Breast Cancer Patients With CYP19 SNP Respond Better to Aromatase Inhibitor Than Those With Normal Gene

NEW ORLEANS—Testing for a specific gene polymorphism may help to identify which patients are candidates for treatment with aromatase inhibitors, according to a presentation at the 40th Annual Meeting of the American Society of Clinical Oncology (abstract 507).

Ramon Colomer, MD, PhD, of the Institut Catala d’Oncologia, Girona, Spain, presented an analysis suggesting that metastatic breast cancer patients with a specific CYP19 single nucleotide polymorphism (SNP) are significantly more likely to respond to the aromatase inhibitor letrozole (Femara) than those with the normal aromatase gene.

Dr. Colomer noted that in a prior analysis, levels of HER2 ECD (extracellular domain) had correlated with letro-zole efficacy measured by time to progression. In the current analysis, the same time to progression endpoint was used to evaluate whether SNPs of the CYP19 aromatase gene have a predictive value. CYP19 is located on chromosome 15q and encodes a steroid aromatase that catalyzes the conversion of C19 androgens to estrogens.

Using PCR allelic discrimination (performed with the ABI Prism 7700 Sequence Detector), the investigators examined three aromatase gene SNPs in DNA obtained from 67 breast carcinomas. All patients were postmenopausal with estrogen-receptor (ER)-positive and/or progesterone-receptor (PR)-positive tumors. Mean age was about 64 years, and median metastatic tumor size was about 2 cm. Dr. Colomer characterized performance status in most patients as "very good."

Analysis showed no correlation between SNPs and age, ER or PR status, HER2 immunohistochemistry, number of metastatic sites, or levels of the serum tumor marker CA 153.

Sixty-five of the patients whose tumor samples were studied for CYP19 SNPs were evaluable for efficacy. With median follow-up of more than 3 years, there were no differences in time to progression between patients with the normal aromatase gene and those with two CYP19 SNPs (rs727479 intronic and rs10046).

"In contrast, another CYP19 SNP (rs4646 3´UTR) indicated a very important difference in the clinical course of these patients who were treated with the aromatase inhibitor letrozole," Dr. Colomer said. Median time to progression was 525 days (a little less than 18 months) in patients with CYP19 SNP rs4646 3´UTR and 196 days (a little more than 6 months) in patients with the wild-type gene (P = .02) (see Figure). Furthermore, in patients who were homozygous for this SNP, time to progression was even longer, more than 1,100 days. "That suggests that these patients with the aromatase gene variant may have a better response to the aromatase inhibitors," Dr. Colomer said.

Among samples from 61 patients evaluable for best response, most complete remissions (6 of 8) were from those patients with the SNP rs4646 variant gene; 14 of 15 of those with progressive disease had the wild-type gene. The rs4646 SNP occurs frequently, since it was found in 28 of these 61 patients (46%).

Dr. Colomer added that recent research is suggesting that evaluation of the same polymorphisms may be possible through examination of blood lymphocytes alone.

What is the effect of this polymorphism? Preliminary data, Dr. Colomer said, show that patients with this SNP under treatment with aromatase inhibitors have lower levels of circulating estrogen than patients with the normal gene. "Of course, this is a first evaluation, but this may become a new possible prognostic marker," Dr. Colomer cautioned. "It needs to be evaluated in additional series."

He concluded, "In hormone-receptor-positive metastatic breast cancer patients treated with the aromatase inhibitor letrozole, the presence of an SNP on the 3´UTR of the CYP19 aromatase gene is associated with improved treatment efficacy and may help in selecting patients for letrozole therapy."