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Preclinical rationale for Herceptin treatment beyond progression in HER2-positive breast cancer

Preclinical rationale for Herceptin treatment beyond progression in HER2-positive breast cancer. Established chemotherapy resistance mechanisms. Impaired drug uptake Active drug efflux, eg by ABC transporters (P-glycoprotein, MDR2, BCRP, MRP1-6 etc)

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Preclinical rationale for Herceptin treatment beyond progression in HER2-positive breast cancer

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  1. Preclinical rationale for Herceptin treatment beyond progression in HER2-positive breast cancer

  2. Established chemotherapy resistance mechanisms Impaired drug uptake Active drug efflux, eg by ABC transporters (P-glycoprotein, MDR2, BCRP, MRP1-6 etc) Enhanced drug metabolism, eg by P450 enzymes Alterations of intracellular target, eg tubulin Upregulation of DNA repair in tumour cells Upregulation of signalling pathways, eg anti-apoptotic genes (bcl-2, XIAP etc)

  3. Hypothetical mechanisms of resistance to Herceptin (1) Selection of HER2-negative cells in a heterogeneous tumour Outgrowth of HER2-negative tumours from an originally mixed tumour cell population Defective interaction of Herceptin with HER2 Masking of Herceptin-binding epitope of HER2 Alterations in Herceptin-binding epitope of HER2 Loss of HER2 ECD by shedding or alternative initiation of translation on HER2 gene • Kunitomo et al 2004; Nagy et al 2005; Tanner et al 2004; Stephens et al 2004; Stephens et al 2005; Anido et al 2006 HER2, human epidermal growth factor receptor 2; ECD, extracellular domain

  4. Hypothetical mechanisms of resistance to Herceptin (2) Changes in downstream signalling proteins which eventually disconnect growth regulation from HER2 PIK3CA mutations resulting in constitutively active PI3-kinase Loss of PTEN function leading to persistent signalling activity via the PI3K/Akt survival pathway Changes in cyclin-dependent kinase inhibitor p27kip1 • Berns et al 2007; Nagata et al 2004; Crowder et al 2004; Pandolfi 2004; Kute et al 2004; Nahta et al 2004

  5. Hypothetical mechanisms of resistance to Herceptin (3) Engagement of alternative growth factor receptor pathways Autocrine production of EGF-like ligands, eg heregulin Upregulation of HER-family receptors, eg HER3 Upregulation of non-HER-family growth factor receptor-mediated signalling, eg IGF-1R, cMET • Motoyama et al 2002; Lee-Hoeflich et al;Lu et al 2001; Albanell et al 2001; Lu et al 2003; Shimizu et al 2004; Altundag et al 2005 EGF, epidermal growth factor

  6. In vitro studies are not predictive of in vivo resistance In vitro resistance was observed in cell lines exposed to Herceptin In vitro resistance models tend to focus on just one biological feature In vitro resistance represents intrinsic insensitivity or artificial manipulation of cells Conclusions from in vitro resistance models cannot be translated to clinical settings ADCC is a key mechanism of Herceptin efficacy in vivo ADCC, antibody-dependent cellular cytotoxicity • Gennari et al 2004; Arnould et al 2006; Musolino et al 2008; Gianni 2008

  7. ADCC is a key mechanism of Herceptin’s antitumour activity in vivo HER2 Herceptin Tumourcell + NK cell ADCC FcgRIII • Once bound to HER2, the Herceptin Fc domain recruits immune cells to target and destroy the tumour

  8. Herceptin inhibits the growth of JIMT-1 xenograft tumours in vivo despite in vitro resistance Surviving cells (%) Tumour volume (mm3) Herceptin Controls:SalineHF(ab’)2 1500 120 100 * 1000 80 * 60 * 500 40 * * 20 0 0 0 14 28 42 56 70 84 Herceptin HF(ab’)2 Days post-inoculation In vitro In vivo *p<0.05; H, Herceptin HF(ab’)2 , Herceptin antigen-binding fragment JIMT-1: a cell line displaying intrinsic insensitivity to Herceptin • Barok et al 2007

  9. Target cell killing (%) Herceptin Controls:HF(ab’)2Rituximab 80 80 * * 60 60 * * * * 40 40 * 20 20 * * * 0 0 2 6 15 30 60 2 6 15 30 60 Effector/target cell ratio Herceptin-activated ADCC kills sensitive and in vitro-resistant tumour cells JIMT-1(Herceptin resistant in vitro) SKBR-3(Herceptin sensitive) Target cell killing (%) Effector/target cell ratio • Barok et al 2007

  10. Herceptin significantly decreased the number of JIMT-1 tumour cells in blood and bone marrow despite progression of the primary tumour Blood Bone marrow No. of circulating tumour cells / 1 ml blood No. of disseminated tumour cells in bone marrow 40 40 30 30 20 20 10 10 * * 0 0 Rituximab (control) Saline (control) Herceptin Herceptin Saline (control) Rituximab (control) Experiments were conducted in JIMT-1 xenografted mice *p<0.05 • Barok et al 2008

  11. JIMT-1 cells isolated from Herceptin-treated progressing tumours retain sensitivity to ADCC JIMT-1 cells resistant to both Herceptin and Herceptin F(ab’)2 fragments in vitro are sensitive to Herceptin, but not Herceptin F(ab’)2 when grown as xenografts in vivo Herceptin significantly reduces the number of circulating / disseminated tumour cells in this xenograft model system despite the primary tumour being unresponsive to Herceptin Activation of the immune system (ADCC) is a key mechanism of Herceptin’s antitumour activity in vivo • Barok et al 2007; Barok et al 2008

  12. Herceptin treatment beyond progression enhances efficacy of combination chemotherapy HER2 remains overexpressed and active in progressive disease HER2 may contribute to an even more aggressive tumour growth if Herceptin treatment is discontinued Inhibition of HER2 signalling may sensitise tumours to chemotherapy in tumours progressing on Herceptin alone

  13. Herceptin treatment beyond progression sensitises tumour cells to chemotherapy Initial treatment Treatment beyond progression Tumour volume (mm3) Tumour volume (mm3) Control lgG 30 mg/kg 1000 1000 Herceptin 30 mg/kg Control lgG 30 mg/kg Paclitaxel 60 mg/kg * Herceptin 30 mg/kg 300 300 * Herceptin +paclitaxel 100 100 1 8 15 22 22 29 36 43 50 57 Days after treatment start Days after treatment start MDA-MB-361 tumour xenograft; *p<0.05 by U-testIgG, immunoglobulin; paclitaxel qw iv; Herceptin or IgG qw ip Shirane et al 2005

  14. Herceptin treatment beyond progression enhances efficacy of combination therapy with targeted agents Herceptin synergistically enhances the antitumour effect of Avastin in tumours progressing on Herceptin Herceptin synergistically enhances the antitumour effect of pertuzumab in tumours progressing on Herceptin Lapatinib enhances the antitumour effect of Herceptin Scheuer et al 2006; Friess et al 2006; Scaltriti et al 2008

  15. Herceptin + Avastin combination eradicates tumours in a breast cancer xenograft model Mean tumour volume (mm3) KPL-4 600 Vehicle control Herceptin (30/15 mg/kg/w ip) Avastin (5 mg/kg 2×/w ip) 500 Avastin + Herceptin Herceptin + Avastin 400 300 200 100 0 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 Treatment period (days) Scheuer et al 2006

  16. Herceptin + pertuzumab combination eradicates tumours in a breast cancer xenograft model Mean tumour volume (mm3) KPL-4 Vehicle control 600 Pertuzumab (30/15 mg/kg/w ip) Herceptin (30/15 mg/kg/w ip) 500 Pertuzumab + Herceptin 400 300 200 6/10 animals cured 100 0 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 Treatment period (days) Friess et al 2006

  17. Combination of Herceptin and lapatinib is clearly synergistic 1800 1600 1400 1200 ControlHerceptinLapatinibHerceptin + lapatinib 1000 800 600 400 200 0 13 16 19 21 23 Days post injection Tumour volume (mm3) • During lapatinib administration, marked accumulation of inactive HER2 occurs at the cell surface which is not reversed by Herceptin. This may play an important role in the synergy between the two drugs Scaltriti et al 2008

  18. Conclusions In vitro studies are not predictive of in vivo resistance Herceptin is not subject to classical chemotherapy resistance mechanisms As activation of the immune system (ADCC) is a key mechanism of action for Herceptin, alternative signalling does not lead to in vivo resistance Preclinical data suggest that continuation of Herceptin treatment beyond progression in combination with chemotherapy or targeted agents can lead to tumour eradication Clinical data confirm the benefits associated with continuation of Herceptin beyond progression

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