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Clinical benefit of lapatinib-based therapy in patients with human epidermal growth factor receptor 2-positive breast tumors coexpressing the truncated p95HER2 receptor.

ABSTRACT: PURPOSE:A subgroup of human epidermal growth factor receptor 2 (HER2)-overexpressing breast tumors coexpresses p95HER2, a truncated HER2 receptor that retains a highly functional HER2 kinase domain but lacks the extracellular domain and results in intrinsic trastuzumab resistance. We hypothesized that lapatinib, a HER2 tyrosine kinase inhibitor, would be active in these tumors. We have studied the correlation between p95HER2 expression and response to lapatinib, both in preclinical models and in the clinical setting. EXPERIMENTAL DESIGN:Two different p95HER2 animal models were used for preclinical studies. Expression of p95HER2 was analyzed in HER2-overexpressing breast primary tumors from a first-line lapatinib monotherapy study (EGF20009) and a second-line lapatinib in combination with capecitabine study (EGF100151). p95HER2 expression was correlated with overall response rate (complete + partial response), clinical benefit rate (complete response + partial response + stable disease > or =24 wk), and progression-free survival using logistic regression and Cox proportional hazard models. RESULTS:Lapatinib inhibited tumor growth and the HER2 downstream signaling of p95HER2-expressing tumors. A total of 68 and 156 tumors from studies EGF20009 and EGF100151 were evaluable, respectively, for p95HER2 detection. The percentage of p95HER2-positive patients was 20.5% in the EGF20009 study and 28.5% in the EGF100151 study. In both studies, there was no statistically significant difference in progression-free survival, clinical benefit rate, and overall response rate between p95HER2-positive and p95HER2-negative tumors. CONCLUSIONS:Lapatinib as a monotherapy or in combination with capecitabine seems to be equally effective in patients with p95HER2-positive and p95HER2-negative HER2-positive breast tumors.

SUBMITTER: Scaltriti M

PROVIDER: S-EPMC3243489 | biostudies-literature | 2010 May

REPOSITORIES: biostudies-literature

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Clinical benefit of lapatinib-based therapy in patients with human epidermal growth factor receptor 2-positive breast tumors coexpressing the truncated p95HER2 receptor.

Scaltriti Maurizio M Chandarlapaty Sarat S Prudkin Ludmila L Aura Claudia C Jimenez José J Angelini Pier Davide PD Sánchez Gertrudis G Guzman Marta M Parra Josep Lluis JL Ellis Catherine C Gagnon Robert R Koehler Maria M Gomez Henry H Geyer Charles C Cameron David D Arribas Joaquin J Arribas Joaquin J Rosen Neal N Baselga José J

Clinical cancer research : an official journal of the American Association for Cancer Research 20100420 9

<h4>Purpose</h4>A subgroup of human epidermal growth factor receptor 2 (HER2)-overexpressing breast tumors coexpresses p95HER2, a truncated HER2 receptor that retains a highly functional HER2 kinase domain but lacks the extracellular domain and results in intrinsic trastuzumab resistance. We hypothesized that lapatinib, a HER2 tyrosine kinase inhibitor, would be active in these tumors. We have studied the correlation between p95HER2 expression and response to lapatinib, both in preclinical model ...[more]

PMID: 20406840

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Project description:The epidermal growth factor receptor (EGFR) is closely associated with tumor development and progression and thus an important target structure for imaging and therapy of various tumors. As a result of its important role in malignancies of various origins and the fact that antibody-based compounds targeting the EGFR have significant drawbacks in terms of in vivo pharmacokinetics, several attempts have been made within the last five years to develop peptide-based EGFR-specific radioligands based on the GE11 scaffold. However, none of these approaches have shown convincing results so far, which has been proposed to be attributed to different potential challenges associated with the GE11 lead structure: first, an aggregation of radiolabeled peptides, which might prevent their interaction with their target receptor, or second, a relatively low affinity of monomeric GE11, necessitating its conversion into a multimeric or polymeric form to achieve adequate EGFR-targeting properties. In the present work, we investigated if these aforementioned points are indeed critical and if the EGFR-targeting ability of GE11 can be improved by choosing an appropriate hydrophilic molecular design or a peptide multimer system to obtain a promising radiopeptide for the visualization of EGFR-overexpressing malignancies by positron emission tomography (PET). For this purpose, we developed several monovalent 68Ga-labeled GE11-based agents, a peptide homodimer and a homotetramer to overcome the challenges associated with GE11. The developed ligands were successfully labeled with 68Ga3+ in high radiochemical yields of ≥97% and molar activities of 41-104 GBq/μmol. The resulting radiotracers presented log D(7.4) values between -2.17 ± 0.21 and -3.79 ± 0.04 as well as a good stability in human serum with serum half-lives of 112 to 217 min for the monovalent radiopeptides and 84 and 62 min for the GE11 homodimer and homotetramer, respectively. In the following in vitro studies, none of the 68Ga-labeled radiopeptides demonstrated a considerable EGF receptor-specific uptake in EGFR-positive A431 cells. Moreover, none of the agents was able to displace [125I]I-EGF from the EGFR in competitive displacement assays in the same cell line in concentrations of up to 1 mM, whereas the endogenous receptor ligand hEGF demonstrated a high affinity of 15.2 ± 3.3 nM. These results indicate that it is not the aggregation of the GE11 sequence that seems to be the factor limiting the usefulness of the peptide as basis for radiotracer design but the limited affinity of monovalent and small homomultivalent GE11-based radiotracers to the EGFR. This highlights that the development of small-molecule GE11-based radioligands is not promising.

Project description:PurposeRisk of recurrence is the primary consideration in breast cancer adjuvant therapy recommendations. The TEXT (Tamoxifen and Exemestane Trial) and SOFT (Suppression of Ovarian Function Trial) trials investigated adjuvant endocrine therapies for premenopausal women with hormone receptor-positive breast cancer, testing exemestane plus ovarian function suppression (OFS), tamoxifen plus OFS, and tamoxifen alone. We examined absolute treatment effect across a continuum of recurrence risk to individualize endocrine therapy decision making for premenopausal women with human epidermal growth factor receptor 2 (HER2) -negative disease.Patients and methodsThe TEXT and SOFT hormone receptor-positive, HER2-negative analysis population included 4,891 women. The end point was breast cancer-free interval (BCFI), defined as time from random assignment to first occurrence of invasive locoregional, distant, or contralateral breast cancer. A continuous, composite measure of recurrence risk for each patient was determined from a Cox model incorporating age, nodal status, tumor size and grade, and estrogen receptor, progesterone receptor, and Ki-67 expression levels. Subpopulation treatment effect pattern plot methodology revealed differential treatment effects on 5-year BCFI according to composite risk.ResultsSOFT patients who remained premenopausal after chemotherapy experienced absolute improvement of 5% or more in 5-year BCFI with exemestane plus OFS versus tamoxifen plus OFS or tamoxifen alone, reaching 10% to 15% at intermediate to high composite risk; the benefit of tamoxifen plus OFS versus tamoxifen alone was apparent at the highest composite risk. The SOFT no-chemotherapy cohort-for whom composite risk was lowest on average-did well with all endocrine therapies. For TEXT patients, the benefit of exemestane plus OFS versus tamoxifen plus OFS in 5-year BCFI ranged from 5% to 15%; patients not receiving chemotherapy and with lowest composite risk did well with both treatments.ConclusionPremenopausal women with hormone receptor-positive, HER2-negative disease and high recurrence risk, as defined by clinicopathologic characteristics, may experience improvement of 10% to 15% in 5-year BCFI with exemestane plus OFS versus tamoxifen alone. An improvement of at least 5% may be achieved for women at intermediate risk, and improvement is minimal for those at lowest risk.

Dataset Information

Clinical benefit of lapatinib-based therapy in patients with human epidermal growth factor receptor 2-positive breast tumors coexpressing the truncated p95HER2 receptor.

Publications

Clinical benefit of lapatinib-based therapy in patients with human epidermal growth factor receptor 2-positive breast tumors coexpressing the truncated p95HER2 receptor.

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