy for breast cancer by evaluation of tumor-infiltrating lymphocytes and residual cancer burden. BMC Cancer. 17:8882017. View Article : Google Scholar : PubMed/NCBI
39	Cortes J, Cescon DW, Rugo HS, Nowecki Z, Im SA, Yusof MM, Gallardo C, Lipatov O, Barrios CH, Holgado E, et al: Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): A randomised, placebo-controlled, double-blind, phase 3 clinical trial. Lancet. 396:1817–1828. 2020. View Article : Google Scholar : PubMed/NCBI
40	Loi S, Adams S, Schmid P, Cortés J, Cescon DW, Winer EP, Toppmeyer DL, Rugo HS, De Laurentiis M, Nanda R, et al: Relationship between tumor infiltrating lymphocyte (TIL) levels and response to pembrolizumab (pembro) in metastatic triple-negative breast cancer (mTNBC): Results from KEYNOTE-086. Ann Oncol. 28:V6082017. View Article : Google Scholar
41	Schmid P, Salgado R, Park YH, Muñoz-Couselo E, Kim SB, Sohn J, Im SA, Foukakis T, Kuemmel S, Dent R, et al: Pembrolizumab plus chemotherapy as neoadjuvant treatment of high-risk, early-stage triple-negative breast cancer: Results from the phase 1b open-label, multicohort KEYNOTE-173 study. Ann Oncol. 31:569–581. 2020. View Article : Google Scholar : PubMed/NCBI
42	Ellis PM, Vella ET and Ung YC: Immune checkpoint inhibitors for patients with advanced non-small-cell lung cancer: A systematic review. Clin Lung Cancer. 18:444–459.e1. 2017. View Article : Google Scholar : PubMed/NCBI
43	Kluger HM, Zito CR, Turcu G, Baine MK, Zhang H, Adeniran A, Sznol M, Rimm DL, Kluger Y, Chen L, et al: PD-L1 studies across tumor types, its differential expression and predictive value in patients treated with immune checkpoint inhibitors. Clin Cancer Res. 23:4270–4279. 2017. View Article : Google Scholar : PubMed/NCBI
44	Blackley EF and Loi S: Targeting immune pathways in breast cancer: Review of the prognostic utility of TILs in early stage triple negative breast cancer (TNBC). Breast. 48 (Suppl 1):S44–S48. 2019. View Article : Google Scholar : PubMed/NCBI