Barriers to the utilization of genetic testing and genetic counseling in patients with suspected hereditary breast and ovarian cancers.

A heritable condition is the identified cause of cancer in 5% to 10% of women with breast cancer and in 25% of women with ovarian cancer. It is critical to identify patients at risk for inherited genetic mutations to implement risk-reducing screening and interventions; however, reports in the medical literature indicate that an alarming number of patients with inherited genetic mutations do not receive recommended genetic counseling, testing, or interventions. In order to improve outcomes for these high-risk patients, barriers to genetic testing and counseling must be identified. We analyzed approximately 200 patients seen at our institution with breast or ovarian cancer who met criteria of the National Comprehensive Cancer Network for genetic counseling and testing. Of these patients, almost 70% had appropriate genetic testing and counseling. Review of the remaining 30% revealed that the largest obstacle to receiving genetic testing and/or counseling was lack of referral from the treating oncologist. Of the patients diagnosed with a pathogenic heritable mutation, most underwent appropriate risk-reducing procedures and surveillance. Thus, the initial referral to genetic counseling is the most significant barrier for at-risk patients at our institution and likely in this population at large. Additional study is needed to identify ways to improve appropriate use of genetic testing and counseling.

Improved efficacy of a next-generation ERT in murine Pompe disease.

Pompe disease is a rare inherited disorder of lysosomal glycogen metabolism due to acid α-glucosidase (GAA) deficiency. Enzyme replacement therapy (ERT) using alglucosidase alfa, a recombinant human GAA (rhGAA), is the only approved treatment for Pompe disease. Although alglucosidase alfa has provided clinical benefits, its poor targeting to key disease-relevant skeletal muscles results in suboptimal efficacy. We are developing an rhGAA, ATB200 (Amicus proprietary rhGAA), with high levels of mannose-6-phosphate that are required for efficient cellular uptake and lysosomal trafficking. When administered in combination with the pharmacological chaperone AT2221 (miglustat), which stabilizes the enzyme and improves its pharmacokinetic properties, ATB200/AT2221 was substantially more potent than alglucosidase alfa in a mouse model of Pompe disease. The new investigational therapy is more effective at reversing the primary abnormality - intralysosomal glycogen accumulation - in multiple muscles. Furthermore, unlike the current standard of care, ATB200/AT2221 dramatically reduces autophagic buildup, a major secondary defect in the diseased muscles. The reversal of lysosomal and autophagic pathologies leads to improved muscle function. These data demonstrate the superiority of ATB200/AT2221 over the currently approved ERT in the murine model.