Optimal strategies for carrier screening and prenatal diagnosis of α- and β-thalassemia

The thalassemias are inherited quantitative disorders of hemoglobin synthesis with a significant worldwide burden, which result in a wide spectrum of disease from the most severe transfusion-dependent form to the mildest asymptomatic carrier state. In this article, we discuss the importance of carrier, prenatal, and newborn screening for thalassemia. We examine the rationale for who should be screened and when, as well as the current methodology for screening. Deficiencies in the newborn screening program are highlighted as well. With the advent of inexpensive and rapid genetic testing, this may be the most practical method of screening in the future, and we review the implications of population-based implementation of this strategy. Finally, a case-based overview of the approach for individuals with the trait as well as prospective parents who have a potential fetal risk of the disease is outlined.

P1934Platelet inhibitory profiles of prasugrel versus ticagrelor in patients with CYP2C19 loss-of-function genotypes undergoing percutaneous coronary intervention: results of a randomized feasibility study

Background Although clopidogrel is the most widely used P2Y12 inhibitor, loss-of-function (LOF) allelic variants located within the hepatic cytochrome P450 (CYP) 2C19 gene lead to attenuated bioactivation, increased rates of high platelet reactivity (HPR), and worse outcomes in patients undergoing percutaneous coronary intervention (PCI). Drug regulating authorities have suggested using alternative P2Y12 inhibitors (i.e., prasugrel or ticagrelor) in these patients. However, tailoring antiplatelet therapy in clinical practice according to results of genetic testing has been limited due to lack of access to promptly available results. Moreover, there are no head-to-head pharmacodynamic (PD) comparisons of prasugrel vs ticagrelor among patients with CYP2C19 LOF alleles. Purpose The aim of this study was to evaluate the feasibility of using rapid genetic testing in clinical practice and to compare the PD effects of prasugrel vs ticagrelor in patients undergoing PCI with CYP2C19 LOF alleles. Methods This was a prospective, randomized study conducted in patients with stable coronary artery disease and non-ST elevation acute coronary syndrome scheduled for left heart catheterization (LHC) with the intent to undergo PCI. Patients underwent rapid genetic testing using the Spartan RX assay, which defines CYP2C19 genetic status within 1 hour, allowing patients to be genotyped the same day of their LHC. Patients who were carriers of at least one LOF (*2 or *3) allele were randomized to receive either prasugrel [60mg loading dose (LD) - 10mg/day maintenance dose (MD)] or ticagrelor (180mg LD - 90mg b.i.d MD). Blood samples for PD analysis by VerifyNow were collected at 5 time points: baseline (prior to PCI), 30 minutes, 2 hours, 24 hours (or at hospital discharge whichever came first), and 1–4 weeks post-LD. All patients were treated with aspirin. The primary endpoint of our study was the non-inferiority in platelet reactivity, measured as PRU, at 24 hours of prasugrel vs ticagrelor in LOF allele carriers. Results A total of 781 consecutive patients scheduled for LHC were genotyped, of whom 223 (28.5%) were carriers of at least one LOF. Of these, 65 patients underwent PCI and randomized to prasugrel (n=32) vs ticagrelor (n=33). PRU levels at 24 hours were 33 vs 36 (prasugrel vs ticagrelor; mean difference = −3; 95% CI: −28 to 22; p=0.814) meeting the primary endpoint of non-inferiority. Both prasugrel and ticagrelor significantly reduced PRU to a similar extent with no differences between groups at all other time points (Figure). Accordingly, HPR rates were low and similar between groups. PRU by VerifyNow Conclusion Rapid genetic testing using the Spartan assay is feasible providing results in a timely fashion in a real-world clinical practice of patients undergoing PCI. Among patients with CYP2C19 LOF carrier status, prasugrel and ticagrelor are associated with similar levels of platelet inhibition. Acknowledgement/Funding Genetic testing was provided by Spartan RX

Outcomes associated with rapid genetic testing for BRCA1 and BRCA2 at time of breast cancer diagnosis.

1577 Background: Bilateral mastectomy improves survival for women with BRCA-associated breast cancer. Most women do not know their BRCA status at the time of BC diagnosis when making surgical decisions. Rapid genetic testing (RGT) allows a woman to have genetic test results prior to treatment decision making, but it is unclear if RGT has an impact on treatment choices. It is also unclear if there are psychosocial implications associated with genetic testing at the time of breast cancer diagnosis. The objective of the current study was to assess the impact of RGT at the time of BC diagnosis on surgical decision-making and psychosocial functioning. Methods: Eligible women were referred from participating surgeons at BC diagnosis. Women completed baseline questionnaires assessing treatment preferences, cancer related distress, anxiety, and depression. All participants received in-person pre-test genetic counselling and genetic test results were given within 10 days. Participants completed surveys at 1 week and 1 year post-genetic testing to assess treatments and psychosocial functioning. Results: 1010 women consented to participate and 60 (5.9%) were identified with a BRCA mutation. 15% of those identified with a BRCA mutation did not meet provincial eligibility criteria for genetic testing, and 20% were eligible prior to a breast cancer diagnosis but had not received testing. Mean levels of cancer-related distress, anxiety and depression declined significantly from baseline to 1 year for all women (all p < .05), and there were no differences at any time point between those with and without a BRCA mutation. Of those identified with a BRCA mutation, 67.3% reported that their surgery choice changed. 73.7% of BRCA carriers had a bilateral mastectomy, compared to 20.2% of BRCA negative (p < 0.001). Most women used genetic testing results for surgical decision making (96.1% of BRCA positive and 86.4% for negative). Conclusions: Rapid genetic testing for BRCA1 and BRCA2 at the time of BC diagnosis does not have a negative impact on psychosocial functioning. There are no differences in cancer-related distress, anxiety or depression between women who receive a positive result compare to a negative genetic test result. Furthermore, surgical choice changed for many women identified with a BRCA mutation, with the majority electing for bilateral mastectomy.