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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 HER2+ MBC: worse survival
Prognosis of metastatic breast cancer by HER2 status and trastuzumab treatment HER2+ 25% 13% OS a 5 anni del 13% circa nelle pts HER2- positive rispetto a circa il 25% delle pts HER2-negative (p<.0001) Dawood S, JCO 2010 HER2+ MBC: worse survival

3 1st line therapy of MBC: anti-HER2 agent + CT
RESULTS from randomized trials N pts/ arm Treatment ORR DOR TTP OS Slamon DJ NEJM 2001 Phase III 92 96 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 94 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) 49 37 lapatinib 1500+ 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 222 w paclitaxel 80 (3/4) 69%* 50% 9.3 mo 5.8 mo 9.7 mo* (PFS) 6.5 mo 27.8 mo* 20.5 mo * : Risultati significativamente superiori, dal punto di vista statistico, rispetto al braccio di controllo senza agente anti-HER2 . * Statistically significant difference versus CT arm

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

5 HER2-positive breast cancer
HR status

6 * * HR-negative HR-positive
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 y-OS HER HER2+ HR mo HR mo HR- and trastuzumab mo HR+ and Trastuzumab 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
ORR PFS OS TAnDEM Kaufman B JCO 2009 103 104 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%) 111 108 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 Outcome by pCR and HR status
Neoadjuvant CT in unselected for HER2 status BC Outcome by pCR and HR status No. PFS 5-y 10-y p OS HR-negative No pCR pCR 423 132 (24%) 50% vs 83% 43% 73% 67% 84% 59% HR-positive 1072 91 (8%) 65% 91% 38% 76% 96% 41% <.0001 .003 Studio retrospettivo- M.D. ANDERSON .002 .04 Guarnieri V, JCO 2006

lapatinib trastuzumab paclitaxel + 12 wks 6 wks docetaxel + pertuzumab L SURGERY FECx3 T FEC X 3 docetaxel + trastuzumab T FECx3 T R Operable T >2 cm R Operable or LABC/IBC trastuzumab + pertuzumab D  FEC T L+T docetaxel + trastuzumab + pertuzumab FECx3 T 3 34 wks 52 wks of anti-HER2 52 wks of anti-HER2 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 NeoSphere: pCR and hormone receptors status
70 60 ER or PR pos ER and PR neg 50 63.2 40 pCR, %  95% CI 30 20 36.8 30.0 10 29.1 26.0 20.0 5.9 17.4 TH THP HP TP H, trastuzumab; P, pertuzumab; T, docetaxel 7

14 CHERLOB: Study plan   A    B   C  LVEF R A C N O D R O E S M I
Z T A C O R E B I P S Y S U R G E 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 Paclitaxel 80 mg/m2 Trastuzumab 2 mg/kg Guarneri V, ASCO 2011 #507 14

15 [TITLE] Guarneri V, ASCO 2011 #507

16 [TITLE]

17 Stato dei Recettori ormonali
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 Stato dei Recettori ormonali
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 Gene- expression profiling
HER2-positive breast cancer Gene- expression profiling

20 Luminal A Luminal A Luminal B Luminal B HER2+ HER2+ Basal Basal OS months RFS months cDNA microarrays 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:

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

22 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 high any HER2-enriched Basal-like absent Cytokeratin 5/6 + and /or HER1+ 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:

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:

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: 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 28

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

30 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

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

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% 10 20 30 40 50 60 Arm A (CT + T) Arm B (CT +L) Arm C (CT + T + L) p95 – n=13/24 p95 – n=5/14 p95 + n=3/12 33.3% 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 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 Lapatinib monotherapy- EGF20009 Lapatinib+ capecitabine- EGF100151 Scaltriti M, Clin Cancer Res 2010

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 HER2- positività: p95 HER2 Setting metastatico
p95HER 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

36 HER2-positive breast cancer
PTEN status

37 (a negative regulator of Akt activities)
IHC expression of PTEN (a negative regulator of Akt activities) EGF, TGF-α P EGFR HER2 PI(4,5)P2 PI3-K SOS PI(3,4,5)P3 P PTEN Grb2 RAS-GDP RAS-GTP PDK1,2 GTP PDK1,2 TKI Akt/PKB RAF Members of the human EGF receptor (HER/erbB) family include EGF receptor (EGFR), HER2, HER3, and HER4 After ligand binding, receptors complex with themselves (homodimers) or with other erbB family members (heterodimers) Cellular responses to signaling are diverse because signals are generated through multiple ligands and receptors EGFR and HER2 are promising targets because They are expressed or overexpressed in many cancers In some cancers, overexpression is associated with poor clinical outcome Blocking EGFR or HER2 could interrupt signaling through several pathways PI3-K (promotes cell survival, protein synthesis, and metabolic processes) RAS-RAF (involved in metabolic processes and in controlling cell cycle, migration, shape, proliferation, and differentiation) Targeting EGFR or HER2 has been studied in breast, lung, and other cancers Novartis Oncology has investigational agents that inhibit the activity of EGFR and HER2 in early-phase clinical trials MEK Survival pathway ERK Proliferation pathway

38 P < 0.001 Nagata Y, Cancer Cell 2004

39 PTEN Impact on Sensitivity or Resistance to Trastuzumab
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

40 PTEN status negative (Nagata score <9): 60%
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).


42 Gianni L, ASCO 2008 #504

43 NCCTG N9831 Trial Incorporating Trastuzumab in Adjuvant Therapy
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) As a brief background, N9831 was a phase III intergroup trial led by the North central cancer Treatment group. This trial examined standard chemotherapy with sequential or concurrent trastuzumab in primary breast cancer pts with HER2-positive disease. Our present analyses included pts randomized to Arms A &C and does not include data from Arm B as these data are not released by the IDMC. HER2 positivity was classified as having a FISH ratio of greater to or equal to 2 or IHC staining in greater than 10% cells. The NCCTG trial N9831 compared 3 regimens: Group A: 4 cycles of doxorubicin and cyclophosphamide (AC) followed by weekly paclitaxel (80 mg/m2/wk) for 12 weeks Group B: 4 cycles of AC followed by 52 weeks of Herceptin® (trastuzumab) after the completion of 12 weeks of weekly paclitaxel (80 mg/m2/wk) therapy Group C: 4 cycles of AC followed by 52 weeks of Herceptin beginning on day 1 of 12 weeks of weekly paclitaxel (80 mg/m2/wk) therapy Hormonal therapy/XRT, if administered, was initiated after chemotherapy Inclusion criteria for this trial included the following: Invasive BC resected by lumpectomy/mastectomy plus axillary dissection with pathologically involved axillary nodes No locally advanced or distant disease Normal hematologic, hepatic, and renal function No prior anthracycline or taxane therapy No significant sensory or motor neuropathy HER2 positivity by FISH or 3+ by IHC Verified centrally in N9831 Normal left ventricular ejection fraction No past or active cardiac disease, including history of myocardial infarction or congestive heart failure, angina pectoris requiring medication, arrhythmia requiring medication, clinically significant valvular disease, uncontrolled hypertension, LVH, or cardiomegaly on CXR 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 Romond et al. N Engl J Med. 2005;353:1673. Herceptin® (trastuzumab) PI. November 2006. 43

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 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)

46 HER2-positive breast cancer
HER3 status


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 A B IHC expression of HER3 in HER2+ MBC (immunoperoxidase, 400 x) A. HER3–negative (positive tumour cells 50%) 30 pts Background: HER3 signalling might contribute to resistance to trastuzumab. To clarify the role of HER3 in HER2-positive breast cancer, it is important to evaluate the level of HER3 and its correlations with clinical outcome in metastatic breast cancer (MBC) patients treated with trastuzumab. 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
Gori S et al, TUMORI 2011 in press

50 NOAH trial Gianni L, ASCO 2008

51 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



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