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Variability in hormone and growth factor receptor expression in primary versus recurrent, metastatic, and post-neoadjuvant breast carcinoma

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Abstract

The introduction of selective molecular targeted therapy, specifically tamoxifen and trastuzumab, has significantly altered the clinical behavior of breast carcinoma. Several questions remain, however, regarding potential phenotypic drifts in estrogen receptor (ER), progesterone receptor (PR), and epidermal growth factor receptor (Her-2/neu) expression between the primary and metastatic site. Whether patients should be tested for ER, PR, and Her-2/neu expression in the nodal or distant metastatic site, local recurrence and following neoadjuvant therapy, and whether this has an effect on prognosis remains elusive. A review of 45 studies addressing ER, PR, and Her-2/neu expression in lymph node metastasis, distant metastasis, local recurrence, and post-neoadjuvant therapy revealed the following average phenotypic drift in ER, PR, and Her-2/neu expression, respectively: 13.1 % (median = 10.0 %), 13.8 % (median = 16.0 %), and 7.7 % (median = 5.0 %) for lymph node metastasis; 21.8 % (median = 19.5 %), 30.8 % (median = 33.5 %), and 7.6 % (median = 6.1 %) for distant metastasis; 19.8 % (median = 13.4 %), 27.1 % (median = 28.6 %), and 6.6 % (median = 1.6 %) for local recurrence; and 12.9 % (median = 8.0 %), 32.0 % (median = 20.0 %), and 8.9 % (median = 0 %) post-neoadjuvant therapy. The above findings support the notion of re-evaluating ER, PR, and Her-2/neu expression in distant metastasis, lymph node metastasis and to a lesser extent local recurrence. The effects of neoadjuvant therapy on receptor expression are more pronounced for PR, which may have a prognostic role in therapy efficacy.

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References

  1. Early Breast Cancer Trialists’ Collaborative G (2005) Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 365(9472):1687–1717. doi:10.1016/S0140-6736(05)66544-0

    Article  Google Scholar 

  2. Vogel CL, Cobleigh MA, Tripathy D, Gutheil JC, Harris LN, Fehrenbacher L, Slamon DJ, Murphy M, Novotny WF, Burchmore M, Shak S, Stewart SJ, Press M (2002) Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol 20(3):719–726

    Article  PubMed  CAS  Google Scholar 

  3. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J, Norton L (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344(11):783–792. doi:10.1056/NEJM200103153441101

    Article  PubMed  CAS  Google Scholar 

  4. Aitken SJ, Thomas JS, Langdon SP, Harrison DJ, Faratian D (2010) Quantitative analysis of changes in ER, PR and HER2 expression in primary breast cancer and paired nodal metastases. Ann Oncol 21(6):1254–1261. doi:10.1093/annonc/mdp427

    Article  PubMed  CAS  Google Scholar 

  5. Mori T, Morimoto T, Komaki K, Monden Y (1991) Comparison of estrogen receptor and epidermal growth factor receptor content of primary and involved nodes in human breast cancer. Cancer 68(3):532–537

    Article  PubMed  CAS  Google Scholar 

  6. Simon R, Nocito A, Hubscher T, Bucher C, Torhorst J, Schraml P, Bubendorf L, Mihatsch MM, Moch H, Wilber K, Schotzau A, Kononen J, Sauter G (2001) Patterns of her-2/neu amplification and overexpression in primary and metastatic breast cancer. J Natl Cancer Inst 93(15):1141–1146

    Article  PubMed  CAS  Google Scholar 

  7. Falck AK, Ferno M, Bendahl PO, Ryden L (2010) Does analysis of biomarkers in tumor cells in lymph node metastases give additional prognostic information in primary breast cancer? World J Surg 34(7):1434–1441. doi:10.1007/s00268-010-0499-z

    Article  PubMed  Google Scholar 

  8. Bogina G, Bortesi L, Marconi M, Venturini M, Lunardi G, Coati F, Massocco A, Manfrin E, Pegoraro C, Zamboni G (2011) Comparison of hormonal receptor and HER-2 status between breast primary tumours and relapsing tumours: clinical implications of progesterone receptor loss. Virchows Arch 459(1):1–10. doi:10.1007/s00428-011-1097-7

    Article  PubMed  CAS  Google Scholar 

  9. Gomez-Fernandez C, Daneshbod Y, Nassiri M, Milikowski C, Alvarez C, Nadji M (2008) Immunohistochemically determined estrogen receptor phenotype remains stable in recurrent and metastatic breast cancer. Am J Clin Pathol 130(6):879–882. doi:10.1309/AJCPD1AO3YSYQYNW

    Article  PubMed  Google Scholar 

  10. Guarneri V, Giovannelli S, Ficarra G, Bettelli S, Maiorana A, Piacentini F, Barbieri E, Dieci MV, D’Amico R, Jovic G, Conte P (2008) Comparison of HER-2 and hormone receptor expression in primary breast cancers and asynchronous paired metastases: impact on patient management. Oncologist 13(8):838–844. doi:10.1634/theoncologist.2008-0048

    Article  PubMed  CAS  Google Scholar 

  11. Hahnel R, Twaddle E (1985) The relationship between estrogen receptors in primary and secondary breast carcinomas and in sequential primary breast carcinomas. Breast Cancer Res Treat 5(2):155–163

    Article  PubMed  CAS  Google Scholar 

  12. Idirisinghe PK, Thike AA, Cheok PY, Tse GM, Lui PC, Fook-Chong S, Wong NS, Tan PH (2010) Hormone receptor and c-ERBB2 status in distant metastatic and locally recurrent breast cancer. Pathologic correlations and clinical significance. Am J Clin Pathol 133(3):416–429. doi:10.1309/AJCPJ57FLLJRXKPV

    Article  PubMed  Google Scholar 

  13. Lower EE, Glass EL, Bradley DA, Blau R, Heffelfinger S (2005) Impact of metastatic estrogen receptor and progesterone receptor status on survival. Breast Cancer Res Treat 90(1):65–70. doi:10.1007/s10549-004-2756-z

    Article  PubMed  CAS  Google Scholar 

  14. Rosen PP, Menendez-Botet CJ, Urban JA, Fracchia A, Schwartz MK (1977) Estrogen receptor protein (ERP) in multiple tumor specimens from individual patients with breast cancer. Cancer 39(5):2194–2200

    Article  PubMed  CAS  Google Scholar 

  15. Shimizu C, Fukutomi T, Tsuda H, Akashi-Tanaka S, Watanabe T, Nanasawa T, Sugihara K (2000) c-erbB-2 protein overexpression and p53 immunoreaction in primary and recurrent breast cancer tissues. J Surg Oncol 73(1):17–20. doi:10.1002/(SICI)1096-9098(200001)73:1<17:AID-JSO5>3.0.CO;2-2

    Article  PubMed  CAS  Google Scholar 

  16. Osborne CK (1998) Steroid hormone receptors in breast cancer management. Breast Cancer Res Treat 51(3):227–238

    Article  PubMed  CAS  Google Scholar 

  17. McGuire WL, Chamness GC, Fuqua SA (1991) Estrogen receptor variants in clinical breast cancer. Mol Endocrinol 5(11):1571–1577

    Article  PubMed  CAS  Google Scholar 

  18. Nomura Y, Tashiro H, Shinozuka K (1985) Changes of steroid hormone receptor content by chemotherapy and/or endocrine therapy in advanced breast cancer. Cancer 55(3):546–551

    Article  PubMed  CAS  Google Scholar 

  19. Coradini D, Cappelletti V, Miodini P, Ronchi E, Scavone G, Di Fronzo G (1984) Distribution of estrogen and progesterone receptors in primary tumor and lymph nodes in individual patients with breast cancer. Tumori 70(2):165–168

    PubMed  CAS  Google Scholar 

  20. Holdaway IM, Bowditch JV (1983) Variation in receptor status between primary and metastatic breast cancer. Cancer 52(3):479–485

    Article  PubMed  CAS  Google Scholar 

  21. Paridaens R, Sylvester RJ, Ferrazzi E, Legros N, Leclercq G, Heuson JC (1980) Clinical significance of the quantitative assessment of estrogen receptors in advanced breast cancer. Cancer 46(12 Suppl):2889–2895

    Article  PubMed  CAS  Google Scholar 

  22. Johnston SR, Saccani-Jotti G, Smith IE, Salter J, Newby J, Coppen M, Ebbs SR, Dowsett M (1995) Changes in estrogen receptor, progesterone receptor, and pS2 expression in tamoxifen-resistant human breast cancer. Cancer Res 55(15):3331–3338

    PubMed  CAS  Google Scholar 

  23. Karlsson E, Lindström LS, Wilking U, Skoog L, Johansson U, Bergh J (2010) Discordance in hormone receptor status in breast cancer during tumor progression. J Clin Oncol 28(suppl 15):116s (abstr 1009)

    Google Scholar 

  24. Hammond ME, Hayes DF, Dowsett M, Allred DC, Hagerty KL, Badve S, Fitzgibbons PL, Francis G, Goldstein NS, Hayes M, Hicks DG, Lester S, Love R, Mangu PB, McShane L, Miller K, Osborne CK, Paik S, Perlmutter J, Rhodes A, Sasano H, Schwartz JN, Sweep FC, Taube S, Torlakovic EE, Valenstein P, Viale G, Visscher D, Wheeler T, Williams RB, Wittliff JL, Wolff AC (2010) American society of clinical oncology/college of American pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. Arch Pathol Lab Med 134(6):907–922. doi:10.1043/1543-2165-134.6.907

    PubMed  Google Scholar 

  25. Hammond ME, Hayes DF, Dowsett M, Allred DC, Hagerty KL, Badve S, Fitzgibbons PL, Francis G, Goldstein NS, Hayes M, Hicks DG, Lester S, Love R, Mangu PB, McShane L, Miller K, Osborne CK, Paik S, Perlmutter J, Rhodes A, Sasano H, Schwartz JN, Sweep FC, Taube S, Torlakovic EE, Valenstein P, Viale G, Visscher D, Wheeler T, Williams RB, Wittliff JL, Wolff AC (2010) American society of clinical oncology/college of American pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Clin Oncol 28(16):2784–2795. doi:10.1200/JCO.2009.25.6529

    Article  PubMed  Google Scholar 

  26. Hoefnagel LD, van de Vijver MJ, van Slooten HJ, Wesseling P, Wesseling J, Westenend PJ, Bart J, Seldenrijk CA, Nagtegaal ID, Oudejans J, van der Valk P, van der Groep P, de Vries EG, van der Wall E, van Diest PJ (2010) Receptor conversion in distant breast cancer metastases. Breast Cancer Res 12(5):75. doi:10.1186/bcr2645

    Article  Google Scholar 

  27. 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. Arch Pathol Lab Med 131(1):18–43. doi:10.1043/1543-2165(2007)131[18:ASOCCO]2.0.CO;2

    PubMed  CAS  Google Scholar 

  28. 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 

  29. Lower EE, Glass E, Blau R, Harman S (2009) HER-2/neu expression in primary and metastatic breast cancer. Breast Cancer Res Treat 113(2):301–306. doi:10.1007/s10549-008-9931-6

    Article  PubMed  CAS  Google Scholar 

  30. Bartlett AI, Starcyznski J, Robson T, Maclellan A, Campbell FM, van de Velde CJ, Hasenburg A, Markopoulos C, Seynaeve C, Rea D, Bartlett JM (2011) Heterogeneous HER2 gene amplification: impact on patient outcome and a clinically relevant definition. Am J Clin Pathol 136(2):266–274. doi:10.1309/AJCP0EN6AQMWETZZ

    Article  PubMed  CAS  Google Scholar 

  31. Iguchi C, Nio Y, Itakura M (2003) Heterogeneic expression of estrogen receptor between the primary tumor and the corresponding involved lymph nodes in patients with node-positive breast cancer and its implications in patient outcome. J Surg Oncol 83(2):85–93. doi:10.1002/jso.10243

    Article  PubMed  CAS  Google Scholar 

  32. Kamby C, Rasmussen BB, Kristensen B (1989) Oestrogen receptor status of primary breast carcinomas and their metastases. Relation to pattern of spread and survival after recurrence. Br J Cancer 60(2):252–257

    Article  PubMed  CAS  Google Scholar 

  33. Liu H, Fan Q, Zhang Z, Li X, Yu H, Meng F (2008) Basal-HER2 phenotype shows poorer survival than basal-like phenotype in hormone receptor-negative invasive breast cancers. Hum Pathol 39(2):167–174. doi:10.1016/j.humpath.2007.06.012

    Article  PubMed  CAS  Google Scholar 

  34. Fernandes RC, Bevilacqua JL, Soares IC, Siqueira SA, Pires L, Hegg R, Carvalho FM (2009) Coordinated expression of ER, PR and HER2 define different prognostic subtypes among poorly differentiated breast carcinomas. Histopathology 55(3):346–352. doi:10.1111/j.1365-2559.2009.03380.x

    Article  PubMed  Google Scholar 

  35. Hamm C, El-Masri M, Poliquin G, Poliquin V, Mathews J, Kanjeekal S, Alam Y, Kulkarni S, Elfiki T (2011) A single-centre chart review exploring the adjusted association between breast cancer phenotype and prognosis. Curr Oncol 18(4):191–196

    Article  PubMed  CAS  Google Scholar 

  36. Kasami M, Uematsu T, Honda M, Yabuzaki T, Sanuki J, Uchida Y, Sugimura H (2008) Comparison of estrogen receptor, progesterone receptor and Her-2 status in breast cancer pre- and post-neoadjuvant chemotherapy. Breast 17(5):523–527. doi:10.1016/j.breast.2008.04.002

    Article  PubMed  Google Scholar 

  37. Li XR, Liu M, Zhang YJ, Wang JD, Zheng YQ, Li J, Ma B, Song X (2010) Evaluation of ER, PgR, HER-2, Ki-67, cyclin D1, and nm23-H1 as predictors of pathological complete response to neoadjuvant chemotherapy for locally advanced breast cancer. Med Oncol. doi:10.1007/s12032-010-9676-z

    Google Scholar 

  38. Adams AL, Eltoum I, Krontiras H, Wang W, Chhieng DC (2008) The effect of neoadjuvant chemotherapy on histologic grade, hormone receptor status, and HER2/neu status in breast carcinoma. Breast J 14(2):141–146. doi:10.1111/j.1524-4741.2007.00544.x

    Article  PubMed  Google Scholar 

  39. D’Alfonso T, Liu YF, Monni S, Rosen PP, Shin SJ (2010) Accurately assessing her-2/neu status in needle core biopsies of breast cancer patients in the era of neoadjuvant therapy: emerging questions and considerations addressed. Am J Surg Pathol 34(4):575–581. doi:10.1097/PAS.0b013e3181d65639

    Article  PubMed  Google Scholar 

  40. Gruvberger-Saal SK, Bendahl PO, Saal LH, Laakso M, Hegardt C, Eden P, Peterson C, Malmstrom P, Isola J, Borg A, Ferno M (2007) Estrogen receptor beta expression is associated with tamoxifen response in ERalpha-negative breast carcinoma. Clin Cancer Res 13(7):1987–1994. doi:10.1158/1078-0432.CCR-06-1823

    Article  PubMed  CAS  Google Scholar 

  41. Bolanz KA, Kovacs GG, Landowski CP, Hediger MA (2009) Tamoxifen inhibits TRPV6 activity via estrogen receptor-independent pathways in TRPV6-expressing MCF-7 breast cancer cells. Mol Cancer Res 7(12):2000–2010. doi:10.1158/1541-7786.MCR-09-0188

    Article  PubMed  CAS  Google Scholar 

  42. Brunn Rasmussen B, Kamby C (1989) Immunohistochemical detection of estrogen receptors in paraffin sections from primary and metastatic breast cancer. Pathol Res Pract 185(6):856–859

    Article  PubMed  CAS  Google Scholar 

  43. Amir E, Miller N, Geddie W, Freedman O, Kassam F, Simmons C, Oldfield M, Dransitaris G, Tomlinson G, Laupacis A, Tannock IF, Clemons M (2012) Prospective study evaluating the impact of tissue confirmation of metastatic disease in patients with breast cancer. J Clin Oncol 30(6):587–592. doi:10.1200/JCO.2010.33.5232

    Google Scholar 

  44. Carlsson J, Nordgren H, Sjostrom J, Wester K, Villman K, Bengtsson NO, Ostenstad B, Lundqvist H, Blomqvist C (2004) HER2 expression in breast cancer primary tumours and corresponding metastases. Original data and literature review. Br J Cancer 90(12):2344–2348. doi:10.1038/sj.bjc.6601881

    PubMed  CAS  Google Scholar 

  45. D’Andrea MR, Limiti MR, Bari M, Zambenedetti P, Montagutti A, Ricci F, Pappagallo GL, Sartori D, Vinante O, Mingazzini PL (2007) Correlation between genetic and biological aspects in primary non-metastatic breast cancers and corresponding synchronous axillary lymph node metastasis. Breast Cancer Res Treat 101(3):279–284. doi:10.1007/s10549-006-9300-2

    Article  PubMed  Google Scholar 

  46. Dikicioglu E, Barutca S, Meydan N, Meteoglu I (2005) Biological characteristics of breast cancer at the primary tumour and the involved lymph nodes. Int J Clin Pract 59(9):1039–1044. doi:10.1111/j.1742-1241.2005.00546.x

    Article  PubMed  CAS  Google Scholar 

  47. Gancberg D, Di Leo A, Cardoso F, Rouas G, Pedrocchi M, Paesmans M, Verhest A, Bernard-Marty C, Piccart MJ, Larsimont D (2002) Comparison of HER-2 status between primary breast cancer and corresponding distant metastatic sites. Ann Oncol 13(7):1036–1043

    Article  PubMed  CAS  Google Scholar 

  48. De la Haba-Rodriguez JR, Ruiz Borrego M, Gomez Espana A, Villar Pastor C, Japon MA, Travado P, Moreno Nogueira JA, Lopez Rubio F, Aranda Aguilar E (2004) Comparative study of the immunohistochemical phenotype in breast cancer and its lymph node metastatic location. Cancer Invest 22(2):219–224

    Article  PubMed  Google Scholar 

  49. Masood S, Bui MM (2000) Assessment of Her-2/neu overexpression in primary breast cancers and their metastatic lesions: an immunohistochemical study. Ann Clin Lab Sci 30(3):259–265

    PubMed  CAS  Google Scholar 

  50. Niehans GA, Singleton TP, Dykoski D, Kiang DT (1993) Stability of HER-2/neu expression over time and at multiple metastatic sites. J Natl Cancer Inst 85(15):1230–1235

    Article  PubMed  CAS  Google Scholar 

  51. Regitnig P, Schippinger W, Lindbauer M, Samonigg H, Lax SF (2004) Change of HER-2/neu status in a subset of distant metastases from breast carcinomas. J Pathol 203(4):918–926. doi:10.1002/path.1592

    Article  PubMed  CAS  Google Scholar 

  52. Simmons C, Miller N, Geddie W, Gianfelice D, Oldfield M, Dranitsaris G, Clemons MJ (2009) Does confirmatory tumor biopsy alter the management of breast cancer patients with distant metastases? Ann Oncol 20(9):1499–1504. doi:10.1093/annonc/mdp028

    Article  PubMed  CAS  Google Scholar 

  53. Tanner M, Jarvinen P, Isola J (2001) Amplification of HER-2/neu and topoisomerase IIalpha in primary and metastatic breast cancer. Cancer Res 61(14):5345–5348

    PubMed  CAS  Google Scholar 

  54. Tapia C, Savic S, Wagner U, Schonegg R, Novotny H, Grilli B, Herzog M, Barascud AD, Zlobec I, Cathomas G, Terracciano L, Feichter G, Bubendorf L (2007) HER2 gene status in primary breast cancers and matched distant metastases. Breast Cancer Res 9(3):R31. doi:10.1186/bcr1676

    Article  PubMed  Google Scholar 

  55. Tsutsui S, Ohno S, Murakami S, Kataoka A, Kinoshita J, Hachitanda Y (2002) EGFR, c-erbB2 and p53 protein in the primary lesions and paired metastatic regional lymph nodes in breast cancer. Eur J Surg Oncol 28(4):383–387

    Article  PubMed  CAS  Google Scholar 

  56. van Agthoven T, Timmermans M, Dorssers LC, Henzen-Logmans SC (1995) Expression of estrogen, progesterone and epidermal growth factor receptors in primary and metastatic breast cancer. Int J Cancer 63(6):790–793

    Article  PubMed  Google Scholar 

  57. Xu R, Perle MA, Inghirami G, Chan W, Delgado Y, Feiner H (2002) Amplification of Her-2/neu gene in Her-2/neu-overexpressing and -nonexpressing breast carcinomas and their synchronous benign, premalignant, and metastatic lesions detected by FISH in archival material. Mod Pathol 15(2):116–124. doi:10.1038/modpathol.3880503

    Article  PubMed  Google Scholar 

  58. Zidan J, Dashkovsky I, Stayerman C, Basher W, Cozacov C, Hadary A (2005) Comparison of HER-2 overexpression in primary breast cancer and metastatic sites and its effect on biological targeting therapy of metastatic disease. Br J Cancer 93(5):552–556. doi:10.1038/sj.bjc.6602738

    Article  PubMed  CAS  Google Scholar 

  59. Quddus RM, Sung JC, Zhang C, Pasqueriello T, Eklund M, Steinhoff MM (2005) HER-2/neu expression in locally advanced breast carcinomas: pre-and post-neoadjuvant chemotherapy. Breast Cancer 12(4):294–298

    Article  PubMed  Google Scholar 

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Jabbour, M.N., Massad, C.Y. & Boulos, F.I. Variability in hormone and growth factor receptor expression in primary versus recurrent, metastatic, and post-neoadjuvant breast carcinoma. Breast Cancer Res Treat 135, 29–37 (2012). https://doi.org/10.1007/s10549-012-2047-z

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