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L’HER2-positività: dall’anatamopatologia alla clinica

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%.

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L’HER2-positività: dall’anatamopatologia alla clinica

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  1. 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

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

  3. * Statistically significant difference versus CT arm

  4. Time from diagnosis (months) Multivariate model HER2+ and trastuzumab vs HER2-negative HR of death 0.56; 95% CI 0.45-0.69; p< .0001 Multivariate model HER2+ and trastuzumab vs HER2+ no trastuzumab HR of death 045; 95% CI 0.33-0.63; p< .0001 Dawood S, JCO 2010

  5. HER2-positive breast cancer HR status

  6. HER2- HER2- HER2+ HER2+ HER2+ HER2+ * * Time from diagnosis-months Time from diagnosis-months HR-negative HR-positive Overall survival by Trastuzumab treatment group and according to hormone receptor status 5y-OS 5y-OS HER2+ HER2+ HR- 8.9 mo HR+ 14.5 mo HR- and trastuzumab 17.7 mo HR+ and Trastuzumab 29.7 mo

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

  8. HER2+ and HR+ MBC:Anti-HER2 plus hormonal therapy

  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+ Taxane Trastuzumab+ Anastrozole Lapatinib+ Letrozole Lapatinib+ Capecitabine

  10. Neoadjuvant CT in unselected for HER2 status BC Outcome by pCR and HR status .003 <.0001 .002 .04 Guarnieri V, JCO 2006

  11. NEOALTTO1 Phase III NEOSPHERE2 Phase II N=417 N=450 docetaxel + pertuzumab SURGERY FECx3 T L lapatinib FEC X 3 paclitaxel docetaxel + trastuzumab S U R GE R Y FECx3 T T R Operable T >2 cm R Operable or LABC/IBC D  FEC T trastuzumab + pertuzumab trastuzumab paclitaxel L+T docetaxel + trastuzumab +pertuzumab FECx3 T 3 lapatinib 34 wks trastuzumab paclitaxel 52 wks of anti-HER2 52 wks of anti-HER2 + 12 wks 6 wks 1. Baselga J. et al, SABC 2010; 2 Gianni L et al, SABC 2010

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

  13. ER or PR pos ER and PR neg NeoSphere: pCR and hormone receptors status 70 60 50 63.2 40 pCR, %  95% CI 30 20 36.8 30.0 29.1 10 26.0 20.0 17.4 5.9 0 TH THP HP TP H, trastuzumab; P, pertuzumab; T, docetaxel 7

  14. Paclitaxel 80 mg/m2 CHERLOB: Study plan   R A N D O M I Z A T I O N A C O R E B I O P S Y S U R G E R Y   B  Lapatinib 1500 mg continuous daily dose (CDD) 121 pts II-IIIA T>2cm   C Lapatinib 1000 mg CDD 5 FU 600 mg/m2 Epi 75 mg/m2 CTX 600 mg/m2  LVEF Trastuzumab 2 mg/kg Guarneri V, ASCO 2011 #507

  15. [TITLE] Guarneri V, ASCO 2011 #507

  16. [TITLE]

  17. 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

  18. 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-

  19. HER2-positive breast cancer Gene- expression profiling

  20. Luminal A Luminal A Luminal B Luminal B HER2+ HER2+ Basal Basal OSmonths RFSmonths 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

  21. Immunohistochemical identification of breast tumour intrinsic subtypes. Carey L A, JAMA 2006; 295: 2492-2502

  22. Cheang MCU, JNCI 2009; 101:736-50 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; 103:1788-93

  24. 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 Survival by 70-gene Mammaprint signature for 89 HER2+ pts who did not receive CT or trastuzumab Knauer M, BJC 2010; 103:1788-93

  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. HER2-positive breast cancer p95-HER2 status

  27. p95HER2 is expressed in 30% of HER2+ BC Trastuzumab …by either proteolytic shedding of ECD1 or by alternative initiation of translation of the HER2 mRNA2 p95HER2 1. Codoni-Servat J, Cancer Res 1999;59:1196-201 2. Anido J, EMBO J 2006; 25:3234-44

  28. p95HER2 and Response to Trastuzumab 46 patients with MBC treated with trastuzumab1 1Scaltriti, M JNCI 2007

  29. p95HER2 and Reponse to Trastuzumab 29 patients with EBC treated with neoadj. trastuzumab (CherLob)2 46 patients with MBC treated with trastuzumab1 1Scaltriti, M JNCI 2007 2Guarneri, V et al. ASCO 2011 #507

  30. 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

  31. Cut-off at 80% P= 0.44 60 P= 0.68 54% P= 1 50 40 35.7% 33% 33.3% 30% 30 25% 20 10 p95 +n=2/6 p95 +n=3/9 p95 –n=7/23 p95 +n=3/12 p95 –n=5/14 p95 –n=13/24 0 Arm A (CT + T) Arm B (CT +L) Arm C (CT + T + L) 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 In all treatment arms, no significant difference in pCR rates at 80% or other cut-offs evaluated Guarneri V- ASCO 2011 #507

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

  33. 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

  34. HER2-positive breast cancer PTEN status

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

  36. P < 0.001 Nagata Y, Cancer Cell 2004

  37. 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

  38. 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).

  39. Gianni L, ASCO 2008 #504

  40. Background NCCTG N9831 Trial Incorporating Trastuzumab in Adjuvant Therapy Arm A (1232 pts) R A N D O M I Z E AC T HER2 positive (FISH ratio ≥2 or IHC 3+ >10%) Arm B (1216 pts) AC T H Arm C (1057 pts) n=3,505 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

  41. 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

  42. 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)

  43. HER2-positive breast cancer HER3 status

  44. 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%) 30 pts B. HER3-positive (positive tumour cells >50%) 31 pts HER3 status by IHC was not significantly associated with clinical outcome

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

  46. NOAH trial Gianni L, ASCO 2008

  47. 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

  48. THANK YOU !

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