Low-grade serous carcinoma (LGSC): A Canadian multicenter review of practice patterns and patient outcomes.

OBJECTIVE: Patients with advanced low-grade serous carcinoma (LGSC) have poor long-term survival rates. As a rare histotype, there are uncertainties regarding the use of current therapies. Thus, we studied practice patterns and treatment outcomes as part of a national initiative to better understand and improve the care of women with advanced LGSC. METHODS: This retrospective cohort study was conducted in 5 Canadian referral institutions from 2000 to 2016. Data collection and pathology reporting were standardized. Outcome measures included overall survival (OS), progression-free survival (PFS), progression-free intervals (PFI), and time to next treatment (TTNT). Cox regression analysis was used to evaluate the effects of clinical and pathologic factors on outcomes and prognosis. RESULTS: There were 134 patients (stage II-IV) with a median follow-up of 32.4 months (range 1.6-228). Four primary treatments were compared across institutions: 1) surgery followed by chemotherapy (56%), 2) neoadjuvant chemotherapy (NACT) followed by surgery (27%), 3) surgery alone (9%), and 4) surgery followed by anti-hormone therapy (4%). Primary platinum/paclitaxel chemotherapy was used in 81%. Patients treated with NACT had worse PFS. Multivariable Cox regression analysis identified lesser residual disease, younger age, and primary peritoneal origin as variables significantly associated with better OS/PFS (p < 0.03). One institution had significantly better PFS than the others (p = 0.025), but this finding could be related to a higher frequency of primary peritoneal LGSC. PFI and TTNT intervals in patients with relapsed disease were not significantly different after the first relapse irrespective of treatment type. CONCLUSIONS: There are notable differences in practice patterns across Canada. This underscores the need for ongoing strategies to measure, evaluate and achieve optimal patient outcomes for women with advanced LGSC.

Hormone receptor expression and outcomes in low-grade serous ovarian carcinoma.

OBJECTIVE: Low-grade serous ovarian carcinomas (LGSC) are frequently ER/PR positive, though the mechanisms by which ER/PR regulate prognosis or anti-estrogen treatment efficacy are poorly understood. We studied ER/PR expression in LGSC tumors and cell lines to evaluate patient outcomes and cellular treatment responses. METHODS: LGSC tumors and patient-derived cell lines were studied from patients with advanced-stage (III/IV) disease. Tumor samples and clinical data were obtained from the Canadian Ovarian Experimental Unified Resource (COEUR-tissue microarray) and the Ovarian Cancer Research (OvCaRe) tissue bank. ER/PR expression was assessed by both Western blot and immunohistochemistry (IHC). Two different IHC scoring systems (simple and Allred) were used. Cox regression was used to identify factors (age, disease residuum, ER/PR status, etc.) associated with progression-free (PFS) and overall survival (OS). Estradiol and tamoxifen proliferation and viability experiments were performed in LGSC cell lines. RESULTS: In 55 LGSC cases studied, median follow-up was 56 months (range 1-227). Fifty-three (96%) cases strongly expressed ER whereas 37 (67%) expressed PR. Cox-regression analysis showed that residuum (p < 0.001) was significantly associated with PFS, whereas both ER Allred score (p = 0.005) and residuum (p = 0.004) were significant for OS. None of the LGSC cell lines expressed PR. Loss of PR and ER expression over time was detected in LGSC tumors and cell lines respectively. Estrogen and tamoxifen treatment did not alter LGSC cell proliferation or viability in-vitro. CONCLUSIONS: In patients with advanced LGSC, higher ER Allred scores were significantly associated with better overall survival. ER/PR expression changed over time in both LGSC tumors and cell lines. Better translational research models are needed to elucidate the molecular mechanisms of ER/PR signalling in LGSC.

Stability of hepatitis B viral load during pregnancy and implications for antepartum prophylaxis: A prospective cohort study.

BACKGROUND: We examined changes in hepatitis B virus (HBV) viral loads (VLs) in pregnancy, their association with hepatitis B e antigen (HBeAg), and the associated infant outcomes. METHODS: We prospectively followed 132 mothers positive for hepatitis B surface antigen (HBsAg) and their 135 infants from 2011 to 2015 in Vancouver, British Columbia. Outcome measures included association between maternal HBeAg and high (>200,000 IU/mL) or low (≤200,000 IU/mL) HBV VL, changes in HBV VL through pregnancy, infant HBsAg status, and infant completion of the HBV vaccination series. RESULTS: f the 91 participants with an available HBV VL, 13 (14.3%) had an HBV VL of more than 200,000 IU/mL. Of 59 participants with paired HBeAg and HBV VL in pregnancy, 6 had an HBV VL of more than 200,000 IU/mL; of interest, 2 of the 6 (33.3%) were HBeAg-negative. Thirty-eight participants had HBV VL results at both mid-trimester and delivery. For these 38 participants, Wilcoxon signed-ranks test for paired data found that an HBV VL remained stable (p = .58). We observed no perinatal transmissions. However, 20.7% of infants did not have a documented complete HBV vaccination series, 20.0% did not have post-vaccination HBsAg testing completed, and 18% did not have anti-HBs titres measured by age 12 months. CONCLUSIONS: Our study demonstrates that HBeAg and HBV VL are not reliably predictive of each other. This supports the improved predictive value of VL measurement in pregnancy to risk stratify pregnant patients to offer antiviral treatment when indicated and further minimize the risk of perinatal transmission.

Costs and Benefits of Extended Endocrine Strategies for Premenopausal Breast Cancer.

Background: After completing 5 years of adjuvant tamoxifen, women with estrogen receptor (ER)-positive breast cancer benefit from 5 more years of endocrine therapy, either with tamoxifen or an aromatase inhibitor (AI). For premenopausal women, ovarian ablation (OA) would be required before starting an AI (OA/AI). According to the SOFT/TEXT studies, OA/AI improves 5-year disease-free survival compared with tamoxifen alone, suggesting that OA/AI could be superior to tamoxifen as extended endocrine therapy. The long-term costs and consequences of premature menopause from OA are unknown, but could be estimated through a cost-effectiveness analysis. Methods: A Markov chain Monte Carlo simulation model estimated the costs and benefits of 3 extended endocrine strategies in a hypothetical cohort of premenopausal women with ER-positive early breast cancer: (1) no further treatment; (2) tamoxifen for 5 years (extended tamoxifen); or (3) OA/AI for 5 years. Effectiveness was measured in years of life expectancy gain. Sensitivity analyses accounted for uncertainty surrounding various parameters. Monte Carlo simulation estimated the number of adverse events and deaths from each strategy in the US population over a 40-year period. Results: Extended tamoxifen yielded a higher average life expectancy gain than OA/AI (17.31 vs 17.06 years) at lower average cost ($3,550 vs $14,312). For 18,000 premenopausal ER-positive women, the simulation estimated 13,236, 12,557, and 11,338 deaths with no further treatment, extended tamoxifen, and OA/AI, respectively, but an additional 1,897 deaths from OA, for a total of 13,235 deaths associated with OA/AI. After 24.6 years of follow-up, more women are expected to die from OA/AI than extended tamoxifen. Conclusions: For premenopausal women with ER-positive cancer who have completed adjuvant tamoxifen, another 5 years of tamoxifen is the preferable extended endocrine strategy. The potential long-term health consequences of OA could affect overall survival when it precedes the use of an AI.

Ovarian ablation for premenopausal breast cancer: A review of treatment considerations and the impact of premature menopause.

Historically, ovarian ablation (OA) was used as therapy for women with recurrent hormone-receptor-positive (HRP) premenopausal breast cancer. With the publication of the SOFT (Suppression of Ovarian Function Trial) and TEXT (Tamoxifen and Exemestane Trial) randomized trials, there is considerable interest in OA as an adjuvant treatment, either in combination with tamoxifen or an aromatase inhibitor (AI). Thus, we have reviewed current guidelines and key studies on this important topic and have highlighted the relevant biological and pharmacological aspects of the various endocrine therapies. The results of two key randomized trials addressing the use and controversies of OA in premenopausal breast cancer are discussed and recent research emphasizing the detrimental consequences of premature menopause and the cost-effectiveness of OA is presented. In low-risk patients with HRP premenopausal breast cancer, OA is not beneficial and tamoxifen remains the anti-hormone treatment of choice. In high-risk women (previous chemotherapy or women younger than 35), OA in combination with AI is more effective but is arguably not cost-effective, particularly when OA is achieved medically using a GnRH agonist/antagonist. Compared to tamoxifen alone, the SOFT trial showed a 4.5-7.7% reduction in breast cancer relapse using OA (in combination with either tamoxifen or AI) in high-risk women, though the 5-year overall survival benefit was limited (1.4-3.6%). Premature menopause is associated with long-term mortality risks and women often experience significant menopausal symptoms that impact on quality of life. These considerations should play a role in the treatment selection of those patients who may benefit from adjuvant OA.

Long-term consequences of ovarian ablation for premenopausal breast cancer.

The TEXT and SOFT trials concluded that an aromatase inhibitor (AI) with ovarian ablation (OA) yields a higher 5-year disease-free survival than tamoxifen alone in premenopausal ER+ high-risk early breast cancer. However, the long-term health consequences and costs of OA, either by GnRH agonist or oophorectomy, have not been evaluated. The objective was to conduct a cost-effectiveness analysis comparing tamoxifen to OA with AI. Markov Monte Carlo simulation model estimated the costs and benefits of 3 endocrine strategies: (1) tamoxifen; (2) GnRH agonist with AI (GnRHa-AI); (3) bilateral salpingo-oophorectomy with AI (BSO-AI). Effectiveness was measured in life expectancy gain (years), and costs were averaged over a lifetime (USD 2015). Adverse events and deaths from each strategy were modeled in the United States population over a time horizon of 40 years. For women without prior chemotherapy (low-risk), tamoxifen alone was more effective (18.03 years) and less costly ($1566) than GnRHa-AI (17.66 years, $93,692) or BSO-AI (17.63 years, $25,892). For those with prior chemotherapy (high-risk), BSO-AI was more costly but more effective (16.78 years, $25,368) than tamoxifen alone (16.55 years, $1523) with an ICER of $102,290, while GnRHa-AI yielded an ICER of $443,376. The simulation estimated 787 and 577 deaths attributable to OA among 9320 high-risk women after BSO-AI and GnRHa-AI, respectively. There may be a role for ovarian ablation in premenopausal women with ER+ high-risk early breast cancer; however, this analysis raises concerns about the long-term health consequences of ovarian ablation and the potential effects on overall survival.

Missed opportunities for prevention of perinatal transmission of hepatitis B: a retrospective cohort study.

BACKGROUND: Perinatal transmission of hepatitis B virus (HBV) can occur despite postexposure prophylaxis (PEP). Recent literature suggests that antiviral treatment during pregnancy when maternal HBV DNA levels are elevated can further decrease vertical transmission. However, HBV DNA screening is not routinely performed antenatally. OBJECTIVE: To determine the rates of HBV prevalence and perinatal transmission in an antenatal cohort. METHODS: A retrospective review of public health records (December 2008 to December 2010) was performed for both mothers and newborns. RESULTS: A total of 725 mother-infant pairs were included. Of these, 574 of 715 (80%) women had antenatal hepatitis B e antigen (HBeAg) testing performed, and 127 of 574 (22%) were HBeAg positive (HBeAg+). Of babies born to hepatitis B surface antigen-positive (HBsAg+) mothers, only 573 of 725 (79%) received complete PEP. In addition, 172 of 725 (24%) infants did not receive post-PEP blood testing or were lost to follow-up. Of the 552 infants with results available, seven cases (1.3%) of mother-to-child HBV transmission were observed, six of which involved infants born to HBeAg+ women. CONCLUSIONS: Our findings suggest that routine HBeAg screening could identify a subset of mother-infant pairs among HBsAg+ pregnant women who are at higher risk for vertical HBV transmission. Determination of viral load in expectant HBeAg+ mothers may provide more precise insight into HBV transmission to their infants.

Bladder base tenderness in the etiology of deep dyspareunia.

INTRODUCTION: Bladder base tenderness can be present on pelvic exam in women with pelvic pain. However, its exact prevalence and clinical implications are not well understood. AIM: The aim of this study was to determine whether bladder base tenderness is associated with specific symptoms or signs in women, particularly dyspareunia. METHODS: Retrospective review of 189 consecutive women seen by a gynecologist in 2012 at a tertiary referral center for pelvic pain was conducted. Associations were tested between bladder base tenderness and variables on history/examination using bivariate analyses and multiple logistic regression. MAIN OUTCOME MEASURE: Deep dyspareunia and superficial dyspareunia (present/absent) were the main outcome measures. RESULTS: Bladder base tenderness was present in 34% of pelvic pain patients (65/189), which was significantly greater than the prevalence of bladder base tenderness of 3% (1/32) in a control sample of women without pelvic pain (odds ratio [OR] = 16.3, 95% confidence interval [CI] 2.17-121.7, Fisher exact test, P < 0.001). For the pelvic pain patients, on bivariate analyses, bladder base tenderness was significantly associated with deep dyspareunia (P < 0.001), superficial dyspareunia (P < 0.001), bladder symptoms (P = 0.026), abdominal wall trigger point (P < 0.001), and pelvic floor tenderness (P < 0.001). In contrast, bladder base tenderness was similarly present in women with or without endometriosis. On logistic regression, bladder base tenderness was independently associated with only deep dyspareunia (OR = 6.40, 95% CI: 1.25-32.7, P = 0.011), abdominal wall trigger point (OR = 3.44, 95% CI: 1.01-11.7, P = 0.037), and pelvic floor tenderness (OR = 8.22, 95% CI: 3.27-20.7, P < 0.001). CONCLUSIONS: Bladder base tenderness is present in one-third of women with pelvic pain, and contributes specifically to the symptom of deep dyspareunia. Bladder base tenderness was also associated with the presence of an abdominal wall trigger point and with pelvic floor tenderness, suggesting a myofascial etiology and/or nervous system sensitization.