Citations

Abstract PURPOSE: Ovarian cancer remains the most lethal gynecological malignancy in the United States even though there are a number of treatment options. For the newly diagnosed ovarian cancer patient, treatment is standard with the majority of patients receiving first-line platinum/taxol treatment following surgical debulking or as part of a neo-adjuvant treatment regimen. Standard response assessment to this chemotherapy combination depends on lengthy clinical follow-up of at least 6 months following the conclusion of the chemotherapy. This course is initially effective in 70-80% of patients, but 20-30% will relapse within the 6 months post-chemotherapy or not respond at all. Additionally, most of the initial responders will also relapse. Early prediction of the patients whose cancers do not respond could lead to earlier intervention with more effective therapy. RESULTS: To perform this prediction, we developed a test utilizing live tumor tissue and 3D cell culture to predict the response of ovarian cancer patients to standard platinum and taxol chemotherapy along with the standard agents used for relapse patients. To validate the assay, we performed a prospective trial involving 86 women with newly diagnosed ovarian cancer from whom live tumor tissue was recovered at surgical resection prior to chemotherapy. Of the 79 patients whose tissues yielded a successful assay result, 27 had sufficient clinical follow-up to determine the accuracy of the response predictions made by the assay. Assay response predictions were made within 7 days following surgery while clinical response was not determined until 6 months or more following the conclusion of first-line chemotherapy. Assay results predicted first-line chemotherapy response in 100% of clinical responders (19 of 19) and first-line chemotherapy non-response in 62.5% of clinical non-responders (5 of 8) as defined by CA-125 and radiographic surveillance. This response prediction was statistically significant by Fisher's Exact test, p < 0.001. The sensitivity of the assay was 86% while the specificity was 100%. When the assay results were examined in terms of progression free survival, 19 of 19 patients identified as responders by the assay remained progression free at least 6 months post-chemotherapy with 14 remaining progression free 10 or more months post-chemotherapy. In contrast, of the 8 assay non-responders, 3 were refractory with progression within 3 months of chemotherapy conclusion and 2 progressed less than 6 months post-chemotherapy with a mean progression free survival of 4.5 months. CONCLUSIONS: Our rapid, ex vivo, 3D cellular assay is capable of accurate patient specific response prediction of first-line combination therapy in newly diagnosed ovarian cancer patients and can serve as a prognostic indicator of progression free survival. This preliminary clinical validation shows the significant potential of this assay as a future tool in personalized cancer care for ovarian cancer patients. Citation Format: Stephen Shuford, Jeffrey Elder, Larry Puls, John Weroha, Xiaonan Hou, Valentina Zanfagnin, Alpa Nick, Michael P. Stany, Larry Maxwell, Thomas Conrads, Chris Corless, Anil K. Sood, Matthew Gevaert, Howland E. Crosswell, and Teresa M. DesRochers. PROSPECTIVE CLINICAL VALIDATION OF EX VIVO, PATIENT-SPECIFIC RESPONSE PREDICTION TO FIRST-LINE CHEMOTHERAPY [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr TMIM-069.

TPS4596 Background: There is no standard adjuvant systemic therapy that increases overall survival (OS) over surgery alone for non-metastatic RCC. Anti-PD-1 nivolumab (nivo) improves OS in metastatic RCC and is well tolerated. In mouse models, priming the immune system prior to surgery with anti-PD-1 results in superior OS compared to adjuvant dosing. Remarkable pathologic responses have been seen with neoadjuvant PD-1 in multiple ph 2 studies in bladder, lung and breast cancers. Phase 2 neoadjuvant RCC trials of nivo show preliminary feasibility and safety with no surgical delays. PROSPER RCC seeks to improve clinical outcomes by priming the immune system with neoadjuvant nivo prior to nephrectomy followed by continued immune system engagement with adjuvant blockade in patients (pts) with high risk RCC compared to standard of care surgery alone. Methods: This global, unblinded, phase 3 National Clinical Trials Network study is accruing pts with clinical stage ≥T2 or TanyN+ RCC of any histology planned for radical or partial nephrectomy. Select oligometastatic disease is permitted if the pt can be rendered ‘no evidence of disease’ within 12 weeks of nephrectomy (≤3 metastases; no brain, bone or liver). In the investigational arm, nivo is administered 480mg IV q4 weeks with 1 dose prior to surgery followed by 9 adjuvant doses. The control arm is nephrectomy followed by standard of care surveillance. There is no placebo. Baseline tumor biopsy is required only in the nivo arm but encouraged in both. Randomized pts are stratified by clinical T stage, node positivity, and M stage. 805 pts provide 84.2% power to detect a 14.4% absolute benefit in recurrence-free survival at 5 years assuming the ASSURE historical control of ̃56% to 70% (HR = 0.70). The study is powered to evaluate a significant increase in OS (HR 0.67). Critical perioperative therapy considerations such as safety, feasibility, and quality of life metrics are integrated. PROSPER RCC embeds a wealth of translational studies to examine the contribution of the baseline immune milieu and neoadjuvant priming with anti-PD-1 on clinical outcomes. As of February 10, 2021, 704 patients have been enrolled (N = 805). Clinical trial information: NCT03055013.

TPS1101 Background: More than two thirds of patients with advanced breast cancer (ABC) have estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2−) tumors. Current standard-of-care first-line treatments include an aromatase inhibitor (AI) or fulvestrant, a selective ER degrader (SERD), combined with cyclin-dependent kinase 4/6 (CDK4/6) inhibitors. Concurrent use of luteinizing hormone-releasing hormone (LHRH) agonists is recommended for men and premenopausal women with ABC. Nevertheless, almost all ABCs eventually become resistant to endocrine therapy (ET) and the disease is incurable. New therapies are needed to combat ET resistance, maintain patient quality of life (QoL), and delay the need for chemotherapy. AZD9833 (camizestrant) is an orally bioavailable, highly potent, next-generation SERD that demonstrated anti-cancer properties across a range of preclinical models, including those with ER-activating mutations (Scott et al, 2020). A phase I study (SERENA-1) has demonstrated that AZD9833 is well tolerated and has a promising antitumor profile when administered alone or in combination with palbociclib, a CDK4/6 inhibitor (Baird et al, SABCS 2020). SERENA-4 (NCT04711252) is a randomized, multicenter, double-blind, phase III trial to evaluate the safety and efficacy of AZD9833 in combination with palbociclib for patients with ER+ HER2− ABC who have not received any systemic treatment in the advanced disease setting. Methods: SERENA-4 will enroll 1,342 patients with de novo or recurrent ER+ HER2– ABC who have not previously received systemic treatment for their locoregionally recurrent or metastatic disease. Patients with recurrent disease must have received adjuvant AI or tamoxifen therapy for at least 24 months without relapse. Patients will be randomized 1:1 to receive orally either (a) AZD9833 (75 mg, once daily), palbociclib (125 mg, once daily for 21 days followed by 7 days off treatment) and anastrozole-matching placebo (once daily) or (b) anastrozole (1 mg, once daily), palbociclib (same as active arm), and AZD9833-matching placebo (once daily). Premenopausal women and men will also receive LHRH agonists. The primary endpoint will be progression-free survival (PFS; up to 5 years). Secondary endpoints will include overall survival (up to 8 years), length of second PFS period, objective response, time to chemotherapy, and changes in QoL measures. Enrollment began in January 2021. Acknowledgments: We thank Rose Goodchild, PhD, of Oxford PharmaGenesis, UK, for providing medical writing assistance. Funding: The SERENA-4 trial is funded and overseen by AstraZeneca. Clinical trial information: NCT04711252 .

Abstract The bone marrow (BM) microenvironment actively promotes multiple myeloma pathogenesis, and therapies targeting both cancer cells and the niche are highly effective. We were interested in identifying novel signaling pathways supporting multiple myeloma–BM cross-talk. Mutations in the transmembrane receptor Roundabout 1 (ROBO1) were recently identified in patients with multiple myeloma; however, their functional consequences are uncertain. Through protein structure–function studies, we discovered that ROBO1 is necessary for multiple myeloma adhesion to BM stromal and endothelial cells and that ROBO1 knockout (KO) compromises BM homing and engraftment in a disseminated mouse model. ROBO1 KO significantly decreases multiple myeloma proliferation in vitro and intra- and extramedullary tumor growth in vivo. Mechanistically, the ROBO1 C-terminus is cleaved in a ligand-independent fashion and is sufficient to promote multiple myeloma proliferation. Vice versa, mutants lacking the cytoplasmic domain, including the human-derived G674* truncation, act dominantly negative. Interactomic and RNA-sequencing studies suggest that ROBO1 may be involved in RNA processing, supporting further studies. Significance: ROBO1 is highly expressed in t(4;14) multiple myeloma and supports homing and dissemination to the BM niche. ROBO1 knockout causes reduced tumor growth in intramedullary and extramedullary myeloma animal models, while the ROBO1 C-terminus is cleaved in multiple fragments and it is necessary and sufficient to sustain myeloma proliferation.

Abstract Alzheimer's disease (AD) is the most common cause of dementia and is associated with serious neurologic sequelae resulting from neurodegenerative changes. Identification of markers of early-stage AD could be important for designing strategies to arrest the progression of the disease. The brain is rich in lipids because they are crucial for signal transduction and anchoring of membrane proteins. Cerebrospinal fluid (CSF) is an excellent specimen for studying the metabolism of lipids in AD because it can reflect changes occurring in the brain. We aimed to identify CSF lipidomic alterations associated with AD, using untargeted lipidomics, carried out in positive and negative ion modes. We found CSF lipids that were significantly altered in AD cases. In addition, comparison of CSF lipid profiles between persons with mild cognitive impairment (MCI) and AD showed a strong positive correlation between the lipidomes of the MCI and AD groups. The novel lipid biomarkers identified in this study are excellent candidates for validation in a larger set of patient samples and as predictive biomarkers of AD through future longitudinal studies. Once validated, the lipid biomarkers could lead to early detection, disease monitoring and the ability to measure the efficacy of potential therapeutic interventions in AD.

Background: Disorders of consciousness (DoC) includes coma, vegetative state (VS), minimally conscious state (MCS), and emergence from the MCS. Aneurysmal rupture with high-grade SAH, traumatic brain injury, and neoplastic brain lesions are some of the frequent pathologies leading to DoC. The diagnostic errors among these DoC are as high as ranging from 25% to 45%, with a probable error in the conclusion of patients’ state, treatment choice, end-of-life decision-making, and prognosis. Some studies also reported that 37–43% of patients were misdiagnosed in VS while demonstrating signs of awareness. Despite its wide acceptance, Coma Recovery Scale-Revised (CRS-r) remained underused or inappropriately utilized, which may lead to substandard or unprofessional patient care. Literature is rare on the knowledge of CRS-r among physicians published from India and across the globe. Therefore, we carried out the present study to ascertain physicians’ knowledge on CRS-r and raise awareness about its justifiable clinical utilization. We also explored the factors associated with this perceived level of experience among participants and recommend frequent physicians’ training for care of patients with DoC. Methods: An institution-based cross-sectional online survey was conducted from June 8 to July 7, 2020, among Ninety-six physicians recruited using a convenient sampling technique. Twenty-item, validated, reliable, and a pilot-tested questionnaire was used to assess the knowledge regarding CRS-r and collect socio-demographic variables. The analysis was performed using the Statistical Package for the Social Sciences version 23. Bivariate and multivariate logistic regression analyses were employed to assess the association of participants’ socio-demographic variables and their parent department of work with the knowledge. P < 0.05 was considered statistically significant in the multivariate analysis. Results: A total of Ninety-six participants were included in the analysis, and only 33.3% of them were found to have adequate knowledge of CRS-r. Multivariate analysis revealed that age (adjusted odds ratio [AOR] = 31.66; 95% CI: 6.25–160.36), gender (AOR = 44.16; 95% CI: 7.43–268.23), and parent department of working (AOR = 0.148; 95% CI: 0.06–0.39) were significantly associated with the knowledge. Conclusion: Knowledge of the physicians on CRS-r is found to be exceptionally low. It has a strong tendency to adversely affect patients’ optimal care with disorders of consciousness (DoC). Therefore, it is crucial to expand physicians’ knowledge and awareness regarding CRS-r to adequately screen patients with DoC.

Abstract Wnt signaling is a major driver of stemness and chemoresistance in ovarian cancer, yet the genetic drivers that stimulate its expression remain largely unknown. Unlike other cancers, mutations in the Wnt pathway are not reported in high-grade serous ovarian cancer (HGSOC). Hence, a key challenge that must be addressed to develop effective targeted therapies is to identify nonmutational drivers of Wnt activation. Using an miRNA sensor-based approach, we have identified miR-181a as a novel driver of Wnt/β-catenin signaling. miR-181ahigh primary HGSOC cells exhibited increased Wnt/β-catenin signaling, which was associated with increased stem-cell frequency and platinum resistance. Consistent with these findings, inhibition of β-catenin decreased stem-like properties in miR-181ahigh cell populations and downregulated miR-181a. The Wnt inhibitor SFRP4 was identified as a novel target of miR-181a. Overall, our results demonstrate that miR-181a is a nonmutational activator of Wnt signaling that drives stemness and chemoresistance in HGSOC, suggesting that the miR–181a–SFRP4 axis can be evaluated as a novel biomarker for β-catenin–targeted therapy in this disease. Significance: These results demonstrate that miR-181a is an activator of Wnt signaling that drives stemness and chemoresistance in HGSOC and may be targeted therapeutically in recurrent disease.