Advertisement

Breast Cancer Research and Treatment

, Volume 173, Issue 2, pp 255–266 | Cite as

A nomogram to predict pathologic complete response (pCR) and the value of tumor-infiltrating lymphocytes (TILs) for prediction of response to neoadjuvant chemotherapy (NAC) in breast cancer patients

  • Hye Won Hwang
  • Hera Jung
  • Jiyeon Hyeon
  • Yeon Hee Park
  • Jin Seok Ahn
  • Young-Hyuck Im
  • Seok Jin Nam
  • Seok Won Kim
  • Jeong Eon Lee
  • Jong-Han Yu
  • Se Kyung Lee
  • Misun Choi
  • Soo Youn ChoEmail author
  • Eun Yoon ChoEmail author
Review

Abstract

Purpose

The value of tumor-infiltrating lymphocytes (TILs) for prediction of pathologic complete response (pCR) in breast cancer (BC) patients treated with neoadjuvant chemotherapy (NAC) has received increasing attention. In human epidermal growth factor receptor 2 (HER2)-positive BC, advances in HER2-targeted therapy have not yet clarified the clinical implications of pre-NAC TILs. Likewise, the prognostic role of TILs for long-term survival is not well established.

Methods

Pre- and post-NAC TIL levels were evaluated in 248 pair-matched pre-NAC biopsy and post-NAC resection samples, and analyzed for predictive and prognostic significance with other clinicopathologic parameters. Additional 60 pre-NAC biopsy samples of HER2-positive BC treated with a TCHP regimen (docetaxel, carboplatin, and a combination of trastuzumab and pertuzumab) were also assessed.

Results

High pre-NAC TILs, clinical nodal stage 0–1 (cN0–1), and negative ER expression were shown to be strong predictive markers for pCR. A nomogram based on these significant clinicopathologic predictors was developed, providing integrated probability of achieving pCR after NAC. The association between high pre-NAC TIL levels and significantly increased pCR rate was also confirmed in HER2-positive BC patients treated with a TCHP regimen. After chemotherapy, increased quantity of post-NAC TILs was shown to have extended BC-specific survival and disease-free survival in univariable and multivariable analyses.

Conclusions

High pre-NAC TIL levels were significantly predictive of pCR in BC, and can act as a surrogate marker for predicting therapeutic effects of a TCHP regimen for HER2-positive BC. Post-NAC TILs in residual disease were a new prognostic marker of risk stratification for long-term survival.

Keywords

Tumor-infiltrating lymphocytes Neoadjuvant chemotherapy Pathologic complete response Nomogram TCHP 

Notes

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. For this type of study, formal consent is not required.

Informed consent

Informed consent was obtained from all individual participants included in the study.

References

  1. 1.
    Pages F, Kirilovsky A, Mlecnik B, Asslaber M, Tosolini M, Bindea G, Lagorce C, Wind P, Marliot F, Bruneval P, Zatloukal K, Trajanoski Z, Berger A, Fridman WH, Galon J (2009) In situ cytotoxic and memory T cells predict outcome in patients with early-stage colorectal cancer. J Clin Oncol 27:5944–5951CrossRefPubMedGoogle Scholar
  2. 2.
    Hwang WT, Adams SF, Tahirovic E, Hagemann IS, Coukos G (2012) Prognostic significance of tumor-infiltrating T cells in ovarian cancer: a meta-analysis. Gynecol Oncol 124:192–198CrossRefPubMedGoogle Scholar
  3. 3.
    Dieu-Nosjean MC, Antoine M, Danel C, Heudes D, Wislez M, Poulot V, Rabbe N, Laurans L, Tartour E, de Chaisemartin L, Lebecque S, Fridman WH, Cadranel J (2008) Long-term survival for patients with non-small-cell lung cancer with intratumoral lymphoid structures. J Clin Oncol 26:4410–4417CrossRefPubMedGoogle Scholar
  4. 4.
    Denkert C, Loibl S, Noske A, Roller M, Muller BM, Komor M, Budczies J, Darb-Esfahani S, Kronenwett R, Hanusch C, von Torne C, Weichert W, Engels K, Solbach C, Schrader I, Dietel M, von Minckwitz G (2010) Tumor-associated lymphocytes as an independent predictor of response to neoadjuvant chemotherapy in breast cancer. J Clin Oncol 28:105–113CrossRefPubMedGoogle Scholar
  5. 5.
    Salgado R, Denkert C, Campbell C, Savas P, Nuciforo P, Aura C, de Azambuja E, Eidtmann H, Ellis CE, Baselga J, Piccart-Gebhart MJ, Michiels S, Bradbury I, Sotiriou C, Loi S (2015) Tumor-infiltrating lymphocytes and associations with pathological complete response and event-free survival in HER2-positive early-stage breast cancer treated with Lapatinib and Trastuzumab: a secondary analysis of the NeoALTTO trial. JAMA Oncol 1:448–454CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Denkert C, von Minckwitz G, Brase JC, Sinn BV, Gade S, Kronenwett R, Pfitzner BM, Salat C, Loi S, Schmitt WD, Schem C, Fisch K, Darb-Esfahani S, Mehta K, Sotiriou C, Wienert S, Klare P, Andre F, Klauschen F, Blohmer JU, Krappmann K, Schmidt M, Tesch H, Kummel S, Sinn P, Jackisch C, Dietel M, Reimer T, Untch M, Loibl S (2015) Tumor-infiltrating lymphocytes and response to neoadjuvant chemotherapy with or without carboplatin in human epidermal growth factor receptor 2-positive and triple-negative primary breast cancers. J Clin Oncol 33:983–991CrossRefPubMedGoogle Scholar
  7. 7.
    Dieci MV, Mathieu MC, Guarneri V, Conte P, Delaloge S, Andre F, Goubar A (2015) Prognostic and predictive value of tumor-infiltrating lymphocytes in two phase III randomized adjuvant breast cancer trials. Ann Oncol 26:1698–1704CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Loi S, Sirtaine N, Piette F, Salgado R, Viale G, Van Eenoo F, Rouas G, Francis P, Crown JP, Hitre E, de Azambuja E, Quinaux E, Di Leo A, Michiels S, Piccart MJ, Sotiriou C (2013) Prognostic and predictive value of tumor-infiltrating lymphocytes in a phase III randomized adjuvant breast cancer trial in node-positive breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy: BIG 02–98. J Clin Oncol 31:860–867CrossRefPubMedGoogle Scholar
  9. 9.
    Adams S, Gray RJ, Demaria S, Goldstein L, Perez EA, Shulman LN, Martino S, Wang M, Jones VE, Saphner TJ, Wolff AC, Wood WC, Davidson NE, Sledge GW, Sparano JA, Badve SS (2014) Prognostic value of tumor-infiltrating lymphocytes in triple-negative breast cancers from two phase III randomized adjuvant breast cancer trials: ECOG 2197 and ECOG 1199. J Clin Oncol 32:2959–2966CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Stanton SE, Adams S, Disis ML (2016) Variation in the incidence and magnitude of tumor-infiltrating lymphocytes in breast cancer subtypes: a systematic review. JAMA Oncol 2:1354–1360CrossRefPubMedGoogle Scholar
  11. 11.
    Stanton SE, Disis ML (2016) Clinical significance of tumor-infiltrating lymphocytes in breast cancer. J Immunother Cancer 4:59CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Hamy AS, Pierga JY, Sabaila A, Laas E, Bonsang-Kitzis H, Laurent C, Vincent-Salomon A, Cottu P, Lerebours F, Rouzier R, Lae M, Reyal F (2017) Stromal lymphocyte infiltration after neoadjuvant chemotherapy is associated with aggressive residual disease and lower disease-free survival in HER2-positive breast cancer. Ann Oncol 28:2233–2240CrossRefPubMedGoogle Scholar
  13. 13.
    Dieci MV, Criscitiello C, Goubar A, Viale G, Conte P, Guarneri V, Ficarra G, Mathieu MC, Delaloge S, Curigliano G, Andre F (2014) Prognostic value of tumor-infiltrating lymphocytes on residual disease after primary chemotherapy for triple-negative breast cancer: a retrospective multicenter study. Ann Oncol 25:611–618CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Schneeweiss A, Chia S, Hickish T, Harvey V, Eniu A, Hegg R, Tausch C, Seo JH, Tsai YF, Ratnayake J, McNally V, Ross G, Cortes J (2013) Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA). Ann Oncol 24:2278–2284CrossRefPubMedGoogle Scholar
  15. 15.
    Gianni L, Pienkowski T, Im YH, Roman L, Tseng LM, Liu MC, Lluch A, Staroslawska E, de la Haba-Rodriguez J, Im SA, Pedrini JL, Poirier B, Morandi P, Semiglazov V, Srimuninnimit V, Bianchi G, Szado T, Ratnayake J, Ross G, Valagussa P (2012) Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol 13:25–32CrossRefPubMedGoogle Scholar
  16. 16.
    Swain SM, Baselga J, Kim SB, Ro J, Semiglazov V, Campone M, Ciruelos E, Ferrero JM, Schneeweiss A, Heeson S, Clark E, Ross G, Benyunes MC, Cortes J (2015) Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med 372:724–734CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Wolff AC, Hammond ME, Schwartz JN, Hagerty KL, Allred DC, Cote RJ, Dowsett M, Fitzgibbons PL, Hanna WM, Langer A, McShane LM, Paik S, Pegram MD, Perez EA, Press MF, Rhodes A, Sturgeon C, Taube SE, Tubbs R, Vance GH, van de Vijver M, Wheeler TM, Hayes DF (2007) American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol 25:118–145CrossRefPubMedGoogle Scholar
  18. 18.
    Coates AS, Winer EP, Goldhirsch A, Gelber RD, Gnant M, Piccart-Gebhart M, Thurlimann B, Senn HJ (2015) Tailoring therapies–improving the management of early breast cancer: St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2015. Ann Oncol 26(8):1533–1546CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Cheang MC, Chia SK, Voduc D, Gao D, Leung S, Snider J, Watson M, Davies S, Bernard PS, Parker JS, Perou CM, Ellis MJ, Nielsen TO (2009) Ki67 index, HER2 status, and prognosis of patients with luminal B breast cancer. J Natl Cancer Inst 101:736–750CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Goldhirsch A, Winer EP, Coates AS, Gelber RD, Piccart-Gebhart M, Thurlimann B, Senn HJ (2013) Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013. Ann Oncol 24:2206–2223CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Edge SB, Compton CC (2010) The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol 17:1471–1474CrossRefPubMedGoogle Scholar
  22. 22.
    Symmans WF, Peintinger F, Hatzis C, Rajan R, Kuerer H, Valero V, Assad L, Poniecka A, Hennessy B, Green M, Buzdar AU, Singletary SE, Hortobagyi GN, Pusztai L (2007) Measurement of residual breast cancer burden to predict survival after neoadjuvant chemotherapy. J Clin Oncol 25:4414–4422CrossRefPubMedGoogle Scholar
  23. 23.
    Salgado R, Denkert C, Demaria S, Sirtaine N, Klauschen F, Pruneri G, Wienert S, Van den Eynden G, Baehner FL, Penault-Llorca F, Perez EA, Thompson EA, Symmans WF, Richardson AL, Brock J, Criscitiello C, Bailey H, Ignatiadis M, Floris G, Sparano J, Kos Z, Nielsen T, Rimm DL, Allison KH, Reis-Filho JS, Loibl S, Sotiriou C, Viale G, Badve S, Adams S, Willard-Gallo K, Loi S (2015) The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014. Ann Oncol 26:259–271CrossRefPubMedGoogle Scholar
  24. 24.
    Cortazar P, Zhang L, Untch M, Mehta K, Costantino JP, Wolmark N, Bonnefoi H, Cameron D, Gianni L, Valagussa P, Swain SM, Prowell T, Loibl S, Wickerham DL, Bogaerts J, Baselga J, Perou C, Blumenthal G, Blohmer J, Mamounas EP, Bergh J, Semiglazov V, Justice R, Eidtmann H, Paik S, Piccart M, Sridhara R, Fasching PA, Slaets L, Tang S, Gerber B, Geyer CE Jr, Pazdur R, Ditsch N, Rastogi P, Eiermann W, von Minckwitz G (2014) Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet 384:164–172CrossRefPubMedGoogle Scholar
  25. 25.
    Loi S, Michiels S, Salgado R, Sirtaine N, Jose V, Fumagalli D, Kellokumpu-Lehtinen PL, Bono P, Kataja V, Desmedt C, Piccart MJ, Loibl S, Denkert C, Smyth MJ, Joensuu H, Sotiriou C (2014) Tumor infiltrating lymphocytes are prognostic in triple negative breast cancer and predictive for trastuzumab benefit in early breast cancer: results from the FinHER trial. Ann Oncol 25:1544–1550CrossRefPubMedGoogle Scholar
  26. 26.
    Dieci MV, Frassoldati A, Generali D, Bisagni G, Piacentini F, Cavanna L, Cagossi K, Puglisi F, Michelotti A, Berardi R, Banna G, Goubar A, Ficarra G, Griguolo G, Conte P, Guarneri V (2017) Tumor-infiltrating lymphocytes and molecular response after neoadjuvant therapy for HR+/HER2- breast cancer: results from two prospective trials. Breast Cancer Res Treat 163:295–302CrossRefPubMedGoogle Scholar
  27. 27.
    Montagna E, Vingiani A, Maisonneuve P, Cancello G, Contaldo F, Pruneri G, Colleoni M (2017) Unfavorable prognostic role of tumor-infiltrating lymphocytes in hormone-receptor positive, HER2 negative metastatic breast cancer treated with metronomic chemotherapy. Breast 34:83–88CrossRefPubMedGoogle Scholar
  28. 28.
    Ades F, Zardavas D, Bozovic-Spasojevic I, Pugliano L, Fumagalli D, de Azambuja E, Viale G, Sotiriou C, Piccart M (2014) Luminal B breast cancer: molecular characterization, clinical management, and future perspectives. J Clin Oncol 32:2794–2803CrossRefPubMedGoogle Scholar
  29. 29.
    Dieci MV, Griguolo G, Miglietta F, Guarneri V (2016) The immune system and hormone-receptor positive breast cancer: is it really a dead end? Cancer Treat Rev 46:9–19CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Hye Won Hwang
    • 1
  • Hera Jung
    • 1
  • Jiyeon Hyeon
    • 2
  • Yeon Hee Park
    • 3
  • Jin Seok Ahn
    • 3
  • Young-Hyuck Im
    • 3
  • Seok Jin Nam
    • 4
  • Seok Won Kim
    • 4
  • Jeong Eon Lee
    • 4
  • Jong-Han Yu
    • 4
  • Se Kyung Lee
    • 4
  • Misun Choi
    • 5
  • Soo Youn Cho
    • 1
    Email author
  • Eun Yoon Cho
    • 1
    Email author
  1. 1.Department of Pathology and Translational Genomics, Samsung Medical CenterSungkyunkwan University School of MedicineSeoulSouth Korea
  2. 2.Department of Pathology, Incheon St. Mary’s Hospital, College of MedicineThe Catholic University of KoreaIncheonSouth Korea
  3. 3.Division of Hematology-Oncology, Department of Medicine, Samsung Medical CenterSungkyunkwan University School of MedicineSeoulSouth Korea
  4. 4.Department of Surgery, Samsung Medical CenterSungkyunkwan University School of MedicineSeoulSouth Korea
  5. 5.Division of Forensic InvestigationNational Forensic Service Seoul InstituteSeoulSouth Korea

Personalised recommendations