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Histologic analysis according to HER2 gene status in HER2 2 + invasive breast cancer: a study of 280 cases comparing ASCO/CAP 2013 and 2018 guideline recommendations

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Abstract

The American Society of Clinical Oncology and College of American Pathologists guidelines for HER2 testing in breast cancer (BC) have been updated with more stringent criteria regarding immunohistochemistry (IHC) 2 + interpretation. The aim of our study was to determine HER2 status in IHC 2 + cases based on 2013 and 2018 guidelines and to investigate specific histologic characteristics that might predict HER2 status in tumors with equivocal IHC staining. Two hundred eighty BC cases reported as IHC 2 + and 24 cases reported as non-IHC 2 + were reviewed with 12 histologic characteristics. Of the IHC 2 + cases based on 2013 guideline, 21% were reclassified to IHC 1 + when applying the 2018 guidelines. Consequently, it led to an 8% increase of HER2 amplification rate in 2018 IHC 2 + group. Seven characteristics were significantly associated with prediction of HER2 amplification in IHC 2 + BCs, including high tumor-infiltrating lymphocytes (TILs), distinct cellular membrane, no apical snout, large nuclear size, nuclear size variation, high nuclear grade, and tubule formation < 10%. Using these criteria, the presence of four or more characteristics significantly indicates HER2 amplification. Moreover, four characteristics among them, including high TILs, distinct cellular membrane, nuclear size variation, and high nuclear grade, were also associated with HER2 amplification in non-IHC 2 + cases, demonstrating their predictive value as complements to IHC. In conclusion, we provide specific morphologic features that will improve pathologist performance in identifying more HER2-positive BCs. We further suggest an algorithm for trastuzumab therapy decisions using a combination of histomorphologic evaluation and the updated 2018 guidelines.

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References

  1. Ballard M, Jalikis F, Krings G, Schmidt RA, Chen YY, Rendi MH, Dintzis SM, Jensen KC, West RB, Sibley RK, Troxell ML, Allison KH (2017) ‘Non-classical’ HER2 FISH results in breast cancer: a multi-institutional study. Modern Pathol 30:227–235. https://doi.org/10.1038/modpathol.2016.175

  2. Barrett C, Magee H, O’Toole D, Daly S, Jeffers M (2007) Amplification of the HER2 gene in breast cancers testing 2+ weak positive by HercepTest immunohistochemistry: false-positive or false-negative immunohistochemistry? J Clin Pathol 60:690–693. https://doi.org/10.1136/jcp.2006.039602

    Article  CAS  PubMed  Google Scholar 

  3. Bast RC Jr, Ravdin P, Hayes DF, Bates S, Fritsche H Jr, Jessup JM, Kemeny N, Locker GY, Mennel RG, Somerfield MR (2001) 2000 update of recommendations for the use of tumor markers in breast and colorectal cancer: clinical practice guidelines of the American Society of Clinical Oncology. J Clin Oncol 19:1865–1878. https://doi.org/10.1200/jco.2001.19.6.1865

    Article  PubMed  Google Scholar 

  4. Bilous M, Ades C, Armes J, Bishop J, Brown R, Cooke B, Cummings M, Farshid G, Field A, Morey A, McKenzie P, Raymond W, Robbins P, Tan L (2003) Predicting the HER2 status of breast cancer from basic histopathology data: an analysis of 1500 breast cancers as part of the HER2000. Int Study Breast (Edinburgh, Scotland) 12:92–98

    Article  CAS  Google Scholar 

  5. Buzdar AU, Ibrahim NK, Francis D, Booser DJ, Thomas ES, Theriault RL, Pusztai L, Green MC, Arun BK, Giordano SH, Cristofanilli M, Frye DK, Smith TL, Hunt KK, Singletary SE, Sahin AA, Ewer MS, Buchholz TA, Berry D, Hortobagyi GN (2005) Significantly higher pathologic complete remission rate after neoadjuvant therapy with trastuzumab, paclitaxel, and epirubicin chemotherapy: results of a randomized trial in human epidermal growth factor receptor 2-positive operable breast cancer. J Clin Oncol 23:3676–3685. https://doi.org/10.1200/jco.2005.07.032

    Article  CAS  PubMed  Google Scholar 

  6. Cobleigh MA, Vogel CL, Tripathy D, Robert NJ, Scholl S, Fehrenbacher L, Wolter JM, Paton V, Shak S, Lieberman G, Slamon DJ (1999) Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol 17:2639–2648. https://doi.org/10.1200/jco.1999.17.9.2639

    Article  CAS  PubMed  Google Scholar 

  7. Fehrenbacher L, Cecchini RS, Geyer CE (2017) NSABP B-47 (NRG oncology): phase III randomized trial comparing adjuvant chemotherapy with adriamycin (A) and cyclophosphamide (C) → (A) weekly paclitaxel (WP), or docetaxel (T) and C with or without a year of trastuzumab (H) in women with node-positive or high-risk node-negative invasive breast cancer (IBC) expressing HER2 staining intensity of IHC 1+ or 2+ with negative FISH (HER2-Low IBC)San Antonio Breast Cancer Symposium, San Antonio, Texas, pp.

  8. Fehrenbacher L, Jeong J-H, Rastogi P, Geyer CE, Paik S, Ganz PA, Land SR, Costantino JP, Swain SM, Mamounas EP, Wolmark N (2013) NSABP B-47: a randomized phase III trial of adjuvant therapy comparing chemotherapy alone to chemotherapy plus trastuzumab in women with node-positive or high-risk node-negative HER2-low invasive breast cancer. J Clin Oncol 31:TPS1139-TPS1139. https://doi.org/10.1200/jco.2013.31.15_suppl.tps1139

  9. Garbar C, Savoye AM, Mascaux C, Brabencova E, Cure H (2014) The human epidermal growth factor receptor 2 screening tests for breast cancer suggested by the new updated recommendation of the american society of clinical oncology/college of american pathologists will involve a rise of the in-situ hybridization tests for the European laboratories of pathology. ISRN Oncol 2014: 793695. https://doi.org/10.1155/2014/793695

  10. Gown AM, Goldstein LC, Barry TS, Kussick SJ, Kandalaft PL, Kim PM, Tse CC (2008) High concordance between immunohistochemistry and fluorescence in situ hybridization testing for HER2 status in breast cancer requires a normalized IHC scoring system. Modern Pathol 21:1271–1277. https://doi.org/10.1038/modpathol.2008.83

  11. Hoff ER, Tubbs RR, Myles JL, Procop GW (2002) HER2/neu amplification in breast cancer: stratification by tumor type and grade. Am J Clin Pathol 117:916–921. https://doi.org/10.1309/4ntu-n6k4-f8jf-ewrx

    Article  CAS  PubMed  Google Scholar 

  12. Hofmann M, Stoss O, Gaiser T, Kneitz H, Heinmoller P, Gutjahr T, Kaufmann M, Henkel T, Ruschoff J (2008) Central HER2 IHC and FISH analysis in a trastuzumab (Herceptin) phase II monotherapy study: assessment of test sensitivity and impact of chromosome 17 polysomy. J Clin Pathol 61:89–94. https://doi.org/10.1136/jcp.2006.043562

    Article  CAS  PubMed  Google Scholar 

  13. Jacobs TW, Gown AM, Yaziji H, Barnes MJ, Schnitt SJ (1999) Specificity of HercepTest in determining HER-2/neu status of breast cancers using the United States Food and Drug Administration-approved scoring system. J Clin Oncol 17:1983–1987. https://doi.org/10.1200/jco.1999.17.7.1983

    Article  CAS  PubMed  Google Scholar 

  14. Martin V, Camponovo A, Ghisletta M, Bongiovanni M, Mazzucchelli L (2012) Internal quality assurance program for ERBB2 (HER2) testing improves the selection of breast cancer patients for treatment with trastuzumab. Pathol Res Int 2012:261857. https://doi.org/10.1155/2012/261857

    Article  Google Scholar 

  15. Prati R, Apple SK, He J, Gornbein JA, Chang HR (2005) Histopathologic characteristics predicting HER-2/neu amplification in breast cancer. Breast J 11:433–439. https://doi.org/10.1111/j.1075-122X.2005.00125.x

    Article  CAS  PubMed  Google Scholar 

  16. Press MF, Sauter G, Buyse M, Fourmanoir H, Quinaux E, Tsao-Wei DD, Eiermann W, Robert N, Pienkowski T, Crown J, Martin M, Valero V, Mackey JR, Bee V, Ma Y, Villalobos I, Campeau A, Mirlacher M, Lindsay MA, Slamon DJ (2016) HER2 gene amplification testing by fluorescent in situ hybridization (FISH): comparison of the ASCO-College of American Pathologists guidelines with FISH scores used for enrollment in Breast Cancer International Research Group Clinical Trials. J Clin Oncol 34:3518–3528. https://doi.org/10.1200/jco.2016.66.6693

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Press MF, Villalobos I, Santiago A, Guzman R, Cervantes M, Gasparyan A, Campeau A, Ma Y, Tsao-Wei DD, Groshen S (2016) Assessing the new American Society of Clinical Oncology/College of American Pathologists guidelines for HER2 testing by fluorescence in situ hybridization: experience of an academic consultation practice. Arch Pathol Lab Med. https://doi.org/10.5858/arpa.2016-0009-OA

    Article  PubMed  PubMed Central  Google Scholar 

  18. Rakha EA, Pigera M, Shaaban A, Shin SJ, D’Alfonso T, Ellis IO, Lee AH (2015) National guidelines and level of evidence: comments on some of the new recommendations in the American Society of Clinical Oncology and the College of American Pathologists human epidermal growth factor receptor 2 guidelines for breast cancer. J Clin Oncol 33:1301–1302. https://doi.org/10.1200/jco.2014.59.7211

    Article  PubMed  Google Scholar 

  19. Ross JS, Fletcher JA (1998) The HER-2/neu oncogene in breast cancer: prognostic factor, predictive factor, and target for therapy. Oncologist 3:237–252

    Article  CAS  PubMed  Google Scholar 

  20. Sarode VR, Xiang QD, Christie A, Collins R, Rao R, Leitch AM, Euhus D, Haley B (2015) Evaluation of HER2/neu status by immunohistochemistry using computer-based image analysis and correlation with gene amplification by fluorescence in situ hybridization assay: a 10-year experience and impact of test standardization on concordance rate. Arch Pathol Lab Med 139:922–928. https://doi.org/10.5858/arpa.2014-0127-OA

    Article  CAS  PubMed  Google Scholar 

  21. Shah MV, Wiktor AE, Meyer RG, Tenner KS, Ballman KV, Green SJ, Sukov WR, Ketterling RP, Perez EA, Jenkins RB (2016) Change in pattern of HER2 fluorescent in situ hybridization (FISH) results in breast cancers submitted for FISH testing: experience of a reference laboratory using US Food and Drug Administration Criteria and American Society of Clinical Oncology and College of American Pathologists Guidelines. J Clin Oncol 34:3502–3510. https://doi.org/10.1200/jco.2015.61.8983

    Article  CAS  PubMed  Google Scholar 

  22. Stewart RL, Caron JE, Gulbahce EH, Factor RE, Geiersbach KB, Downs-Kelly E (2017) HER2 immunohistochemical and fluorescence in situ hybridization discordances in invasive breast carcinoma with micropapillary features. Modern Pathol 30:1561–1566. https://doi.org/10.1038/modpathol.2017.65

  23. Valachis A, Mauri D, Polyzos NP, Chlouverakis G, Mavroudis D, Georgoulias V (2011) Trastuzumab combined to neoadjuvant chemotherapy in patients with HER2-positive breast cancer: a systematic review and meta-analysis. Breast (Edinburgh, Scotland) 20:485–490. https://doi.org/10.1016/j.breast.2011.06.009

    Article  Google Scholar 

  24. Varga Z, Noske A, Ramach C, Padberg B, Moch H (2013) Assessment of HER2 status in breast cancer: overall positivity rate and accuracy by fluorescence in situ hybridization and immunohistochemistry in a single institution over 12 years: a quality control study. BMC Cancer 13:615. https://doi.org/10.1186/1471-2407-13-615

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Vergara-Lluri ME, Moatamed NA, Hong E, Apple SK (2012) High concordance between HercepTest immunohistochemistry and ERBB2 fluorescence in situ hybridization before and after implementation of American Society of Clinical Oncology/College of American Pathology 2007 guidelines. Modern Pathol 25:1326–1332. https://doi.org/10.1038/modpathol.2012.93

  26. Vingiani A, Maisonneuve P, Dell’orto P, Farante G, Rotmensz N, Lissidini G, Del Castillo A, Renne G, Luini A, Colleoni M, Viale G, Pruneri G, (2013) The clinical relevance of micropapillary carcinoma of the breast: a case-control study. Histopathology 63:217–224. https://doi.org/10.1111/his.12147

    Article  PubMed  Google Scholar 

  27. Wolff AC, Hammond ME, Hicks DG, Allison KH, Bartlett JM, Bilous M, Fitzgibbons P, Hanna W, Jenkins RB, Mangu PB, Paik S, Perez EA, Press MF, Spears PA, Vance GH, Viale G, Dowsett M, McShane LM, Hayes DFReply to E.A. Rakha, et al (2015) Clin Oncol 33:1302–1304. https://doi.org/10.1200/jco.2014.59.7559

    Article  Google Scholar 

  28. Wolff AC, Hammond ME, Hicks DG, Dowsett M, McShane LM, Allison KH, Allred DC, Bartlett JM, Bilous M, Fitzgibbons P, Hanna W, Jenkins RB, Mangu PB, Paik S, Perez EA, Press MF, Spears PA, Vance GH, Viale G, Hayes DF (2013) Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol 31:3997–4013. https://doi.org/10.1200/jco.2013.50.9984

    Article  PubMed  Google Scholar 

  29. 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 25:118–145. https://doi.org/10.1200/jco.2006.09.2775

    Article  CAS  PubMed  Google Scholar 

  30. Wolff AC, Hammond MEH, Allison KH, Harvey BE, Mangu PB, Bartlett JMS, Bilous M, Ellis IO, Fitzgibbons P, Hanna W, Jenkins RB, Press MF, Spears PA, Vance GH, Viale G, McShane LM, Dowsett M (2018) Human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update. J Clin Oncol 36:2105–2122. https://doi.org/10.1200/jco.2018.77.8738

    Article  CAS  PubMed  Google Scholar 

  31. Yaziji H, Goldstein LC, Barry TS, Werling R, Hwang H, Ellis GK, Gralow JR, Livingston RB, Gown AM (2004) HER-2 testing in breast cancer using parallel tissue-based methods. JAMA 291:1972–1977. https://doi.org/10.1001/jama.291.16.1972

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Pathology, Chung-Ang University Hospital, Seoul, Republic of Korea

    Hye Won Hwang

  2. Department of Pathology, College of Medicine, Chung-Ang University, Seoul, Republic of Korea

    Soon Auck Hong

  3. Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea

    Seok Jin Nam, Seok Won Kim, Jeong Eon Lee, Jong-Han Yu & Se Kyung Lee

  4. Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 06351, Republic of Korea

    Soo Youn Cho & Eun Yoon Cho

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Contributions

Hye Won Hwang: conceptualization, investigation, methodology, formal analysis, writing—original draft, and writing—review and editing. Soon Auck Hong: data curation, investigation, methodology, formal analysis, validation, visualization. Seok Jin Nam: data curation, investigation, validation. Seok Won Kim: data curation, investigation, validation. Jeong Eon Lee: data curation, investigation, validation. Jong-Han Yu: data curation, investigation, validation. Se Kyung Lee: data curation, investigation, validation. Soo Youn Cho: conceptualization, investigation, methodology, formal analysis, writing—original draft, and writing—review and editing. Eun Yoon Cho: conceptualization, investigation, methodology, formal analysis, writing—original draft, and writing—review and editing.

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Correspondence to Soo Youn Cho or Eun Yoon Cho.

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Hwang, H.W., Hong, S.A., Nam, S.J. et al. Histologic analysis according to HER2 gene status in HER2 2 + invasive breast cancer: a study of 280 cases comparing ASCO/CAP 2013 and 2018 guideline recommendations. Virchows Arch 480, 749–758 (2022). https://doi.org/10.1007/s00428-022-03280-0

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