Lapatinib Restores Endocrine Sensitivity in Selected Patients with Estrogen Receptor (ER) Positive Metastatic Breast Cancer.

Background:Breast cancer cell lines achieve a state of resistance to antiestrogens and to estrogen withdrawal or aromatase inhibitors by utilizing other growth factor pathways to transactivate ERα and undergo estrogen-independent growth. Breast cancer cell lines consistently overexpress the epidermal growth factor family of receptors (ErbB) and/or the epidermal growth factor (EGF) ligands when they achieve endocrine-independent growth. Our hypothesis is that the ErbB family of receptors is the dominant pathway utilized by breast cancers in our patients with endocrine-resistant tumors. Because ErbB2 is the dominant partner in ErbB heterodimerization, a tyrosine kinase inhibitor with ErbB2 activity such as lapatinib would be the preferred agent to block transactivation of ERα. Lapatinib has minimal activity as a single agent against ErbB2 unamplified cancers, and any clinical benefit from the combination of lapatinib and endocrine therapy indicates evidence of an interaction between the ER and ErbB pathways.Materials and Methods:Patients with hormone receptor positive, metastatic breast carcinoma with an initial clinical benefit from any line of endocrine therapy, were enrolled within six weeks of documentation of clinical progression on endocrine therapy. Subjects had an ECOG performance status of 0-2, adequate organ function, and recovery from prior cancer treatment. They were continued on the same endocrine therapy, with the addition of lapatinib at 1500 mg once daily. Patients were restaged at 14 and 26 weeks, and those with stable disease or better at 26 weeks were eligible to continue the combination of lapatinib and endocrine therapy until disease progression.Results:Twenty one patients have been enrolled to date. The median age is 60 (range 39-77), one patient has ErbB2 amplified disease, one patient has borderline amplification, and 19 patients are unamplified for ErbB2. Fifteen patients were treated with aromatase inhibitors, while six patients used antiestrogens. Ten patients had bone only metastatic disease, and only three patients had visceral metastases at enrollment. The treatment was well-tolerated; four patients had Grade 3 diarrhea, there were five episodes of diarrhea-related Grade 3 electrolyte abnormalities, and one patient went off study due to a reversible Grade 3 elevation in ALT. Seven of sixteen evaluable patients had stable disease at 26 weeks. The median time to disease progression is 179 days (range 94-513 days), and four patients remain on study free of disease progression. The use of, or duration of prior tamoxifen treatment was not predictive of progression-free survival on study.Conclusions:In a highly selected group of patients with metastatic breast cancer, the addition of lapatinib to the endocrine agent on which the cancer had just progressed maintained the duration of response by an average of six months. This demonstrates a favorable interaction between lapatinib and both aromatase inhibitors and antiestrogens in patients with newly acquired endocrine resistance. Accrual to this study is continuing. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3089.