Document Type : Original Research
Authors
1 Breast Diseases Research Center, Cancer Institute, Tehran University of Medical Sciences, Tehran, Iran
2 Department of Surgical Oncology, Cancer Institute, Tehran University of Medical Sciences, Tehran, Iran
3 Islamic Azad University, Tehran Medical Sciences branch, Tehran, Iran
4 Department of Surgery, Arash Women’s Hospital, Tehran University of Medical Sciences, Tehran, Iran
5 Department of Pathology, School of Medicine, Imam Khomeini Hospital, Tehran University of Medical Sciences Tehran, Iran
Abstract
Background & Objective: Human epidermal growth receptor-2 (HER2) gene amplification is an important predictive and prognostic factor in breast cancer treatment. However, the expression of HER2 determined by immunohistochemistry (IHC) is considered as borderline in some cases, and confirmation of the HER2 status by either fluorescent in situ hybridization (FISH) or chromogenic in situ hybridization (CISH) is necessary for correct treatment decision-making. Considering the high cost of FISH and CISH, we aimed to investigate whether clinicopathological findings of the tumor could predict the HER2 status.
Methods: A retrospective study was performed using the data from 584 patients with breast cancer with HER2-borderline disease, confirmed by IHC. Final HER2 status, pathologic tumor size and type, nodal involvement, Ki67 index, presence of estrogen and progesterone receptors (ER, PR), lymphovascular invasion (LVI), and stage were retrieved from the clinical records.
Results: One hundred twenty-one (20.7%) patients were HER2-positive according to the FISH or CISH results. Logistic regression analysis showed that the pathologic size was positively associated with HER2 positivity with an odds ratio (OR) of 1.02 (95% CI: 1.01-1.04). In addition, the adjusted OR illustrated a statistically significant association between HER2 positivity and PR negativity (OR= 2.22, 95% CI: 1.29-3.83).
Conclusion: In HER2 borderline breast cancer, HER2 positivity significantly increases with tumor size and PR negativity. Further studies are recommended that may find an applicable model to predict the actual status of HER2 in borderline cases.
Keywords
Main Subjects
- Rubin I, Yarden Y. The basic biology of HER2. Ann Oncol. 2001;12:S3-S8. [DOI:10.1093/annonc/12.suppl_1.S3] [PMID]
- Krishnamurti U, Silverman JF. HER2 in breast cancer: a review and update. Adv Anat Pathol. 2014;21(2):100-7. [DOI:10.1097/PAP.0000000000000015] [PMID]
- Keyhani E, Muhammadnejad A, Karimlou M. Prevalence of HER-2-positive invasive breast cancer: a systematic review from Iran. Asian Pac J Cancer Prev. 2012;13(11):5477-82. [DOI:10.7314/APJCP.2012.13.11.5477] [PMID]
- Buzdar AU, Ibrahim NK, Francis D, Booser DJ, Thomas ES, Theriault RL, et al. 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. 2005;23(16):3676-85. [DOI:10.1200/JCO.2005.07.032] [PMID]
- Bhattacharjee A, Rajendra J, Dikshit R, Dutt S. HER2 borderline is a negative prognostic factor for primary malignant breast cancer. Breast Cancer Res Treat. 2020:1-7. [DOI:10.1007/s10549-020-05608-3] [PMID]
- Kadivar M, Mafi N, Joulaee A, Shamshiri A, Hosseini N. Breast cancer molecular subtypes and associations with clinicopathological characteristics in Iranian women, 2002-2011. Asian Pac J Cancer Prev. 2012;13(5):1881-6. [DOI:10.7314/APJCP.2012.13.5.1881] [PMID]
- Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE, et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science. 1989;244(4905):707-12. [DOI:10.1126/science.2470152] [PMID]
- Roses RE, Paulson EC, Sharma A, Schueller JE, Nisenbaum H, Weinstein S, et al. HER-2/neu overexpression as a predictor for the transition from in situ to invasive breast cancer. Cancer Epidemiol Biomark Prev. 2009;18(5):1386-9. [DOI:10.1158/1055-9965.EPI-08-1101] [PMID]
- Cayre A, Mishellany F, Lagarde N, Penault-Llorca F. Comparison of different commercial kits for HER2 testing in breast cancer: looking for the accurate cutoff for amplification. Breast Cancer Res. 2007;9(5):1-10. [DOI:10.1186/bcr1770] [PMID] []
- Prati R, Apple SK, He J, Gornbein JA, Chang HR. Histopathologic characteristics predicting HER‐2/neu amplification in breast cancer. Breast J. 2005;11(6):433-9. [DOI:10.1111/j.1075-122X.2005.00125.x] [PMID]
- Ellis C, Dyson M, Stephenson T, Maltby E. HER2 amplification status in breast cancer: a comparison between immunohistochemical staining and fluorescence in situ hybridisation using manual and automated quantitative image analysis scoring techniques. J Clin Pathol. 2005;58(7):710-4. [DOI:10.1136/jcp.2004.023424] [PMID]
- Reddy JC, Reimann JD, Anderson SM, Klein PM. Concordance between central and local laboratory HER2 testing from a community-based clinical study. Clin Breast Cancer. 2006;7(2):153-7. [DOI:10.3816/CBC.2006.n.025] [PMID]
- Chibon F, De Mascarel I, Sierankowski G, Brouste V, Bonnefoi H, Debled M, et al. Prediction of HER2 gene status in Her2 2+ invasive breast cancer: a study of 108 cases comparing ASCO/CAP and FDA recommendations. Mod Pathol. 2009;22(3):403-9. [DOI:10.1038/modpathol.2008.195] [PMID]
- Guo Q, Chen K, Lin X, Su Y, Xu R, Dai Y, et al. A nomogram to predict HER2 status in breast cancer patients with HER2-borderline disease as determined via immunohistochemistry. Oncotarget. 2017;8(55):93492. [DOI:10.18632/oncotarget.19313] [PMID]
- Okaly GVP, Panwar D, Lingappa KB, Kumari P, Anand A, Kumar P, et al. FISH and HER2/neu equivocal immunohistochemistry in breast carcinoma. Indian J Cancer. 2019;56(2):119. [DOI:10.4103/ijc.IJC_333_18] [PMID]
- Panjwani P, Epari S, Karpate A, Shirsat H, Rajsekharan P, Basak R, et al. Assessment of HER-2/neu status in breast cancer using fluorescence in situ hybridization & immunohistochemistry: Experience of a tertiary cancer referral centre in India. Indian J Med Res. 2010;132(2):287-94.
- Lin L, Sirohi D, Coleman JF, Gulbahce HE. American society of clinical oncology/college of American pathologists 2018 focused update of breast cancer HER2 FISH testing GuidelinesResults from a national reference laboratory. Am J Clin Pathol. 2019;152(4):479-85. [DOI:10.1093/ajcp/aqz061] [PMID]
- Wei CH, Garcia L, Murata-Collins J, Schmolze D, Apple S. Quantitative Impact of the 2018 American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) Practice Guideline Update on Human Epidermal Growth Factor Receptor 2 (HER2) Testing in Breast Cancer: A Systematic Analysis. Arch Pathol Lab Med. 2020. [DOI:10.5858/arpa.2020-0378-OA] [PMID]
- Taucher S, Rudas M, Mader RM, Gnant M, Dubsky P, Bachleitner T, et al. Do we need HER‐2/neu testing for all patients with primary breast carcinoma? Cancer. 2003;98(12):2547-53. [DOI:10.1002/cncr.11828] [PMID]
- Pinhel I, Hills M, Drury S, Salter J, Sumo G, A'Hern R, et al. ER and HER2 expression are positively correlated in HER2 non-overexpressing breast cancer. Breast Cancer Res. 2012;14(2):R46. [DOI:10.1186/bcr3145] [PMID]
- Van de Vijver M. Assessment of the need and appropriate method for testing for the human epidermal growth factor receptor-2 (HER2). Eur J Cancer. 2001;37:11-7. [DOI:10.1016/S0959-8049(00)00403-2] [PMID]
- Konecny G, Pauletti G, Pegram M, Untch M, Dandekar S, Aguilar Z, et al. Quantitative association between HER-2/neu and steroid hormone receptors in hormone receptor-positive primary breast cancer. J Natl Cancer Inst. 2003;95(2):142-53. [DOI:10.1093/jnci/95.2.142] [PMID]
- Lal P, Tan LK, Chen B. Correlation of HER-2 status with estrogen and progesterone receptors and histologic features in 3,655 invasive breast carcinomas. Am J Clin Pathol. 2005;123(4):541-6. [DOI:10.1309/YMJ3A83TB39MRUT9] [PMID]
- Shaikh F, Jamal Q, Baig S, Hadi NI, Majeed N. Correlation of Hormone Receptor and HER2/neu Expression with Clinicopathologic Parameters in Primary Breast Tumors. Asian Pac J Cancer Prev. 2016;17(7):3363-7.
- Pothos A, Plastira K, Plastiras A, Vlachodimitropoulos D, Goutas N, Angelopoulou R. Comparison of chromogenic in situ hybridisation with fluorescence in situ hybridisation and immunohistochemistry for the assessment of her-2/neu oncogene in archival material of breast carcinoma. Acta Histochem Cytoc. 2008:41(3):59-64. [DOI:10.1267/ahc.07029] [PMID]
- Porter PL, Garcia R, Moe R, Gown AM, Corwin DJ. C‐ERBB‐2 oncogens protein in In situ and invasive lobular breast neoplasia. Cancer. 1991;68(2):331-4. [DOI:10.1002/1097-0142(19910715)68:23.0.CO;2-X] [PMID]
- Kee G, Tan R, Sultana R, Zaw M, Lian W, Tan K, et al. HER2 positive rates in invasive lobular breast carcinoma: A study amongst 1,095 consecutive Asian patients. Ann Oncol. 2018;29:ix1. [DOI:10.1093/annonc/mdy426.002]
- Yu J, Dabbs DJ, Shuai Y, Niemeier LA, Bhargava R. Classical-type invasive lobular carcinoma with HER2 overexpression: clinical, histologic, and hormone receptor characteristics. Am J Clin Pathol. 2011;136(1):88-97. [DOI:10.1309/AJCP7URIW0QETTAT] [PMID]
- Haines GK, Wiley E, Susnik B, Apple SK, Frkovic-Grazio S, Reyes C, et al. HER2 in well differentiated breast cancer: is testing necessary? Breast Cancer Res Treat. 2008;112(3):551-6. [DOI:10.1007/s10549-008-9893-8] [PMID]
- Bethune GC, Pettit AS, Veldhuijzen van Zanten D, Barnes PJ. Well‐differentiated invasive breast cancers with equivocal HER 2 immunohistochemistry: what is the yield of routine reflex in‐situ hybridization testing? Histopathology. 2017;70(6):966-74. [DOI:10.1111/his.13160] [PMID]
- Hoff ER, Tubbs RR, Myles JL, Procop GW. HER2/neu amplification in breast cancer: stratification by tumor type and grade. Am J Clin Pathol. 2002;117(6):916-21. [DOI:10.1309/4NTU-N6K4-F8JF-EWRX] [PMID]
- Arnould L, Denoux Y, MacGrogan G, Penault-Llorca F, Fiche M, Treilleux I, Mathieu MC, Vincent-Salomon A, Vilain MO, Couturier J. Agreement between chromogenic in situ hybridisation (CISH) and FISH in the determination of HER2 status in breast cancer. British journal of cancer. 2003;88(10):1587-91. [DOI:10.1038/sj.bjc.6600943] [PMID]
)