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Abstract 2282: The K303R estrogen receptor α mutation and hormone resistance in breast cancer

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL

Introduction: We have previously identified a A to G somatic mutation at nucleotide 908 of ERα (A908G) in premalignant and invasive breast cancers. This mutation results in a lysine to arginine transition at residue 303 (K303R) in the hinge domain which confers hypersensitivity to estrogen. We discovered that the K303R ERα mutation also confers resistance to the aromatase inhibitor anastrazole and blocks tamoxifen's (Tam) antagonist action when engaged in crosstalk with growth factor receptor signaling pathways. The resistant phenotype associated with expression of the K303R ERα mutation is dependent on activation of phospho-S305 within the receptor.

Aims and Methods: We are currently using mass spectroscopy (sequenom) to detect the mutation in 204 breast cancer patients treated with monotherapy Tam, along with detection of specific mutations in PIK3CA (E545K and H1047R/L) and AKT1 (E17K), and will correlate the presence of these mutations with clinical outcomes. Patients were diagnosed between 1973 and 1993 with primary breast cancer, treated with mastectomy or lumpectomy plus axillary dissestion, with or without post-operative radiation therapy, and all of the women underwent adjuvant tamoxifen monotherapy treatment. A larger validation study is ongoing to confirm these results using DNA samples from 500 Tam-treated patients. We will use also the ABI 3730XL SNAPSHOT machine to confirm these mutations in order to compare the sensitivity of the two techniques. Immunohistochemistry staining will be developed for the ERα phospho-S305 to further evaluate correlations with clicnical outcome of the patients.

Results and Conclusion: We sequenced DNA from n=204 breast tumor samples archived in formalin-fixed, paraffin-embedded tissue microarrays. The frequency of the ERα mutation was 57%, replicating the high frequency we previousl reported in untreated breast cancer patients. The PIK3CA A3140G/T mutation, which occurs in the catalytic domain of PIK3CA, was also found at a high frequency (19%). A previous publication reported the A3140G/T mutation at 13% in DNA samples from a tumor bank of 547 patients, thus confirming the relative frequency of this mutation. The percentage of the PIK3CA G1633A mutation was 13% and AKT1 G49A was 3.4%. We found that the PIK3CA mutation was significantly associated with the presence of the K303R ERα mutation in Tam-treated patients. Survival analyses are ongoing to determine if these mutations are predictive of treatment outcome with Tam.

In summary, our finding will answer the question whether these gain of function mutations or combination might have worse clinical outcomes for Tam treated patients and establish new prognostic markers for breast cancer treatment.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2282. doi:10.1158/1538-7445.AM2011-2282