Tamoxifen significantly reduces tumor recurrence in certain patients with early-stage estrogen receptor-positive breast cancer, but markers predictive of treatment failure have not been identified. Here, we generated gene expression profiles of hormone receptor-positive primary breast cancers in a set of 60 patients treated with adjuvant tamoxifen monotherapy. An expression signature predictive of disease-free survival was reduced to a two-gene ratio, HOXB13 versus IL17BR, which outperformed existing biomarkers. Ectopic expression of HOXB13 in MCF10A breast epithelial cells enhances motility and invasion in vitro, and its expression is increased in both preinvasive and invasive primary breast cancer. The HOXB13:IL17BR expression ratio may be useful for identifying patients appropriate for alternative therapeutic regimens in early-stage breast cancer.
BACKGROUNDWomen with HER‐2 overexpressing metastatic breast carcinoma benefit from trastuzumab‐based therapy, but trastuzumab does not cross the blood‐brain barrier. The authors characterized central nervous system (CNS) disease in these women.METHODSUsing pharmacy records, the authors retrospectively identified 153 women treated with trastuzumab alone or with chemotherapy for HER‐2–positive metastatic breast carcinoma at Dana‐Farber Partners Cancer Care from June 1998 to December 2000. A study cohort of 122 patients was identified after excluding patients without adequate clinical follow‐up or who had CNS disease before trastuzumab treatment. Central nervous system disease was defined as one or more brain metastases or as leptomeningeal carcinomatosis. The median follow‐up of this cohort was 23 months.RESULTSCentral nervous system metastases were identified in 34% of patients (95% confidence interval, 26–44%) at a median of 16 months after diagnosis of metastatic breast carcinoma and 6 months from the beginning of trastuzumab therapy. Ninety‐three percent of patients with CNS disease presented with clinical symptoms. Five percent of patients with CNS disease had leptomeningeal involvement alone, although 14% had leptomeningeal involvement and parenchymal brain metastases. Fifty percent of patients were responding or had stable disease while receiving trastuzumab at other disease sites at the time of diagnosis of CNS metastasis. The median survival period after CNS metastases was 13 months. Fifty percent of patients died of progressive CNS disease. Patients receiving trastuzumab as first‐line therapy for metastatic disease frequently developed brain metastases while responding to or stable on trastuzumab at other disease sites.CONCLUSIONSMetastatic breast carcinoma to the CNS is common among patients receiving trastuzumab‐based therapy, including patients responding to therapy outside the CNS. This may be due either to predilection for the CNS by HER‐2–positive tumor cells and/or poor penetration of the CNS by trastuzumab or to improved visceral disease control leading to a longer life and onset of late tumor spread to the CNS. Efforts to characterize other risk factors for development of CNS disease, optimal screening algorithms, and new treatment strategies may be warranted. Cancer 2003;97:2972–7. © 2003 American Cancer Society.DOI 10.1002/cncr.11436
Purpose-One third of women with advanced human epidermal growth factor receptor 2 (HER-2)-positive breast cancer develop brain metastases; a subset progress in the CNS despite standard approaches. Medical therapies for refractory brain metastases are neither well-studied nor Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTERESTAlthough 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 Author Manuscript Author ManuscriptAuthor Manuscript Author Manuscript established. We evaluated the safety and efficacy of lapatinib, an oral inhibitor of epidermal growth factor receptor (EGFR) and HER-2, in patients with HER-2-positive brain metastases. Results-Thirty-nine patients were enrolled. All patients had developed brain metastases while receiving trastuzumab; 37 had progressed after prior radiation. One patient achieved a PR in the brain by RECIST (objective response rate 2.6%, 95% conditional CI, 0.21% to 26%). Seven patients (18%) were progression free in both CNS and non-CNS sites at 16 weeks. Exploratory analyses identified additional patients with some degree of volumetric reduction in brain tumor burden. The most common adverse events (AEs) were diarrhea (grade 3, 21%) and fatigue (grade 3, 15%). Patients and Methods-Patients Conclusion-The study did not meet the predefined criteria for antitumor activity in highly refractory patients with HER-2-positive brain metastases. Because of the volumetric changes observed in our exploratory analysis, further studies are underway utilizing volumetric changes as a primary end point.
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