HER2 Support Group Forums - View Single Post - Lapatinib: A competitor or companion to trastuzumab?

Rich66 · 11-05-2009, 06:48 PM

A Phase I Study of a 2-Day Lapatinib Chemosensitization Pulse Preceding Nanoparticle Albumin-Bound Paclitaxel for Advanced Solid Malignancies

Amy J. Chien¹^,6, Julie A. Illi⁶, Andrew H. Ko¹^,6, Wolfgang M. Korn¹^,6, Lawrence Fong¹^,6, Lee-may Chen²^,6, Mohammed Kashani-Sabet³^,6, Charles J. Ryan¹^,6, Jonathan E. Rosenberg¹^,6, Sarita Dubey¹^,6, Eric J. Small¹^,6, Thierry M. Jahan¹^,6, Nola M. Hylton⁴^,6, Benjamin M. Yeh⁴^,6, Yong Huang⁵, Kevin M. Koch⁷ and Mark M. Moasser¹^,6 Authors' Affiliations: Departments of ¹ Medicine, ² Obstetrics, Gynecology, and Reproductive Sciences, ³ Dermatology, ⁴ Radiology, ⁵ Biopharmaceutical Sciences, and ⁶ Helen Diller Comprehensive Cancer Center, University of California San Francisco, San Francisco, California and ⁷ Clinical Pharmacology Modeling and Simulation, GlaxoSmithKline, Research Triangle Park, North Carolina
Requests for reprints: Mark M. Moasser, Helen Diller Comprehensive Cancer Center, University of California, San Francisco, Box 0875, San Francisco, CA 94143-0875. Phone: 415-476-0158; Fax; 415-353-7692; E-mail: mmoasser@medicine.ucsf.edu.
Purpose: Systemic chemotherapy fails to access much of the tumorburden in patients with advanced cancer, significantly limitingits efficacy. In preclinical studies, brief high doses of tyrosinekinase inhibitors (TKI) targeting the human epidermal growthfactor receptor (HER) family can prime tumor vasculature foroptimal chemotherapeutic delivery and efficacy. This study investigatesthe clinical relevance of this approach.
Experimental Design: A phase I clinical study of escalatingdoses of the HER TKI lapatinib given as a 2-day pulse beforea weekly infusion of nab-paclitaxel (100 mg/m²) was conductedin patients with advanced solid tumors.
Results: Twenty-five patients were treated. Treatment was associatedwith grade 1 to 2 toxicities including diarrhea, nausea, rash,neutropenia, neuropathy, fatigue, alopecia, and anemia. Thetwo dose-limiting toxicities were grade 3 vomiting and grade4 neutropenia, and the maximum tolerated dose of lapatinib wasdefined as 5250 mg/day in divided doses. Lapatinib concentrationsincreased with increasing dose. Dynamic Contrast Enhanced MagneticResonance Imaging studies in a subset of patients confirmeda decrease in tumor vascular permeability immediately followinga lapatinib pulse. Sixty-five percent of evaluable patientsexperienced a partial or stable response on this therapy, 72%of whom were previously taxane-refractory.
Conclusion: A 2-day pulse of high-dose lapatinib given beforeweekly nab-paclitaxel is a feasible and tolerable clinical regimen,suitable for testing this novel vascular-priming chemosensitizationhypothesis developed in preclinical models. (Clin Cancer Res2009;15(17):5569–75)

Anticancer Drugs. 2009 Nov;20(10):918-25.
Role of efflux pump activity in lapatinib/caelyx combination in breast cancer cell lines.

Vannini I, Zoli W, Fabbri F, Ulivi P, Tesei A, Carloni S, Brigliadori G, Amadori D.
Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Meldola (FC), Italy.
The aim of this study was to investigate, at preclinical level, efflux pump modulation induced by lapatinib, a small-molecule dual inhibitor of the epidermal growth factor receptor (EGFR), in HER2-negative or HER2-positive breast cancer cell lines (SkBr3 and BRC230). We also evaluated the cytotoxic activity and modulation of biomolecular cellular pathways regulated by caelyx and lapatinib, used singly or in combination, at concentrations corresponding to peak plasma level in the two cell lines. Lapatinib was active in the HER2-overexpressing cell line, SkBr3, but not in BRC230 cell line, which does not express HER2. Conversely, caelyx exerted a cytotoxic effect on both the cell lines. Simultaneous exposure to lapatinib and caelyx in SkBr3 cell line produced an additive cytotoxic effect with dephosphorylation of HER2 and EGFR, an upregulation of p21, and an induction of apoptosis through dephosphorylation of BAD and caspase cleavage. In BRC230, simultaneous treatment induced a synergistic effect that was because of, at least in part, an upregulation of p21. Lapatinib also blocked efflux pumps, such as the breast cancer resistance protein I by increasing the length of time in which caelyx was present in tumor cell cytoplasm, which led to caspase cleavage, BAD dephosphorylation, and apoptosis. Our data indicate that lapatinib used in combination with caelyx is active in HER2-expressing cells, probably because of lapatinib-induced dephosphorylation of the HER2-EGFR pathway, and also in non-HER2-expressing cells, possibly because lapatinib blocks efflux pump activity, increasing the length of time of intracellular exposure to caelyx and thereby increasing its cytotoxic effect.

PMID: 19752719 [PubMed - indexed for MEDLINE]

Cancer Res. 2008 Oct 1;68(19):7905-14.
Lapatinib (Tykerb, GW572016) reverses multidrug resistance in cancer cells by inhibiting the activity of ATP-binding cassette subfamily B member 1 and G member 2.

Dai CL, Tiwari AK, Wu CP, Su XD, Wang SR, Liu DG, Ashby CR Jr, Huang Y, Robey RW, Liang YJ, Chen LM, Shi CJ, Ambudkar SV, Chen ZS, Fu LW.
State Key Laboratory for Oncology in South China, Cancer Center, Sun Yat-Sen University, Guangzhou, China.
Erratum in:

Cancer Res. 2008 Dec 15;68(24):10387.

Lapatinib is active at the ATP-binding site of tyrosine kinases that are associated with the human epidermal growth factor receptor (Her-1 or ErbB1) and Her-2. It is conceivable that lapatinib may inhibit the function of ATP-binding cassette (ABC) transporters by binding to their ATP-binding sites. The aim of this study was to investigate the ability of lapatinib to reverse tumor multidrug resistance (MDR) due to overexpression of ABC subfamily B member 1 (ABCB1) and ABC subfamily G member 2 (ABCG2) transporters. Our results showed that lapatinib significantly enhanced the sensitivity to ABCB1 or ABCG2 substrates in cells expressing these transporters, although a small synergetic effect was observed in combining lapatinib and conventional chemotherapeutic agents in parental sensitive MCF-7 or S1 cells. Lapatinib alone, however, did not significantly alter the sensitivity of non-ABCB1 or non-ABCG2 substrates in sensitive and resistant cells. Additionally, lapatinib significantly increased the accumulation of doxorubicin or mitoxantrone in ABCB1- or ABCG2-overexpressing cells and inhibited the transport of methotrexate and E(2)17betaG by ABCG2. Furthermore, lapatinib stimulated the ATPase activity of both ABCB1 and ABCG2 and inhibited the photolabeling of ABCB1 or ABCG2 with [(125)I]iodoarylazidoprazosin in a concentration-dependent manner. However, lapatinib did not affect the expression of these transporters at mRNA or protein levels. Importantly, lapatinib also strongly enhanced the effect of paclitaxel on the inhibition of growth of the ABCB1-overexpressing KBv200 cell xenografts in nude mice. Overall, we conclude that lapatinib reverses ABCB1- and ABCG2-mediated MDR by directly inhibiting their transport function. These findings may be useful for cancer combinational therapy with lapatinib in the clinic.

PMID: 18829547 [PubMed - indexed for MEDLINE]

Int J Cancer. 2009 Oct 23. [Epub ahead of print]
Synergism from combined immunologic and pharmacologic inhibition of HER2 in vivo.

Morse MA, Wei J, Hartman Z, Xia W, Ren XR, Lei G, Barry WT, Osada T, Hobeika AC, Peplinski S, Jiang H, Devi GR, Chen W, Spector N, Amalfitano A, Lyerly HK, Clay TM.
Department of Medicine, Division of Medical Oncology, Duke University Medical Center, Durham, NC 27710.
The monoclonal antibody trastuzumab and the EGFR/HER2 tyrosine kinase inhibitor lapatinib improve the clinical outcome of patients with HER2-overexpressing breast cancer. However, the majority of metastatic cancers will eventually progress suggesting the need for other therapies. Because HER2 overexpression persists, we hypothesized that the anti-HER2 immune response induced by cancer vaccines would be an effective strategy for treating trastuzumab and lapatinib-refractory tumors. Furthermore, we hypothesized that the antibody response could synergize with lapatinib to enhance tumor inhibition. We developed a recombinant adenoviral vector expressing a kinase-inactive HER2 (Ad-HER2-ki) to use as a cancer vaccine. Vaccine-induced polyclonal HER2-specific anti-serum was analyzed for receptor internalization and signaling effects alone and in combination with lapatinib. Ad-HER2-ki vaccine induced potent T cell and antibody responses in mice and the vaccine-induced polyclonal HER2-specific anti-serum mediated receptor internalization and degradation much more effectively than trastuzumab. Our in vitro studies demonstrated that HER2-vaccine induced antibodies effectively caused a decrease in HER2 expression, but when combined with lapatinib caused significant inhibition of HER2 signaling, decreased pERK and pAKT levels, and reduced breast tumor cell proliferation. In addition, a known mechanism of resistance to lapatinib, induction of survivin, was inhibited. The combination of Ad-HER2-ki plus lapatinib also showed superior anti-tumor efficacy in vivo. Based on these results, we feel clinical studies using this approach to target HER2-overexpressing breast cancer, including trastuzumab- and lapatinib-resistant tumors is warranted. (c) 2009 UICC.

Cancer Res. 2008 Sep 1;68(17):7083-9.
Synergistic inhibition with a dual epidermal growth factor receptor/HER-2/neu tyrosine kinase inhibitor and a disintegrin and metalloprotease inhibitor.

Witters L, Scherle P, Friedman S, Fridman J, Caulder E, Newton R, Lipton A.
Department of Medicine, The Milton S. Hershey Medical Center/Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
The ErbB family of receptors is overexpressed in numerous human tumors. Overexpression correlates with poor prognosis and resistance to therapy. Use of ErbB-specific antibodies to the receptors (Herceptin or Erbitux) or ErbB-specific small-molecule inhibitors of the receptor tyrosine kinase activity (Iressa or Tarceva) has shown clinical efficacy in several solid tumors. An alternative method of affecting ErbB-initiated tumor growth and survival is to block sheddase activity. Sheddase activity is responsible for cleavage of multiple ErbB ligands and receptors, a necessary step in availability of the soluble, active form of the ligand and a constitutively activated ligand-independent receptor. This sheddase activity is attributed to the ADAM (a disintegrin and metalloprotease) family of proteins. ADAM 10 is the main sheddase of epidermal growth factor (EGF) and HER-2/neu cleavage, whereas ADAM17 is required for cleavage of additional EGF receptor (EGFR) ligands (transforming growth factor-alpha, amphiregulin, heregulin, heparin binding EGF-like ligand). This study has shown that addition of INCB3619, a potent inhibitor of ADAM10 and ADAM17, reduces in vitro HER-2/neu and amphiregulin shedding, confirming that it interferes with both HER-2/neu and EGFR ligand cleavage. Combining INCB3619 with a lapatinib-like dual inhibitor of EGFR and HER-2/neu kinases resulted in synergistic growth inhibition in MCF-7 and HER-2/neu-transfected MCF-7 human breast cancer cells.Combining the INCB7839 second-generation sheddase inhibitor with lapatinib prevented the growth of HER-2/neu-positive BT474-SC1 human breast cancer xenografts in vivo. These results suggest that there may be an additional clinical benefit of combining agents that target the ErbB pathways at multiple points.

PMID: 18757423 [PubMed - indexed for MEDLINE]

J Clin Oncol. 2009 Aug 20;27(24):3908-15. Epub 2009 Jul 20.
Estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2 (HER2), and epidermal growth factor receptor expression and benefit from lapatinib in a randomized trial of paclitaxel with lapatinib or placebo as first-line treatment in HER2-negative or unknown metastatic breast cancer.

Finn RS, Press MF, Dering J, Arbushites M, Koehler M, Oliva C, Williams LS, Di Leo A.
Geffen School of Medicine at University of California, Los Angeles, CA, USA. Rfinn@mednet.ucla.edu
PURPOSE: Lapatinib is a dual inhibitor of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) with activity in HER2-amplified metastatic breast cancer (MBC). Its role in non-HER2-amplified MBC remains unclear. EGF30001, a phase III trial of lapatinib and paclitaxel versus paclitaxel and placebo, demonstrated lapatinib does not significantly benefit HER2-negative or HER2-unselected patients with MBC. Published data support interactions between steroid hormone and peptide growth factor signaling. We hypothesized that molecular subgroups may exist within EGF30001 that would benefit from lapatinib. METHODS: A blinded, retrospective biomarker evaluation was performed using immunohistochemistry to semiquantitate estrogen (ER), progesterone (PR), and EGFR expression. HER2 amplification was determined by fluorescent in situ hybridization. Effects of these biomarkers on event-free survival (EFS) were examined in patients with available tissue (n = 493). RESULTS: Lapatinib improved median EFS in HER2-amplified, ER- or PR-positive MBC (n = 36; 5.7 v 4.5 months; P = .351); benefit was greater and statistically significant in HER2-amplified, ER-negative, PR-negative MBC (n = 42; 8.3 v 5.0 months; P = .007). In HER2-negative, ER-positive MBC, median EFS improvement varied by degree of PR expression (H-score): no benefit if PR-strong (n = 133; 9.3 v 7.3 months; P = .373), benefit if PR-weak (n = 50; 7.3 v 2.4 months; P = .026), and potential antagonism if PR-negative (n = 40; 3.7 v 7.2 months; P = .004). No benefit was seen in triple-negative MBC (n = 131; median EFS, 4.6 v 4.8 months; P = .255). EGFR expression was not correlated with benefit from lapatinib. CONCLUSION: Although subgroups are small, these analyses support the hypothesis that semiquantitative determination of hormone receptor status may be a surrogate for EGFR and/or HER2 dependency.

PMID: 19620495 [PubMed - indexed for MEDLINE]

11-05-2009, 06:48 PM	#6
Rich66 Senior Member Join Date: Feb 2008 Location: South East Wisconsin Posts: 3,431	Re: Lapatinib: A competitor or companion to trastuzumab? A Phase I Study of a 2-Day Lapatinib Chemosensitization Pulse Preceding Nanoparticle Albumin-Bound Paclitaxel for Advanced Solid Malignancies Amy J. Chien¹^,6, Julie A. Illi⁶, Andrew H. Ko¹^,6, Wolfgang M. Korn¹^,6, Lawrence Fong¹^,6, Lee-may Chen²^,6, Mohammed Kashani-Sabet³^,6, Charles J. Ryan¹^,6, Jonathan E. Rosenberg¹^,6, Sarita Dubey¹^,6, Eric J. Small¹^,6, Thierry M. Jahan¹^,6, Nola M. Hylton⁴^,6, Benjamin M. Yeh⁴^,6, Yong Huang⁵, Kevin M. Koch⁷ and Mark M. Moasser¹^,6 Authors' Affiliations: Departments of ¹ Medicine, ² Obstetrics, Gynecology, and Reproductive Sciences, ³ Dermatology, ⁴ Radiology, ⁵ Biopharmaceutical Sciences, and ⁶ Helen Diller Comprehensive Cancer Center, University of California San Francisco, San Francisco, California and ⁷ Clinical Pharmacology Modeling and Simulation, GlaxoSmithKline, Research Triangle Park, North Carolina Requests for reprints: Mark M. Moasser, Helen Diller Comprehensive Cancer Center, University of California, San Francisco, Box 0875, San Francisco, CA 94143-0875. Phone: 415-476-0158; Fax; 415-353-7692; E-mail: mmoasser@medicine.ucsf.edu. Purpose: Systemic chemotherapy fails to access much of the tumorburden in patients with advanced cancer, significantly limitingits efficacy. In preclinical studies, brief high doses of tyrosinekinase inhibitors (TKI) targeting the human epidermal growthfactor receptor (HER) family can prime tumor vasculature foroptimal chemotherapeutic delivery and efficacy. This study investigatesthe clinical relevance of this approach. Experimental Design: A phase I clinical study of escalatingdoses of the HER TKI lapatinib given as a 2-day pulse beforea weekly infusion of nab-paclitaxel (100 mg/m²) was conductedin patients with advanced solid tumors. Results: Twenty-five patients were treated. Treatment was associatedwith grade 1 to 2 toxicities including diarrhea, nausea, rash,neutropenia, neuropathy, fatigue, alopecia, and anemia. Thetwo dose-limiting toxicities were grade 3 vomiting and grade4 neutropenia, and the maximum tolerated dose of lapatinib wasdefined as 5250 mg/day in divided doses. Lapatinib concentrationsincreased with increasing dose. Dynamic Contrast Enhanced MagneticResonance Imaging studies in a subset of patients confirmeda decrease in tumor vascular permeability immediately followinga lapatinib pulse. Sixty-five percent of evaluable patientsexperienced a partial or stable response on this therapy, 72%of whom were previously taxane-refractory. Conclusion: A 2-day pulse of high-dose lapatinib given beforeweekly nab-paclitaxel is a feasible and tolerable clinical regimen,suitable for testing this novel vascular-priming chemosensitizationhypothesis developed in preclinical models. (Clin Cancer Res2009;15(17):5569–75) Anticancer Drugs. 2009 Nov;20(10):918-25. Role of efflux pump activity in lapatinib/caelyx combination in breast cancer cell lines. Vannini I, Zoli W, Fabbri F, Ulivi P, Tesei A, Carloni S, Brigliadori G, Amadori D. Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Meldola (FC), Italy. The aim of this study was to investigate, at preclinical level, efflux pump modulation induced by lapatinib, a small-molecule dual inhibitor of the epidermal growth factor receptor (EGFR), in HER2-negative or HER2-positive breast cancer cell lines (SkBr3 and BRC230). We also evaluated the cytotoxic activity and modulation of biomolecular cellular pathways regulated by caelyx and lapatinib, used singly or in combination, at concentrations corresponding to peak plasma level in the two cell lines. Lapatinib was active in the HER2-overexpressing cell line, SkBr3, but not in BRC230 cell line, which does not express HER2. Conversely, caelyx exerted a cytotoxic effect on both the cell lines. Simultaneous exposure to lapatinib and caelyx in SkBr3 cell line produced an additive cytotoxic effect with dephosphorylation of HER2 and EGFR, an upregulation of p21, and an induction of apoptosis through dephosphorylation of BAD and caspase cleavage. In BRC230, simultaneous treatment induced a synergistic effect that was because of, at least in part, an upregulation of p21. Lapatinib also blocked efflux pumps, such as the breast cancer resistance protein I by increasing the length of time in which caelyx was present in tumor cell cytoplasm, which led to caspase cleavage, BAD dephosphorylation, and apoptosis. Our data indicate that lapatinib used in combination with caelyx is active in HER2-expressing cells, probably because of lapatinib-induced dephosphorylation of the HER2-EGFR pathway, and also in non-HER2-expressing cells, possibly because lapatinib blocks efflux pump activity, increasing the length of time of intracellular exposure to caelyx and thereby increasing its cytotoxic effect. PMID: 19752719 [PubMed - indexed for MEDLINE] Cancer Res. 2008 Oct 1;68(19):7905-14. Lapatinib (Tykerb, GW572016) reverses multidrug resistance in cancer cells by inhibiting the activity of ATP-binding cassette subfamily B member 1 and G member 2. Dai CL, Tiwari AK, Wu CP, Su XD, Wang SR, Liu DG, Ashby CR Jr, Huang Y, Robey RW, Liang YJ, Chen LM, Shi CJ, Ambudkar SV, Chen ZS, Fu LW. State Key Laboratory for Oncology in South China, Cancer Center, Sun Yat-Sen University, Guangzhou, China. Erratum in: Cancer Res. 2008 Dec 15;68(24):10387. Lapatinib is active at the ATP-binding site of tyrosine kinases that are associated with the human epidermal growth factor receptor (Her-1 or ErbB1) and Her-2. It is conceivable that lapatinib may inhibit the function of ATP-binding cassette (ABC) transporters by binding to their ATP-binding sites. The aim of this study was to investigate the ability of lapatinib to reverse tumor multidrug resistance (MDR) due to overexpression of ABC subfamily B member 1 (ABCB1) and ABC subfamily G member 2 (ABCG2) transporters. Our results showed that lapatinib significantly enhanced the sensitivity to ABCB1 or ABCG2 substrates in cells expressing these transporters, although a small synergetic effect was observed in combining lapatinib and conventional chemotherapeutic agents in parental sensitive MCF-7 or S1 cells. Lapatinib alone, however, did not significantly alter the sensitivity of non-ABCB1 or non-ABCG2 substrates in sensitive and resistant cells. Additionally, lapatinib significantly increased the accumulation of doxorubicin or mitoxantrone in ABCB1- or ABCG2-overexpressing cells and inhibited the transport of methotrexate and E(2)17betaG by ABCG2. Furthermore, lapatinib stimulated the ATPase activity of both ABCB1 and ABCG2 and inhibited the photolabeling of ABCB1 or ABCG2 with [(125)I]iodoarylazidoprazosin in a concentration-dependent manner. However, lapatinib did not affect the expression of these transporters at mRNA or protein levels. Importantly, lapatinib also strongly enhanced the effect of paclitaxel on the inhibition of growth of the ABCB1-overexpressing KBv200 cell xenografts in nude mice. Overall, we conclude that lapatinib reverses ABCB1- and ABCG2-mediated MDR by directly inhibiting their transport function. These findings may be useful for cancer combinational therapy with lapatinib in the clinic. PMID: 18829547 [PubMed - indexed for MEDLINE] Int J Cancer. 2009 Oct 23. [Epub ahead of print] Synergism from combined immunologic and pharmacologic inhibition of HER2 in vivo. Morse MA, Wei J, Hartman Z, Xia W, Ren XR, Lei G, Barry WT, Osada T, Hobeika AC, Peplinski S, Jiang H, Devi GR, Chen W, Spector N, Amalfitano A, Lyerly HK, Clay TM. Department of Medicine, Division of Medical Oncology, Duke University Medical Center, Durham, NC 27710. The monoclonal antibody trastuzumab and the EGFR/HER2 tyrosine kinase inhibitor lapatinib improve the clinical outcome of patients with HER2-overexpressing breast cancer. However, the majority of metastatic cancers will eventually progress suggesting the need for other therapies. Because HER2 overexpression persists, we hypothesized that the anti-HER2 immune response induced by cancer vaccines would be an effective strategy for treating trastuzumab and lapatinib-refractory tumors. Furthermore, we hypothesized that the antibody response could synergize with lapatinib to enhance tumor inhibition. We developed a recombinant adenoviral vector expressing a kinase-inactive HER2 (Ad-HER2-ki) to use as a cancer vaccine. Vaccine-induced polyclonal HER2-specific anti-serum was analyzed for receptor internalization and signaling effects alone and in combination with lapatinib. Ad-HER2-ki vaccine induced potent T cell and antibody responses in mice and the vaccine-induced polyclonal HER2-specific anti-serum mediated receptor internalization and degradation much more effectively than trastuzumab. Our in vitro studies demonstrated that HER2-vaccine induced antibodies effectively caused a decrease in HER2 expression, but when combined with lapatinib caused significant inhibition of HER2 signaling, decreased pERK and pAKT levels, and reduced breast tumor cell proliferation. In addition, a known mechanism of resistance to lapatinib, induction of survivin, was inhibited. The combination of Ad-HER2-ki plus lapatinib also showed superior anti-tumor efficacy in vivo. Based on these results, we feel clinical studies using this approach to target HER2-overexpressing breast cancer, including trastuzumab- and lapatinib-resistant tumors is warranted. (c) 2009 UICC. Cancer Res. 2008 Sep 1;68(17):7083-9. Synergistic inhibition with a dual epidermal growth factor receptor/HER-2/neu tyrosine kinase inhibitor and a disintegrin and metalloprotease inhibitor. Witters L, Scherle P, Friedman S, Fridman J, Caulder E, Newton R, Lipton A. Department of Medicine, The Milton S. Hershey Medical Center/Pennsylvania State University College of Medicine, Hershey, PA 17033, USA. The ErbB family of receptors is overexpressed in numerous human tumors. Overexpression correlates with poor prognosis and resistance to therapy. Use of ErbB-specific antibodies to the receptors (Herceptin or Erbitux) or ErbB-specific small-molecule inhibitors of the receptor tyrosine kinase activity (Iressa or Tarceva) has shown clinical efficacy in several solid tumors. An alternative method of affecting ErbB-initiated tumor growth and survival is to block sheddase activity. Sheddase activity is responsible for cleavage of multiple ErbB ligands and receptors, a necessary step in availability of the soluble, active form of the ligand and a constitutively activated ligand-independent receptor. This sheddase activity is attributed to the ADAM (a disintegrin and metalloprotease) family of proteins. ADAM 10 is the main sheddase of epidermal growth factor (EGF) and HER-2/neu cleavage, whereas ADAM17 is required for cleavage of additional EGF receptor (EGFR) ligands (transforming growth factor-alpha, amphiregulin, heregulin, heparin binding EGF-like ligand). This study has shown that addition of INCB3619, a potent inhibitor of ADAM10 and ADAM17, reduces in vitro HER-2/neu and amphiregulin shedding, confirming that it interferes with both HER-2/neu and EGFR ligand cleavage. Combining INCB3619 with a lapatinib-like dual inhibitor of EGFR and HER-2/neu kinases resulted in synergistic growth inhibition in MCF-7 and HER-2/neu-transfected MCF-7 human breast cancer cells.Combining the INCB7839 second-generation sheddase inhibitor with lapatinib prevented the growth of HER-2/neu-positive BT474-SC1 human breast cancer xenografts in vivo. These results suggest that there may be an additional clinical benefit of combining agents that target the ErbB pathways at multiple points. PMID: 18757423 [PubMed - indexed for MEDLINE] J Clin Oncol. 2009 Aug 20;27(24):3908-15. Epub 2009 Jul 20. Estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2 (HER2), and epidermal growth factor receptor expression and benefit from lapatinib in a randomized trial of paclitaxel with lapatinib or placebo as first-line treatment in HER2-negative or unknown metastatic breast cancer. Finn RS, Press MF, Dering J, Arbushites M, Koehler M, Oliva C, Williams LS, Di Leo A. Geffen School of Medicine at University of California, Los Angeles, CA, USA. Rfinn@mednet.ucla.edu PURPOSE: Lapatinib is a dual inhibitor of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) with activity in HER2-amplified metastatic breast cancer (MBC). Its role in non-HER2-amplified MBC remains unclear. EGF30001, a phase III trial of lapatinib and paclitaxel versus paclitaxel and placebo, demonstrated lapatinib does not significantly benefit HER2-negative or HER2-unselected patients with MBC. Published data support interactions between steroid hormone and peptide growth factor signaling. We hypothesized that molecular subgroups may exist within EGF30001 that would benefit from lapatinib. METHODS: A blinded, retrospective biomarker evaluation was performed using immunohistochemistry to semiquantitate estrogen (ER), progesterone (PR), and EGFR expression. HER2 amplification was determined by fluorescent in situ hybridization. Effects of these biomarkers on event-free survival (EFS) were examined in patients with available tissue (n = 493). RESULTS: Lapatinib improved median EFS in HER2-amplified, ER- or PR-positive MBC (n = 36; 5.7 v 4.5 months; P = .351); benefit was greater and statistically significant in HER2-amplified, ER-negative, PR-negative MBC (n = 42; 8.3 v 5.0 months; P = .007). In HER2-negative, ER-positive MBC, median EFS improvement varied by degree of PR expression (H-score): no benefit if PR-strong (n = 133; 9.3 v 7.3 months; P = .373), benefit if PR-weak (n = 50; 7.3 v 2.4 months; P = .026), and potential antagonism if PR-negative (n = 40; 3.7 v 7.2 months; P = .004). No benefit was seen in triple-negative MBC (n = 131; median EFS, 4.6 v 4.8 months; P = .255). EGFR expression was not correlated with benefit from lapatinib. CONCLUSION: Although subgroups are small, these analyses support the hypothesis that semiquantitative determination of hormone receptor status may be a surrogate for EGFR and/or HER2 dependency. PMID: 19620495 [PubMed - indexed for MEDLINE] __________________ Mom's treatment history (link)