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Old 08-31-2010, 02:08 PM   #1
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Genomic Index of Sensitivity to Endocrine Therapy for Breast Cancer

Supplementary editorial provided by OncologySTAT


In estrogen-receptor (ER)−positive breast cancer, an index of 165 ER-related genes predicted survival benefit from adjuvant endocrine therapy, not inherent prognosis.


The estrogen receptor (ER) activates transcription of numerous genes. In breast cancer patients, overall gene transcription is principally determined by ER status. Symmans et al hypothesized that measuring the level of ER-associated gene expression in a breast tumor sample would show the extent of ER transcriptional activity and thus its dependence on estrogen stimulation. Such a measurement could predict the intrinsic sensitivity of the tumor to endocrine therapy. Using 437 microarray profiles from newly diagnosed patients with stage I to III breast cancer as a discovery cohort, the researchers, from M. D. Anderson Cancer Center and Europe, identified an ER-related transcriptional signature. From this signature, they derived an index of sensitivity to endocrine therapy (SET) that measures the combined expression of 165 genes strongly related to expression of the ER gene ESR1. Of these 165 genes, 106 had a positive and 59 a negative correlation with ESR1.

The first validation cohort consisted of tumor tissue from 245 patients at the Institut Jules Bordet, Brussels, Belgium, who had ER-positive invasive breast cancer that was treated with adjuvant tamoxifen alone for 5 years. The researchers noted a significant association between the SET index (continuous) and the risk of distant relapse-free survival (DRFS) (unadjusted hazard ratio [HR], 0.70], but no significant association for ESR1 expression. Based on these continuous SET index data, cut points were established to categorize SET index values as low, intermediate, or high.

The second validation cohort was made up of tumor tissue from 310 patients with ER-positive invasive breast cancer at M.D. Anderson or the Institut Jules Bordet who also had received adjuvant tamoxifen alone for 5 years. The previous findings were confirmed, with an unadjusted HR for DRFS of 0.76 (P = .007) for the continuous SET index.

The patients in this cohort (24%) who were in the high SET index category had significantly improved DRFS, compared with patients in the intermediate or low SET index categories (HR, 0.25; P < .001). The point estimates of DRFS at 5 years of follow-up were 94.1%, 87.5%, and 79.4%, for high, intermediate, and low SET index, respectively. Of note, in patients with node-negative disease and a high SET index, the 10-year point estimate of DRFS was 100% (no events).

The researchers also studied the SET index in 2 cohorts of patients (n = 343) with node-negative, ER-positive disease who had received no adjuvant systemic therapy. In these patients, neither the gene expression level of ESR1 nor the SET index was associated with 5-year DRFS.

Finally, the SET index was tested in a cohort of 131 patients with ER-positive cancer who had received neoadjuvant chemotherapy followed by endocrine therapy. At the 5-year follow-up, point estimates of DRFS were 100% for high or intermediate SET and 82.4% for low SET index.

Both pathologic response to chemotherapy (residual cancer burden [RCB]) and SET index independently predicted DRFS. Furthermore, in the high or intermediate SET index patients, the association with reduced DRFS appeared stronger in patients who had evidenced some response to prior chemotherapy (low RCB). Among those with chemotherapy-resistant disease (high RCB), prognosis remained poor regardless of SET index status. This result challenges the view that, for ER-positive breast cancers, chemosensitive tumors and endocrine-sensitive tumors are mutually exclusive.

In summary, the SET index predicted DRFS in tamoxifen-treated patients but was not prognostic in untreated patients. The SET index can be used to estimate DRFS in patients receiving adjuvant endocrine therapy alone, and it could help determine whether or not such patients should receive additional treatment.

According to the authors, patients with an intermediate SET index should consider sequential chemo-endocrine therapy or prolonged and different endocrine therapy, while those with a low SET index should be advised to consider chemo-endocrine therapy or a clinical trial.


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