Originally published as JCO Early Release 10.1200/JCO.2008.17.1462 on December 15 2008

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Relevance of Breast Cancer Antiestrogen Resistance Genes in Human Breast Cancer Progression and Tamoxifen Resistance

From the Departments of Pathology and Medical Oncology, Cancer Genomics Center, Josephine Nefkens Institute, Erasmus MC-University Medical Center Rotterdam, Rotterdam, the Netherlands.

Corresponding author: Lambert C.J. Dorssers, Department of Pathology, Josephine Nefkens Institute, Be 432, Erasmus MC, PO Box 2040, 3000 CA, Rotterdam, the Netherlands; e-mail: l.dorssers{at}erasmusmc.nl.

Purpose We have previously identified a set of breast cancer antiestrogen resistance (BCAR) genes causing estrogen independence and tamoxifen resistance in vitro using a functional genetic screen. Here, we explored whether these BCAR genes provide predictive value for tamoxifen resistance and prognostic information for tumor aggressiveness in breast cancer patients.

Patients and Methods mRNA levels of 10 BCAR genes (AKT1, AKT2, BCAR1, BCAR3, EGFR, ERBB2, GRB7, SRC, TLE3, and TRERF1) were measured in estrogen receptor–positive breast tumors using quantitative reverse-transcriptase polymerase chain reaction. Normalized mRNA levels were evaluated for association with progression-free survival (PFS) in 242 patients receiving tamoxifen as first-line monotherapy for recurrent disease, and with distant metastasis-free survival (MFS) in 413 lymph node-negative (LNN) primary breast cancer patients who did not receive systemic adjuvant therapy.

Results Concerning tamoxifen resistance, BCAR3, ERBB2, GRB7, and TLE3 mRNA levels were predictive for PFS, independent of traditional predictive factors. By combining GRB7 (or ERBB2) and TLE3 mRNA levels, patients could be classified in three subgroups with distinct PFS. For the evaluation of tumor aggressiveness, AKT2, EGFR, and TRERF1 mRNA levels were all significantly associated with MFS, independent of traditional prognostic factors. Using the combined AKT2 and EGFR mRNA status, four prognostic groups were identified with different MFS outcomes.

Conclusion The majority of BCAR genes, which were revealed to confer tamoxifen resistance and estrogen independence in vitro by functional screening, have clinical relevance, and associate with tamoxifen resistance and/or tumor aggressiveness in breast cancer patients.

Supported by Grants No. DDHK96-1245, 99-1883, and 02-2675 from the Dutch Cancer Society, Grants No. BCTR0100675 and 0402594 from the Susan G. Komen Breast Cancer Foundation, Grant No. 04-148 from the Association for International Cancer Research, and by the Netherlands Genomic Initiative/Netherlands Organization for Scientific Research.

Presented in abstract format at the Annual Meeting of the American Association for Cancer Research in San Diego, CA, April 12-16, 2008.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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