Precision Endocrine Therapy Possible in Breast Cancer Patients?

In a potential step toward precision endocrine therapy, a new study found that certain single nucleotide polymorphisms (SNPs) within CSMD1 are associated with changes in estrogen levels in postmenopausal breast cancer patients, and that anastrozole may be more effective than letrozole or exemestane when a certain SNP is present.

The new study shows that “the germline genome can contribute to aromatase inhibitor response,” said Junmei Cairns, PhD, of the Mayo Clinic in Rochester. She presented the study during a poster discussion session at the San Antonio Breast Cancer Symposium, held December 6–10 in San Antonio, Texas.

Cairns and colleagues conducted a genome-wide association study of 624 postmenopausal breast cancer patients treated with anastrozole in the M³ study, and then attempted to replicate the SNPs identified in another population of women undergoing treatment with exemestane or letrozole in the MA.27 trial.

They found that the CSMD1 SNP rs6990851 was associated with changes in estrogen levels on anastrozole therapy. Also, one allele of this gene was associated with a significantly improved time to distant recurrence among anastrozole treated patients, with a hazard ratio of 0.4861 (95% CI, 0.304–0.7772; P = .0026). There was no such association among exemestane-treated patients. Another analysis showed that the CSMD1 SNP increased sensitivity to anastrozole, but not to either exemestane or to letrozole.

The effect can likely be traced to mechanistic properties of the drugs: anastrozole binds directly to estrogen receptor–alpha, while the other agents do not. That binding is mediated by the CSMD1 SNP, which could explain the singular effect on anastrozole but not the other aromatase inhibitors. A further analysis also showed that anastrozole acts as an estrogen receptor–alpha agonist, causing its degradation especially in the presence of estradiol.

Taken together, these findings suggest that when this particular SNP is present in postmenopausal breast cancer patients, anastrozole may be the preferred aromatase inhibitor over letrozole or exemestane.

Andrea L. Richardson, MD, PhD, of the Johns Hopkins School of Medicine in Baltimore, was the discussant for the session, and said that “precision medicine going forward may require identifying drug-specific predictors of response.” She pointed out that it may not always be possible to find such predictors by analyzing the tumor itself, in the case of drug-induced changes to expression, for example. Still, she said this new study “is going to be an interesting approach.”