Citations

Abstract Metastasis causes poor prognosis and yet remains the least understood aspect of cancer. To identify key regulators of ovarian cancer metastasis that drive early colonization and are also essential for advanced metastasis, we have applied a novel, comprehensive approach of combining the analysis of an organotypic 3D culture model of early metastasis with ovarian cancer patient tumors. Using matched primary and metastatic tumors from 42 OC patients, we have compared the fully formed metastatic tumors with the primary tumor of the same patient. Since this is an end-point analysis and reveals little about the intermediated regulatory steps, we have also studied the changes occurring during early metastatic colonization as a result of the interactions with the metastatic microenvironment by using an organotypic 3D culture model of omental metastasis. By combining these two approaches, we have identified key master regulators of metastasis that are essential for early metastatic colonization and remain important in the fully formed metastatic tumor. We specifically focused on microRNAs because of their pleotropic effects through translational inhibition of multiple targets, and also our previous studies have demonstrated their important role in metastasis. Using this approach, we identified a novel microRNA miR-4454, downregulated in the metastasizing ovarian cancer cells through their specific paracrine interactions with fibroblasts in the metastatic microenvironment. The downregulation of miR-4454 promoted high-grade serous ovarian cancer cell migration, invasion, proliferation, and clonogenic growth as well as metastasis in xenografts. The targets of miR-4454 were identified by RNA-seq in high-grade serous ovarian cancer cells overexpressing the microRNA. SPARC and BAG5 were found to be the functional effectors of miR-4454. SPARC activated FAK signaling and promoted metastasis, while BAG5 inhibited apoptosis and helped the metastasizing cancer cells tide over adverse conditions in the microenvironment. Since miR-4454 is essential for early metastatic colonization as well as in advanced metastasis, targeting it is a promising approach to treat metastatic ovarian cancer. Citation Format: Subramanyam Dasari, Taruni Pandhiri, Tommaso Grassi, Daniel W. Visscher, Francesco Multinu, Komal Agarwal, Andrea Mariani, Viji Shridhar, Anirban K. Mitra. Paracrine interactions with microenvironmental fibroblasts promote ovarian cancer metastasis through downregulation of miR-4454 [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B66.

8603 Background: Steroids, primarily dexamethasone (Dex), remains an integral part of the therapy for myeloma. Prior to the advent of novel agents, Dex as a single agent was demonstrated to produce overall response rates of around 50%. The toxicity associated with pulsed high dose Dex has led to this approach being abandoned. This study investigates whether responsiveness to Dex correlates with biological qualities of the plasma cell clone that predicts outcome. Methods: We identified from our prospectively maintained database, patients with newly diagnosed myeloma, who were seen at Mayo Clinic within 30 days of diagnosis and were treated with single agent Dex. The M-protein measurements and responses were assessed using the IMWG criteria. Results: 182 patients seen between March 1998 and June 2007, initially treated with single agent Dex for at least 4 weeks, were included in the analysis. The median age at diagnosis was 63 (range; 39–81) and 59% were male. The actuarial median survival for the entire group was 55 months. The median duration of Dex therapy was 15 weeks (range; 4–193). Ninety one (50%) had a partial response or better and 11 (6%) were not evaluable, with the remaining patients (44%) having less than PR or progression. 10 patients (5%) achieved a VGPR or CR. The median overall survival from diagnosis for the 91 responders was 75 months compared to 71 months for the remaining patients; p = 0.6. There was no correlation between baseline disease characteristics and Dex responsiveness. One hundred thirty (70%) patients proceeded to an autologous SCT after a median of 15 weeks (range 1–46 months) of Dex. While the median overall survival was longer among the group of patients who underwent SCT, among either group, there were no survival benefit between those with a PR or better to Dex compared to the rest. Conclusions: Among this group of patients with newly diagnosed myeloma treated with single agent Dex, failure to respond to Dex induction therapy did not impact overall survival. Failure to respond to single agent steroid does not have an adverse impact on outcome in newly diagnosed myeloma. [Table: see text]

8513 Background: Waldenström's macroglobulinemia is a low-grade lymphoplasmacytic lymphoma that is responsive to rituximab. Uniform response criteria define an objective response as a 50% reduction in the IgM level, and a minor response as a 25% reduction in IgM level. No publications in the literature exist that justify the use of the minor response. Clinicians who treat patients that achieve a minor response are left uncertain as to whether the response is adequate and patients should be monitored for progression or whether they should be considered therapy failures and crossover to an alternate chemotherapy regimen in an effort to achieve a deeper response. Methods: 69 patients, 34 previously untreated, and 35 previously treated (but rituximab naive) were included. All patients were treated with a single four-week course of rituximab 375 mg/m2 and were monitored with no further therapy until progression. Results: There were 19 objective and 17 minor responses out of 69 eligible patients (52.2%). Response rate and progression-free survival (26.6 mo) were similar whether patients were previously untreated or previously treated. Previously treated rituximab-naïve and previously untreated patients had, five-year survivals of 48% and 85%, respectively. There was no difference in overall or progression free survival between patients who achieved an objective response when compared to those who achieved a minor response. There was no difference between objective and minor responders by age, time from diagnosis to treatment in the treated group, bone marrow lymphoplasmacytes, hemoglobin level, creatinine, IgM level, or M-spike. The pre-treatment level of IgM did not predict overall survival, progression-free survival, time to progression, or response rate (All p>0.05). This lack of significance was found whether IgM was assessed as a continuous or discrete variable. Conclusions: These results reconfirm rituximab's efficacy as a single-agent for the treatment of Waldenström's macroglobulinemia, and patients who have a 25–50% reduction in their IgM protein derive significant clinical benefits that are durable and appear to not have an impact on overall survival. No significant financial relationships to disclose.

e19513 Background: The outcome of patients with MM relapsing after ASCT used early in the disease course or after failure of initial therapy, is not well defined. We undertook this study to understand treatment approaches for patients relapsing after single ASCT. Methods: Patients relapsing after single ASCT were identified from a prospectively maintained database and relevant clinical data were extracted from medical records. Relapse and treatment responses were according to IMWG Uniform Response Criteria. Patients relapsing between Jan 2000 and 2008 were included in order to capture a recent cohort contemporaneous to availability of novel drugs. Results: We studied 487 patients who had relapsed following a single ASCT, of whom 351 (72%) had an early SCT (≤ 12 mos from diagnosis). The median estimated follow up for all patients was 27 mos, 50 mos and 69 mos from relapse, SCT and diagnosis respectively. The median overall survival (OS) from the time of relapse was 30 mos for the early SCT group and 21 months for the late SCT group. The median time to relapse following transplant was 15 mos (3–119) among early SCT group and 12 mos (3–76) among the late SCT group. Longer time to relapse as well as longer time from relapse to initiation of therapy were independent predictors of better outcome. Among the early group, nearly a third of the patients achieved a PR or better to first salvage therapy (Table), with another third achieving stable disease and 25% of patients did not have response data. The median progression free survival for the first salvage regimen was 8 mos; 18 mos for those with PR or better and 5 mos for those with SD as the best response. Data on the regimen 2, 3, 4, 5, and 6 were available for 211, 133, 84, 53 and 28 patients respectively. As expected, the response rates and the response duration decreased with increasing number of relapses. Conclusions: Patients relapsing after ASCT can obtain prolonged response duration with the currently available treatments. Those with a durable response to transplant and those not requiring initiation of therapy for long periods after disease relapse have favorable disease biology and have prolonged survival after relapse. The natural history of the disease provides a valuable benchmark for evaluation of newer treatment approaches. No significant financial relationships to disclose.

OBJECTIVENational databases collect large amounts of clinical information, yet application of these data can be challenging. The authors present the NeuroPoint Alliance and Institute for Healthcare Improvement (NPA-IHI) program as a novel attempt to create a quality improvement (QI) tool informed through registry data to improve the quality of care delivered. Reducing the length of stay (LOS) and readmission after elective lumbar fusion was chosen as the pilot module.METHODSThe NPA-IHI program prospectively enrolled patients undergoing elective 1- to 3-level lumbar fusions across 8 institutions. A three-pronged approach was taken that included the following phases: 1) Research Phase, 2) Development Phase, and 3) Implementation Phase. Primary outcomes were LOS and readmission. From January to June 2017, a learning system was created utilizing monthly conference calls, weekly data submission, and continuous refinement of the proposed QI tool. Nonparametric tests were used to assess the impact of the QI intervention.RESULTSThe novel QI tool included the following three areas of intervention: 1) preoperative discharge assessment (location, date, and instructions), 2) inpatient changes (LOS rounding checklist, daily huddle, and pain assessments), and 3) postdischarge calls (pain, primary care follow-up, and satisfaction). A total of 209 patients were enrolled, and the most common procedure was a posterior laminectomy/fusion (60.2%). Seven patients (3.3%) were readmitted during the study period. Preoperative discharge planning was completed for 129 patients (61.7%). A shorter median LOS was seen in those with a known preoperative discharge date (67 vs 80 hours, p = 0.018) and clear discharge instructions (71 vs 81 hours, p = 0.030). Patients with a known preoperative discharge plan also reported significantly increased satisfaction (8.0 vs 7.0, p = 0.028), and patients with increased discharge readiness (scale 0–10) also reported higher satisfaction (r = 0.474, p < 0.001). Those receiving postdischarge calls (76%) had a significantly shorter LOS than those without postdischarge calls (75 vs 99 hours, p = 0.020), although no significant relationship was seen between postdischarge calls and readmission (p = 0.342).CONCLUSIONSThe NPA-IHI program showed that preoperative discharge planning and postdischarge calls have the potential to reduce LOS and improve satisfaction after elective lumbar fusion. It is our hope that neurosurgical providers can recognize how registries can be used to both develop and implement a QI tool and appreciate the importance of QI implementation as a separate process from data collection/analysis.

Abstract Purpose: Romidepsin dosing recommendations for patients with malignancy and varying degrees of hepatic dysfunction was lacking at the time of regulatory approval for T-cell lymphoma. We conducted a multicenter phase I clinical trial (ETCTN-9008) via the NCI Organ Dysfunction Working Group to investigate safety, first cycle MTD, and pharmacokinetic profile of romidepsin in this setting. Patients and Methods: Patients with select advanced solid tumors or hematologic malignancies were stratified according to hepatic function. Romidepsin was administered intravenously on days 1, 8, and 15 of a 28-day cycle and escalation followed a 3 + 3 design in moderate and severe impairment cohorts. Blood samples for detailed pharmacokinetic analyses were collected after the first dose. Results: Thirty-one patients received one dose of romidepsin and were evaluable for pharmacokinetic analyses in normal (n = 12), mild (n = 8), moderate (n = 5), and severe (n = 6) cohorts. Adverse events across cohorts were similar, and dose-limiting toxicity occurred in two patients (mild and severe impairment cohorts). The MTD was not determined because the geometric mean AUC values of romidepsin in moderate (7 mg/m2) and severe (5 mg/m2) impairment cohort were 114% and 116% of the normal cohort (14 mg/m2). Conclusions: Data from the ETCTN-9008 trial led to changes in the romidepsin labeling to reflect starting dose adjustment for patients with cancer and moderate and severe hepatic impairment, with no adjustment for mild hepatic impairment.

PURPOSE BRCA1 or BRCA2 ( BRCA) alterations are common in men with metastatic castration-resistant prostate cancer (mCRPC) and may confer sensitivity to poly(ADP-ribose) polymerase inhibitors. We present results from patients with mCRPC associated with a BRCA alteration treated with rucaparib 600 mg twice daily in the phase II TRITON2 study. METHODS We enrolled patients who progressed after one to two lines of next-generation androgen receptor–directed therapy and one taxane-based chemotherapy for mCRPC. Efficacy and safety populations included patients with a deleterious BRCA alteration who received ≥ 1 dose of rucaparib. Key efficacy end points were objective response rate (ORR; per RECIST/Prostate Cancer Clinical Trials Working Group 3 in patients with measurable disease as assessed by blinded, independent radiology review and by investigators) and locally assessed prostate-specific antigen (PSA) response (≥ 50% decrease from baseline) rate. RESULTS Efficacy and safety populations included 115 patients with a BRCA alteration with or without measurable disease. Confirmed ORRs per independent radiology review and investigator assessment were 43.5% (95% CI, 31.0% to 56.7%; 27 of 62 patients) and 50.8% (95% CI, 38.1% to 63.4%; 33 of 65 patients), respectively. The confirmed PSA response rate was 54.8% (95% CI, 45.2% to 64.1%; 63 of 115 patients). ORRs were similar for patients with a germline or somatic BRCA alteration and for patients with a BRCA1 or BRCA2 alteration, while a higher PSA response rate was observed in patients with a BRCA2 alteration. The most frequent grade ≥ 3 treatment-emergent adverse event was anemia (25.2%; 29 of 115 patients). CONCLUSION Rucaparib has antitumor activity in patients with mCRPC and a deleterious BRCA alteration, but with a manageable safety profile consistent with that reported in other solid tumor types.