Citations

This systematic review and meta‐analysis sought to summarize the available evidence on the use of transcatheter aortic valve replacement (TAVR) in patients with Native Aortic Valve Regurgitation (NAVR) and compare outcomes between first and second generation valves. Owing to the improvements in transcatheter heart valve design and procedural success, TAVR has become increasingly performed in broader aortic valve pathologies. We searched Medline, Embase, Cochrane, and Scopus databases from 2007 to 2018 and performed a systematic review on reports with at least 10 patients with aortic valve regurgitation undergoing TAVR procedure. The main outcome of interest was all‐cause mortality at 30 days. A total of 638 patients across 12 studies were included. Mean age ranged from 68 to 84. Society of Thoracic Surgeons score ranged from 5.4% to 13.1% and Logistic EuroSCORE ranged from 18.2% to 33%. The incidence rate of all‐cause mortality at 30 days was found to be 11% (95% CI 7%‐16%; I2 = 20.86%). All‐cause mortality at 30 days for first generation valves had an incidence rate of 15% (95% CI 10%‐20%; I2 = 10%) compared to 7% (95% CI 3%‐13%; I2 = 37%) in second generation valves with subgroup interaction analysis P = 0.059. Device success incidence rate in second generation valves was 92% (95% CI 83%‐99%; I2 = 67%) vs 68% (95% CI 59%‐77%; I2 = 53%) in first generation valves with P = 0.001. TAVR appears to be a feasible treatment choice for NAVR patients at high risk for surgical valve replacement. Second generation valves show promising results in terms of short‐term outcomes.

Abstract Rationale Improved therapeutic options are needed for patients with treatment-refractory nontuberculous mycobacterial lung disease caused by Mycobacterium avium complex (MAC). Objectives To evaluate the efficacy and safety of daily amikacin liposome inhalation suspension (ALIS) added to standard guideline-based therapy (GBT) in patients with refractory MAC lung disease. Methods Adults with amikacin-susceptible MAC lung disease and MAC-positive sputum cultures despite at least 6 months of stable GBT were randomly assigned (2:1) to receive ALIS with GBT (ALIS + GBT) or GBT alone. Once-daily ALIS was supplied in single-use vials delivering 590 mg amikacin to the nebulizer. The primary endpoint was culture conversion, defined as three consecutive monthly MAC-negative sputum cultures by Month 6. Measurements and Main Results Enrolled patients (ALIS + GBT, n = 224; GBT-alone, n = 112) were a mean 64.7 years old and 69.3% female. Most had underlying bronchiectasis (62.5%), chronic obstructive pulmonary disease (14.3%), or both (11.9%). Culture conversion was achieved by 65 of 224 patients (29.0%) with ALIS + GBT and 10 of 112 (8.9%) with GBT alone (odds ratio, 4.22; 95% confidence interval, 2.08–8.57; P < 0.001). Patients in the ALIS + GBT arm versus GBT alone were more likely to achieve conversion (hazard ratio, 3.90; 95% confidence interval, 2.00–7.60). Respiratory adverse events (primarily dysphonia, cough, and dyspnea) were reported in 87.4% of patients receiving ALIS + GBT and 50.0% receiving GBT alone; serious treatment-emergent adverse events occurred in 20.2% and 17.9% of patients, respectively. Conclusions Addition of ALIS to GBT for treatment-refractory MAC lung disease achieved significantly greater culture conversion by Month 6 than GBT alone, with comparable rates of serious adverse events. Clinical trial registered with www.clinicaltrials.gov (NCT02344004).

6531 Background: Annual mammography is recommended to screen residual breast tissue for new cancers and recurrent disease after treatment for early stage breast cancer. This study aimed to assess mammography rates over time in breast cancer survivors. Methods: We used administrative claims data from a large U.S. commercial insurance database, OptumLabs, to retrospectively identify privately- and Medicare Advantage-insured women with operable breast cancer who had residual breast tissue after definitive breast surgery between 2006 and 2015. We required coverage for at least 13 months following surgery. For each subsequent 13-month time period, we only included women without a loss of coverage, bilateral mastectomy, metastatic breast cancer diagnosis, or non-breast cancer diagnosis. We calculated the proportion of patients who had a mammogram during each 13-month period following breast surgery. We used multivariable logistic regression to test for factors associated with mammography in the first 13 months. Results: The cohort included 26,011 women followed for a median of 2.9 years (IQR 1.9-4.6) after surgery; 63.1% were less than 65 years of age, and 74.4% were white. In their first year of follow-up, 86% underwent mammography, but by year 7, this decreased to 73%. Fewer than 1% underwent MRI instead of mammography. In multivariable analysis, mammograms were less likely during the first year after surgery among women aged < 50 years (odds ratio [OR], 0.7; 95% confidence interval [CI], 0.6 to 0.8), African Americans (OR, 0.7; 95% CI, 0.7 to 0.8), patients who underwent mastectomy (OR, 0.7; 95% CI, 0.6 to 0.7), and patients residing in the Western part of the country (OR, 0.9; 95% CI, 0.7 to 0.9). Those with 1-2 comorbidities were more likely (OR, 1.1; 95% CI 1.1-1.2) than those with none to have a mammogram during that period. Mammography use did not differ significantly by year of diagnosis (2006-2015). Conclusions: Even in an insured cohort, a substantial proportion of breast cancer survivors do not undergo annual surveillance mammography. Mammography use falls as the time from the early stage breast cancer diagnosis increases. Understanding factors associated with lack of mammographic screening may help improve survivorship care.

5000 Background: It is clinically challenging to integrate genomic classifier results that report a continuous numerical risk of recurrence into treatment decisions for prostate cancer (PCa). We aimed to develop a novel clinical-genomic risk system that can readily be incorporated into treatment guidelines for localized PCa. Methods: Four multi-center cohorts (n = 6928 men; 5937 prospective samples and 991 retrospective samples with long-term follow-up) were utilized to identify and validate our clinical-genomic risk system in radical prostatectomy (RP) samples and subsequently in pre-treatment biopsy samples. All patients’ FFPE tissue underwent microarray analysis, and the expression values for 22 prespecified biomarkers that constitute Decipher were extracted. Cumulative incidence curves were constructed to estimate metastasis risk. C-indices were calculated to compare NCCN and CAPRA score to our clinical-genomic system. Results: With a median follow-up of 8 years for men in our RP cohort, the 10-year distant metastasis rates for NCCN low, favorable-intermediate, unfavorable-intermediate, and high-risk were 7.8%, 9.4%, 40.1%, and 41.4%, respectively. Our 3-tier clinical-genomic risk groups had 10-year distant metastasis rates of 3.7%, 30.7%, and 57.7%, for low, intermediate, and high-risk, which were validated in our pre-treatment biopsy cohort with 10-year rate of distant metastasis of 0%, 30.3%, and 63.2%, respectively. C-indices for the clinical-genomic system (0.84, 95%CI 0.62-0.92) were significantly improved over NCCN (0.71, 95%CI 0.59-0.84) and CAPRA (0.71, 95%CI 0.60-0.81) score. A total of 33.4% of men would be reclassified by the clinical-genomic system, and specifically 17.1%, 41.3%, and 19.4% of men in NCCN low, intermediate and high risk groups would be reclassified by our new system. Conclusions: The use of a readily available genomic classifier in combination with clinicopathologic variables can generate a simple to use 3-tier clinical-genomic risk system that is highly prognostic for distant metastasis, is more accurate than clinical risk, and can be easily incorporated into NCCN guidelines to inform treatment decisions.

1043 Background: In estrogen receptor (ER) positive MBC, mutations (e.g. ESR1), identified from tumor biopsies or cfDNA, confer resistance. The concordance between mutations observed in tumor and cfDNA and the implications for response to Z-endoxifen, a potent anti-estrogen, are unknown. Methods: We previously conducted a phase I trial of Z-endoxifen in endocrine refractory, ER positive MBC. Seven dose levels were considered ranging from 20 to 160 mg/day followed by expansion cohorts (EC) of 40, 80, and 100 mg/day. Pretreatment blood samples (all pts) and fresh tumor biopsies (EC) were collected prospectively. Tumor and cfDNA were evaluated by targeted NGS. Results: 41 pts (38 evaluable) were enrolled. Prior endocrine therapy included aromatase inhibitors (37/38, 97%), fulvestrant (22/38, 58%) and tamoxifen (26/38, 68%). Substantial endoxifen exposure without DLTs at doses above 80 mg/day led to a halt in dose escalation and opening of the EC. Overall clinical benefit (stable > 6 months [7 pts.] or partial response by RECIST criteria [3 pts.]) rate was 26.3% (95%CI: 13.4-43.1%). cfDNA was obtained from 36 pts and mutations were identified in 13 (36%) including ESR1 [ Y537N or D538G] (5), PIK3CA [ H1047R or E542K] (8), TP53 [ K132R, R248Q, R267Q, or H179Y] (4), AKT ( Q79K) (1), and KRAS ( G12D) (1). In 5 pts with cf ESR1 mutations, 4 had additional cfDNA mutations including PIK3CA (3), and TP53 (1). PFS was shorter in pts with cfDNA mutations relative to those without (median: 61 vs.132 days; log-rank p = 0.021). Discordance was observed between tumor and cfDNA mutations where 3/7 PIK3CA tumor mutations were detected by cfDNA, 1/2 TP53 tumor mutations were detected by cfDNA, and 0/1 AKT tumor mutations were detected by cfDNA. Conversely, 2 pts had cfDNA mutations (either ESR1, TP53 or AKT) undetected in tumor. Conclusions: The absence of cfDNA mutations in patients with endocrine resistant, MBC treated with Z-Endoxifen was associated with significantly longer PFS. Given the discordance between tumor and cfDNA sequence data, future studies must determine which approach maximizes prognosis and prediction of benefit for estrogen-targeted therapy. Clinical trial information: NCT01327781.