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L’HER2-positività: dall’anatamopatologia alla clinica Cosa altro è importante sapere oltre l’HER2 status: recettori ormonali, profili di espressione genica… Stefania Gori Oncologia Medica- Perugia Prognosis of metastatic breast cancer by HER2 status and trastuzumab treatment HER2+ 25% 13% HER2+ MBC: worse survival Dawood S, JCO 2010 1st line therapy of MBC: anti-HER2 agent + CT RESULTS from randomized trials Slamon DJ NEJM 2001 Phase III Marty M JCO 2005 Phase IIR Di Leo A JCO 2007 (subgroup of pts) Zhong-Zhen G SABCS 2010 Phase III N pts/ arm Treatment ORR DOR TTP OS 92 w trastuzumab + paclitaxel 175 38%* 10.5 mo* 6.9 mo* 22.1 mo* 96 w paclitaxel 16% 4.5 mo 3.0 mo 18.4 mo 92 w trastuzumab+ docetaxel 100 61%* 11.7 mo 11.7 mo* 31.2 mo* 94 docetaxel 34% 5.7 mo 6.1 mo 22.7 mo 49 lapatinib 1500+ paclitaxel 175 63%* 8.0 mo 8.1 mo * 24.0 mo 37 paclitaxel 38% 6.O mo 5.1 mo 19.1 mo 222 lapatinib 1500+ w paclitaxel 80 (3/4) 69%* 9.3 mo 9.7 mo* (PFS) 27.8 mo* 222 w paclitaxel 50% 5.8 mo 6.5 mo 20.5 mo * Statistically significant difference versus CT arm Time from diagnosis (months) Multivariate model HER2+ and trastuzumab HR of death vs HER2-negative 0.56; 95% CI 0.45-0.69; p< .0001 Multivariate model HER2+ and trastuzumab HR of death vs HER2+ no trastuzumab 045; 95% CI 0.33-0.63; p< .0001 Dawood S, JCO 2010 HER2-positive breast cancer HR status HER2HER2+ HER2HER2+ HER2+ HER2+ * * Time from diagnosis-months HR-negative Time from diagnosis-months HR-positive Overall survival by Trastuzumab treatment group and according to hormone receptor status 5y-OS HER2+ HR8.9 mo HR- and trastuzumab 17.7 mo 5y-OS HER2+ HR+ 14.5 mo HR+ and Trastuzumab 29.7 mo Even in presence of trastuzumab, HR status is still a prognostic factor in MBC Dawood S, JCO 2010 HER2+ and HR+ MBC: Anti-HER2 plus hormonal therapy ORR PFS OS TAnDEM Kaufman B 103 Anastrozole+Trastuzumab 4.8%* 5.6 mo* 28.5 mo JCO 2009 104 Anastrozole 2.4% 3.8 mo 23.9 mo Letrozole+ lapatinib 28%* 8.2 mo* 34.1 mo Letrozole+ placebo 15% 3.0 mo 28.6 mo Schwarzberg LS 111 Oncologist 2010 (219 out of 1,286 =17%) 108 1st line therapy in HR+ and HER2+ MBC Poor PS No/limited visceral metastases Slowly Progression Expression of HR Good PS Visceral metastases Rapidly progressing Trastuzumab+ Anastrozole Trastuzumab+ Taxane Lapatinib+ Letrozole Lapatinib+ Capecitabine Neoadjuvant CT in unselected for HER2 status BC Outcome by pCR and HR status No. PFS 5-y 10-y 50% vs 83% 43% vs 73% 65% vs 91% 38% vs 76% p OS 5-y 10-y 67% vs 84% 59% vs 84% 84% vs 96% 41% vs 96% p HR-negative No pCR 423 pCR 132 (24%) <.0001 .003 HR-positive No pCR pCR 1072 91 (8%) .002 Guarnieri V, JCO 2006 .04 NEOALTTO1 NEOSPHERE2 Phase III lapatinib paclitaxel R trastuzumab paclitaxel Operable T >2 cm Phase II N=450 lapatinib trastuzumab paclitaxel 6 wks docetaxel + pertuzumab L S U R G E R Y F E T C X 3 + 12 wks L+T R Operable or LABC/IBC docetaxel + trastuzumab trastuzumab + pertuzumab docetaxel + trastuzumab + pertuzumab 3 N=417 S U R G E R Y FECx3 T FECx3 T D FEC T FECx3 T 34 wks 52 wks of anti-HER2 1. Baselga J. et al, SABC 2010; 2 Gianni L et al, SABC 2010 52 wks of anti-HER2 NEOALTTO:pCR by Hormone Receptor Status L: lapatinib; T: trastuzumab; L+T: lapatinib plus trastuzumab pCR pathologic complete response HR: hormone receptors NeoSphere: pCR and hormone receptors status 70 pCR, % 95% CI 60 ER or PR pos ER and PR neg 50 63.2 40 30 20 36.8 10 0 26.0 5.9 20.0 TH H, trastuzumab; P, pertuzumab; T, docetaxel THP 30.0 29.1 17.4 HP TP 7 CHERLOB: Study plan C O R E 121 pts II-IIIA T>2cm B I O P S Y Paclitaxel 80 R A N D O M I Z A T I O N mg/m2 A B Lapatinib 1500 mg continuous daily dose (CDD) S U R G E R Y C Lapatinib 1000 mg CDD 5 FU 600 mg/m2 Epi 75 mg/m2 CTX 600 mg/m2 Trastuzumab 2 mg/kg LVEF Guarneri V, ASCO 2011 #507 [TITLE] Guarneri V, ASCO 2011 #507 [TITLE] HER2- positività: Stato dei Recettori ormonali Setting metastatico • Lo stato dei recettori ormonali identifica sottogruppi con diversa prognosi, indipendentemente dal trattamento con trastuzumab • Possono essere identicabili , da un punto di vista clinico, sottogruppi di pts HR+ candidabili a terapia di 1a linea con ormonoterapia + agente antiHER2 HER2- positività: Stato dei Recettori ormonali Setting neoadiuvante • Predice il tasso di pCR ottenibile con CT+ agenti anti-HER2 pCR % inferiore nei tumori HR+ vs HR- HER2-positive breast cancer Gene- expression profiling Luminal A Luminal A Luminal B Luminal B HER2+ Basal OS months HER2+ Basal RFS months Survival analysis of the 49 breast cancer patients , uniformly treated in a prospective study, based on different gene expression classification Sorlie T, PNAS 2001; 98:10869-10874 Immunohistochemical identification of breast tumour intrinsic subtypes. Carey L A, JAMA 2006; 295: 2492-2502 Ki-67 labeling index is important in the distinction between Luminal A and Luminal B-HER2 -negative subtypes ER and/orPgR HER2 Ki-67 Cytokeratin Luminal A positive negative low (<14%) -- Luminal B positive negative high -- positive positive any -- HER2-enriched negative positive -- -- Basal-like absent negative -- Cytokeratin 5/6 + and /or HER1+ Cheang MCU, JNCI 2009; 101:736-50 Cheang MCU, JNCI 2009;101:736-50 Survival by 70-gene Mammaprint signature for 89 HER2+ pts who did not receive CT or trastuzumab Knauer M, BJC 2010; 103:1788-93 The 70-gene prognosis signature is an independent prognostic indicator that identifies a Survival by 70-gene Mammaprint signature for 89 HER2+ pts who did not subgroup of HER2-positive early BC with a receive CT or trastuzumab Knauer M, BJC 2010; 103:1788-93 favorable long-term outcome Mechanisms of resistance to trastuzumab Prevention of trastuzumab binding to HER2 Inhibition of immune-mediate mechanisms Upregulation of signaling pathways downstream of HER2 Upregulation of alternative growth factor receptor – signaling pathways HER2-positive breast cancer p95-HER2 status p95HER2 is expressed in 30% of HER2+ BC Trastuzumab p95HER2 …by either proteolytic shedding of ECD1 or by alternative initiation of translation of the HER2 mRNA2 1. Codoni-Servat J, Cancer Res 1999;59:1196-201 2. Anido J, EMBO J 2006; 25:3234-44 p95HER2 and Response to Trastuzumab 46 patients with MBC treated with trastuzumab1 1Scaltriti, M JNCI 2007 p95HER2 and Reponse to Trastuzumab 46 patients with MBC treated with trastuzumab1 1Scaltriti, M JNCI 2007 V et al. ASCO 2011 #507 2Guarneri, 29 patients with EBC treated with neoadj. trastuzumab (CherLob)2 GeparQuattro: p95HER2 and Response to Trastuzumab (N=145 patients treated with EC+T Doc+T) P<0.0001 (>20% strongly positive for 611 CTF) (≤20% strongly positive for 611 CTF) Loibl S et al, ASCO 2011 Abstr #530 pCR rate according to p95HER2 expression: p95HER2 status does not predict pCR rate following treatment with CT+ trastuzumab or lapatinib or the combination of both Cut-off at 80% P= 0.44 60 54% P= 0.68 50 P= 1 40 33.3% 35.7% 33% 30% 30 25% 20 10 p95 + n=2/6 p95 – n=7/23 p95 + n=3/12 p95 – n=5/14 p95 + n=3/9 p95 – n=13/24 0 Arm A (CT + T) Arm B (CT +L) Arm C (CT + T + L) In all treatment arms, no significant difference in pCR rates at 80% or other cut-offs evaluated Guarneri V- ASCO 2011 #507 p95HER2 and clinical response to lapatinib (PFS) Results from 68 and 156 MBC pts Lapatinib monotherapy- Lapatinib+ capecitabine- EGF20009 EGF100151 Scaltriti M, Clin Cancer Res 2010 HER2- positività: p95 HER2 Setting metastatico • p95HER2+ resistenza al trastuzumab 1 • Lapatinib efficace sia nei tumori p95HER2+ che p95HER- 2 Setting neoadiuvante • Risultati contrastanti 3-4 1. Scaltriti 2007; 2.Scaltriti 2010; 3.Guarneri ASCO 2011; 4.Lobi ASCO 2011 HER2-positive breast cancer PTEN status IHC expression of PTEN (a negative regulator of Akt activities) EGF, TGF-α HER2 EGFR PI(4,5)P2 PI(3,4,5)P3 PI3-K P P P P Grb2 SOS P RAS-GDP PTEN GTP PDK1,2 PDK1,2 Akt/PKB RAS-GTP TKI RAF Survival pathway MEK ERK Proliferation pathway P < 0.001 Nagata Y, Cancer Cell 2004 Background PTEN Impact on Sensitivity or Resistance to Trastuzumab • Preclinical data suggest PTEN loss associated with trastuzumab resistance – O’Brien 2010; Stemke-Hale 2008; Saal 2005; Nagata 2004 • Clinical data available to date: limited and conflicting – PTEN loss associated with trastuzumab resistance • Dave 2011; Esteva 2010 ; Razi SE 2011 – PTEN loss NOT associated with trastuzumab resistance • Fabi 2010; Gori 2009; Yonemori 2009 Perez EA – ASCO 2011 Gori S, et al PTEN status negative (Nagata score <9): 60% (Nagata score <4): 15% PTEN status evaluated by IHC in 45 HER2+ MBC treated with trastuzumab-based therapy was not significantly associated with outcome (ORR, TTP, OS). Gianni L, ASCO 2008 #504 Background NCCTG N9831 Trial Incorporating Trastuzumab in Adjuvant Therapy Arm A (1232 pts) HER2 positive (FISH ratio ≥2 or IHC 3+ >10%) n=3,505 R A N D O M I Z E AC T Arm B (1216 pts) AC T H Arm C (1057 pts) AC T H = AC (doxorubicin/cyclophosphamide 60/600 mg/m2 q3w × 4) = T (paclitaxel 80 mg/m2/wk × 12) = H (trastuzumab 4 mg/kg loading + 2 mg/kg/wk × 51) Perez EA. Protocol NCCTG-N9831 Conclusions • Data and results were similar across both analyses • In contrast to some preclinical and limited clinical studies, loss of PTEN protein expression was not associated with decreased tumor sensitivity to adjuvant trastuzumab – Data demonstrate benefit of treating HER2+ breast cancer pts with adjuvant trastuzumab regardless of PTEN protein expression status Perez EA, et al. J Clin Oncol 2011; 29(15s)Part I: 631s HER2- positività: PTEN status Setting metastatico • Risultati contrastanti PTEN –: ORR % inferiori rispetto ai PTEN+ (Nagata Y, Cancer Cell 2004) Nessuna differenza in outcome tra PTEN- e PTEN + (Gori S, Ann Oncol 2009) Setting neoadiuvante • Espressione di PTEN non è associata a pCR (NOAH- Gianni L, ASCO 2008) Setting adiuvante • PTEN-negatività non si correla ad una ridotta DFS nei gruppi trattati con Trastuzumab (Perez EA; ASCO 2011) HER2-positive breast cancer HER3 status HER3 status by immunohistochemistry in HER2-positive metastatic breast cancer patients treated with trastuzumab: correlation with clinical outcome. Gori S et al, TUMORI 2011 in press A B IHC expression of HER3 in HER2+ MBC (immunoperoxidase, 400 x) A. HER3–negative (positive tumour cells 50%) B. HER3-positive (positive tumour cells >50%) 30 pts 31 pts HER3 status by IHC was not significantly associated with clinical outcome HER3-negative status by IHC in HER2-positive MBC: longer OS and TTP A 1,0 1,0 HER3 cut-off 50% HER3 cut-off 50% HER3 <= 50% HER3 <= 50% HER3 >50% HER3 >50% HER3 <= 50%-censored HER3 <= 50%-censored HER3 >50%-censored 0,8 0,6 0,6 Cum Survival Cum Survival HER3 >50%-censored 0,8 0,4 0,4 log rank= 0.131 log rank= 0.304 0,2 0,2 0,0 0,0 0,0 25,0 50,0 75,0 100,0 OS from start of herceptin 125,0 0,0 20,0 40,0 60,0 80,0 TTP_from start trastuzumab Gori S et al, TUMORI 2011 in press NOAH trial Gianni L, ASCO 2008 Oltre lo stato di HER2- positività CONCLUSIONI 1. I tumori HER2+ non sono un gruppo omogeneo 2. Ad oggi, nei tumori HER2+, l’unico altro dato a disposizione utile a fini prognostici e terapeutici, è lo stato dei recettori ormonali THANK YOU !