Objective: Undertreated pain around the world includes the acute and chronic pain caused by sickle cell disease (SCD). In collaboration with a Caribbean association that aims to provide assistance to those diagnosed with SCD, we surveyed adults with SCD about pain management and impact of SCD pain. Methods: Participants were recruited from a group of 55 adults with SCD. A survey was administered to those who agreed to participate. Questions centred on their self-assessed level of pain due to SCD, the extent to which that pain interferes with daily activities, and how they seek and obtain pain relief. Results: Responses were received from 39 participants (female: n = 28, 72%, male: n = 11, 28%; mean age: 31.6 (SD ± 13.7) years. Sickle cell disease pain significantly disrupts participants' daily activities (62%), mood (72%), work (64%) and sleep (69%). Prescription medicine was ineffective for 41% and about half (n = 19) sought alternate means of relief. Conclusion: Sickle cell disease pain is undertreated in the Caribbean, disrupts daily activities and affects quality of life by impinging on education, employment and marital status. Sickle cell disease and other types of pain can be clinically managed safely, effectively and inexpensively. By failing to palliate and overcome the problem of undertreated pain, healthcare systems and providers contribute to socioeconomic amongst other repercussions for sufferers, their families and caregivers, and their nations.

Background: Recurrent breast cancers arise from minimal residual disease (MRD): the pool of disseminated and circulating tumor cells (DTCs and CTCs) that survive in their host following treatment of primary breast cancer. Detection of DTCs in the bone marrow (BM) after treatment is strongly associated with an increased risk of recurrence. Through the analysis of novel genetically-engineered mouse models, we have generated a substantial body of evidence that autophagy and mTOR signaling play key roles in the survival of DTCs. Moreover, administration of agents that block these pathways in mice harboring MRD reduces DTC burden and concomitantly reduces tumor recurrence, providing the rationale for translating these findings to patients (pts). Trial Design: The PENN-SURMOUNT screening study uses a clinically validated IHC assay (DTC-IHC) to identify at-risk pts who harbor DTCs. DTC+ pts are eligible for enrollment on the CLEVER trial, which will determine the feasibility, safety and efficacy of administering hydroxychloroquine (HCQ) and/or everolimus (EVE) in DTC+ patients to target MRD and prevent recurrence. PENN-SURMOUNT is single center, prospective cohort study of pts who have completed therapy for primary breast cancer, are within 5 yrs of diagnosis and are at increased risk for relapse by virtue of nodal positivity, triple negative disease, ER+/Oncotype DX RS ≥ 25, or residual disease after neoadjuvant therapy. Pts undergo screening BM aspirate to test for DTCs following completion of adjuvant chemo and radiotherapy. The primary objective of the study is to determine the incidence and frequency of MRD in pts who have completed primary treatment for breast cancer and to ascertain eligibility for the CLEVER recurrence prevention trial. CLEVER is a randomized, controlled, open label phase II pilot trial. Target enrollment is 60 pts, with 15 pts allocated to each of 4 treatment arms: HCQ (600 mg BID), EVE (10mg daily), combination HCQ/EVE, or control/observation. A cycle is 28 days of continuous dosing. After a 3-month observation period, control pts will be offered HCQ/EVE therapy for 6 cycles; thus, the control group is actually a delayed treatment group and all pts will receive treatment. Pts who demonstrate persistent DTCs after 6 cycles will continue on combination therapy for an additional 6 cycles. The primary endpoint is feasibility of administering HCQ, EVE or the combination in this population. Secondary objectives include safety, efficacy (DTC reduction), and 3-year RFS. The principal translational objective is to assess the utility of a novel DTC assay, "DTC-Flow", for more sensitive detection and response to study therapy, compared to DTC-IHC. Additional translational objectives include determining whether patient DTCs, CTCs, and cell-free circulating plasma tumor DNA (ptDNA) biologically reflect the primary tumor and predict response. As of 5/23/17, 58 patients have been enrolled to PENN SURMOUNT, with a DTC-positivity rate of 22.6%; CLEVER opened in 2/2017; 11 patients are currently enrolled. Contact information: angela.demichele@uphs.upenn.edu Key words: Recurrence, disseminated tumor cells, dormancy, minimal residual disease, autophagy, mTOR, Everolimus, hydroxychloroquine Citation Format: Bayne LJ, Nivar I, Goodspeed B, Wileyto P, Savage J, Shih NNC, Feldman MD, Edwards J, Clark AS, Fox KR, Matro JM, Domchek SM, Bradbury AR, Shah PD, Chislock EM, Belka GK, Wang J, Amaravadi R, Chodosh LA, DeMichele AM. Detection and targeting of minimal residual disease in breast cancer to reduce recurrence: The PENN-SURMOUNT and CLEVER trials [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT2-07-09.

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Background: Few reports describe the spectrum of mutations in breast and ovarian cancer predisposition genes found specifically in African Americans. Methods: 560 women who self-identified as African American (AA) from the University of Pennsylvania and Wayne State University were included in this IRB-approved, case-control study. Cases (n=218 with a personal history of breast and/or ovarian cancer) and controls (n=342 without breast or ovarian cancer) underwent germline genetic testing using the Color Genomics 19-gene breast and ovarian cancer risk panel. The subset of AA patients diagnosed with breast cancer ≤40 (n=185) was compared to an institutional cohort of white patients with breast cancer diagnosed ≤40 (n=189). Results: Of 218 AA cases, 70 had pathogenic or likely pathogenic (P/LP) mutations (BRCA1: n=36; BRCA2: n=24; TP53: n=3; RAD51D: n=2; ATM: n=2; CHEK2: n=2 and MSH6: n=1). Forty-two of 218 patients (19%) had at least one variant of uncertain significance (VUS). Of 342 AA controls, 5 women had P mutations in 5 distinct genes: BRCA2, ATM, BRIP1, PALB2 and PMS2. 55 control patients (16%) had at least one VUS. Many of the 75 P/LP mutations (cases, 70 mutations; controls, 5 mutations) in the full AA cohort were unique variants. In the 135 patients who had BRCA1/BRCA2 sequencing prior to testing under this protocol, the Color Genomics platform identified all 56 pathogenic mutations. Among AA patients diagnosed with breast cancer ≤40 (n=185), the incidence of TP53 and ATM pathogenic mutations was similar to the white, early-onset breast cancer cohort (n=189): TP53, 1% in both cohorts; ATM = 1% in AA patients and 2% in whites. However, no patients in the AA, early-onset cohort had germline CHEK2 mutations, compared to 4% of white, early-onset breast cancer patients (p=0.007). Conclusions: Taken together, the results of this study demonstrate the importance of considering germline mutation testing in the AA population. Examination of mutations and disease phenotypes within the AA population may facilitate understanding of the clinical risk associated with variants of uncertain significance. Further comparative data between the AA and white cohorts will be presented. Citation Format: Shah PD, Digiovanni L, Maxwell KN, Bradbury AR, Van Den Akker J, Kim S, Gil E, Simon MS, Nathanson KL, Domchek SM. Spectrum of hereditary breast and ovarian cancer gene variants in an African American cohort [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-10-04.