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  1. 1. Grand RoundsGrand Rounds 12-15-200612-15-2006 Her-2 or notHer-2 or not Coy HeldermonCoy Heldermon
  2. 2. CaseCase 1999 - T1cN0M0, ER+/PR+/Her-2 negative1999 - T1cN0M0, ER+/PR+/Her-2 negative by IHC, invasive ductal carcinoma of rightby IHC, invasive ductal carcinoma of right breast treated with MRM and 4 cycles ACbreast treated with MRM and 4 cycles AC and tamoxifen for five years.and tamoxifen for five years. 2005 – paratracheal node biopsied –2005 – paratracheal node biopsied – ER+/PR+/Her-2 amplified by FISH.ER+/PR+/Her-2 amplified by FISH.
  3. 3. Is the node from a differentIs the node from a different primary?primary? Was the first breast cancerWas the first breast cancer pathology incorrect?pathology incorrect? Did her original cancer evolveDid her original cancer evolve into a Her-2 positive form?into a Her-2 positive form?
  4. 4. Differences in Estrogen Receptor Status, HER2, and p53 Comparing Metachronous Bilateral Breast Carcinoma KANEYUKI MATSUO, MD,1 TAKASHI FUKUTOMI, MD,1 HITOSHI TSUDA, MD,2 SADAKO AKASHI-TANAKA, MD,1 CHIKAKO SHIMIZU, MD,1 and TADASHI HASEGAWA, MD Journal of Surgical Oncology 2001;77:31±34
  5. 5. Predicting the HER2 status of breast cancer from basic histopathology data: an analysis of 1500 breast cancers as part of the HER2000 International Study M. Bilous, C. Ades, J. Armes, J. Bishop, R. Brown, B. Cooke, M. Cummings, G. Farshid, A. Field, A. Morey, P. McKenzie, W. Raymond, P. Robbins and L. Tan The Breast (2003) 12, 92–98
  6. 6.  Maybe a new primaryMaybe a new primary  What about the test?What about the test?
  7. 7. Evaluating HER2 amplification and overexpression in breast cancer John M. S. Bartlett*, James J. Going, Elizabeth A. Mallon, Amanda D. Watters, Jonathan R. Reeves, Peter Stanton, Jim Richmond, Brian Donald, Rhona Ferrier and Timothy G. Cooke J Pathol 2001; 195: 422–428.
  8. 8. JAMA, April 28, 2004—Vol 291, No. 16 2963 patients (median age,56 years) with breast cancer received from 135 hospitals and cancer centers in 29 states, was performed at a reference laboratory from January 1, 1999, to May 15, 2003. Every specimen evaluated by FISH was parallel tested with immunohistochemistry tests.
  9. 9. Assessment of Methods for Tissue-Based Detection of the HER-2/neu Alteration in Human Breast Cancer: A Direct Comparison of Fluorescence In Situ Hybridization and Immunohistochemistry By Giovanni Pauletti, Suganda Dandekar, HongMei Rong, Lilllian Ramos, HongJun Peng, Ram Seshadri, and Dennis J. Slamon Journal of Clinical Oncology, Vol 18, No 21 (November 1), 2000: pp 3651-3664
  10. 10. Targeted Therapy in Breast Cancer THE HER-2/neu GENE AND PROTEIN Jeffrey S. Ross‡§¶, Jonathan A. Fletcher, Kenneth J. Bloom**, Gerald P. Linette§‡‡, James Stec§, W. Fraser Symmans§§, Lajos Pusztai§§, and Gabriel N. Hortobagyi§§ Molecular & Cellular Proteomics 3.4
  11. 11. Diagnostic Evaluation of HER-2 as a MolecularTarget: An Assessment of Accuracy and Reproducibility of Laboratory Testing in Large, Prospective, Randomized ClinicalTrials Michael F. Press,1,2 Guido Sauter,5 Leslie Bernstein,1,3 Ivonne E.Villalobos,2MartinaMirlacher,5 Jian-Yuan Zhou,2 RoobaWardeh,2 Yong-Tian Li,2 Roberta Guzman,2 Yanling Ma,2 Jane Sullivan- Halley,3 Angela Santiago,2 Jinha M. Park,4 Alessandro Riva,6 and Dennis J.Slamon4 Clin Cancer Res 2005;11(18) September 15, 2005 BCIRG clinical trial Participants analyzed By FISH and/or IHC n-2600, FISH n-2507
  12. 12.  So the test may not be so good….So the test may not be so good….  Could it be the tumor is changing?Could it be the tumor is changing?
  13. 13. Monitoring expression of HER-2 on circulating epithelial cells in patients with advanced breast cancer D.F. HAYES1,4, T.M. WALKER1, B. SINGH1, E.S. VITETTA2, J.W. UHR2, S. GROSS3, C. RAO3, G.V. DOYLE3 and L.W.M.M. TERSTAPPEN3 INTERNATIONAL JOURNAL OF ONCOLOGY 21: 1111-1117, 2002
  14. 14. Heterogeneous gene alterations in primary breast cancer contribute to discordance between primary and asynchronous metastatic/recurrent sites:HER2 gene amplification and p53 mutation YASUTOMO SEKIDO1, SHINOBU UMEMURA1, SUSUMU TAKEKOSHI1, YASUHIRO SUZUKI2, YUTAKA TOKUDA2, TOMOO TAJIMA2 and R. YOSHIYUKI OSAMURA1 INTERNATIONAL JOURNAL OF ONCOLOGY 22: 1225-1232, 2003
  15. 15. Comparison of HER-2 status between primary breast cancer and corresponding distant metastatic sites.Comparison of HER-2 status between primary breast cancer and corresponding distant metastatic sites. GancbergGancberg DD,, Di Leo ADi Leo A,, CardosoCardoso FF,, RouasRouas GG,, PedrocchiPedrocchi MM,, PaesmansPaesmans MM,, VerhestVerhest AA,, BernardMartyBernardMarty CC,, PiccartPiccart MJMJ ,, LarsimontLarsimont DD.. Ann Oncol. 2002 Jul;13(7):1036-43.Ann Oncol. 2002 Jul;13(7):1036-43. Analyzed Her-2 by FISH and IHCAnalyzed Her-2 by FISH and IHC (Herceptest) for 107 patients with a(Herceptest) for 107 patients with a primary and metastatic biopsy.primary and metastatic biopsy. By IHC 6% and by FISH 7% (40% + in 1By IHC 6% and by FISH 7% (40% + in 1°,°, 60% + in met.)60% + in met.) were discordant.were discordant. For 17 patients with multiple metastatic sitesFor 17 patients with multiple metastatic sites biopsied: 18% IHC and 19% FISHbiopsied: 18% IHC and 19% FISH discordance.discordance.
  16. 16.  For our patient it doesn’t matter now. SheFor our patient it doesn’t matter now. She received Herceptin and endocrine therapyreceived Herceptin and endocrine therapy with a good response for > 1 year.with a good response for > 1 year.  Does it matter? - If she was actuallyDoes it matter? - If she was actually originally Her-2 positive and being seen inoriginally Her-2 positive and being seen in the adjuvant setting now, she mightthe adjuvant setting now, she might possibly get herceptin (though not likelypossibly get herceptin (though not likely given her original stage) and possibly notgiven her original stage) and possibly not be dealing with recurrence OR be in heartbe dealing with recurrence OR be in heart failure.failure.  Current guidelines call for initial IHC withCurrent guidelines call for initial IHC with FISH follow-up if 2+, or FISH to start.FISH follow-up if 2+, or FISH to start.
  17. 17.  The adjuvant trials allowed either strategyThe adjuvant trials allowed either strategy but mostly saw IHC done.but mostly saw IHC done.  These trials, as shown and in otherThese trials, as shown and in other articles, demonstrated 20-33%articles, demonstrated 20-33% discordance for local and central IHCdiscordance for local and central IHC testing and 8-26% discordance for FISHtesting and 8-26% discordance for FISH testing.testing.  The more tests a center did the more likelyThe more tests a center did the more likely it corresponded to the central lab.it corresponded to the central lab.
  18. 18.  Be aware and interactive with yourBe aware and interactive with your pathology lab.pathology lab.  Repeat outside lab tests if done at non-Repeat outside lab tests if done at non- tertiary centers, especially if FISH was nottertiary centers, especially if FISH was not done.done.
  19. 19.  Don’t get me started on ER testing…….Don’t get me started on ER testing…….

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