TPMT and NUDT15 Variants Predict Discontinuation of Azathioprine for Myelotoxicity in Patients with Inflammatory Disease: Real-World Clinical Results.

Azathioprine is used frequently to treat several inflammatory conditions. However, treatment is limited by adverse events-in particular, myelotoxicity. Thiopurine-S-methyltransferase (TPMT) and nudix hydrolase-15 (NUDT15) are enzymes involved in azathioprine metabolism; variants in the genes encoding these enzymes increase the risk for azathioprine myelotoxicity. The Clinical Pharmacogenetics Implementation Consortium (CPIC) has recommended dose adjustments based on the results of TPMT and NUDT15 genotyping. However, little is known about the importance of this genetic information in routine clinical care. We hypothesized that in patients with inflammatory diseases, TPMT and NUDT15 genotype data predict the risk of discontinuing azathioprine due to myelotoxicity. This was a retrospective cohort study in 1,403 new adult azathioprine users for the management of inflammatory conditions for whom we had genetic information and clinical data. Among patients who discontinued azathioprine, we adjudicated the reason(s). Genotyping was performed using the Illumina Infinium Expanded Multi-Ethnic Genotyping Array plus custom content. We used CPIC guidelines to determine TPMT and NUDT15 metabolizer status; patients were grouped as either: (i) poor/intermediate, or (ii) normal/indeterminate metabolizers. We classified 110 patients as poor/intermediate, and 1,293 patients as normal/indeterminate metabolizers. Poor/intermediate status was associated with a higher risk for azathioprine discontinuation due to myelotoxicity compared to normal/indeterminate metabolizers (hazard ratio (HR) = 2.90, 95% confidence interval (CI): 1.58-5.31, P = 0.001). This association remained significant after adjustment for race, age at initiation, sex, primary indication, and initial daily dose of azathioprine (adjusted HR (aHR) = 2.67, 95% CI: 1.44-4.94, P = 0.002). In conclusion, TPMT and NUDT15 metabolizer status predicts discontinuation due to myelotoxicity for patients taking azathioprine for inflammatory conditions.

Interdependence of radial scar and proliferative disease with respect to invasive breast carcinoma risk in patients with benign breast biopsies.

BACKGROUND: Radial scars (RS) are benign breast lesions that have been implicated as independent risk factors for invasive breast carcinoma (IBC). METHODS: A retrospective cohort study of 9556 women who underwent biopsy between 1950-1986 and enrolled in the Nashville Breast Cohort was performed to investigate the association between RS in a benign breast biopsy and the risk of IBC. The risk associated with RS and coexistent proliferative disease (PD) was assessed adjusting for age at biopsy using a Cox hazards regression analysis with time-dependent covariates. RESULTS: RS were identified in 880 women (9.2%). The average follow-up time was 20.4 years. Sixty-two women (7.0%) with RS developed IBC compared with 5.5% of controls. The relative risk of IBC associated with RS was 1.82 (95% confidence interval [95% CI], 1.2-2.7) at 10 years. Restricting the analysis to women age > 49 years increased the risk to 2.14 (95% CI, 0.6-2.8). These risks decreased with increasing years of follow-up. Approximately 92% of women with RS also had PD, but RS were present in only 1.3% of biopsies without PD. Analyses stratifying relative risk with regard to PD found RS to minimally elevate the relative risk of subsequent IBC. CONCLUSIONS: RS in the absence of PD is uncommon. Although the presence of RS in a benign breast biopsy mildly elevates the risk of IBC risk, the current analysis indicated that this risk can be largely attributed to the category of coexistent PD. In women with both RS and atypical hyperplasia, recommendations for interventions beyond biopsy should be based on the extent of atypical hyperplasia.