Presentation is loading. Please wait.

Presentation is loading. Please wait.

Cosa altro è importante sapere oltre lHER2 status: recettori ormonali, profili di espressione genica… LHER2-positività: dallanatamopatologia alla clinica.

Similar presentations


Presentation on theme: "Cosa altro è importante sapere oltre lHER2 status: recettori ormonali, profili di espressione genica… LHER2-positività: dallanatamopatologia alla clinica."— Presentation transcript:

1 Cosa altro è importante sapere oltre lHER2 status: recettori ormonali, profili di espressione genica… LHER2-positività: dallanatamopatologia alla clinica Stefania Gori Oncologia Medica- Perugia

2 Dawood S, JCO 2010 HER2+ HER2+ MBC: worse survival Prognosis of metastatic breast cancer by HER2 status and trastuzumab treatment 13% 25%

3 1st line therapy of MBC: anti-HER2 agent + CT RESULTS from randomized trials N pts/ arm TreatmentORRDORTTPOS Slamon DJ NEJM 2001 Phase III w trastuzumab + paclitaxel 175 w paclitaxel 38%* 16% 10.5 mo* 4.5 mo 6.9 mo* 3.0 mo 22.1 mo* 18.4 mo Marty M JCO 2005 Phase IIR w trastuzumab+ docetaxel 100 docetaxel 61%* 34% 11.7 mo 5.7 mo 11.7 mo* 6.1 mo 31.2 mo* 22.7 mo Di Leo A JCO 2007 (subgroup of pts) lapatinib paclitaxel 175 paclitaxel 63%* 38% 8.0 mo 6.O mo 8.1 mo * 5.1 mo 24.0 mo 19.1 mo Zhong-Zhen G SABCS 2010 Phase III 222 lapatinib w paclitaxel 80 (3/4) w paclitaxel 69%* 50% 9.3 mo 5.8 mo 9.7 mo* (PFS) 6.5 mo 27.8 mo* 20.5 mo * Statistically significant difference versus CT arm

4 Dawood S, JCO 2010 Multivariate model HER2+ and trastuzumab vs HER2-negative HR of death 0.56; 95% CI ; p<.0001 Time from diagnosis (months) Multivariate model HER2+ and trastuzumab vs HER2+ no trastuzumab HR of death 045; 95% CI ; p<.0001

5 HR status HER2-positive breast cancer

6 HR-negativeHR-positive Overall survival by Trastuzumab treatment group and according to hormone receptor status HER2+ HER2- 5y-OS 5y-OS HER2+ HR- 8.9 mo HR mo HR- and trastuzumab 17.7 mo HR+ and Trastuzumab 29.7 mo Time from diagnosis-months * *

7 Dawood S, JCO 2010 Even in presence of trastuzumab, HR status is still a prognostic factor in MBC

8 HER2+ and HR+ MBC: Anti-HER2 plus hormonal therapy ORRPFSOS TAnDEM Kaufman B JCO Anastrozole+Trastuzumab Anastrozole 4.8%* 2.4% 5.6 mo* 3.8 mo 28.5 mo 23.9 mo Schwarzberg LS Oncologist 2010 (219 out of 1,286 =17%) Letrozole+ lapatinib Letrozole+ placebo 28%* 15% 8.2 mo* 3.0 mo 34.1 mo 28.6 mo

9 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 Lapatinib+ Letrozole Trastuzumab+ Taxane Lapatinib+ Capecitabine

10 No.PFS 5-y10-y p OS 5-y10-y p HR-negative No pCR pCR (24%) 50% vs 83% 43% vs 73% 67% vs 84% 59% vs 84% HR-positive No pCR pCR (8%) 65% vs 91% 38% vs 76% 84% vs 96% 41% vs 96% Guarnieri V, JCO 2006 Neoadjuvant CT in unselected for HER2 status BC Outcome by pCR and HR status <

11 3 1. Baselga J. et al, SABC 2010; 2 Gianni L et al, SABC 2010 SURGERYSURGERY lapatinib trastuzumab lapatinib trastuzumab paclitaxel + 12 wks 6 wks docetaxel + trastuzumab FEC X3FEC X3 L T L+T 34 wks trastuzumab + pertuzumab docetaxel + pertuzumab docetaxel + trastuzumab + pertuzumab SURGERYSURGERY FECx3 T D FEC T FECx3 T 52 wks of anti-HER2 NEOALTTO 1 Phase III NEOSPHERE 2 Phase II N=450 N=417 R Operable T >2 cm R Operable or LABC/IBC

12 NEOALTTO:pCR by Hormone Receptor Status L: lapatinib; T: trastuzumab; L+T: lapatinib plus trastuzumab pCR pathologic complete response HR: hormone receptors

13 THTHPHPTP ER or PR pos ER and PR neg NeoSphere: pCR and hormone receptors status pCR, % 95% CI H, trastuzumab; P, pertuzumab; T, docetaxel 7

14 5 FU 600 mg/m 2 Epi 75 mg/m 2 CTX 600 mg/m 2 Paclitaxel 80 mg/m 2 Trastuzumab 2 mg/kg RANDOMIZATIONRANDOMIZATION Lapatinib 1000 mg CDD Lapatinib 1500 mg continuous daily dose (CDD) COREBIOPSYCOREBIOPSY SURGERYSURGERY A B C CHERLOB: Study plan LVEF 121 pts II-IIIA T>2cm Guarneri V, ASCO 2011 #507

15 [TITLE] Guarneri V, ASCO 2011 #507

16 [TITLE]

17 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

18 Setting neoadiuvante Predice il tasso di pCR ottenibile con CT+ agenti anti-HER2 pCR % inferiore nei tumori HR+ vs HR- HER2- positività: Stato dei Recettori ormonali

19 Gene- expression profiling HER2-positive breast cancer

20 Survival analysis of the 49 breast cancer patients, uniformly treated in a prospective study, based on different gene expression classification OS months RFS months Sorlie T, PNAS 2001; 98: Luminal A Luminal B HER2+ Basal

21 Immunohistochemical identification of breast tumour intrinsic subtypes. Carey L A, JAMA 2006; 295:

22 Cheang MCU, JNCI 2009;101: Ki-67 labeling index is important in the distinction between Luminal A and Luminal B-HER2 -negative subtypes ER and/orPgRHER2Ki-67Cytokeratin Luminal A positivenegative low (<14%)-- Luminal B positivenegativehigh-- positive any-- HER2-enriched negativepositive-- Basal-like absentnegative--Cytokeratin 5/6 + and /or HER1+ Cheang MCU, JNCI 2009; 101:736-50

23 Survival by 70-gene Mammaprint signature for 89 HER2+ pts who did not receive CT or trastuzumab Knauer M, BJC 2010; 103:

24 Survival by 70-gene Mammaprint signature for 89 HER2+ pts who did not receive CT or trastuzumab Knauer M, BJC 2010; 103: The 70-gene prognosis signature is an independent prognostic indicator that identifies a subgroup of HER2-positive early BC with a favorable long-term outcome

25 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

26 p95-HER2 status HER2-positive breast cancer

27 p95HER2 is expressed in 30% of HER2+ BC Trastuzumab p95HER2 …by either proteolytic shedding of ECD 1 or by alternative initiation of translation of the HER2 mRNA 2 1. Codoni-Servat J, Cancer Res 1999;59: Anido J, EMBO J 2006; 25:

28 p95HER2 testing: rationale p95HER2 is an NH(2)-terminally truncated form of HER2 that lacks the trastuzumab binding site p95HER2 is expressed in approximately 30% of HER2 positive breast cancer patients Preclinical and initial clinical evidence suggest that p95HER2 confers resistance to trastuzumab p95HER2 might retain sensitivity to kinase inhibitors Molina, et al. Clin Cancer Res 2002;8:347-53; Scaltriti, et al. J Natl Cancer Inst 2007; 99(8):628-38

29 p95HER2 and Response to Trastuzumab 46 patients with MBC treated with trastuzumab 1 1 Scaltriti, M JNCI 2007

30 46 patients with MBC treated with trastuzumab 1 29 patients with EBC treated with neoadj. trastuzumab (CherLob) 2 1 Scaltriti, M JNCI Guarneri, V et al. ASCO 2011 #507 p95HER2 and Reponse to Trastuzumab

31 GeparQuattro: p95HER2 and Response to Trastuzumab (N=145 patients treated with EC+T Doc+T) P< Loibl S et al, ASCO 2011 Abstr #530 (>20% strongly positive for 611 CTF) (20% strongly positive for 611 CTF)

32 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 p95 – n=7/23 30% 35.7% 54% Arm A (CT + T)Arm B (CT +L)Arm C (CT + T + L) p95 – n=13/24 p95 – n=5/14 p95 + n=3/ % 25% 33% p95 + n=2/6 p95 + n=3/9 Cut-off at 80% P= 1 P= 0.68 P= 0.44 In all treatment arms, no significant difference in pCR rates at 80% or other cut-offs evaluated Guarneri V- ASCO 2011 #507

33 p95HER2 and clinical response to lapatinib (PFS) Results from 68 and 156 MBC pts Scaltriti M, Clin Cancer Res 2010 Lapatinib monotherapy- EGF20009 Lapatinib+ capecitabine- EGF100151

34 CherLob: p95HER2 and Response to Lapatinib (N=59 patients treated with CT+L or CT +TL) (>80% strongly positive for 611 CTF) (80% strongly positive for 611 CTF) Guarneri, V et al. ASCO 2011 #507

35 Setting metastatico p95HER2+ resistenza al trastuzumab 1 Lapatinib efficace sia nei tumori p95HER2+ che p95HER- 2 Setting neoadiuvante Risultati contrastanti 3-4 HER2- positività: p95 HER2 1. Scaltriti 2007; 2.Scaltriti 2010; 3.Guarneri ASCO 2011; 4.Lobi ASCO 2011

36 PTEN status HER2-positive breast cancer

37 Proliferation pathway Grb2 Survival pathway Akt/PKB MEK ERK PI3-K RAF PI(4,5)P2 PI(3,4,5)P3 PTEN P P P P EGF, TGF-α EGFR HER2 PDK1,2 RAS-GTP SOS GTP P RAS-GDP TKI IHC expression of PTEN (a negative regulator of Akt activities)

38 P < Nagata Y, Cancer Cell 2004

39 PTEN Impact on Sensitivity or Resistance to Trastuzumab Preclinical data suggest PTEN loss associated with trastuzumab resistance – OBrien 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 Background Perez EA – ASCO 2011

40 Gori S, et al PTEN status evaluated by IHC in 45 HER2+ MBC treated with trastuzumab-based therapy was not significantly associated with outcome (ORR, TTP, OS). PTEN status negative (Nagata score <9): 60% (Nagata score <4): 15%

41

42 Gianni L, ASCO 2008 #504

43 NCCTG N9831 Trial Incorporating Trastuzumab in Adjuvant Therapy RANDOMIZERANDOMIZE HER2 positive (FISH ratio 2 or IHC 3+ >10%) Arm A (1232 pts) Arm C (1057 pts) Arm B (1216 pts) AC T T H H T = AC(doxorubicin/cyclophosphamide 60/600 mg/m 2 q3w × 4) = T(paclitaxel 80 mg/m 2 /wk × 12) = H(trastuzumab 4 mg/kg loading + 2 mg/kg/wk × 51) n=3,505 Perez EA. Protocol NCCTG-N9831 Background

44 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

45 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- positività: PTEN status

46 HER3 status HER2-positive breast cancer

47

48 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 IHC expression of HER3 in HER2+ MBC (immunoperoxidase, 400 x) A. HER3–negative (positive tumour cells 50%) 30 pts A B B. HER3-positive (positive tumour cells >50%) 31 pts HER3 status by IHC was not significantly associated with clinical outcome

49 HER3-negative status by IHC in HER2-positive MBC: longer OS and TTP A Gori S et al, TUMORI 2011 in press

50 NOAH trial Gianni L, ASCO 2008

51 1. I tumori HER2+ non sono un gruppo omogeneo 2. Ad oggi, nei tumori HER2+, lunico altro dato a disposizione utile a fini prognostici e terapeutici, è lo stato dei recettori ormonali Oltre lo stato di HER2- positività CONCLUSIONI

52 THANK YOU !

53


Download ppt "Cosa altro è importante sapere oltre lHER2 status: recettori ormonali, profili di espressione genica… LHER2-positività: dallanatamopatologia alla clinica."

Similar presentations


Ads by Google