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Tumor-infiltrating lymphocytes are correlated with response to neoadjuvant chemotherapy in triple-negative breast cancer

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Abstract

The purpose of the present study was to identify histological surrogate predictive markers of pathological complete response (pCR) to neoadjuvant chemotherapy (NAC) in triple-negative breast cancer (TNBC). Among 474 patients who received NAC and subsequent surgical therapy for stage II–III invasive breast carcinoma between 1999 and 2007, 102 (22%) had TNBC, and 92 core needle biopsy (CNB) specimens obtained before NAC were available. As controls, CNB specimens from 42 tumors of the hormone receptor-negative and HER2-positive (HR−/HER2+) subtype and 46 tumors of the hormone receptor-positive and HER2-negative (HR+/HER2−) subtype were also included. Histopathological examination including tumor-infiltrating lymphocytes (TIL) and tumor cell apoptosis, and immunohistochemical studies for basal markers were performed, and the correlation of these data with pathological therapeutic effect was analyzed. The rates of pCR at the primary site were higher for TNBC (32%) and the HR−/HER2+ subtype (21%) than for the HR+/HER2− subtype (7%) (P = 0.006). Expression of basal markers and p53, histological grade 3, high TIL scores, and apoptosis were more frequent in TNBC and the HR−/HER2+ subtype than in the HR+/HER2− subtype (P = 0.002 for TIL and P < 0.001 for others). In TNBC, the pCR rates of tumors showing a high TIL score and of those showing a high apoptosis score were 37 and 47%, respectively, and significantly higher or tended to be higher than those of the tumors showing a low TIL score and of the tumors showing a low apoptosis score (16 and 27%, respectively, P = 0.05 and 0.10). In a total of 180 breast cancers, the pCR rates of the tumors showing a high TIL score (34%) and of those showing a high apoptosis score (35%) were significantly higher than those of the tumors showing a low TIL score (10%) and those of the tumors showing a low apoptosis score (19%) (P = 0.0001 and 0.04, respectively). Histological grade and basal marker expression were not correlated with pCR. Although the whole analysis was exploratory, the degree of TIL correlated with immune response appear to play a substantial role in the response to NAC in TNBC.

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References

  1. Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, Pollack JR, Ross DT, Johnsen H, Akslen LA, Fluge O, Pergamenschikov A, Williams C, Zhu SX, Lonning PE, Borresen-Dale AL, Brown PO, Botstein D (2000) Molecular portraits of human breast tumours. Nature 406(6797):747–752. doi:10.1038/35021093

    Article  PubMed  CAS  Google Scholar 

  2. Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, Hastie T, Eisen MB, van de Rijn M, Jeffrey SS, Thorsen T, Quist H, Matese JC, Brown PO, Botstein D, Eystein Lonning P, Borresen-Dale AL (2001) Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA 98(19):10869–10874. doi:10.1073/pnas.191367098

    Article  PubMed  CAS  Google Scholar 

  3. Sorlie T, Tibshirani R, Parker J, Hastie T, Marron JS, Nobel A, Deng S, Johnsen H, Pesich R, Geisler S, Demeter J, Perou CM, Lonning PE, Brown PO, Borresen-Dale AL, Botstein D (2003) Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci USA 100(14):8418–8423. doi:10.1073/pnas.0932692100

    Article  PubMed  CAS  Google Scholar 

  4. Carey LA, Perou CM, Livasy CA, Dressler LG, Cowan D, Conway K, Karaca G, Troester MA, Tse CK, Edmiston S, Deming SL, Geradts J, Cheang MC, Nielsen TO, Moorman PG, Earp HS, Millikan RC (2006) Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. JAMA 295(21):2492–2502. doi:10.1001/jama.295.21.2492

    Article  PubMed  CAS  Google Scholar 

  5. Desmedt C, Haibe-Kains B, Wirapati P, Buyse M, Larsimont D, Bontempi G, Delorenzi M, Piccart M, Sotiriou C (2008) Biological processes associated with breast cancer clinical outcome depend on the molecular subtypes. Clin Cancer Res 14(16):5158–5165. doi:10.1158/1078-0432.CCR-07-4756

    Article  PubMed  CAS  Google Scholar 

  6. Hugh J, Hanson J, Cheang MC, Nielsen TO, Perou CM, Dumontet C, Reed J, Krajewska M, Treilleux I, Rupin M, Magherini E, Mackey J, Martin M, Vogel C (2009) Breast cancer subtypes and response to docetaxel in node-positive breast cancer: use of an immunohistochemical definition in the BCIRG 001 trial. J Clin Oncol 27(8):1168–1176. doi:10.1200/JCO.2008.18.1024

    Article  PubMed  CAS  Google Scholar 

  7. Nielsen TO, Hsu FD, Jensen K, Cheang M, Karaca G, Hu Z, Hernandez-Boussard T, Livasy C, Cowan D, Dressler L, Akslen LA, Ragaz J, Gown AM, Gilks CB, van de Rijn M, Perou CM (2004) Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin Cancer Res 10(16):5367–5374. doi:10.1158/1078-0432.CCR-04-0220

    Article  PubMed  CAS  Google Scholar 

  8. Rouzier R, Perou CM, Symmans WF, Ibrahim N, Cristofanilli M, Anderson K, Hess KR, Stec J, Ayers M, Wagner P, Morandi P, Fan C, Rabiul I, Ross JS, Hortobagyi GN, Pusztai L (2005) Breast cancer molecular subtypes respond differently to preoperative chemotherapy. Clin Cancer Res 11(16):5678–5685. doi:10.1158/1078-0432.CCR-04-2421

    Article  PubMed  CAS  Google Scholar 

  9. Dent R, Trudeau M, Pritchard KI, Hanna WM, Kahn HK, Sawka CA, Lickley LA, Rawlinson E, Sun P, Narod SA (2007) Triple-negative breast cancer: clinical features and patterns of recurrence. Clin Cancer Res 13(15 Pt 1):4429–4434. doi:10.1158/1078-0432.CCR-06-3045

    Article  PubMed  Google Scholar 

  10. Carey LA, Dees EC, Sawyer L, Gatti L, Moore DT, Collichio F, Ollila DW, Sartor CI, Graham ML, Perou CM (2007) The triple negative paradox: primary tumor chemosensitivity of breast cancer subtypes. Clin Cancer Res 13(8):2329–2334. doi:10.1158/1078-0432.CCR-06-1109

    Article  PubMed  CAS  Google Scholar 

  11. Liedtke C, Mazouni C, Hess KR, Andre F, Tordai A, Mejia JA, Symmans WF, Gonzalez-Angulo AM, Hennessy B, Green M, Cristofanilli M, Hortobagyi GN, Pusztai L (2008) Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. J Clin Oncol 26(8):1275–1281. doi:10.1200/JCO.2007.14.4147

    Article  PubMed  Google Scholar 

  12. Fisher B, Bryant J, Wolmark N, Mamounas E, Brown A, Fisher ER, Wickerham DL, Begovic M, DeCillis A, Robidoux A, Margolese RG, Cruz AB Jr, Hoehn JL, Lees AW, Dimitrov NV, Bear HD (1998) Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. J Clin Oncol 16(8):2672–2685

    PubMed  CAS  Google Scholar 

  13. Toi M, Nakamura S, Kuroi K, Iwata H, Ohno S, Masuda N, Kusama M, Yamazaki K, Hisamatsu K, Sato Y, Kashiwaba M, Kaise H, Kurosumi M, Tsuda H, Akiyama F, Ohashi Y, Takatsuka Y (2008) Phase II study of preoperative sequential FEC and docetaxel predicts of pathological response and disease free survival. Breast Cancer Res Treat 110(3):531–539. doi:10.1007/s10549-007-9744-z

    Article  PubMed  CAS  Google Scholar 

  14. Mazouni C, Peintinger F, Wan-Kau S, Andre F, Gonzalez-Angulo AM, Symmans WF, Meric-Bernstam F, Valero V, Hortobagyi GN, Pusztai L (2007) Residual ductal carcinoma in situ in patients with complete eradication of invasive breast cancer after neoadjuvant chemotherapy does not adversely affect patient outcome. J Clin Oncol 25(19):2650–2655. doi:10.1200/JCO.2006.08.2271

    Article  PubMed  CAS  Google Scholar 

  15. Rouzier R, Extra JM, Klijanienko J, Falcou MC, Asselain B, Vincent-Salomon A, Vielh P, Bourstyn E (2002) Incidence and prognostic significance of complete axillary downstaging after primary chemotherapy in breast cancer patients with T1 to T3 tumors and cytologically proven axillary metastatic lymph nodes. J Clin Oncol 20(5):1304–1310

    Article  PubMed  Google Scholar 

  16. Elston CW, Ellis IO (1991) Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathology 19(5):403–410

    Article  PubMed  CAS  Google Scholar 

  17. Turner NC, Reis-Filho JS (2006) Basal-like breast cancer and the BRCA1 phenotype. Oncogene 25(43):5846–5853. doi:10.1038/sj.onc.1209876

    Article  PubMed  CAS  Google Scholar 

  18. Allred DC, Harvey JM, Berardo M, Clark GM (1998) Prognostic and predictive factors in breast cancer by immunohistochemical analysis. Mod Pathol 11(2):155–168

    PubMed  CAS  Google Scholar 

  19. 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(1):118–145. doi:10.1200/JCO.2006.09.2775

    Article  PubMed  CAS  Google Scholar 

  20. Carlomagno C, Perrone F, Lauria R, de Laurentiis M, Gallo C, Morabito A, Pettinato G, Panico L, Bellelli T, Apicella A et al (1995) Prognostic significance of necrosis, elastosis, fibrosis and inflammatory cell reaction in operable breast cancer. Oncology 52(4):272–277

    Article  PubMed  CAS  Google Scholar 

  21. Lipponen P, Aaltomaa S, Kosma VM, Syrjanen K (1994) Apoptosis in breast cancer as related to histopathological characteristics and prognosis. Eur J Cancer 30A(14):2068–2073

    Article  PubMed  CAS  Google Scholar 

  22. Lee AH, Gillett CE, Ryder K, Fentiman IS, Miles DW, Millis RR (2006) Different patterns of inflammation and prognosis in invasive carcinoma of the breast. Histopathology 48(6):692–701. doi:10.1111/j.1365-2559.2006.02410.x

    Article  PubMed  CAS  Google Scholar 

  23. Marques LA, Franco EL, Torloni H, Brentani MM, da Silva-Neto JB, Brentani RR (1990) Independent prognostic value of laminin receptor expression in breast cancer survival. Cancer Res 50(5):1479–1483

    PubMed  CAS  Google Scholar 

  24. Nixon AJ, Neuberg D, Hayes DF, Gelman R, Connolly JL, Schnitt S, Abner A, Recht A, Vicini F, Harris JR (1994) Relationship of patient age to pathologic features of the tumor and prognosis for patients with stage I or II breast cancer. J Clin Oncol 12(5):888–894

    PubMed  CAS  Google Scholar 

  25. Rilke F, Colnaghi MI, Cascinelli N, Andreola S, Baldini MT, Bufalino R, Della Porta G, Menard S, Pierotti MA, Testori A (1991) Prognostic significance of HER-2/neu expression in breast cancer and its relationship to other prognostic factors. Int J Cancer 49(1):44–49

    Article  PubMed  CAS  Google Scholar 

  26. Kreike B, van Kouwenhove M, Horlings H, Weigelt B, Peterse H, Bartelink H, van de Vijver MJ (2007) Gene expression profiling and histopathological characterization of triple-negative/basal-like breast carcinomas. Breast Cancer Res 9(5):R65. doi:10.1186/bcr1771

    Article  PubMed  Google Scholar 

  27. Demaria S, Volm MD, Shapiro RL, Yee HT, Oratz R, Formenti SC, Muggia F, Symmans WF (2001) Development of tumor-infiltrating lymphocytes in breast cancer after neoadjuvant paclitaxel chemotherapy. Clin Cancer Res 7(10):3025–3030

    PubMed  CAS  Google Scholar 

  28. Ladoire S, Arnould L, Apetoh L, Coudert B, Martin F, Chauffert B, Fumoleau P, Ghiringhelli F (2008) Pathologic complete response to neoadjuvant chemotherapy of breast carcinoma is associated with the disappearance of tumor-infiltrating foxp3+ regulatory T cells. Clin Cancer Res 14(8):2413–2420. doi:10.1158/1078-0432.CCR-07-4491

    Article  PubMed  CAS  Google Scholar 

  29. Teschendorff AE, Miremadi A, Pinder SE, Ellis IO, Caldas C (2007) An immune response gene expression module identifies a good prognosis subtype in estrogen receptor negative breast cancer. Genome Biol 8(8):R157. doi:10.1186/gb-2007-8-8-r157

    Article  PubMed  Google Scholar 

  30. Apetoh L, Ghiringhelli F, Tesniere A, Obeid M, Ortiz C, Criollo A, Mignot G, Maiuri MC, Ullrich E, Saulnier P, Yang H, Amigorena S, Ryffel B, Barrat FJ, Saftig P, Levi F, Lidereau R, Nogues C, Mira JP, Chompret A, Joulin V, Clavel-Chapelon F, Bourhis J, Andre F, Delaloge S, Tursz T, Kroemer G, Zitvogel L (2007) Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat Med 13(9):1050–1059. doi:10.1038/nm1622

    Article  PubMed  CAS  Google Scholar 

  31. Lake RA, Robinson BW (2005) Immunotherapy and chemotherapy—a practical partnership. Nat Rev Cancer 5(5):397–405. doi:10.1038/nrc1613

    Article  PubMed  CAS  Google Scholar 

  32. Cheang MC, Voduc D, Bajdik C, Leung S, McKinney S, Chia SK, Perou CM, Nielsen TO (2008) Basal-like breast cancer defined by five biomarkers has superior prognostic value than triple-negative phenotype. Clin Cancer Res 14(5):1368–1376. doi:10.1158/1078-0432.CCR-07-1658

    Article  PubMed  CAS  Google Scholar 

  33. Jumppanen M, Gruvberger-Saal S, Kauraniemi P, Tanner M, Bendahl PO, Lundin M, Krogh M, Kataja P, Borg A, Ferno M, Isola J (2007) Basal-like phenotype is not associated with patient survival in estrogen-receptor-negative breast cancers. Breast Cancer Res 9(1):R16. doi:10.1186/bcr1649

    Article  PubMed  Google Scholar 

  34. Tischkowitz M, Brunet JS, Begin LR, Huntsman DG, Cheang MC, Akslen LA, Nielsen TO, Foulkes WD (2007) Use of immunohistochemical markers can refine prognosis in triple negative breast cancer. BMC Cancer 7:134. doi:10.1186/1471-2407-7-134

    Article  PubMed  Google Scholar 

  35. Bidard FC, Matthieu MC, Chollet P, Raoefils I, Abrial C, Domont J, Spielmann M, Delaloge S, Andre F, Penault-Llorca F (2008) p53 status and efficacy of primary anthracyclines/alkylating agent-based regimen according to breast cancer molecular classes. Ann Oncol 19(7):1261–1265. doi:10.1093/annonc/mdn039

    Article  PubMed  Google Scholar 

  36. Harris LN, Broadwater G, Lin NU, Miron A, Schnitt SJ, Cowan D, Lara J, Bleiweiss I, Berry D, Ellis M, Hayes DF, Winer EP, Dressler L (2006) Molecular subtypes of breast cancer in relation to paclitaxel response, outcomes in women with metastatic disease: results from CALGB 9342. Breast Cancer Res 8(6):R66. doi:10.1186/bcr1622

    Article  PubMed  Google Scholar 

  37. 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(1):105–113. doi:10.1200/JCO.2009.23.7370

    Article  PubMed  CAS  Google Scholar 

  38. Hornychova H, Melichar B, Tomsova M, Mergancova J, Urminska H, Ryska A (2008) Tumor-infiltrating lymphocytes predict response to neoadjuvant chemotherapy in patients with breast carcinoma. Cancer Invest 26(10):1024–1031. doi:10.1080/07357900802098165

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We thank Mrs. Sachiko Miura and Mrs. Chizu Kina for excellent technical assistance. This study was supported in part by grants from the Ministry of Health, Labor, and Welfare, Japan, the Ministry of Education, Culture, Sports, Science, and Technology, Japan, and the Princess Takamatsu Cancer Research Fund, Japan.

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Authors and Affiliations

  1. Breast and Medical Oncology Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan

    Makiko Ono, Chikako Shimizu, Harukaze Yamamoto, Taizo Hirata, Kan Yonemori, Masashi Ando, Kenji Tamura, Noriyuki Katsumata & Yasuhiro Fujiwara

  2. Clinical Laboratory Division, Department of Pathology, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo, 104-0045, Japan

    Hitoshi Tsuda

  3. Department of Basic Pathology, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan

    Sohei Yamamoto

  4. Cancer Genomics Project, Pathology Division, Center for Medical Genomics, National Cancer, Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan

    Tatsuhiro Shibata

  5. Breast Surgery Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan

    Takayuki Kinoshita

  6. Department of Respirology, Graduate School of Medicine, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba, 260-8670, Japan

    Yuichi Takiguchi

  7. Department of Clinical Molecular Biology, Graduate School of Medicine, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba, 260-8670, Japan

    Makiko Ono & Hideki Tanzawa

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  1. Makiko Ono
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  2. Hitoshi Tsuda
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Correspondence to Hitoshi Tsuda.

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Ono, M., Tsuda, H., Shimizu, C. et al. Tumor-infiltrating lymphocytes are correlated with response to neoadjuvant chemotherapy in triple-negative breast cancer. Breast Cancer Res Treat 132, 793–805 (2012). https://doi.org/10.1007/s10549-011-1554-7

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