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Novel tumor-infiltrating lymphocytes ultrasonography score based on ultrasonic tissue findings predicts tumor-infiltrating lymphocytes in breast cancer

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Abstract

Background

The presence of tumor-infiltrating lymphocytes (TILs) is a prognostic factor for breast cancer. However, because of tumor tissue heterogeneity, an accurate and simple evaluation method is needed. We determined if preoperative characteristic ultrasonography (US) image findings are predictive of lymphocyte-predominant breast cancer (LPBC).

Methods

We evaluated 191 patients with invasive breast cancer treated by curative surgery between January 2014 and December 2017. Stromal lymphocytes in surgical pathological specimens were evaluated. Fifty-two patients with ≥ 50% stromal TILs were defined as having LPBC. Preoperative US images were examined for indicators of TILs. The US images with characteristic TILs were scored for prediction of LPBC.

Results

Shape (more lobulated), internal echo level (weaker), and posterior echoes (stronger) were predictors of LPBC and used to assign the TILs-US scores (0–7 points); the score cutoff for predicting LPBC was 4 points (sensitivity, 0.73; specificity, 0.87; accuracy, 0.83) based on the receiver operating characteristics (ROC) curves (AUC 0.88). Multivariate logistic regression analysis identified nuclear grade (NG), OR 3.4; estrogen receptor (ER), OR 5.7; human epidermal growth factor receptor type-2 (HER2), OR 4.1; and TILs-US score, OR 14.9 as LPBC predictors (all, p < 0.05). The sensitivity, specificity, and accuracy for predicting LPBC were 0.75, 0.69, and 0.71 for NG and 0.33, 0.96, and 0.79 for ER and HER2, respectively. ROC analysis showed that the diagnostic abilities of NG, ER, and HER2 were lower than that of the TILs-US score.

Conclusions

LPBC showed characteristic US imaging findings. The TILs-US score was an accurate preoperative predictor of LPBC.

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References

  1. 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;32:2959–66.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Ali HR, Provenzano E, Dawson SJ, Blows FM, Liu B, Shah M, et al. Association between CD8+ T-cell infiltration and breast cancer survival in 12,439 patients. Ann Oncol. 2014;25:1536–43.

    Article  CAS  PubMed  Google Scholar 

  3. Dieci MV, Criscitiello C, Goubar A, Viale G, Conte P, Guarneri V, et al. Prognostic value of tumor-infiltrating lymphocytes on residual disease after primary chemotherapy for triple-negative breast cancer: a retrospective multicenter study. Ann Oncol. 2014;25:611–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Perez EA, Ballman KV, Tenner KS, Thompson EA, Badve SS, Bailey H, et al. Association of stromal tumor-infiltrating lymphocytes with recurrence-free survival in the N9831 adjuvant trial in patients with early-stage HER2-positive breast cancer. JAMA Oncol. 2016;2:56–64.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Salgado R, Denkert C, Campbell C, Savas P, Nuciforo P, Aura C, et al. 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. 2015;1:448–55.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Loi S, Michiels S, Salgado R, Sirtaine N, Jose V, Fumagalli D, et al. 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. 2014;25:1544–50.

    Article  CAS  PubMed  Google Scholar 

  7. Salgado R, Denkert C, Campbell C, Savas P, Nuciforo P, Aura C, et al. 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. 2013;31:860–7.

    Article  PubMed  Google Scholar 

  8. Denkert C, Loibl S, Noske A, Roller M, Muller BM, Komor M, et al. Tumor-associated lymphocytes as an independent predictor of response to neoadjuvant chemotherapy in breast cancer. J Clin Oncol. 2010;28:105–13.

    Article  CAS  PubMed  Google Scholar 

  9. 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;33:983–91.

    Article  CAS  PubMed  Google Scholar 

  10. Issa-Nummer Y, Darb-Esfahani S, Loibl S, Kunz G, Nekljudova V, Schrader I, et al. Prospective validation of immunological infiltrate for prediction of response to neoadjuvant chemotherapy in HER2-negative breast cancer—A substudy of the neoadjuvant GeparQuinto trial. PloS One. 2013;8:e79775.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. West NR, Milne K, Truong PT, Macpherson N, Nelson BH. Watson PH Tumor-infiltrating lymphocytes predict response to anthracycline-based chemotherapy in estrogen receptor-negative breast cancer. Breast Cancer Res. 2011;13:R126.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Ingold Heppner B, Untch M, Denkert C, Pfitzner BM, Lederer B, Schmitt W, et al. Tumor-infiltrating lymphocytes: a predictive and prognostic biomarker in neoadjuvant-treated HER2-positive breast cancer. Clin Cancer Res. 2016;22:5747–54.

    Article  CAS  PubMed  Google Scholar 

  13. Denkert C, von Minckwitz G, Darb-Esfahani S, Lederer B, Heppner BI, Weber KE, 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. 2018;19:40–50.

    Article  PubMed  Google Scholar 

  14. 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;26:259–71.

    Article  CAS  PubMed  Google Scholar 

  15. Crystal P, Strano SD, Shcharynski S, Koretz MJ. Using sonography to screen women with mammographically dense breasts. Am J Roentgenol. 2003;181:177–82.

    Article  Google Scholar 

  16. Kolb TM, Lichy J, Newhouse JH. Comparison of the performance of screening mammography, physical examination, and breast US and evaluation of factors that influence them: an analysis of 27,825 patient evaluations. Radiology. 2002;225:165–75.

    Article  Google Scholar 

  17. Weinstein SP, Localio AR, Conant EF, Rosen M, Thomas KM, Schnall MD. Multimodality screening of high-risk women: a prospective cohort study. J Clin Oncol. 2009;27:6124–8.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Berg WA, Blume JD, Cormack JB, Mendelson EB, Lehrer D, Böhm-Vélez M, et al. Combined screening with ultrasound and mammography vs mammography alone in women at elevated risk of breast cancer. JAMA. 2008;299:2151–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Tohno E, Umemoto T, Sasaki K, Morishima I, Ueno E. Effect of adding screening ultrasonography to screening mammography on patient recall and cancer detection rates: a retrospective study in Japan. Eur J Radiol. 2013;82:1227–30.

    Article  PubMed  Google Scholar 

  20. Tohno E, Takahashi H, Tamada T, Fujimoto Y, Yasuda H, Ohuchi N. Educational program and testing using images for the standardization of breast cancer screening by ultrasonography. Breast Cancer. 2012;19:138–46.

    Article  PubMed  Google Scholar 

  21. Ohuchi N, Suzuki A, Sobue T, Kawai M, Yamamoto S, Zheng YF, et al. Sensitivity and specificity of mammography and adjunctive ultrasonography to screen for breast cancer in the Japan strategic anti-cancer randomized trial (J-START): a randomised controlled trial. Lancet. 2016;387:341–8.

    Article  PubMed  Google Scholar 

  22. Chen SC, Cheung YC, Su CH, Chen MF, Hwang TL, Hsueh S. Analysis of sonographic features for the differentiation of benign and malignant breast tumors of different sizes. Ultrasound Obstet Gynecol. 2004;23:188–93.

    Article  PubMed  Google Scholar 

  23. Costantini M, Belli P, Lombardi R, Franceschini G, Mulè A, Bonomo L. Characterization of solid breast masses: use of the sonographic breast imaging reporting and data system lexicon. J Ultrasound Med. 2006;25:649–59.

    Article  PubMed  Google Scholar 

  24. Rahbar G, Sie AC, Hansen GC, Prince JS, Melany ML, Reynolds HE, et al. Benign versus malignant solid breast masses: US differentiation. Radiology. 1999;213:889–94.

    Article  CAS  Google Scholar 

  25. Dieci MV, Mathieu MC, Guarneri V, Conte P, Delaloge S, Andre F, et al. Prognostic and predictive value of tumor infiltrating lymphocytes in two phase randomized adjuvant breast cancer trials. Ann Oncol. 2015;26:1698–704.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Masumoto N, Kadoya T, Amioka A, Kajitani K, Shigematsu H, Emi A, et al. Evaluation of malignancy grade of breast cancer using perflubutane-enhanced ultrasonography. Ultrasound Med Biol. 2016;42:1049–57.

    Article  PubMed  Google Scholar 

  27. Wan CF, Du J, Fang H, Li FH, Zhu JS, Liu Q. Enhancement patterns and parameters of breast cancers at contrast-enhanced US: correlation with prognostic factors. Radiology. 2012;262:450–9.

    Article  Google Scholar 

  28. Kadoya T, Aogi K, Kiyoto S, Masumoto N, Sugawara Y, Okada M. Role of maximum standardized uptake value in fluorodeoxyglucose positron emission tomography/computed tomography predicts malignancy grade and prognosis of operable breast cancer: a multi-institute study. Breast Cancer Res Treat. 2013;141:269–75.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Aogi K, Kadoya T, Sugawara Y, Kiyoto S, Shigematsu H, Masumoto N, et al. Utility of 18F FDG-PET/CT for predicting prognosis of luminal-type breast cancer. Breast Cancer Res Treat. 2015;50:209–17.

    Article  CAS  Google Scholar 

  30. Cintolo JA, Tchou J, Pryma DA. Diagnostic and prognostic application of positron emission tomography in breast imaging: emerging uses and the role of PET in monitoring treatment response. Breast Cancer Res Treat. 2013;138:331–46.

    Article  PubMed  Google Scholar 

  31. Masumoto N, Kadoya T, Sasada S, Emi A, Arihiro K, Okada M. Intratumoral heterogeneity on dedicated breast positron emission tomography predicts malignancy grade of breast cancer. Breast Cancer Res Treat. 2018;171:315–23.

    Article  PubMed  Google Scholar 

  32. Japan Association of Breast and Thyroid Sonology. Guideline for breast ultrasound-management and diagnosis, 3rd ed. Tokyo: Nankoudo Co., Ltd.; 2014.

    Google Scholar 

  33. Calderon C, Vilkomerson D, Mezrich R, Etzold KF, Kingsley B, Haskin M. Differences in the attenuation of ultrasound by normal, benign, and malignant breast tissue. J Clin Ultrasound. 1976;4:249–54.

    Article  CAS  PubMed  Google Scholar 

  34. Kobayashi T. Gray-scale echography for breast cancer. Radiology. 1977;122:207–14.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Division of Laboratory Medicine, Hiroshima University Hospital, Hiroshima, Japan

    Kayo Fukui, Akiko Kanou & Michiya Yokozaki

  2. Department of Surgical Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3-Kasumi, Minami-ku, Hiroshima, Hiroshima, 734-0037, Japan

    Norio Masumoto, Shinsuke Sasada, Akiko Emi, Takayuki Kadoya & Morihito Okada

  3. Department of Anatomical Pathology, Hiroshima University Hospital, Hiroshima, Japan

    Noriyuki Shiroma & Koji Arihiro

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  1. Kayo Fukui
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Correspondence to Norio Masumoto.

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Fukui, K., Masumoto, N., Shiroma, N. et al. Novel tumor-infiltrating lymphocytes ultrasonography score based on ultrasonic tissue findings predicts tumor-infiltrating lymphocytes in breast cancer. Breast Cancer 26, 573–580 (2019). https://doi.org/10.1007/s12282-019-00958-3

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  • DOI: https://doi.org/10.1007/s12282-019-00958-3

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