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Originally published as JCO Early Release 10.1200/JCO.2007.13.9949 on January 22 2008 © 2008 American Society of Clinical Oncology. Phase II Study of Predictive Biomarker Profiles for Response Targeting Human Epidermal Growth Factor Receptor 2 (HER-2) in Advanced Inflammatory Breast Cancer With Lapatinib Monotherapy
From the Department of Medicine-Breast Unit, Royal Marsden Hospital, London, United Kingdom; Medical Oncology & Hematology, Sunnybrook and Women's College Health Sciences Centre, Toronto, Ontario, Canada; Oncology Institute, The Chaim Sheba Medical Center, Tel Hashomer, Israel; Institut Shalah Azaiz, Tunis; Department of Service de Carcinologie Médicale, CHU Farhat Hached, Sousse, Tunisia; Duke University Medical Center, Durham, NC; Karmanos Cancer Institute, Detroit, MI; Washington University Medical Center, St Louis, MO; Midwestern Regional Medical Center, Zion, IL; and Oncology Medicines Development Center, Statistics and Programming, and Biomarker Strategy and Analysis, GlaxoSmithKline, Collegeville, PA Corresponding author: Neil L. Spector, MD, Duke University Medical Center, 2424 Erwin Road, Hock Plaza Suite 601, Durham, NC, 28807; e-mail: neil.spector{at}duke.edu
Purpose Inflammatory breast cancer (IBC) is one of the most aggressive forms of breast cancer. Lapatinib, an oral reversible inhibitor of epidermal growth factor receptor (EGFR) and human EGFR 2 (HER-2), demonstrated clinical activity in four of five IBC patients in phase I trials. We conducted a phase II trial to confirm the sensitivity of IBC to lapatinib, to determine whether response is HER-2 or EGFR dependent, and to elucidate a molecular signature predictive of lapatinib sensitivity. Patients and Methods Our open-label multicenter phase II trial (EGF103009) assessed clinical activity and safety of lapatinib monotherapy in patients with recurrent or anthracycline-refractory IBC. Patients were assigned to cohorts A (HER-2–overexpressing [HER-2+]) or B(HER-2–/EGFR+) and fresh pretreatment tumor biopsies were collected. Results Forty-five patients (30 in cohort A; 15 in cohort B) received lapatinib 1,500 mg once daily continuously. Clinical presentation and biomarker analyses demonstrated a tumor molecular signature consistent with IBC. Lapatinib was generally well tolerated, with primarily grade 1/2 skin and GI toxicities. Fifteen patients (50%) in cohort A had clinical responses to lapatinib in skin and/or measurable disease (according to Response Evaluation Criteria in Solid Tumors) compared with one patient in cohort B. Within cohort A, phosphorylated (p) HER-3 and lack of p53 expression predicted for response to lapatinib (P < .05). Tumors coexpressing pHER-2 and pHER-3 were more likely to respond to lapatinib (nine of 10 v four of 14; P = .0045). Prior trastuzumab therapy and loss of phosphate and tensin homolog 10 (PTEN) did not preclude response to lapatinib. Conclusion Lapatinib is well tolerated with clinical activity in heavily pretreated HER-2+, but not EGFR+/HER-2–, IBC. In this study, coexpression of pHER-2 and pHER-3 in tumors seems to predict for a favorable response to lapatinib. These findings warrant further investigation of lapatinib monotherapy or combination therapy in HER-2+ IBC.
Inflammatory breast cancer (IBC), which accounts for 1% to 6% of breast cancers in the United States and approximately 20% of newly diagnosed breast cancers in North Africa, is one of the most aggressive forms of breast cancer.1 At the time of diagnosis, the majority of IBC patients have lymph node involvement, and 30% have distant metastatic disease.2 Despite recent treatment advances, the prognosis for advanced IBC remains poor, with a 3-year survival rate of 40% compared with 85% in non-IBC.1-4 IBC is a distinct clinicopathologic entity characterized by rapid onset of swelling, erythema, and brawny edema (peau d'orange) of the involved breast, often without a discrete underlying palpable mass.3,4 The presence of dermal lymphatic invasion by tumor emboli is a frequent histologic finding in IBC. Although recent gene expression analyses indicate that IBC is a heterogeneous disease,5,6 a molecular profile of IBC has nonetheless emerged distinguishing it from non-IBC.7 First, gene amplification of the HER-2 receptor tyrosine kinase, a genetic mutation associated with a poorer clinical outcome in breast cancer,8 occurs more frequently in IBC compared with non-IBC.9 Second, IBC is more likely to (a) be estrogen-receptor (ER)–negative, (b) express increased membrane E-cadherin, (c) exhibit increased cytoplasmic MUC1 staining, and (d) proliferate more rapidly compared with non-IBC.7,10 Third, IBC tends to overexpress RhoC, a small GTPase involved in cytoskeletal reorganization, more frequently compared with stage-matched non-IBC.11 And finally, loss of the tumor suppressor gene LIBC (Lost in Inflammatory Breast Cancer) occurs more frequently in IBC compared with non-IBC.12 LIBC encodes for the low-affinity insulin-like growth factor (IGF)–binding family of proteins (IGFBP-rP), which interferes with growth/survival signals by blocking IGF from binding its cognate receptor, IGF-1R.13 These findings implicate deregulation of the IGF/IGF-1R signaling pathway in the pathogenesis of IBC. Lapatinib is an oral small-molecule reversible dual inhibitor of EGFR and HER-2 tyrosine kinases14 recently approved in combination with capecitabine for treating advanced-stage HER-2–overexpressing (HER-2+) breast cancers that have progressed during prior anthracycline, taxane, and trastuzumab therapies.15 Lapatinib blocks downstream mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (PI3K) proliferation and survival signaling pathways in HER-2+ breast cancer cell lines, tumor xenografts, and patients with HER-2+ breast cancers.16,17 Of the five heavily pretreated IBC patients enrolled in phase I clinical trials of lapatinib monotherapy or combination therapies, three had partial responses and one had a prolonged complete remission (3+ years); all four responding IBC tumors overexpressed HER-2.18,19 In light of these initial clinical responses and the sensitivity of HER-2+ IBC cell lines to lapatinib, we conducted a phase II clinical trial to (a) evaluate the clinical activity and safety of lapatinib in patients with recurrent or anthracycline-refractory IBC, and (b) to identify a molecular signature predicting for response to lapatinib monotherapy.
Patients Eligible adults (  18 years of age) had histologically confirmed IBC and a clinical diagnosis of IBC (eg, presence of diffuse erythema and edema [peau d'orange], with or without an underlying palpable mass, involving the majority of the skin of the breast). Pathologic evidence of dermal lymphatic invasion was not required. Inclusion criteria included (a) locally advanced or metastatic disease that was refractory or had recurred after treatment with an anthracycline-containing regimen in the adjuvant or metastatic setting; (b) tumor that was accessible for biopsy; (c) tumor that overexpressed HER-2 and/or expressed EGFR; (d) adequate renal, hepatic, bone marrow, and cardiac function; (e) an Eastern Cooperative Oncology (ECOG) performance status of 0 to 2; and (f) a life expectancy of at least 12 weeks. The number of prior chemotherapies, biologics (other than lapatinib), and antiestrogens was not restricted, with the last administration at least 4 weeks before study entry. EGF103009 was approved by the institutional review board from each participating institution, and written informed consent was obtained from all patients.
Study Design
Patients were assigned to cohort A if their tumor overexpressed HER-2 protein (2+ or 3+ IHC) or exhibited gene amplification (positive on fluorescence in situ hybridization; ratio of HER-2:CEP17 Patients underwent regular physical examinations and evaluations of performance status, body weight, CBC, serum chemistry, left ventricular ejection fraction by multiple gated acquisition scan or echocardiogram, and if applicable, digital photography to evaluate changes in chest wall/skin disease or assessment by imaging studies, computed tomography scan or magnetic resonance imaging.
Efficacy and Safety Evaluation
Immunohistochemical Analyses
Statistical Analysis
Baseline biomarkers β-catenin, bcl-2, ER, heregulin, p53, pEGFR, pHER-2, pHER3, PR, RhoC, TGF-
Patients Forty-five patients who could be assigned to cohort A or B were recruited between March 2005 and February 2006 at 16 centers. Patient characteristics are summarized in Table 1. Dermal lymphatic invasion was present in the majority of tumor biopsies (73% in cohort A; 80% in cohort B). Histopathology was reviewed centrally, and invasive adenocarcinoma of the breast was confirmed. Protein analysis of fresh tumor biopsies exhibited a molecular profile consistent with that of IBC including (a) ER-negative (74%), (b) E-cadherin overexpression (80%), and (c) RhoC overexpression (100%). Patients in cohorts A and B received a median of four and three prior therapies, respectively (Table 1). All assessable patients had received at least one prior anthracycline-containing chemotherapy regimen, 86% and 80% of patients in cohorts A and B respectively had prior treatment with a taxane, and 50% (15 of 30) of the patients in cohort A received prior trastuzumab (Table 1). Two patients with confirmed IBC had recurrent metastatic disease without skin involvement at time of enrolment.
Clinical Response The details of confirmed clinical responses are summarized in Table 2. Fifty percent (15 of 30) of patients with HER-2+ IBC (cohort A) experienced response. Of the 15 patients in cohort A who received prior trastuzumab therapy, six had response to lapatinib. Among the responders in cohort A were two patients (7%) whose best clinical response was a CR in the chest wall/skin or in RECIST-measurable lesions (Fig 1). An additional 13 patients (43%) had a PR in chest wall/skin and/or RECIST-measurable lesions as their best response. All responses in the skin occurred by the first assessment (week 4). Median duration of overall response (skin and RECIST) was 16.9 weeks (range, 8 to 31.7+ weeks). The median PFS of cohort A patients was 14 weeks (95% CI, 15 to 32 weeks) with a median follow-up time of 15.3 weeks (Fig 1F).
In contrast, only one of 15 patients in cohort B had a clinical response (PR in skin/chest disease). Consequently, enrollment of patients into cohort B was closed. The median PFS of cohort B patients was 4 weeks (95% CI, 4 to 12 weeks) with a median follow-up of 4.1 weeks (Fig 1F).
Safety
Tumor Profile Predictive for Response Tumors in both cohorts exhibited similar biomarker profiles indicative of an IBC phenotype (ie, RhoC and E-cadherin protein overexpression).7,10,11 Most tumors expressed the HER-family ligands TGF-  and heregulin; however, tumors from HER-2+ patients had increased expression of heregulin protein by IHC compared with tumors from HER-2–patients (P = .012 by Wilcoxon statistic on IHC scores; data not shown). The baseline molecular profile (14 biomarkers) of tumors that responded to lapatinib versus those that did not in cohort A was explored by a multivariate analysis of the IHC scores (0 to 3+; Table 4). pHER-3 expression and lack of p53 expression were significantly associated with response (P < .05 by multivariate analysis; P = .021 and .033, respectively, by univariate analysis). Patients in cohort A whose tumors coexpressed pHER-2 and pHER-3 were more likely to respond (nine of 10 v four of 14; P = .0045) than were patients whose tumors did not coexpress the phosphorylated receptors.
Bcl-2 and β-catenin expression did not correlate with response to lapatinib. PTEN deficiency (0 or 1+ by IHC) has been associated with resistance to trastuzumab monotherapy21 but did not preclude response to lapatinib, because 67% of the responders were PTEN-deficient. In addition, coexpression of IGF-1R, which has also been associated with trastuzumab resistance22,23 occurred in 83% and 87% of responders and nonresponders, respectively, and did not affect the likelihood of response to lapatinib.
Deregulated HER-2 signaling promotes the growth and survival of breast and ovarian carcinomas.8 The increased frequency of HER-2 overexpression in IBC compared with non-IBC9 suggests that aberrant HER-2 signaling contributes to the aggressiveness of IBC, making HER-2 an attractive therapeutic target in this disease. Here we show that treatment with once-daily oral lapatinib monotherapy is well tolerated in heavily pretreated IBC, resulting in a 50% response rate (15 of 30 patients) in HER-2+ IBC. By comparison, there was a 4% to 8% response rate to lapatinib monotherapy in a similar population of heavily pretreated HER-2+ non-IBC breast cancers,24 supporting a more prominent role for HER-2 signaling in regulating cell growth and survival in IBC compared with non-IBC. In contrast, only one tumor in cohort B responded to lapatinib. These findings are consistent with preclinical data in breast cancer cell lines in which HER-2 overexpression, not EGFR, is predictive of response to lapatinib.25 Furthermore, the lack of clinical activity of selective EGFR tyrosine kinases inhibitors as monotherapy in breast cancer further indicate HER-2 as having a more prominent role in regulating breast cancer cell growth and survival compared with EGFR.26 HER receptors do not signal as monomers but rather as homo- or heterodimers, with the latter a more potent signaling complex whose formation is triggered by the binding of exogenous EGF-family peptide ligands.27-30 HER-2 is the preferred heterodimeric partner for HER family receptors.28 It is the only HER receptor lacking an exogenous ligand, instead transactivated by its HER partners.27 Activation and subsequent dimerization lead to increased phosphorylation of specific tyrosine residues within the cytoplasmic domain of each receptor, establishing docking sites for phosphotyrosine-binding domain and/or Src-homology-2 (SH2)–containing adaptor proteins. Activation of these adapter proteins initiates a signaling cascade that regulates cell growth and survival.27-30 Certain SH2 and phosphotyrosine-binding domain proteins preferentially associate with specific HER receptors. In particular, HER-3, which is activated by its ligand, heregulin β 1 (HRG),31,32 contains six cytoplasmic docking sites for the p85 subunit of PI3K,33 which in turn activates Akt, a prosurvival factor involved in resistance to antiestrogens and chemotherapy.34 HER-3 lacks intrinsic kinase activity requiring transphosphorylation by its heterodimerization partner for activation.35 Consequently, HER-2–HER-3 heterodimers potently activate PI3K-Akt and other antiapoptotic signaling networks.36,37 HER-2–HER-3 heterodimers are the most transforming and mitogenic receptor complex within the HER family.36,37 Coexpression of HER-3 and HER-2 predicts for early escape from HER-2–directed monoclonal antibody therapy with trastuzumab.38 We have shown in preclinical studies that targeting the internal tyrosine kinase domain of HER-2 with lapatinib inhibits transphosphorylation of HER-3 by HER-2, preventing subsequent signaling via PI3K-Akt.39 Here, we show in clinical samples of HER-2+ IBC that coexpression of the activated, phosphorylated forms of HER-3 and HER-2 seems to predictor for clinical response to lapatinib, thus implicating activated HER-2–HER-3 heterodimers and their prosurvival signals in the biology of these aggressive tumors. Moreover, we show the presence of HRG in HER-2+ IBC, implicating an autocrine or paracrine activation loop whereby HRG binds HER-3, stimulating the formation of HER-2–HER-3 heterodimers, which in turn transactivates HER-3, promoting downstream survival signals. On the basis of these findings, we propose that the presence of pHER-3 in HER-2+ IBC identifies tumors whose survival is more likely to be dependent on HER-2–HER-3 heterodimer signaling, which consequently may be more sensitive to the antitumor effects of potent HER-2 tyrosine kinase inhibitors such as lapatinib. In contrast, selective EGFR inhibitors such as gefitinib or erlotinib seem to be ineffective against breast cancer cell lines with activated HER-2–HER-3 heterodimers.40 Although provocative, these findings require confirmation in larger clinical trials. Although there were patients in cohort A who did not receive prior trastuzumab, there are reasons to suspect that trastuzumab might not be as effective in this population. First, absent or low expression of PTEN, which abrogates PI3K-Akt signaling, occurs in approximately 30% of all breast cancers,41 and was recently shown to mediate resistance to trastuzumab monotherapy.21 PTEN loss in cell lines does not induce resistance in vitro to lapatinib.42 In our study, 67% of clinical responders to lapatinib were PTEN deficient, suggesting that PTEN status does not preclude response to lapatinib monotherapy in IBC. Second, the presence of activated IGF-1R signaling as a consequence of LIBC mutations in IBC serves as a redundant survival pathway that has been shown to mediate resistance to trastuzumab.12,22,23 In contrast to trastuzumab, lapatinib blocks the transactivation of EGFR and HER-2 by IGF-1R,43 providing an explanation as to why IGF-1R coexpression does not preclude response to lapatinib in HER-2+ IBC. Finally, patients experienced response to lapatinib despite having had disease progression during prior trastuzumab-based therapy, suggesting that progression during prior trastuzumab therapy does not necessarily preclude response to lapatinib, although this will require confirmation in a larger data set of lapatinib-treated HER-2+ IBC. Breast cancer treatment will be increasingly based on molecular profiling of tumors rather than on histology alone. It is unlikely that any one biomarker will serve as a sensitive predictor of response to targeted therapy alone, particularly in carcinomas, where complex redundant signaling networks regulate tumor cell growth and survival. We now provide provocative evidence that the presence of pHER-3 in HER-2+ IBC may identify tumors that are dependent on HER-2–HER-3 signaling for survival, which in turn may be more sensitive to HER-2 kinase inhibition. Although the predictive nature of this molecular signature requires confirmation in larger clinical trials, the single-agent activity for lapatinib observed in this phase II study warrants subsequent investigation of lapatinib monotherapy and combination therapies in refractory and chemotherapy-naïve HER-2+ IBC.
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: Michelle L. DeSilvio, GlaxoSmithKline (C); Jennifer Harris, GlaxoSmithKline (C); Ron E. Westlund, GlaxoSmithKline (C); Vanessa Salazar, GlaxoSmithKline (C); Tal Z. Zaks, GlaxoSmithKline (C); Neil L. Spector, GlaxoSmithKline (C) Consultant or Advisory Role: Maureen Trudeau, GlaxoSmithKline (C); Bella Kaufman, GlaxoSmithKline (C); Kimberley Blackwell, GlaxoSmithKline (C); Neil L. Spector, Consults on breast cancer products, GlaxoSmithKline (C) Stock Ownership: Michelle L. DeSilvio, GlaxoSmithKline; Jennifer Harris, GlaxoSmithKline; Ron E. Westlund, GlaxoSmithKline; Vanessa Salazar, GlaxoSmithKline; Tal Z. Zaks, GlaxoSmithKline; Neil L. Spector, GlaxoSmithKline Honoraria: Maureen Trudeau, GlaxoSmithKline; Bella Kaufman, GlaxoSmithKline; Neil L. Spector, Presentations at international congresses, GlaxoSmithKline Research Funding: Stephen Johnston, Bella Kaufman, Hamouda Boussen; Kimberley Blackwell, Patricia LoRusso, Donald P. Lombardi, Slim Ben Ahmed, Dennis L. Citrin, Neil L. Spector Expert Testimony: Maureen Trudeau (U); Bella Kaufman (U); Neil L. Spector (U) Other Remuneration: None
Conception and design: Stephen Johnston, Neil L. Spector Administrative support: Vanessa Salazar Provision of study materials or patients: Stephen Johnston, Maureen Trudeau, Bella Kaufman, Hamouda Boussen, Kimberley Blackwell, Patricia LoRusso, Donald P. Lombardi, Slim Ben Ahmed, Dennis L. Citrin, Neil L. Spector Collection and assembly of data: Maureen Trudeau, Bella Kaufman, Hamouda Boussen, Kimberley Blackwell, Patricia LoRusso, Donald P. Lombardi, Slim Ben Ahmed, Dennis L. Citrin, Jennifer Harris, Vanessa Salazar, Tal Z. Zaks, Neil L. Spector Data analysis and interpretation: Michelle L. DeSilvio, Jennifer Harris, Ron E. Westlund, Vanessa Salazar, Tal Z. Zaks, Neil L. Spector Manuscript writing: Stephen Johnston, Maureen Trudeau, Bella Kaufman, Michelle L. DeSilvio, Ron E. Westlund, Vanessa Salazar, Tal Z. Zaks, Neil L. Spector Final approval of manuscript: Stephen Johnston, Maureen Trudeau, Bella Kaufman, Michelle L. DeSilvio, Vanessa Salazar, Tal Z. Zaks, Neil L. Spector
We thank Ginny Mason and Owen Johnson from the Inflammatory Breast Cancer Foundation for their support, and Francine Carrick for her assistance in preparing this manuscript.
S.J., M.T., and B.K. contributed equally to this work. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article. published online ahead of print at www.jco.org on January 22, 2008.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
B (pNF
