NEO ADJUVANT THERAPY IN HER 2 ENRIHED CANCER
- 1. NEOADJUVANT THERAPY IN HER2+ BREAST CANCER
- 2. HUMAN EPIDERMAL GROWTH FACTOR RECEPTOR 2  One of the Tyrosine kinase receptor 1,2,3,4  Function – Heterodimerization with HER 1/3 and initiates various signaling pathways and causes cell proliferation,survival,differentiation,angiogenesis & invasion  Overexpressed in 15-30% cases
- 3. TESTING FOR HER2 IHC – 0, 1+, 2+, 3+ FISH  HER 2/CEP 17 ratio  Average copy number signals FISH + Ratio >-2 and signals >-4 Ratio <2 and signals >-6
- 4. HER 2 BLOCKERS ï‚¢ TRASTUZUMAB HUMANISED IgG1 1998 ï‚¢ PERTUZUMAB 2012 ï‚¢ ADO TRASTUZUMAB EMTANSINE IgG1 (DM1) 2013 ï‚¢ TRASTUZUMAB DERUXTECAN DX8951 2019 ï‚¢ MARGETUXIMAB CHIMERIC 2020
- 5. PCR  pCR –  15 -40%  > 50% - HER2 ENRICHED
- 6. INDICATION FOR NEOADJUVANT THERAPY IN HER2+  Facilitates breast conservation , Render inoperable tumors operable  Provides important prognostic information  pCR - favourable DFS & OS  Residual disease - higher risk for relapse – modify adjuvant therapy  Early addressal of micrometastatic disease  Allows time for genetic testing  Allows time to plan breast reconstruction  Allows time for delayed decision-making for definitive surgery
- 7. PREFERRED REGIMENS ï‚¢ Paclitaxel +Trastuzumab ï‚¢ TCH ï‚¢ TCHP ï‚¢ AC f/b Pacli/Doce + trastuzumab ï‚¢ AC f/b Pacli/Doce + H+P ï‚¢ Pacli + H+P
- 8. EVIDENCES FAVOURING ADDITION OF TRASTUZUMAB WITH PREOP SYSTEMIC CHEMO  NeOAdjuvant Herceptin (NOAH) trial - 2010  HER2-positive Locally advanced or inflammatory breast cancer  2002 – 2005 N - 235 pCR 5yr DFS 5 yr OS Chemo + H 117 45 58 % 74 Chemo 118 23 43 63
- 9. A.U. BUZDAR, N.K. IBRAHIM, D. FRANCIS, 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, 23 (2005), PP. 3676-3685 ï‚¢ 42 pts with HER 2+ operable breast cancer ï‚¢ Study stopped prematurely because of superiority of trastuzumab arm ï‚¢ Adding trastuzumab to chemo increases pCR 42 pCR DFS 4 Pacli +4 FEC 19 25% 85.3 4 Pacli + 4 FEC +H (weekly 24ks) 23 66.7% 100
- 10. GeparQuattro study ï‚¢ 2010 STAGE III 620pts 24 wks ï‚¢ NSABP B41 pCR 4EC/L f/b 4Doce +L 22.7 % 4EC/H f/b 4Doce +H 30.3 % NSABP B41 28wks 529 pts AC+TH 52.5 AC+TL 53.2 AC+THL 62
- 11.  4 EC (90/600 mg/m(2)) f/b 4 paclitaxel (175 mg/m(2)) & trastuzumab (6 mg/kg) before surgery. Trastuzumab was continued after surgery to complete 1 year of treatment. Primary end point was pathologic complete response (pCR)  pCR – 38.7%  3 yr DFS in pCR pts - 88%  3 yr OS - 96% Untch M, Fasching PA, Konecny GE, Hasmüller S, Lebeau A, Kreienberg R, Camara O, Müller V, du Bois A, Kühn T, Stickeler E, Harbeck N, Höss C, Kahlert S, Beck T, Fett W, Mehta KM, von Minckwitz G, Loibl S. Pathologic complete response after neoadjuvant chemotherapy plus trastuzumab predicts favorable survival in human epidermal growth factor receptor 2-overexpressing breast cancer: results from the TECHNO trial of the AGO and GBG study groups. J Clin Oncol. 2011 Sep 1;29(25):3351-7. doi: 10.1200/JCO.2010.31.4930. Epub 2011 Jul 25. PMID: 21788566.
- 12. LAPATINIB WITH TRASTUZUMAB FOR HER2-POSITIVE EARLY BREAST CANCER (NEOALTTO): SURVIVAL OUTCOMES OF A RANDOMISED, OPEN-LABEL, MULTICENTRE, PHASE 3 TRIAL AND THEIR ASSOCIATION WITH PATHOLOGICAL COMPLETE RESPONSE 18 wks N - 450 pCR LAPATINIB 24.7 TRASUZUMAB 29.5 LAPATINIB + TRASTUZUMAB 51.3% pCR Non pCR 3Yr DFS 86 72 3yr OS 94 87 50% HR+ 50 HR- 60 %T2 80% N0/1
- 13. PERTUZUMAB ï‚¢ Stage II, III ï‚¢ Binds to HER 2& 3 ,prevents dimerization
- 14. NEOPHERE TRIAL GIANNI ET AL ï‚¢ No difference in cardiotoxicity with addition of pertuzumab ï‚¢ 417, Phase II ï‚¢ Neoadj f/b surgery f/b FEC 3 cycles with maintenance trastuzumb N - 417 pCR 5 yr DFS 4Doce + H 107 29 81 4Doce + H + P 107 45.8 84 4Doce + P 96 16.8 75 4H + P 107 24 80
- 15. TRYPHAENA TRIAL  Phase II 225 pCR PFS 3FEC+H+P f/b 3Doce+H+P 61.6 87 3FEC f/b 3Doce+H+P 57.3 88 TCHP 66.2 89 FEC – 500,100,600 mg/m2 CARBO AUC 6 DOCE 75 H 8mg/kg f/b 6mg/kg P 840mg f/b 420mg
- 18. TDM1 ï‚¢ Ab - Trastuzumab ï‚¢ Cytotoxic - DM1 ï‚¢ Stable linker - MCC ï‚¢ Antibody drug conjugate ï‚¢ Induces cell death by inhibiting microtubule polymerization ï‚¢ Activates antibody dependent cell mediated cytotoxicity
- 19. KRISTINE ï‚¢ 432 Phase III ï‚¢ I SPY 2 248 PHASE 2/3 pCR TDM1+P 44.4 Pacli+Carbo+H+P 55.7 pCR TDM1+P 52 H+Doce 22
- 20. CALBG 40601 pCR TRASTUZUMB+ Pacli 46 LAPATINIB+ Pacli 32 LAPATINIB+H+Pacli 56 NSABP B41 phase III 529 pCR AC f/b Pacli+H 52.5 AC f/b Lapatinib+pacli 53.2 A f/b Pali+H+Lapatinib 62
- 21. THANK YOU