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Open Access 01-12-2021 | Breast Cancer | Research

Clinical verification of body mass index and tumor immune response in patients with breast cancer receiving preoperative chemotherapy

Authors: Koji Takada, Shinichiro Kashiwagi, Yuka Asano, Wataru Goto, Sae Ishihara, Tamami Morisaki, Masatsune Shibutani, Hiroaki Tanaka, Kosei Hirakawa, Masaichi Ohira

Published in: BMC Cancer | Issue 1/2021

Abstract

Purpose

The body mass index (BMI) is commonly used as a simple indicator of obesity; patients with early-stage breast cancer who are obese (OB) per BMI measurements have been shown to have high postoperative recurrence and low survival rates. On the other hand, it has been shown that lymphocytes present in the vicinity of malignant growths that are involved in the tumors’ immune responses influence the efficacy chemotherapy. Therefore, we hypothesized that OB patients with breast cancer have a lower density of tumor-infiltrating lymphocytes (TILs), which may influence the therapeutic effect of preoperative chemotherapy (POC). In this study, we measured pretreatment BMI and TILs in patients with breast cancer who underwent POC, examined the correlations between these two factors, and retrospectively analyzed their therapeutic outcomes and prognoses.

Methods

The participants in this study were 421 patients with breast cancer who underwent surgical treatment after POC between February 2007 and January 2019. The patient’s height and weight were measured before POC to calculate the BMI (weight [kg] divided by the square of the height [m²]). According to the World Health Organization categorization, patients who weighed under 18.5 kg/m² were classified as underweight (UW), those ≥18.5 kg/m² and > 25 kg/m² were considered normal weight (NW), those ≥25 kg/m² and < 30 kg/m² were overweight (OW), and those ≥30 kg/m² were OB. The TILs were those lymphocytes that infiltrated the tumor stroma according to the definition of the International TILs Working Group 2014.

Results

The median BMI was 21.9 kg/m² (range, 14.3–38.5 kg/m²); most patients (244; 64.5%) were NW. Among all 378 patients with breast cancer, the TIL density was significantly lower in OB than in NW and OW patients (vs. NW: p = 0.001; vs. OW: p = 0.003). Furthermore, when examining patients with each breast cancer type individually, the OS of those with TNBC who had low BMIs was significantly poorer than that of their high-BMI counterparts (log rank p = 0.031).

Conclusions

Our data did not support the hypothesis that obesity affects the tumor immune microenvironment; however, we showed that being UW does affect the tumor immune microenvironment.

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Kroenke CH, Chen WY, Rosner B, Holmes MD. Weight, weight gain, and survival after breast cancer diagnosis. J Clin Oncol. 2005;23(7):1370–8. https://doi.org/10.1200/JCO.2005.01.079.CrossRefPubMed

Tartter PI, Papatestas AE, Ioannovich J, Mulvihill MN, Lesnick G, Aufses AH Jr. Cholesterol and obesity as prognostic factors in breast cancer. Cancer. 1981;47(9):2222–7. https://doi.org/10.1002/1097-0142(19810501)47:9<2222::aid-cncr2820470919>3.0.co;2-5.CrossRefPubMed

Caan BJ, Kwan ML, Hartzell G, Castillo A, Slattery ML, Sternfeld B, et al. Pre-diagnosis body mass index, post-diagnosis weight change, and prognosis among women with early stage breast cancer. Cancer Causes Control. 2008;19(10):1319–28. https://doi.org/10.1007/s10552-008-9203-0.CrossRefPubMedPubMedCentral

Dawood S, Broglio K, Gonzalez-Angulo AM, Kau SW, Islam R, Hortobagyi GN, et al. Prognostic value of body mass index in locally advanced breast cancer. Clin Cancer Res. 2008;14(6):1718–25. https://doi.org/10.1158/1078-0432.CCR-07-1479.CrossRefPubMed

Goodwin PJ, Ennis M, Pritchard KI, Trudeau ME, Koo J, Madarnas Y, et al. Fasting insulin and outcome in early-stage breast cancer: results of a prospective cohort study. J Clin Oncol. 2002;20(1):42–51. https://doi.org/10.1200/JCO.2002.20.1.42.CrossRefPubMed

McTiernan A, Rajan KB, Tworoger SS, Irwin M, Bernstein L, Baumgartner R, et al. Adiposity and sex hormones in postmenopausal breast cancer survivors. J Clin Oncol. 2003;21(10):1961–6. https://doi.org/10.1200/JCO.2003.07.057.CrossRefPubMed

Orecchioni S, Reggiani F, Talarico G, Bertolini F. Mechanisms of obesity in the development of breast cancer. Discov Med. 2015;20(109):121–8.PubMed

Harvey AE, Lashinger LM, Hursting SD. The growing challenge of obesity and cancer: an inflammatory issue. Ann N Y Acad Sci. 2011;1229(1):45–52. https://doi.org/10.1111/j.1749-6632.2011.06096.x.CrossRefPubMed

Hursting SD, Dunlap SM. Obesity, metabolic dysregulation, and cancer: a growing concern and an inflammatory (and microenvironmental) issue. Ann N Y Acad Sci. 2012;1271(1):82–7. https://doi.org/10.1111/j.1749-6632.2012.06737.x.CrossRefPubMedPubMedCentral

10.

van Kruijsdijk RC, van der Wall E, Visseren FL. Obesity and cancer: the role of dysfunctional adipose tissue. Cancer Epidemiol Biomarkers Prev. 2009;18(10):2569–78. https://doi.org/10.1158/1055-9965.EPI-09-0372.CrossRefPubMed

11.

Fontanella C, Lederer B, Gade S, Vanoppen M, Blohmer JU, Costa SD, et al. Impact of body mass index on neoadjuvant treatment outcome: a pooled analysis of eight prospective neoadjuvant breast cancer trials. Breast Cancer Res Treat. 2015;150(1):127–39. https://doi.org/10.1007/s10549-015-3287-5.CrossRefPubMed

12.

Raman R, Mott SL, Schroeder MC, Phadke S, El Masri J, Thomas A. Effect of body mass index- and actual weight-based neoadjuvant chemotherapy doses on pathologic complete response in operable breast Cancer. Clin Breast Cancer. 2016;16(6):480–6. https://doi.org/10.1016/j.clbc.2016.06.008.CrossRefPubMedPubMedCentral

13.

Litton JK, Gonzalez-Angulo AM, Warneke CL, Buzdar AU, Kau SW, Bondy M, et al. Relationship between obesity and pathologic response to neoadjuvant chemotherapy among women with operable breast cancer. J Clin Oncol. 2008;26(25):4072–7. https://doi.org/10.1200/JCO.2007.14.4527.CrossRefPubMedPubMedCentral

14.

Chen S, Chen CM, Zhou Y, Zhou RJ, Yu KD, Shao ZM. Obesity or overweight is associated with worse pathological response to neoadjuvant chemotherapy among Chinese women with breast cancer. PLoS One. 2012;7(7):e41380. https://doi.org/10.1371/journal.pone.0041380.CrossRefPubMedPubMedCentral

15.

Salgado R, Denkert C, Demaria S, Sirtaine N, Klauschen F, Pruneri G, et al. The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an international TILs working group 2014. Ann Oncol. 2015;26(2):259–71. https://doi.org/10.1093/annonc/mdu450.CrossRefPubMed

16.

Zitvogel L, Kepp O, Kroemer G. Immune parameters affecting the efficacy of chemotherapeutic regimens. Nat Rev Clin Oncol. 2011;8(3):151–60. https://doi.org/10.1038/nrclinonc.2010.223.CrossRefPubMed

17.

Fridman WH, Pages F, Sautes-Fridman C, Galon J. The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer. 2012;12(4):298–306. https://doi.org/10.1038/nrc3245.CrossRefPubMed

18.

Couzin-Frankel J. Breakthrough of the year 2013. Cancer immunotherapy. Science. 2013;342(6165):1432–3. https://doi.org/10.1126/science.342.6165.1432.CrossRefPubMed

19.

Adams S, Gray RJ, Demaria S, Goldstein L, Perez EA, Shulman LN, et al. 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. 2014;32(27):2959–66. https://doi.org/10.1200/JCO.2013.55.0491.CrossRefPubMedPubMedCentral

20.

Denkert C, von Minckwitz G, Brase JC, Sinn BV, Gade S, Kronenwett R, et al. 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. 2015;33(9):983–91. https://doi.org/10.1200/JCO.2014.58.1967.CrossRefPubMed

21.

Asano Y, Kashiwagi S, Goto W, Takada K, Takahashi K, Hatano T, et al. Prediction of treatment response to neoadjuvant chemotherapy in breast Cancer by subtype using tumor-infiltrating lymphocytes. Anticancer Res. 2018;38(4):2311–21. https://doi.org/10.21873/anticanres.12476.CrossRefPubMed

22.

Ohtani H, Mori-Shiraishi K, Nakajima M, Ueki H. Defining lymphocyte-predominant breast cancer by the proportion of lymphocyte-rich stroma and its significance in routine histopathological diagnosis. Pathol Int. 2015;65(12):644–51. https://doi.org/10.1111/pin.12355.CrossRefPubMedPubMedCentral

23.

Stanton SE, Adams S, Disis ML. Variation in the incidence and magnitude of tumor-infiltrating lymphocytes in breast Cancer subtypes: a systematic review. JAMA Oncol. 2016;2(10):1354–60. https://doi.org/10.1001/jamaoncol.2016.1061.CrossRefPubMed

24.

Niraula S, Ocana A, Ennis M, Goodwin PJ. Body size and breast cancer prognosis in relation to hormone receptor and menopausal status: a meta-analysis. Breast Cancer Res Treat. 2012;134(2):769–81. https://doi.org/10.1007/s10549-012-2073-x.CrossRefPubMed

25.

Ando S, Gelsomino L, Panza S, Giordano C, Bonofiglio D, Barone I, et al. Obesity, leptin and breast Cancer: epidemiological evidence and proposed mechanisms. Cancers (Basel). 2019;11(1). https://doi.org/10.3390/cancers11010062.

26.

Goldhirsch A, Wood WC, Coates AS, Gelber RD, Thurlimann B, Senn HJ, et al. Strategies for subtypes--dealing with the diversity of breast cancer: highlights of the St. Gallen international expert consensus on the primary therapy of early breast Cancer 2011. Ann Oncol. 2011;22(8):1736–47. https://doi.org/10.1093/annonc/mdr304.CrossRefPubMedPubMedCentral

27.

Mauri D, Pavlidis N, Ioannidis JP. Neoadjuvant versus adjuvant systemic treatment in breast cancer: a meta-analysis. J Natl Cancer Inst. 2005;97(3):188–94. https://doi.org/10.1093/jnci/dji021.CrossRefPubMed

28.

Mieog JS, van der Hage JA, van de Velde CJ. Preoperative chemotherapy for women with operable breast cancer. Cochrane Database Syst Rev. 2007;2:CD005002. https://doi.org/10.1002/14651858.CD005002.pub2.CrossRef

29.

Kawajiri H, Takashima T, Onoda N, Kashiwagi S, Noda S, Ishikawa T, et al. Efficacy and feasibility of neoadjuvant chemotherapy with FEC 100 followed by weekly paclitaxel for operable breast cancer. Oncol Lett. 2012;4(4):612–6. https://doi.org/10.3892/ol.2012.801.CrossRefPubMedPubMedCentral

30.

Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228–47. https://doi.org/10.1016/j.ejca.2008.10.026.CrossRefPubMed

31.

Kashiwagi S, Onoda N, Asano Y, Kurata K, Morisaki T, Noda S, et al. Partial mastectomy using manual blunt dissection (MBD) in early breast cancer. BMC Surg. 2015;15(1):117. https://doi.org/10.1186/s12893-015-0102-5.CrossRefPubMedPubMedCentral

32.

Wolmark N, Wang J, Mamounas E, Bryant J, Fisher B. Preoperative chemotherapy in patients with operable breast cancer: nine-year results from National Surgical Adjuvant Breast and bowel project B-18. J Natl Cancer Inst Monogr. 2001;30(30):96–102. https://doi.org/10.1093/oxfordjournals.jncimonographs.a003469.CrossRef

33.

Kashiwagi S, Asano Y, Goto W, Takada K, Takahashi K, Noda S, et al. Use of tumor-infiltrating lymphocytes (TILs) to predict the treatment response to eribulin chemotherapy in breast cancer. PLoS One. 2017;12(2):e0170634. https://doi.org/10.1371/journal.pone.0170634.CrossRefPubMedPubMedCentral

34.

Gennari R, Curigliano G, Rotmensz N, Robertson C, Colleoni M, Zurrida S, et al. Breast carcinoma in elderly women: features of disease presentation, choice of local and systemic treatments compared with younger postmenopasual patients. Cancer. 2004;101(6):1302–10. https://doi.org/10.1002/cncr.20535.CrossRefPubMed

35.

Robinson B, Currie M, Phillips E, Dachs G, Strother M, Morrin H, et al. Body mass index (BMI): association with clinicopathological factors and outcome of women with newly diagnosed breast cancer in New Zealand. N Z Med J. 2017;130(1451):46–56.PubMed

36.

Lee KH, Keam B, Im SA, Kim TY, Han SW, Oh DY, et al. Body mass index is not associated with treatment outcomes of breast cancer patients receiving neoadjuvant chemotherapy: korean data. J Breast Cancer. 2012;15(4):427–33. https://doi.org/10.4048/jbc.2012.15.4.427.CrossRefPubMedPubMedCentral

37.

Jeon YW, Kang SH, Park MH, Lim W, Cho SH, Suh YJ. Relationship between body mass index and the expression of hormone receptors or human epidermal growth factor receptor 2 with respect to breast cancer survival. BMC Cancer. 2015;15(1):865. https://doi.org/10.1186/s12885-015-1879-4.CrossRefPubMedPubMedCentral

38.

Kawai M, Tomotaki A, Miyata H, Iwamoto T, Niikura N, Anan K, et al. Body mass index and survival after diagnosis of invasive breast cancer: a study based on the Japanese National Clinical Database-Breast Cancer Registry. Cancer Med. 2016;5(6):1328–40. https://doi.org/10.1002/cam4.678.CrossRefPubMedPubMedCentral

39.

Lote H, Sharp A, Redana S, Papadimitraki E, Capelan M, Ring A. Febrile neutropenia rates according to body mass index and dose capping in women receiving chemotherapy for early breast Cancer. Clin Oncol (R Coll Radiol). 2016;28(9):597–603. https://doi.org/10.1016/j.clon.2016.02.003.CrossRef

40.

Farr A, Stolz M, Baumann L, Bago-Horvath Z, Oppolzer E, Pfeiler G, et al. The effect of obesity on pathological complete response and survival in breast cancer patients receiving uncapped doses of neoadjuvant anthracycline-taxane-based chemotherapy. Breast. 2017;33:153–8. https://doi.org/10.1016/j.breast.2017.04.001.CrossRefPubMed

41.

Chung IY, Lee JW, Lee JS, Park YR, Min YH, Lee Y, et al. Interaction between body mass index and hormone-receptor status as a prognostic factor in lymph-node-positive breast cancer. PLoS One. 2017;12(3):e0170311. https://doi.org/10.1371/journal.pone.0170311.CrossRefPubMedPubMedCentral

42.

Gondo N, Sawaki M, Hattori M, Yoshimura A, Kotani H, Adachi Y, et al. Impact of BMI for clinical outcomes in Japanese breast cancer patients. Jpn J Clin Oncol. 2020;50(3):230–40. https://doi.org/10.1093/jjco/hyz175.CrossRefPubMed

43.

Moon HG, Han W, Noh DY. Underweight and breast cancer recurrence and death: a report from the Korean breast Cancer society. J Clin Oncol. 2009;27(35):5899–905. https://doi.org/10.1200/JCO.2009.22.4436.CrossRefPubMed

44.

Wang K, Wu YT, Zhang X, Chen L, Zhu WM, Zhang AJ, et al. Clinicopathologic and prognostic significance of body mass index (BMI) among breast Cancer patients in Western China: a retrospective multicenter cohort based on Western China clinical cooperation group (WCCCG). Biomed Res Int. 2019;2019:3692093–14. https://doi.org/10.1155/2019/3692093.CrossRefPubMedPubMedCentral

45.

Nichols HB, Trentham-Dietz A, Egan KM, Titus-Ernstoff L, Holmes MD, Bersch AJ, et al. Body mass index before and after breast cancer diagnosis: associations with all-cause, breast cancer, and cardiovascular disease mortality. Cancer Epidemiol Biomarkers Prev. 2009;18(5):1403–9. https://doi.org/10.1158/1055-9965.EPI-08-1094.CrossRefPubMedPubMedCentral

46.

Chen B, Lai J, Guo L, Dai D, Chen R, Wei G, et al. Adverse effects of being underweight on young female breast cancer patients with lymph node metastases. J Cancer. 2020;11(7):1976–84. https://doi.org/10.7150/jca.38567.CrossRefPubMedPubMedCentral

47.

Kim JY, Lee DW, Lee KH, Min A, Ryu HS, Lee HB, et al. Prognostic role of body mass index is different according to menopausal status and tumor subtype in breast cancer patients. Breast Cancer Res Treat. 2019;176(2):453–60. https://doi.org/10.1007/s10549-019-05249-1.CrossRefPubMed

48.

Kawai M, Minami Y, Nishino Y, Fukamachi K, Ohuchi N, Kakugawa Y. Body mass index and survival after breast cancer diagnosis in Japanese women. BMC Cancer. 2012;12(1):149. https://doi.org/10.1186/1471-2407-12-149.CrossRefPubMedPubMedCentral

49.

Abubakar M, Sung H, Bcr D, Guida J, Tang TS, Pfeiffer RM, et al. Breast cancer risk factors, survival and recurrence, and tumor molecular subtype: analysis of 3012 women from an indigenous Asian population. Breast Cancer Res. 2018;20(1):114. https://doi.org/10.1186/s13058-018-1033-8.CrossRefPubMedPubMedCentral

50.

Zhang M, Cai H, Bao P, Xu W, Qin G, Shu XO, et al. Body mass index, waist-to-hip ratio and late outcomes: a report from the Shanghai breast Cancer survival study. Sci Rep. 2017;7(1):6996. https://doi.org/10.1038/s41598-017-07320-7.CrossRefPubMedPubMedCentral

51.

Cunningham-Rundles S, McNeeley DF, Moon A. Mechanisms of nutrient modulation of the immune response. J Allergy Clin Immunol. 2005;115(6):1119–28; quiz 1129. https://doi.org/10.1016/j.jaci.2005.04.036.CrossRefPubMed

52.

Chirumbolo S. Vitamin D3 in cancer prevention and therapy: the nutritional issue. Horm Mol Biol Clin Invest. 2015;23(3):71–8. https://doi.org/10.1515/hmbci-2015-0011.CrossRef

53.

Giuseppe F, François R, Anne-SH LJ, Hans W, Jan A, Kevin P, et al. Body mass index and tumor-infiltrating lymphocytes in triple-negative breast Cancer. J Natl Cancer Inst. 2021;113(2):146–53. https://doi.org/10.1093/jnci/djaa090.CrossRef

54.

Ziming W, Ethan GA, Jesus IL, Cordelia D, Lam TK, Catherine TL, et al. Paradoxical effects of obesity on T cell function during tumor progression and PD-1 checkpoint blockade. Nat Med. 2019;25(1):141–51. https://doi.org/10.1038/s41591-018-0221-5.CrossRef

55.

Nora LS, Neil MI, Rohan B, Akanksha V, Maxine SJ, Dilip DG, et al. Obesity-associated extracellular matrix remodeling promotes a macrophage phenotype similar to tumor-associated macrophages. Am J Pathol. 2019;189(10):2019–35. https://doi.org/10.1016/j.ajpath.2019.06.005.CrossRef

56.

Payal T, Ariane B, Chang C, Kelly QS, Guolin Z, Yanfei X, et al. Metabolically activated adipose tissue macrophages link obesity to triple-negative breast cancer. J Exp Med. 2019;216(6):1345–58. https://doi.org/10.1084/jem.20181616.CrossRef

57.

Chlebowski RT, Aiello E, McTiernan A. Weight loss in breast cancer patient management. J Clin Oncol. 2002;20(4):1128–43. https://doi.org/10.1200/JCO.2002.20.4.1128.CrossRefPubMed

58.

Thivat E, Therondel S, Lapirot O, Abrial C, Gimbergues P, Gadea E, et al. Weight change during chemotherapy changes the prognosis in non metastatic breast cancer for the worse. BMC Cancer. 2010;10(1):648. https://doi.org/10.1186/1471-2407-10-648.CrossRefPubMedPubMedCentral

59.

Nikolaidi A, Kotoula V, Koliou GA, Giannoulatou E, Papadopoulou K, Zagouri F, et al. Tumor mutational patterns and infiltrating lymphocyte density in young and elderly patients with breast Cancer. Cancer Genomics Proteomics. 2020;17(2):181–93. https://doi.org/10.21873/cgp.20179.CrossRefPubMedPubMedCentral

60.

Alessio C, Melissa B, Sebastiano B, Katia C, Daniele S, Fabiana P, et al. A multicenter study of body mass index in cancer patients treated with anti-PD-1/PD-L1 immune checkpoint inhibitors: when overweight becomes favorable. J Immunother Cancer. 2019;7(1):57. https://doi.org/10.1186/s40425-019-0527-y.CrossRef

61.

Ganessan K, John OM, Arduino AM, Andrew R, Ashley MH, Michael JS. Association between body mass index and overall survival with immune checkpoint inhibitor therapy for advanced non-small cell lung Cancer. JAMA Oncol. 2020;6(4):512–8. https://doi.org/10.1001/jamaoncol.2019.5241.CrossRef

62.

Angela E, Antonio M, Vincenzo B, Samuele F, Stefania M, Giulia V, et al. Body mass index, adiposity and tumour infiltrating lymphocytes as prognostic biomarkers in patients treated with immunotherapy: a multi-parametric analysis. Eur J Cancer. 2021;145:197–209. https://doi.org/10.1016/j.ejca.2020.12.028.CrossRef

Title: Clinical verification of body mass index and tumor immune response in patients with breast cancer receiving preoperative chemotherapy
Authors: Koji Takada
Shinichiro Kashiwagi
Yuka Asano
Wataru Goto
Sae Ishihara
Tamami Morisaki
Masatsune Shibutani
Hiroaki Tanaka
Kosei Hirakawa
Masaichi Ohira
Publication date: 01-12-2021
Publisher: BioMed Central
Keywords: Breast Cancer
Underweight
Breast Cancer
Underweight
Overweight
Cytostatic Therapy
Published in: BMC Cancer / Issue 1/2021
Electronic ISSN: 1471-2407
DOI: https://doi.org/10.1186/s12885-021-08857-7

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Keynote webinar | Spotlight on antibody–drug conjugates in cancer

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