Denise J. Roe’s research while affiliated with University of Arizona and other places

Objective Obesity is a risk factor for endometrial cancer (EC). Five-year survival is over 80%; however, mortality rates have increased in recent years. Post-menopausal women with EC frequently present with obesity-related comorbidities or develop comorbidities after diagnosis. Survival may vary related to this comorbidity burden. This analysis describes modifiable comorbidities (diabetes, cardiovascular disease, hypertension, and fractures) among post-menopausal EC survivors and evaluates the relationship between obesity-related comorbidities and mortality after an endometrial cancer diagnosis. Methods Epidemiological analysis of overall mortality in relation to incidence of obesity-related comorbidity (obesity, diabetes, cardiovascular disease, hypertension and fractures) after EC diagnosis. The participants are Post-menopausal women from 40 clinical sites across the U.S. participating in the Women’s Health Initiative (WHI) observational or clinical trials and diagnosed with incident EC during follow-up. Adjusted Cox proportional hazards regression models for incident EC were used to evaluate the relationship between comorbidities and all-cause mortality. Results 1661 incident cases of EC were identified. Mortality rates were 55.5% for women with EC. Prevalence increased from baseline to 18 y follow-up for each comorbidity. Regression analyses for incident EC indicated that severe obesity HR (95% CI): 2.13 (1.52, 2.97), cardiovascular disease, 1.50 (1.26, 1.78), and fracture, 1.17 (1.07, 1.27) were associated with greater overall mortality. Conclusions Obesity-associated comorbidities are common and are associated with greater mortality in post-menopausal women diagnosed with endometrial cancer. Interventions to modify risk for comorbidity in EC survivors may improve survival and should be evaluated. Clinical Trial Registration: NCT 00000611

Merkel Cell Carcinoma (MCC) is an aggressive neuroendocrine cutaneous malignancy arising from either ultraviolet-induced mutagenesis or Merkel cell polyomavirus (MCPyV) integration. Despite extensive research, our understanding of the molecular mechanisms driving the transition from normal cells to MCC remains limited. To address this knowledge gap, we assessed the impact of inducible MCPyV T antigens on normal human fibroblasts by performing RNA sequencing. Our data uncovered changes in expression and regulation of Wnt signaling pathway members. Building on this observation, we bioinformatically evaluated various Wnt pathway perturbagens for their ability to reverse the MCC gene expression signature and identified pyrvinium pamoate, an FDA-approved anthelminthic drug known for its anti-tumor activity in other cancers. Leveraging transcriptomic, network, and molecular analyses, we found that pyrvinium targets multiple MCC vulnerabilities. Pyrvinium not only reverses the neuroendocrine features of MCC by modulating canonical and non-canonical Wnt signaling but also inhibits cancer cell growth by activating p53-mediated apoptosis, disrupting mitochondrial function, and inducing endoplasmic reticulum stress. Finally, we demonstrated that pyrvinium reduces tumor growth in an MCC mouse xenograft model. These findings offer a new understanding of the role of Wnt signaling in MCC and highlight the utility of pyrvinium as a potential treatment for MCC.

Purpose There is a consistent relationship with greater ovulation frequency and increased risk of ovarian cancer. However, prior research on infertility, which may be associated with ovulation frequency through multiple mechanisms, and ovarian cancer has yielded conflicting results, possibly due to prior research conflating fertility treatment with infertility and restricting follow-up to premenopausal cases. Our objective was to determine the association between infertility and risk of postmenopausal ovarian cancer, overall and by histotype, in a population that had not received treatment with IVF. Methods We utilized data from the Women’s Health Initiative (n = 112,925 postmenopausal participants) with over 25 years of follow-up. At baseline, participants were asked whether they had ever tried to become pregnant for more than one year without becoming pregnant and whether a reason was found. Cox proportional hazards models were used to calculate hazard ratios (HRs) of incident adjudicated ovarian cancer comparing participants with a history of infertility to fertile participants overall and by histotype. Results 17% of participants reported a history of infertility at baseline and 1,109 ovarian cancer cases were diagnosed during follow-up. No statistically significant association was observed between infertility and risk of any ovarian cancer (HR: 1.09, 95% CI 0.92–1.29), but those reporting infertility had a 90% higher risk of endometrioid and clear cell ovarian cancers (HR: 1.90 95% CI 1.09–3.34) compared to fertile participants. The reported reason(s) for infertility had no discernable impact on these associations. Conclusions Infertility may be associated with clear cell and endometrioid ovarian cancer but not other ovarian tumor histotypes.

Background Obesity, classified by body mass index (BMI), is associated with higher postmenopausal breast cancer (BCa) risk. Yet, the associations between abdominal visceral (VAT) and subcutaneous adipose tissue (SAT) with BCa are unclear. Methods We assessed BCa associations with abdominal VAT and SAT in a prospective cohort of postmenopausal women without a history of cancer and with 27 years follow-up (N = 9950), during which all new cancers were adjudicated. Dual-energy X-ray absorptiometry scans assessed adiposity at baseline, year 3, and year 6. Competing risks multivariable sub-hazard ratios (SHR), with adjustments for sociodemographic, behavioral, reproductive, and anthropometric characteristics, were estimated for baseline and time-dependent associations between VAT, SAT, and incident BCa. Results Participants averaged 63.3 ± 7.4 years of age and a BMI of 28.20 ± 5.72 kg/m2 at baseline. The models included 738 incident BCa cases (N = 593 invasive; N = 145 in situ). Baseline VAT and SAT area were associated with significantly increased BCa risk, by 36% and 19% respectively. Increasing VAT/SAT ratio was associated with an 8% increase in incident BCa. Time-dependent models produced similar results. VAT and VAT/SAT associated BCa risk was highest for African American/Black women, though not significantly different from other groups. Quartiles (Q) of VAT/SAT were also explored; the SHR for Q4 compared to Q1 was 1.49 (95% CI: 1.18, 1.87). Conclusion Higher abdominal VAT and SAT are associated with an increased risk of postmenopausal BCa, and VAT/SAT may provide a distinctive risk estimate. Potential racial and ethnic differences require replication in a larger sample.(NCT00000611)

Lessons learned Intravenous paricalcitol did not improve the efficacy of pembrolizumab, likely related to the short half-life. Background Immunotherapy has limited benefit in the treatment of advanced pancreatic cancer with the tumor microenvironment playing a key role in immune resistance. In preclinical studies, vitamin D receptor (VDR) agonists have been shown to sensitize pancreatic tumors to PD-1 blockade. Methods This was a randomized, double-blinded, placebo-controlled, phase II trial to evaluate pembrolizumab with or without paricalcitol as maintenance therapy for patients with metastatic pancreatic ductal adenocarcinoma (PDAC). Participants were ≥18 years; histologically or cytologically confirmed metastatic PDAC showing no disease progression after frontline systemic therapy, and achieving maximal cytoreduction (eg, with no further antitumor effect), Eastern Cooperative Oncology Group (ECOG) status of 0 or 1; adequate organ function. Study treatment included: pembrolizumab 200 mg IV every 3 weeks and either paricalcitol 25 mcg IV 3 times per week or placebo. The primary objective was to evaluate 6-month progression free survival (PFS). Secondary objectives include evaluating the toxicity of the combination and overall survival (OS). Results There was no significant difference in 6-month PFS, median PFS, median OS, nor treatment-related AEs between the 2 arms. Conclusions and relevance Paricalcitol did not improve the efficacy of pembrolizumab likely related to its short half-life of only 5-7 hours. Microbiome analysis revealed significant difference between long-term (>12 weeks) and short-term (<12 weeks) survival groups across treatment arms. Modulation of the tumor microenvironment will likely require more sustained VDR activity. Trial Registration Clinicaltrials.gov, ID: NCT03331562.

Endometrial cancer (EC) rates are continuing to rise and it remains the most common gynecologic cancer in the US. Existing diagnostic methods are invasive and can cause pain and anxiety. Hence, there is a need for less invasive diagnostics for early EC detection. The study objective was to evaluate the utility of growth factors collected through minimally invasive cervicovaginal lavage (CVL) sampling as diagnostic and prognostic biomarkers for EC. CVL samples from 192 individuals undergoing hysterectomy for benign or malignant conditions were collected and used to quantify the concentrations of 19 growth and angiogenic factors using multiplex immunoassays. Patients were categorized based on disease groups: benign conditions ( n = 108), endometrial hyperplasia ( n = 18), and EC ( n = 66). EC group was stratified into grade 1/2 endometrial endometrioid cancer ( n = 53) and other EC subtypes ( n = 13). Statistical associations were assessed using receiver operating characteristics, Spearman correlations and hierarchical clustering. Growth and angiogenic factors: angiopoietin-2, endoglin, fibroblast activation protein (FAP), melanoma inhibitory activity, and vascular endothelial growth factor-A (VEGF-A) were significantly ( p < 0.0001) elevated in EC patients. A multivariate model combining 11 proteins with patient age and body mass index exhibited excellent discriminatory potential (area under curve = 0.918) for EC, with a specificity of 90.7% and a sensitivity of 87.8%. Moreover, angiopoietin-2, FAP and VEGF-A significantly ( p < 0.05–0.001) associated with tumor grade, size, myometrial invasion, and mismatch repair status. Our results highlight the innovative use of growth and angiogenic factors collected through CVL sampling for the detecting endometrial cancer, showcasing not only their diagnostic potential but also their prognostic value.

Background Several studies have suggested an association between infertility and risk of endometrial cancer. However, most studies have evaluated this relationship in premenopausal people, yet the mean age of endometrial cancer is 60 years, after the average age of menopause. Methods Our study included Women’s Health Initiative participants who self-reported whether they had a history of infertility. Cox proportional hazards models were used to examine the association between infertility and incident endometrial cancer. Given that all infertility diagnoses occurred prior to study enrollment, we conducted secondary analyses using logistic regression examining prevalent endometrial cancer cases diagnosed before study baseline. Results Approximately 18% of participants reported a history of infertility. No statistically significant association was observed between infertility and risk of incident endometrial cancer overall [incident cases = 1,622; HR = 1.12; 95% confidence interval (CI) = 0.99–1.26]. Although point estimates suggested an increase in risk of endometrial cancer among women with body mass index (BMI) ≥25 (HR = 1.15; 95% CI = 0.99–1.33), none of the associations were statistically significant. There was an association between history of infertility and prevalent endometrial cancer cases (OR = 1.19; 95% CI = 1.06–1.34), with the strongest association for infertility diagnosis due to endometriosis (OR 2.42; 95% CI = 1.83–3.19). Conclusions In a population of postmenopausal participants, we observed a modest, but not statistically significant, association between overall infertility and incident endometrial cancer, with the suggestion of a higher risk among those with a BMI ≥ 25. Impact Our findings highlight, as observed in previous studies, that risk factors for endometrial cancer may vary by BMI.

Purpose Tumor progression has been linked to stiffening of the extracellular matrix caused by fibrosis. Cancer cells can be mechanically conditioned by stiff extracellular matrix, exhibiting a 1,004-gene signature [mechanical conditioning (MeCo) score]. Nintedanib has demonstrated antifibrotic activity in idiopathic pulmonary fibrosis. This study explores nintedanib’s antifibrotic effect on breast cancer outcomes. Experimental Design We present long-term follow-up and analysis of a neoadjuvant randomized phase II trial in early HER2-negative breast cancer. Patients (N = 130) underwent a baseline biopsy and received 12 paclitaxel courses alone (control arm) or in combination with nintedanib (experimental arm). The tumor MeCo score was determined by RNA sequencing. The primary aim was to assess nintedanib’s impact on event-free survival based on MeCo scores. Results Follow-up data were retrieved from 111 patients; 75 baseline and 24 post-run-in phase samples were sequenced. After median follow-up of 9.67 years, median event-free survival was not statistically different between arms (P = 0.37). However, in the control arm, high- versus low-MeCo patients had a statistically higher relapse risk: HR = 0.21; P = 0.0075. This risk was corrected by nintedanib in the experimental arm: HR = 0.37; P = 0.16. Nintedanib demonstrated pharmacodynamic engagement, reducing the MeCo score by 25% during the run-in phase (P < 0.01). Patients with low MeCo after run-in had the best long-term prognosis (HR = 0.087; P = 0.03). Conclusions High MeCo is predictive of poor outcomes in HER2-negative early breast cancer, although this risk can be mitigated by nintedanib, which is able to specifically reduce MeCo.