Background: Structural inequities, in part, undergird urban–rural differences in cancer care. The current study aims to understand the potential consequences of structural inequities on rural and urban cancer patients’ access to and perceived importance of supportive cancer care resources. Methods: We used data collected from November 2017 to May 2018 from a larger cross-sectional needs assessment about patients’ support needs, use of services, and perceptions at a Midwestern United States cancer center. Oncology patients received a study packet during their outpatient clinic visit, and interested patients consented and completed the questionnaires. Results: Among the sample of 326 patients, 27% of the sample was rural. In adjusted logistic regression models, rural patients were less likely to report using any secondary support services (15% vs. 27%; OR = 0.43, 95%CI [0.22, 0.85], p = 0.02) and less likely than urban counterparts to perceive secondary support services as very important (51% vs. 64%; OR = 0.57, 95%CI [0.33, 0.94], p = 0.03). Conclusion: Structural inequities likely have implications on the reduced access to and importance of supportive care services observed for rural cancer patients. To eliminate persistent urban–rural disparities in cancer care, rural residents must have programs and policies that address cancer care and structural inequities.

Endometrial carcinoma (EC) is the most common type of gynecologic malignant epithelial tumor, with the death rate from this disease doubling over the past 20 years. Mitochondria provide cancer cells with necessary anabolic building blocks such as amino acids, lipids, and nucleotides, and EC samples have been shown to increase mitochondrial biogenesis. In cancer, mitochondrial DNA (mtDNA) heteroplasmy studies suggest that heteroplasmic variants encode predicted pathogenic proteins. We investigated the mtDNA genotypes within peri-normal and tumor specimens obtained from three individuals diagnosed with EC. DNA extracts from peri-normal and tumor tissues were used for mtDNA-specific next-generation sequencing and analyses of mtDNA content and topoisomers. The three tumors harbor heteroplasmic somatic mutations, and at least one mutation in each carcinoma is predicted to deleteriously alter a mtDNA-encoded protein. Somatic heteroplasmy linked to two mtDNA tRNA genes was found in separate tumors, and two heteroplasmic non-coding variants were identified in a single EC tumor. While two tumors had altered mtDNA content, all three displayed increased mtDNA catenanes. Our findings support that EC cells require wild-type mtDNA, but heteroplasmic mutations may alter mitochondrial metabolism to help promote cancer cell growth and proliferation.

Background: Bone marrow (BM)-derived myeloid–lymphatic endothelial cell progenitors (M-LECPs) promote formation of tumor lymphatics that are responsible for metastasis to lymph nodes. The regenerative capacity of BM progenitors to other lineages is mediated through cell fusion, a process that delivers a pro-mitotic message directly to division-restricted cells. This suggested that M-LECPs might use a similar mechanism to induce division of lymphatic endothelial cells (LECs). Methods: To test this hypothesis, we determined expression of fusogenic markers in M-LECP produced in vitro and recruited to human or mouse tumors in vivo as well as quantified their fusion with LECs in both settings. Fusion in vivo was determined in female chimera mice grafted with male BM that have been implanted with MDA-MB-231 or EMT6 breast tumors. Co-staining for Y-chromosome and LEC-specific markers allowed us to quantify tumor lymphatic vessels fused with BM progenitors. Results: We found that both tumor-recruited and in-vitro-produced M-LECPs expressed multiple fusogenic regulators and possessed a significant fusogenic activity towards cultured and vessel-lining LECs. Y-chromosomes, a marker of fusion, were detected in nearly half of tumor lymphatics and were associated with mitotic division, vessel formation, and node metastasis. Both in vitro and in vivo assays showed dependency of fusion on Th2 and Toll-like receptor-4 (TLR4) pathways. Conclusions: This novel mechanism of tumor lymphatic formation triggered by fusion with BM myeloid–lymphatic progenitors suggests a variety of new targets for inhibition of metastatic spread.

E21546 Background: Tobacco use remains the single largest contributor to preventable death in the U.S. Women who consume alcohol have a 15% higher risk of hormone-receptor-positive breast cancer and obese women are at higher risk of developing breast cancer compared to non-obese women after menopause. There is limited information about the combined impact of smoking, alcohol and BMI on clinical outcomes among elderly patients . The purpose of this study was to analyze the effects of smoking, alcohol and BMI on clinical outcomes in geriatric breast cancer patients. Methods: Among 1659 patients in the institutional Breast Cancer Registry database, a total of 269 patients with histologically confirmed invasive or in-situ breast cancer with age 65 years or older at the time of diagnosis were reviewed in an IRB approved fashion. Clinical outcomes included assessment of the following risk factors: current/former smoking, current/former alcohol usage and BMI at time of diagnosis. Kaplan-Meyer and Cox proportional hazards methods were used to calculate clinical outcomes which included overall survival (OS) and disease free survival (DFS). Results: There were 110 (40.9%) never smokers, 41 (15.2%) current smokers and 80 (29.7%) former smokers. A total of 129 (48%) of women had never consumed alcohol, 73 (27.1%) currently consumed alcohol, and 19 (17.1%) previously consumed alcohol. Mean BMI at the time of diagnosis was 30.62. The OS and DFS was longer among patients who were never smokers compared to current and former smokers (P = 0.0125, P = .0.0077) (P = 0.0107, P = 0.0146). There was also no statistically significant decrease in OS, DFS among those who never consumed alcohol compared to current and former alcoholic users (P = 0.7516, P = 0.2027) (P = 0.8892, P = 0.2432). Neither was there a statistically significant decrease in OS, DFS based on BMI at time of diagnosis (P = 0.5045) (P = 0.5233). In patients with combined cigarette and alcohol usage with BMI > 25, there was also no statistically significant decrease in OS (P = 0.3572). Conclusions: In patients 65 years old or older diagnosed with breast cancer, prognosis for current or former smokers is worse compared to never smokers. Alcohol consumption and BMI have no impact on DFS or OS.

The loss of RAB25 expression—RAS superfamily of GTPase characteristic of numerous breast cancers—corresponds with H-RAS point mutations, particularly in triple-negative breast cancers (TNBC), a subtype associated with a poor prognosis. To address the poorly understood factors dictating the progression of TNBC tumors, we examine the cooperative effects that loss of RAB25 expression in human mammary epithelial cell (HMEC) lines with H-RAS mutations confers in tumorigenesis. HMECs were immortalized by transduction with LXSN CDK4 R24C, a mutant form of cyclin-dependent kinase, followed by transduction with hTERT, a catalytic subunit of the telomerase enzyme. We found that with the loss of RAB25 and overexpression of mutant H-RAS61L, immortal HMECs transformed toward anchorage-independent growth and acquired an increased ability to migrate. Furthermore, cells express low CD24, high CD44, and low claudin levels, indicating stem-like properties upon transformation. Besides, loss of RAB25 and overexpression of H-RAS61L resulted in increased expression of transcription factors Snail and Slug that drive these cells to lose E-cadherin and undergo epithelial-mesenchymal transition (EMT). This study confirms that loss of RAB25 and overexpression of mutant H-RAS can drive HMECs toward a mesenchymal stem-like state. Our findings reveal that RAB25 functions as a tumor suppressor gene, and loss of RAB25 could serve as a novel biomarker of the claudin-low type of TNBC.