Clinical outcomes associated with pathogenic genomic instability mutations in prostate cancer: a retrospective analysis of US pharmacy and medical claims data.

Background: Prostate cancer (PC) is a clinically heterogenous disease, and genetic mutations may be useful for patient risk stratification. This retrospective cohort study compared clinical outcomes, pharmacy use, and outpatient resource use in PC patients with and without pathogenic genomic instability mutations, including DNA repair deficiency (DRD) mutations and those in TP53, PTEN, and RB1. Methods: Patients ≥18 years newly-diagnosed with PC between June 2011-March 2016 were identified in medical and prescription claims databases linked to a genomic dataset. All-cause and PC-specific pharmacy use and outpatient resource use (office visits, laboratory tests, radiology examinations, and radiation therapies) over 1, 2, and 3 years and time to evidence of disease progression after PC diagnosis, based on secondary cancer diagnosis codes and treatments received, were evaluated in mutation carriers with ≥1 of 24 gene mutations and in a sub-set of DRD gene mutation carriers, with each compared to non-mutation carriers. Results: Mutation carriers (n = 274) and non-mutation carriers (n = 74) had similar demographic and clinical features. Non-mutation carriers had lower risks of developing metastasis and castration-resistant PC than mutation carriers (hazard ratio [HR] = 0.7, 95% CI = 0.5-0.9; HR = 0.5, 95% CI = 0.3-0.9, respectively) and DRD mutation carriers (HR = 0.5, 95% CI = 0.3-0.7; HR = 0.4, 95% CI = 0.2-0.7, respectively). Compared to non-mutation carriers, mutation carriers had more all-cause pharmacy claims over 2 years of follow-up (74.4 vs 59.1, p = 0.04) and more PC-specific pharmacy claims over 2 years (11.1 vs 6.5, p = 0.01) and 3 years (17.9 vs 9.8, p = 0.01) of follow-up. No differences were observed in outpatient resource use during the follow-up period by mutation status. Conclusion: PC patients carrying ≥1 pathogenic DNA instability mutation, and DRD mutation carriers specifically, had higher clinical burden than non-mutation carriers. Targeted therapies for these patients are needed to reduce clinical burden and associated healthcare resource utilization.

Plasma estrogen concentrations after oral and vaginal estrogen administration in women with atrophic vaginitis.

In this open-label, randomized, multiple-dose, two-treatment crossover study, 24 postmenopausal women with moderate to severe atrophic vaginitis received 0.3 mg conjugated estrogens daily for 14 days: 7 days orally (0.3 mg tablet) and 7 days vaginally (0.5 g cream). Steady-state plasma concentrations of E2 and estrone were one-third lower after vaginal versus oral administration of conjugated estrogens.

The effects of bazedoxifene on mammographic breast density in postmenopausal women with osteoporosis.

OBJECTIVE: This study aimed to assess quantitative changes in mammographic breast density after 24 months of therapy with bazedoxifene compared with raloxifene or placebo in postmenopausal women with osteoporosis. METHODS: This was a retrospective, ancillary study of a subset of women enrolled in a multicenter, double-blind, randomized, placebo- and active-controlled phase 3 trial evaluating bazedoxifene for the treatment of postmenopausal osteoporosis. Participants were randomly assigned to receive bazedoxifene 20 or 40 mg, raloxifene 60 mg, or placebo once daily for 3 years. To be eligible for breast density evaluation, participants had to be 62 years or younger and completed 24 months of treatment, with mammograms at baseline and 24 months. Original mammogram pairs (left craniocaudal views) for each participant were digitized and analyzed by a radiologist. Breast density was measured using interactive thresholding to segment the mammogram, and percent density was determined using a validated software program. RESULTS: Mammogram pairs were obtained from 444 participants. Baseline and demographic characteristics were similar among groups (mean age, 58.7 y). After 24 months, the mean percent changes in breast density from baseline were low (bazedoxifene 20 mg, -1.2%; bazedoxifene 40 mg, -0.4%; raloxifene 60 mg, -0.5%; placebo, -0.2%) and not significantly different among groups. CONCLUSIONS: Treatment with bazedoxifene for 2 years did not affect age-related changes in breast density in this population of postmenopausal women with osteoporosis. The changes in breast density with bazedoxifene 20 or 40 mg were similar to those with raloxifene 60 mg or placebo.

Efficacy and safety of low-dose regimens of conjugated estrogens cream administered vaginally.

OBJECTIVE: The aim of this study was to evaluate the efficacy and safety of low-dose conjugated estrogens (CE) cream for treatment of atrophic vaginitis. METHODS: Postmenopausal women (N = 423) with moderate-to-severe vaginal atrophy were randomized to CE cream 0.3 mg or placebo once daily (21 days on/7 days off) or twice weekly for 12 weeks, followed by open-label treatment with CE cream for 40 weeks consistent with their prior regimen. Primary endpoints were changes in vaginal maturation index (VMI; percentage of superficial cells), vaginal pH, and severity of participant-reported most bothersome symptom (vaginal dryness, itching, burning, or dyspareunia) at week 12. Endometrial safety was assessed by transvaginal ultrasound and endometrial biopsy for 52 weeks. RESULTS: At week 12, improvements in VMI with daily and twice-weekly use of low-dose CE cream (27.9% and 25.8%, respectively) were significantly greater compared with placebo (3.0% and 1.0%, respectively; P < 0.001). Improvements in vaginal pH with daily and twice-weekly CE cream (-1.6 for both) were also significantly greater relative to placebo (-0.4 and -0.3, respectively; P < 0.001). VMI and vaginal pH responses were sustained through 52 weeks. Both CE cream regimens significantly reduced most bothersome symptom scores compared with placebo (P < or = 0.001), including those for dyspareunia (P < or = 0.01). There was no report of endometrial hyperplasia or carcinoma. Adverse events occurred with similar frequency among the active and placebo groups during the double-blind phase. CONCLUSIONS: Daily and twice-weekly use of low-dose CE cream was equally effective in relieving symptoms of vulvovaginal atrophy. Both regimens showed endometrial safety and sustained efficacy during 1 year of therapy.