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Estrogen is a powerful, beneficial regulator of skeletal muscle mitochondria. Premenopausal women with type 2 diabetes (T2D) have relatively greater complications associated with their T2D compared with the effect of the disease in men. We hypothesize that this impact of T2D in women is in part due to the impairment of estrogen-mediated regulation of skeletal muscle mitochondrial content and function. To explore the interaction between estrogen, diabetes and mitochondrial biogenesis in a rat model, 4-week-old, female Wistar Rats were fed a chow or a high fat/high sugar diet (HFHS) . At 8 weeks all mice underwent an ovariectomy (OVX) and randomized to estradiol (E2) replacement or none. One week prior to sacrifice, deuterium oxide was administered to determine skeletal muscle mitochondrial biogenesis. OVX +/- E2, animals were sacrificed 6 weeks post-randomization. Endpoints: body weight, gonadal fat mass, blood glucose and insulin levels, and gastrocnemius (mitochondrial biogenesis and function) . OVX+E2 rats had lower body mass compared with OVX (P = 0.0028) . HFHS fed rats had greater relative fat mass independent of E2 status (P = 0.0007) , and the OVX+E2 fed the HFHS diet were hyperglycemic (P = 0.00for the diet x E2 interaction) . State 3 mitochondrial respiration with carbohydrate-linked substrates was elevated in chow fed animals with E2, and this response was absent in HFHS animals (P = 0.0138 for the diet x E2 interaction) . Contrary to our hypothesis, there was no effect of diet or E2 on mitochondrial biogenesis measured with deuterium oxide (P > 0.4) . These data support the hypothesis that, in the context of a HFHS diet, the beneficial effect of E2 on skeletal muscle mitochondrial function is impaired. However, mitochondrial biogenesis does not appear to mediate this interaction of diet and E2. Future studies will focus on the E2-mediated regulation of mitochondrial quality to determine their role in the impairment of mitochondrial function. Disclosure N.A.Hulett: None. S.Hull: None. L.Knaub: None. G.Pott: None. B.F.Miller: None. J.Reusch: Advisory Panel; Medtronic. R.L.Scalzo: None. Funding Veterans Affairs (BX004533)

Functional Exercise Capacity (FEC) , a universal predictor of cardiovascular and all-cause mortality, is lower in adults and youth with diabetes for reasons that are poorly understood. Skeletal muscle is key determinant of FEC. We hypothesized that skeletal muscle capillary and mitochondrial density are lower with hyperglycemia and respond to exercise training. To test this hypothesis we generated a model of short-term hyperglycemia (HG) with inducible beta cell deletion of glucokinase (GKlox/lox;PdxCreER) . Male (M) and female (F) HG mice and euglycemic littermate controls (EG) completed 3 weeks of treadmill training (Ex) or remained sedentary (Sed) . The gastrocnemius was collected 24 hours after the final exercise bout. Expression of COX1 (mitochondrial marker) , Dystrophin (muscle fiber sarcolemma boundary marker) , and CD31 (capillary marker) was detected by immunofluorescence. Sirtuin 3 (SIRT3) , an NAD+ dependent deacetylase (mitochondrial homeostasis) was measured using the JESS system. (Fig 1) Mitochondrial density (mitochondria per fiber as quantified by fluorescence intensity units per fiber [FIU/fiber]) was significantly lower in HG vs. EG (p Disclosure L.Knaub: None. G.Pott: None. N.A.Hulett: None. S.Hull: None. R.L.Scalzo: None. J.Reusch: Advisory Panel; Medtronic. Funding VA Merit (BX002046)

5522 Background: Neoadjuvant chemotherapy has demonstrated limited activity in low-grade serous carcinomas (LGSOC) of the ovary, fallopian tube, and peritoneum, with objective response rate of 11% and complete gross resection (CGR) rate of 38% at the time of interval cytoreductive surgery (ICS). LGSOC has many similarities to hormone receptor positive (HR+) breast cancer, including clinical benefit from endocrine therapies in the recurrent and maintenance settings. Based on the activity of antiestrogen plus CDK4/6 inhibitor combination therapy in HR+ breast cancer, we conducted a phase II pilot study to assess the clinical benefit of neoadjuvant treatment with fulvestrant and abemaciclib for women with advanced LGSOC. Methods: Women with unresectable, untreated stage III or IV LGSOC of the ovary, fallopian tube or peritoneum were eligible. Patients received fulvestrant (500 mg IM on day 1 and 15 of the first 28-day cycle, followed by day 1 of subsequent cycles) and abemaciclib 150 mg orally BID. Pre/perimenopausal patients also received goserelin 10.8 mg subcutaneously every 12 weeks for ovarian suppression. Patients continued treatment until deemed resectable by the treating surgeon with imaging re-assessment every 8 weeks using RECIST 1.1. Following ICS, patients receive 4 cycles of adjuvant fulvestrant and abemaciclib and then transition to maintenance letrozole. Patients with progressive disease (PD) were removed from study and received standard of care chemotherapy. Primary endpoint is clinical benefit rate (CBR). Results: Fifteen patients were enrolled and evaluable. At data cutoff date (January 20, 2022), 7 of 15 patients (47%) had partial response (PR) (one patient with radiologic PR had a pathologic complete response at ICS), 5 of 15 (33%) had stable disease (SD), and 3 of 15 (20%) had progressive disease (PD), resulting in a CBR of 80%. Of the 7 patients with PR, 3 have had ICS with CGR, 3 have not yet had ICS, and 1 underwent resection of supraclavicular disease with small volume residual disease in the chest. Of the 5 patients with SD, one underwent ICS with CGR, and two have been on treatment for 8 and 16 weeks with reduction in measurable disease but not yet deemed to be candidates for surgery. Four of the 5 patients (80%) who had ICS, had CGR. Median time on study prior to surgery was 24 weeks. Adverse events (grade 3 or 4) possibly related to abemaciclib occurred in 2 patients (13.3%) and included acute kidney injury (6.7%) and neutropenia (6.7%). Conclusions: Neoadjuvant treatment with fulvestrant and abemaciclib was tolerable and demonstrated unprecedented response and CGR rates in this pilot study. These results compare favorably to published outcomes of neoadjuvant chemotherapy in LGSOC. Further studies are planned to explore this new treatment option in a larger study population. Clinical trial information: NCT03531645.

Objectives: The androgen receptor (AR) is more widely expressed than the estrogen or progesterone receptor in endometrial cancer (EC), including up to 90% of endometrioid type. Enzalutamide binds to the AR thereby nuclear translocation of receptors and blocking the association of the AR with DNA. We sought to evaluate the efficacy of paclitaxel, carboplatin and enzalutamide in a phase II study of advanced or recurrent endometrioid EC. Methods: Women with chemo-naive, advanced-stage or recurrent endometrioid EC with measurable disease and adequate end organ function were eligible. Documented AR expression was not required. A safety lead in of the triplet was performed to confirm dose. In phase II, patients received 28 days of enzalutamide (160mg daily) as a single agent before starting triplet therapy. Pre- and post-treatment biopsies were obtained during the single agent lead in for evaluation of molecular markers including AR receptor expression and activation, expression of AR-related genes/proteins, and DNA copy number alterations and mutations. Patients then received carboplatin (AUC 6 IV Q3wk), paclitaxel (175 mg/m2), and enzalutamide (160mg daily). Response per RECIST 1.1 was assessed every 3 cycles for a maximum of 9 cycles. Evaluable patients received at least 6 cycles of triplet therapy. Progression free survival (PFS) was calculated from date of treatment initiation to earliest date of progression, death, or last contact. This study was approved and funded in part by the National Comprehensive Cancer Network (NCCN) Oncology Research Program from general research support provided by Astellas Pharma Global Development, Inc. Results: A total 81 patients were screened with 49 patients treated to date (safety lead in n=7; phase II n=42). Median age was 64 years (range 41-81) and the majority of patients had grade 2 histology (53.1%) and recurrent disease (81.6%). There were no dose-limiting toxicities observed during the safety lead in. Patients received a median of 9 cycles of triplet therapy (range 0-9). 8 patients (16.3%) did not receive chemotherapy due to rapid progression during single agent enzalutamide (n=3), unrelated death (n=2), withdrawal (n=2), and unrelated stroke (n=1). PFS for the entire cohort was 11.47 months (95% CI 9.86 - 17.94; Figure 1a) and 6-month PFS probability was 0.77 (95% CI 0.61-0.87). Among 35 evaluable patients, confirmed objective response rate was 71% (95% CI 54–85%), 6 months PFS probability was 0.83 (95% CI 0.66-0.92) and median PFS was 14.42 months (95% CI 11.2-25.5; Figure 1B). The most common adverse events were as expected for chemotherapy alone, including neutropenia (20%), anemia (18%), fatigue (18%), neuropathy (10%), hyperglycemia (14%), nausea (8%), and thrombocytopenia (8%). Download : Download high-res image (41KB) Download : Download full-size image Conclusions: The combination of enzalutamide, carboplatin, and paclitaxel was tolerable and had promising clinical outcomes in chemo-naive advanced or recurrent endometrioid EC. Further analyses are ongoing regarding predictors of response and resistance to androgen-inhibitor therapy. Clinical Trials Registration: NCT02684227.

Despite rapid technical progress and demonstrable effectiveness for some types of diagnosis and therapy, much remains to be learned about clinical genome and exome sequencing (CGES) and its role within the practice of medicine. The Clinical Sequencing Exploratory Research (CSER) consortium includes 18 extramural research projects, one National Human Genome Research Institute (NHGRI) intramural project, and a coordinating center funded by the NHGRI and National Cancer Institute. The consortium is exploring analytic and clinical validity and utility, as well as the ethical, legal, and social implications of sequencing via multidisciplinary approaches; it has thus far recruited 5,577 participants across a spectrum of symptomatic and healthy children and adults by utilizing both germline and cancer sequencing. The CSER consortium is analyzing data and creating publically available procedures and tools related to participant preferences and consent, variant classification, disclosure and management of primary and secondary findings, health outcomes, and integration with electronic health records. Future research directions will refine measures of clinical utility of CGES in both germline and somatic testing, evaluate the use of CGES for screening in healthy individuals, explore the penetrance of pathogenic variants through extensive phenotyping, reduce discordances in public databases of genes and variants, examine social and ethnic disparities in the provision of genomics services, explore regulatory issues, and estimate the value and downstream costs of sequencing. The CSER consortium has established a shared community of research sites by using diverse approaches to pursue the evidence-based development of best practices in genomic medicine.

a Office of Rare Diseases Research, National Institutes of Health, Bethesda, MD, United States b Office of the Clinical Director, National Human Genome Research Institute, Department of Bioethics, Clinical Center, National Institutes of Health, Bethesda, MD, United States c Department of Health and Human Services, Office for Human Research Protections, Rockville, MD, United States d Combined NeuroScience Institutional Review Board, National Institute of Health, Bethesda, MD, United States e Office of Biorepositories and Biospecimen Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States f Case Western University, Cleveland, OH, United States g University of Rochester School of Medicine and Dentistry, Rochester, NY, United States h Patient Crossroads, Innolyst, Inc., San Mateo, CA, United States i University of Maryland School of Law, College Park, MD, United States

As more research studies incorporate next-generation sequencing (including whole-genome or whole-exome sequencing), investigators and institutional review boards face difficult questions regarding which genomic results to return to research participants and how. An American College of Medical Genetics and Genomics 2013 policy paper suggesting that pathogenic mutations in 56 specified genes should be returned in the clinical setting has raised the question of whether comparable recommendations should be considered in research settings. The Clinical Sequencing Exploratory Research (CSER) Consortium and the Electronic Medical Records and Genomics (eMERGE) Network are multisite research programs that aim to develop practical strategies for addressing questions concerning the return of results in genomic research. CSER and eMERGE committees have identified areas of consensus regarding the return of genomic results to research participants. In most circumstances, if results meet an actionability threshold for return and the research participant has consented to return, genomic results, along with referral for appropriate clinical follow-up, should be offered to participants. However, participants have a right to decline the receipt of genomic results, even when doing so might be viewed as a threat to the participants’ health. Research investigators should be prepared to return research results and incidental findings discovered in the course of their research and meeting an actionability threshold, but they have no ethical obligation to actively search for such results. These positions are consistent with the recognition that clinical research is distinct from medical care in both its aims and its guiding moral principles.