CASI CLINICI: trattamento dei tumori HER2 positivi T1a,b N0 terapia sequenziale vs concomitante Federico Piacentini MD Department of Oncology, Hematology and Respiratory Diseases Modena University Hospital – Italy Nonantola 18-19 Novembre 2011

CLINICAL CASE - CASE HISTORY - 46-year old pre-menopausal woman APRIL 1985: diagnosis of stage II Hodgkin Lymphoma, treated with MOPP x6 and mantle field RT SEPTEMBER 2010: screen detected left breast carcinoma conservative surgery and axillary node dissection pT1b (0.6 cm) N0 (0/13), high grade, infiltrating ductal carcinoma ER 95%, PgR 90%, MIB1 20% HER2 score 3+ by IHC, HER2 amplification by FISH: HER2/CEP17 >3 normal echocardiography with LVEF 60% MOPP MECLORETAMINA-VINCRISTINA–PROCARBAZINA-PREDNISONE

Would you recommend adjuvant treatment(s) ? - CLINICAL CASE - pT1b N0, infiltrating ductal carcinoma G3, ER 95%, PgR 90%, MIB1 20%, FISH positive Would you recommend adjuvant treatment(s) ? Yes No

Clinical outcome of pts Clinical outcome of pts. with HER2+, T1a,bN0M0 BC treated w/o trastuzumab

Which regimen would you recommend? - CLINICAL CASE - pT1b N0, infiltrating ductal carcinoma G3, ER 95%, PgR 90%, MIB1 20%, FISH positive Which regimen would you recommend? Chemotherapy plus trastuzumab - endocrine therapy at the end of chemoRx Chemotherapy followed by endocrine therapy without trastuzumab Endocrine therapy alone Endocrine therapy (w/o chemoRx) + trastuzumab (off label)

Adjuvant trastuzumab trials: patient characteristics Regimen N° T ≤ 2 cm (%) N0 (%) HR+ HERA Observation 1698 43 33 50 H (1 year) 1703 39 32 Joint analysis B31/N9831 AC  T 2017 40 15 52 AC  TH (1 year) 2028 38 14 51 BCIRG 006 AC  D 1073 41 29 54 AC  DH (1 year) 1074 28 DCcH (1 year) 1075 FinHER DV  FEC 116 30 22 NR DVH (9 weeks)  FEC 10 PACS-04 FEC or ED 268 49 - 61 FEC or ED  H (1 year) 260 58

DFS improvement in node-negative cohort of HERA trial The node negative subgroup included 93 (8.5%) patients with tumor < 1cm in size Untch M et al, Ann Oncol 2008; 19: 1090-1096

DFS in node-negative cohort of BCIRG 006 trial T1a,b tumors eligible if N+ or N- with at least one of the following: ER-/PgR-; G2-3; <35 years DFS by tumor size in BCIRG 006 trial p 0.03 p 0.09 Supplement to: Slamon et al., NEJM 2011; 365:1273-83

- CLINICAL CASE – pre-treated for Hodgkin Lymphoma pT1b N0, infiltrating ductal carcinoma G3, ER 95%, PgR 90%, MIB1 20%, FISH positive If you choose chemoRx + trastuzumab, which regimen would you recommend? AC followed by taxane plus 1 yr trastuzumab Non anthra-based regimen plus 1 yr trastuzumab ChemoRx with short duration of trastuzumab (ShortHER trial) Other

Which schedule of trastuzumab? - CLINICAL CASE – pre-treated for Hodgkin Lymphoma pT1b N0, infiltrating ductal carcinoma G3, ER 95%, PgR 90%, MIB1 20%, FISH positive Which schedule of trastuzumab? Trastuzumab administered sequentially for 1 year after the completion of chemotherapy Trastuzumab started concomitantly with chemotherapy and administered up to 1 year

Sequential vs Concurrent trastuzumab NCCTG N9831 trial - Follow up mediano di 6 anni - When testing - Whether DFS differed with respect to the timing of trastuzumab addition to AC then paclitaxel, the log-rank P value was .0216, which did not cross the prespecified O’Brien-Fleming boundary of significance (.00116) at this first interim analysis Perez EA et al., JCO 2011

BCIRG 006 ADVERSE EVENTS Slamon et al., NEJM 2011; 365:1273-83

adjuvant trastuzumab and cardiotoxicity Trial CHF NYHA 3-4 % Syst. dysf. % No trastuzumab 0-0.7 NR BCIRG 006 DCH 0.4 HERA 0.6 1.4 N9831 armB (seq) 2.8 5.0 BCIRG 006 AC-DH 2.0 N9831 armC (comb) 3.3 6.6 NSABP B31 3.8 11.7

… OUR CHOICE … RT* OT** q 3w, for one year * IG-IMRT by Tomotherapy Related citations 8. Image-guided intensity-modulated radiotherapy RT* OT** Docetaxel + Carboplatin Trastuzumab * IG-IMRT by Tomotherapy ** LhRh-agonist plus Tamoxifen