Citations

Abstract Purpose: Pancreatic ductal adenocarcinoma (PDAC) remains a deadly disease urgently requiring new treatments. Overexpression of the protein transporter exportin-1 (XPO1) leads to mislocalization of tumor-suppressor proteins (TSP) and their inactivation. Earlier, we showed that blocking XPO1 by CRISPR/Cas9 validated Selective Inhibitor of Nuclear Export (SINE) compounds (selinexor and analogs) restores the antitumor activity of multiple TSPs leading to suppression of PDAC in vitro and in orthotopic models. Experimental Design: We evaluate the synergy between SINE compounds and standard-of-care treatments in preclinical models and in a PDAC Phase Ib trial. Results: SINE compounds synergize with gemcitabine (GEM) and nanoparticle albumin–bound (nab)-paclitaxel leading to suppression of PDAC cellular growth and cancer stem cell (CSC) spheroids disintegration. Label-free quantitative proteome profiling with nuclear and cytoplasmic enrichment showed superior enhancement in nuclear protein fraction in combination treatment. Selinexor inhibited the growth of PDAC CSC and two patient-derived (PDX) subcutaneous xenografts. Selinexor–GEM–nab-paclitaxel blocked PDX and orthotopic tumor growth. In a phase 1b study (NCT02178436), 9 patients were exposed to selinexor (60 mg oral) with GEM (1,000 mg/m2 i.v.) and nab-paclitaxel (125 mg/m2 i.v.) on days 1, 8, and 15 of 28-day cycle. Two patients showed partial response, and 2 had stable disease. An outstanding, durable objective response was observed in one of the responders with progression-free survival of 16 months and overall survival of 22 months. Conclusions: Our preclinical and ongoing clinical study lends support to the use of selinexor–GEM–nab-paclitaxel as an effective therapy for metastatic PDAC.

Abstract Background: Multiple myeloma (MM) is characterized by the invasion of malignant plasma cells into the bone marrow. While first line treatment options result in significant clinical benefit to patients, spatiotemporal clonal evolution results in disease relapse and mortality. Advances in genomics have armed clinicians with unprecedented insight into the molecular architecture of MM cells, however, the clinical benefit derived by genomics-guided intervention has been limited. We present a novel computational biology modelling (CBM) tool, which takes into account the combined effect of individual mutations, gene copy number abnormalities and large scale chromosomal changes in order to predict the salient molecular pathways utilized by the MM cell for survival. By reverse-engineering MM cell architecture in silico, the CBM tool is able to predict drug response and resistance mechanisms. Thus, our aim was to determine the accuracy of the CBM tool in predicting treatment response of relapsed/refractory MM patients for future management of their disease, in a more individualized manner. Methods: Cytogenetics and somatic mutations (by targeted NGS) for 15 MM patients were input into the CBM model to predict responses to different therapeutic combinations. All patients were relapsed to prior treatment. CBM uses PubMed and other online resources to generate patient-specific protein network maps of activated and inactivated disease pathways. We simulated the specific combinations of the drugs per patient and measured the quantitative drug effect on a composite MM disease inhibition score (i.e., cell proliferation, viability, apoptosis and paraproteins). The actual clinical outcome of the treatments was compared with predicted outcomes. Results: Fifteen patients were analysed using CBM for prediction of treatment response after NGS was performed. 13/15 were clinically evaluable, of which 1 was a responder and 12 were non-responder. 6/13 patients were treated on clinical trial and 7/13 were on drug combinations per physician decision. CBM correctly predicted 1 responder and 11 non-responder with a PPV of 50%, NPV 100%, specificity 91.67%, sensitivity 100%. The accuracy of CBM prediction was 92.30%. CBM also predicted the response of prior drug therapies for its non-response at relapse. For prior drug treatment options, 14 patients were evaluable. All the 14 patients were clinically non-responders and CBM correctly predicted for 13 patients with NPV 100%, Specificity 92.85% and overall accuracy of 92.85%. The majority of patients did not respond to therapies recommended at relapse. As an example, the operative molecular pathways from 2 patients who did not respond to combination treatment, either pre-NGS or post-NGS profiling, are shown in Fig. 1 and Table 1. CBM identified amplification (AMP) of chromosome (chr) 1 (WNT3A, IL6R, CKS1B, MCL1, PIK3C2B, USF1), chr 3 (HES1, PIK3CA, CTNNB1, WNT7A, FANCD2), chr 5 (IL6ST, IRF1, GLRX, SKP2), chr 7 (CDK5, EZH2, IL6, CAV1, ABCB1), chr 9 (NOTCH1, HSPA5, FANCC, FANCG), chr 15 (DLL4, FANCI, ALDH1A2), chr 19 (ERCC1, ERCC2, USF2); deletion(DEL) of chr 13 (CUL4A) , chr 16 (AXIN1, CDH1) and TP53 mutation in different combinations, which confer resistance to therapies at relapse. Conclusions: The CBM technology represents a potential means to identify therapeutic options for MM patients based on the patients individual tumor-genome profile and which can also be deployed for uncovering drug resistance mechanisms. This tool may aid clinicians in decision making for recommending the most appropriate therapy based on standard of care agents or clinical trials; thus improving patient outcomes and reducing unnecessary costs or drug-related toxicities. Disclosures Singh: Cellworks Research India Private Limited: Employment. Sauban:Cellworks Research India Private Limited: Employment. Husain:Cellworks Research India Private Limited: Employment. Kumar:Cellworks Research India Private Limited: Employment. Kumari:Cellworks Research India Private Limited: Employment. Tyagi:Cellworks Research India Private Limited: Employment. Abbasi:Cell Works Group Inc.: Employment. Vali:Cell Works Group Inc.: Employment. Ailawadhi:Pharmacyclics: Research Funding; Takeda: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Janssen: Consultancy.

ABSTRACTObjectives:The aim of the present study was to investigate the natural history of chronic pancreatitis (CP); patients in the North American Pancreatitis Study2 (NAPS2, adults) and INternational Study group of Pediatric Pancreatitis: In search for a cuRE (INSPPIRE, pediatric) were compared.Methods:Demographics, risk factors, disease duration, management and outcomes of 224 children and 1063 adults were compared using appropriate statistical tests for categorical and continuous variables.Results:Alcohol was a risk in 53% of adults and 1% of children (P < 0.0001); tobacco in 50% of adults and 7% of children (P < 0.0001). Obstructive factors were more common in children (29% vs 19% in adults, P = 0.001). Genetic risk factors were found more often in children. Exocrine pancreatic insufficiency was similar (children 26% vs adult 33%, P = 0.107). Diabetes was more common in adults than children (36% vs 4% respectively, P < 0.0001). Median emergency room visits, hospitalizations, and missed days of work/school were similar across the cohorts. As a secondary analysis, NAPS2 subjects with childhood onset (NAPS2‐CO) were compared with INSPPIRE subjects. These 2 cohorts were more similar than the total INSPPIRE and NAPS2 cohorts, including for genetic risk factors. The only risk factor significantly more common in the NAPS2‐CO cohort compared with the INSPPIRE cohort was alcohol (9% NAPS2‐CO vs 1% INSPPIRE cohorts, P = 0.011).Conclusions:Despite disparity in age of onset, children and adults with CP exhibit similarity in demographics, CP treatment, and pain. Differences between groups in radiographic findings and diabetes prevalence may be related to differences in risk factors associated with disease and length of time of CP.

Abstract Background: Pathological complete response (pCR) is accepted by FDA as a surrogate endpoint for accelerated approval of targeted agents in combination with chemotherapy based on better long-term outcomes compared to residual disease (Cortazar 2014). Methods: The multi-center, adaptively-randomized I-SPY2 platform trial uses pCR as the primary endpoint to identify investigational agents that will improve outcomes in women with stage 2/3 breast cancer with high risk of early recurrence, across all signatures, based on hormone receptor (HR), HER2, and 70-gene (MammaPrint) status. For patients with HR+ HER2- tumors, only 70-gene (Mammaprint) high-risk patients are enrolled. To date, 1200+ patients have been randomized to one of 14 arms: control (paclitaxel followed by AC); veliparib/carboplatin; neratinib; MK2206; trebananib; trastuzumab/pertuzumab; ado-trastuzumab emtansine/pertuzumab; pembrolizumabx4; ganitumab/metformin; ganetespib; PLX-3397. 7 agents graduated in at least one signature (&gt; 85% probability of success in a 300-patient phase III confirmatory trial); 2 did not graduate; 1 stopped for toxicity, and 3 are enrolling (patritumab/trastuzumab, talazoparib/irinotecan, pembrolizumabx8). Local pathologists were centrally trained using the Residual Cancer Burden (RCB) assessment to ensure uniform evaluation and response classification; RCB 0 = pCR. Results: We evaluated the relationship between pCR and event free (EFS) and distant disease free survival (DDFS) in the first 522 pts (median follow-up:2.5 years). 180 pts achieved pCR (36%) while 338 did not (RCB=1-3). There were 82 EFS and 65 DRFS events. Over the entire group (including all arms), pCR was highly associated with 3-year EFS (p&lt;0.001 for both). Pts achieving pCR had a 3% recurrence risk (RR) at 3 years; those with non-pCR had 24% RR over this time period. For distant recurrence, the 3-year RR with pCR was 2%, compared to 20% in pts with non-pCR. As expected, pCR rates varied by breast cancer subtype (HR+/HER2: 18% (35/196), HR+/HER2+: 40% (33/82), HR-/HER2+:68% (34/50), HR-/HER2-:41% (76/188)). The relationship between pCR and EFS was significant and clinically impactful within each subtype. 3-year survival (pCR group)Hazard Ratio OverallOverallHR+/HER2-HER2+TNBCEFS97%0.08 (0.03-0.23)0.14 (0.02-1.04)0 (NA)0.11 (0.03-0.37)DDFS98%0.08 (0.03-0.26)0.17 (0.01-1.23)0 (NA)0.09 (0.02-0.40) Conclusions: The first long-term efficacy results from the I-SPY2 TRIAL demonstrate that achieving pCR is a very strong surrogate endpoint for improved EFS and DDFS in a high-risk population, across all treatment arms, regardless of subtype. I-SPY2 shows substantially lower estimated EFS hazards for patients achieving pCR, compared to the 5 yr EFS hazard ratio for pCR vs not in Cortazar (hazard ratio 0.49), demonstrating important differences between a metaanalysis compared to a platform trial with uniform high-risk eligibility, standardized pathology assessment, and multiple targeted therapies. Our data support the use of pCR as a primary endpoint for accelerated approval of new drugs if EFS is evaluated in the same population. Based on these findings, the I-SPY2 TRIAL will test whether therapy can be deescalated or escalated for individual patients with the goal of achieving pCR for all. Citation Format: Yee D, DeMichele A, Isaacs C, Symmans F, Yau C, Albain KS, Hylton NM, Forero-Torres A, van't Veer LJ, Perlmutter J, Rugo HS, Melisko M, Chen Y-Y, Balassanian R, Krings G, Datnow B, Hasteh F, Tipps A, Weidner N, Zhang H, Tickman R, Thornton S, Ritter J, Amin K, Klein M, Chen B, Keeney G, Ocal T, Feldman M, Klipfel N, Sattar H, Mueller J, Gwin K, Baker G, Kallakury B, Zeck J, Duan X, Ersahin C, Gamez R, Troxell M, Mansoor A, Grasso LeBeau L, Sams S, Wisell J, Wei S, Harada S, Vinh T, Stamatakos MD, Tawfik O, Fan F, Adams A, Rendi M, Minton S, Magliocco A, Sahoo S, Fang Y, Hirst G, Singhrao R, Asare SM, Wallace AM, Chien AJ, Ellis ED, Han HS, Clark AS, Boughey JC, Elias AD, Nanda R, Korde L, Murthy R, Lang J, Northfelt D, Khan Q, Edmiston KK, Viscusi R, Haley B, Kemmer K, Zelnak A, Berry DA, Esserman LJ. Pathological complete response predicts event-free and distant disease-free survival in the I-SPY2 TRIAL [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 GS3-08.

BACKGROUNDFine‐needle aspiration of the thyroid is a common procedure, with an established role in reducing unnecessary thyroid surgery and identifying neoplasms and malignancies.METHODSThe study evaluated 1558 responses in the American Society for Clinical Pathology (ASCP) Non‐GYN Assessment program of aspirates of thyroid neoplasms and malignancies and placed them into the following groups: group A (target or correct interpretation), group B (incorrect interpretation as a benign thyroid nodule), group C (incorrect interpretation malignant aspirate as thyroid neoplasm), and group D (malignant diagnosis with incorrect interpretation). In clinical practice, responses in groups A, C, and D would lead to surgical excision, whereas responses in group B would not.RESULTSOf a total of 1558 responses, 78.5% of the responses were in group A, 8.5% in group B, 3.75% in group C, and 9.25% in group D. By individual diagnosis, the group rates were 86.5%, 0%, 11%, and 2.5% for anaplastic thyroid carcinoma; 83%, 5.5%, 4.25%, and 7.25% for papillary thyroid carcinoma; 79%, 7%, 6%, and 8% for medullary thyroid carcinoma; 83.5% 6.75%, 0%, and 9.75% for Hürthle cell neoplasm; and 61%, 22%, 0%, and 17% for follicular neoplasm in groups A, B, C, and D respectively.CONCLUSIONSFine‐needle aspiration was effective in diagnosing thyroid neoplasms and malignancies and in separating thyroid nodules into surgical and nonsurgical categories. Data from a large group of cytology professionals showed good performance; however, there is room for improvement, especially in making specific diagnoses. In particular, follicular neoplasm and follicular variant of papillary thyroid carcinoma were challenging diagnoses for participants. Cancer (Cancer Cytopathol) 2014;122:745–750. © 2014 The Authors. Cancer Cytopathology published by Wiley Periodicals, Inc. on behalf of American Cancer Society.