Citations

TPS504 Background: Patients with high-risk MIBC have a poor prognosis. Radical cystectomy remains the standard treatment. Yet despite substantial improvements in surgical techniques, mortality from metastatic recurrence remains high. A large number of MIBC patients are ineligible for cisplatin-based chemotherapy or have persistent muscle-invasive disease despite neoadjuvant chemotherapy (NAC). Pembrolizumab, a PD-1 inhibitor, has demonstrated significant activity and is FDA-approved for patients with advanced/chemotherapy-refractory metastatic urothelial carcinoma. We hypothesize that pembrolizumab given post-cystectomy will improve overall survival (OS) and disease-free survival (DFS) in patients with high-risk MIBC. Methods: Patients must have histologically confirmed muscle-invasive urothelial carcinoma of the bladder or upper tract, have received NAC and have ≥ pT2 and/or pN+ at surgery or be cisplatin-ineligible and have ≥ pT3 and/or pN+ at surgery or have declined adjuvant cisplatin-based therapy and have ≥ pT3 and/or pN+ at surgery. Surgery could be radical cystectomy, nephrectomy, or ureterectomy. Patients are stratified by pathologic stage, central PD-L1 status, and prior NAC. Patients are randomized to receive pembrolizumab 240 mg every 3 weeks for 1 year, or observation. The dual primary objectives are to determine DFS and OS. Secondary objectives are to determine DFS and OS in PD-L1-positive and -negative patients and assess safety. Correlative objectives are to determine whether 12 immune gene signatures, tumor molecular subtypes, diversity of T-cell receptor (TCR) clonotypes, persistence of TCR clonotypes, tumor and neoantigen burden, HLA subtypes, and plasma HGF and VEGF levels with IL-10 and IL-17 are associated with OS and DFS. Quality of Life Correlative objectives are to compare health-related quality of life as assessed by the EORTC QLQ-C30. Clinical trial information: NCT03244384.

PURPOSE Pegylated recombinant human hyaluronidase (PEGPH20) degrades hyaluronan (HA) and, in combination with chemotherapy, prolongs survival in preclinical models. The activity of PEGPH20 with modified fluorouracil, leucovorin, irinotecan, and oxaliplatin (mFOLFIRINOX) was evaluated in patients with metastatic pancreatic cancer (mPC). MATERIALS AND METHODS Patients had untreated mPC, a performance status of 0 to 1, and adequate organ function. Tumor HA status was not required for eligibility. After a phase Ib dose-finding study of mFOLFIRINOX plus PEGPH20, the phase II open-label study randomly assigned patients (1:1) to the combination arm or to mFOLFIRINOX alone (n = 138). The primary end point was overall survival (OS). RESULTS PEGPH20 dosages of 3 µg/kg every 2 weeks were more tolerable than twice-weekly dosages used in the phase I study, so 3 µg/kg every 2 weeks was the phase II dosage. An amendment instituted enoxaparin prophylaxis in the PEGPH20 combination arm as a result of increased thromboembolic (TE) events. The planned interim futility analysis when 35 deaths (of 103 analyzable patients) occurred resulted in an OS hazard ratio (HR) of 2.07 that favored the control arm, and the study was closed to accrual. The treatment-related grade 3 to 4 toxicity was significantly increased in the PEGPH20 combination arm relative to control (odds ratio, 2.7; 95% CI, 1.1 to 7.1). The median OS in the mFOLFIRINOX arm was 14.4 months (95% CI, 10.1 to 15.7 months) versus 7.7 months (95% CI, 4.6 to 9.3 months) in the PEGPH20 combination arm. CONCLUSION Addition of PEGPH20 to mFOLFIRINOX seems to be detrimental in patients unselected for tumor HA status. This combination caused increased toxicity (mostly GI and TE events) and resulted in decreased treatment duration compared with mFOLFIRINOX alone. The median OS in the mFOLFIRINOX control arm (14.4 months) is, to our knowledge, the longest yet reported and can be considered for patients with good PS.

Abstract Purpose: Young age has been shown to be an independent predictor of poor outcome in breast cancer. In HER2-positive breast cancer, the effects of aging remain largely unknown. Experimental Design: A total of 4,547 patients were included [3,132 from North Central Cancer Treatment Group (NCCTG) N9831 and 1,415 from National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31]. Pathologic stromal tumor-infiltrating lymphocyte (sTIL) and molecular tumor infiltrating lymphocyte (mTIL) signatures were evaluated. Results: In NCCTG N9831, comparable benefit of trastuzumab was observed in all patients [age ≤ 40; HR, 0.43; 95% confidence interval (CI), 0.28–0.66; P < 0.001; and age > 40; HR, 0.56; 95% CI, 0.45–0.69; P < 0.001]. Similar results were observed in NSABP B-31 (age ≤ 40; HR, 0.45; 95% CI, 0.29–0.68; P < 0.001; and age > 40; HR, 0.42; 95% CI, 0.33–0.54; P < 0.001). Among patients who received chemotherapy alone, younger age was associated with poor outcome in the hormone receptor–positive subset, but not the hormone receptor–negative subset, in both trials. Although there was no association between sTILs and age, a small, but significant increase in mTIL CD45 and some immune subset signatures were observed. Among patients who received chemotherapy alone, patients over 40 years of age with lymphocyte-predominant breast cancer had excellent outcome, with 95% remaining recurrence free at 15 years. Conclusions: Among patients treated with trastuzumab, there was no significant difference in outcome related to age. Our study suggests that trastuzumab can negate the poor prognosis associated with young age.

Abstract OBJECTIVES Limited literature is available on the best management strategy for tricuspid valve (TV) disease in adults. We sought to review our long-term outcomes of TV surgery with regard to survival and reoperation. METHODS A retrospective analysis of all patients ≥18 years of age [n = 2541, aged 67 ± 13years, 1433 (56%) females] who underwent first-time TV surgery between January 1993 and December 2013 was done. There were 1735 patients who received TV repair and 806 patients underwent replacement. A gradient boosting machine model was used to derive a propensity score for predicting replacement using 27 preoperative characteristics. Four hundred and eighteen propensity-matched pairs of TV repair and replacement were identified. Cox proportional hazard regression was used on the matched subset to determine the effect of replacement. RESULTS Functional TV regurgitation was present in 54% (n = 1369). A bioprosthesis was used in 84% (n = 680) of replacements, while 54% (n = 934) of TV repairs were ring annuloplasties. Operative mortality was 8% (n = 212). Overall survival was 54%, 29% and 13% at 5, 10 and 15 years, respectively. After propensity score matching, replacement was significantly associated with increased mortality [hazard ratio (HR) 1.54, 95% confidence interval (CI) 1.18–2.00; P = 0.001]. The cumulative incidence of TV reoperation was similar between the 2 groups when accounting for the competing risk of death [Fine–Gray HR 1.56, 95% CI 0.9–2.8; P = 0.144]. CONCLUSIONS TV surgery is associated with poor outcomes due to multiple patient comorbidities. TV repair results in better survival compared to replacement in patients with similar comorbidities with no increased risk of getting a reoperation.

AbstractPrimary aneurysmal bone cyst (ABC) is a benign multiloculated cystic lesion of bone that is defined cytogenetically by USP6 gene rearrangements. Rearrangements involving USP6 are promoter swaps, usually generated by fusion of the noncoding upstream exons of different partner genes with exon 1 or 2 of USP6, thus leading to transcriptional upregulation of full‐length USP6 coding sequence. Testing for USP6 rearrangements is used diagnostically to distinguish it from secondary ABC and other giant cell‐rich primary bone tumors. In this report, we present a case of a 16‐year‐old male with a primary ABC of the left distal femur. USP6 break apart fluorescence in situ hybridization was positive for a rearrangement and conventional chromosome analysis identified a reciprocal X;17 translocation. In order to identify the putative USP6 fusion partner, we performed RNA sequencing and uncovered a novel USP9X‐USP6 promoter swap fusion. This result was confirmed by reverse transcription‐polymerase chain reaction (RT‐PCR) and by mate pair sequencing thus showing the utility of these alternative methodologies in identifying novel fusion candidates. Ubiquitin‐specific protease 9X (USP9X), like USP6, encodes a highly conserved substrate‐specific deubiquitylating enzyme. USP9X is highly expressed in a number of tissue types and acts as both an oncogene and tumor suppressor in several human cancers. We conclude that oncogenic activation of USP6 via USP9X promoter exchange represents a novel driver of primary ABC formation.

AbstractWhole exome sequencing (WES) has become a fundamental component of genetic evaluation and diagnosing rare genetic diseases. This test is now offered to patients from a wide variety of cultural backgrounds and in various clinical and research settings. This commentary is a reflection of one group of clinical genetic counselors’ experiences in facilitating WES for patients who come from outside the United States for genetic evaluation and pursue WES. This patient population in our clinic primarily consists of individuals from the Middle East and presents recurrent logistical and counseling challenges. We aim to describe our international patient population, illuminate the challenges we have faced and illustrate how we have addressed these challenges.