tbuckley/cabot-search huggingface dataset:
Adjuvant enzalutamide for the treatment of early-stage androgen receptor-positive (AR+) TNBC.
Authors: Tiffany A. Traina, Leigh Ann Boyle, Artavazd Arumov, Sujata Patil, Marcia Edelweiss, Patricia Anne DeFusco, Mila Gorsky, Nicholas E. Lamparella, Shanu Modi, Rachel Ann Sanford, Ayca Gucalp
Journal: Journal of Clinical Oncology (2019)

546 Background: A subset of TNBC is dependent on AR signaling. Enzalutamide (ENZA), an AR-antagonist, has activity in patients (pts) with metastatic AR+ TNBC, with a clinical benefit rate of 33%. This study tests the feasibility of adjuvant ENZA for the treatment (tx) of early stage, AR+ TNBC. We now report the primary endpoint (endpt) and safety. Methods: Eligible pts have centrally confirmed, Stage I-III, ER/PR &lt; 1%, HER2(-), AR ≥1% BC and completed all planned surgery, chemotx and radiation (RT) &lt; 6 months of tx start. AR testing by IHC per MSK methods. Tx consists of ENZA 160mg daily for 1 year (y) with the option to extend tx to 2y. Toxicity per NCI CTCAEv4 every (q) 4 weeks (wk) for 12 wk, then q3 months. Primary endpt: feasibility of 1y ENZA defined as the discontinuation rate due to toxicity, consent withdrawal or tolerability. 50 pts are enrolled to have 46 evaluable pts required to discriminate between feasibility of 50% and 70%, with type I error 5% and 88% power. Pts who have disease progression (PD) or die during 1 st y of ENZA and do not have tx discontinuation due to the above will not be included in the primary analysis. If 29 pts complete 1y, adjuvant ENZA will be deemed feasible. Secondary endpts: safety and 3y DFS and OS. Exploratory endpts: PROs and biomarker development. Results: Between 5/2016-6/2018, 50 pts were enrolled. Pt and tumor characteristics (N = 50): Median age 55y (33-81); Stage: I 20 (40%), II 23 (46%), III 7 (14%); Grade (gr): 2 = 26%, 3 = 74%. AR &gt; 10% = 35 (70%), AR ≤10% = 15 (30%). Chemotx 47/50 (94%): Neoadjuvant (neo) 40%, Adjuvant (adj) 60%; Anthracycline/Taxane-based 38/47 (81%), Platinum 1/47 (2%), Docetaxel/Cyclophosphamide 3/47 (6%), other 5/47 (11%). 13/19 who received neo tx failed pCR; 9/13 (69.2%) received adj capecitabine. RT: 38/50 (76%). 27 pts completed 1y of tx. 7 pts will be evaluable by 6/1/19. 1 pt to complete 1y 6/21/19. 15 pts are off tx: PD (3), toxicity (5), noncompliance (4), withdrawal of consent (3). Tx-related AEs, any gr, &gt; 10% (N = 50): fatigue (48%), hot flashes (22%), headache (18%), hyperglycemia (18%), nausea (18%), WBC decreased (16%), dizziness (14%), arthralgia (12%), dyspnea (12%). Tx-related, gr 3 AEs: fatigue (6%), hyperglycemia (2%), hypertension (2%). No gr 4/5 AEs or seizures. 11 pts had dose reduction. Conclusions: Feasibility of adjuvant ENZA will be fully evaluable in 4/2019 and is anticipated to meet the prespecified statistical expectations for primary endpt. ENZA is well tolerated following locoregional tx and standard of care systemic tx. Secondary analyses and correlatives are ongoing to define the role of AR in TNBC. Clinical trial information: NCT02750358.
ARID1a as a marker of prognosis and increased sensitivity to CDK4/6, mTOR 1/2 and Src homology region 2 phosphatase (SHP 1/2) inhibitors in breast cancer (BC).
Authors: Veronica Mariotti, Howard L. McLeod, Hatem Hussein Soliman
Journal: Journal of Clinical Oncology (2019)

1082 Background: ARID1a (AT Rich Interactive Domain 1A) is part of the SWI/SNF complex, which regulates gene transcription, and is believed to be a tumor suppressor gene. Low ARID1a expression has been associated with poor prognosis in BC. The aim of this study was to explore the clinical significance of ARID1a mutation and expression loss, and its potential as a therapeutic target in BC. Methods: We analyzed publicly available genomic databases to study the clinical implication of ARID1a mutations and gene expression in BC. Results: ARID1a was mutated in ~5-7 % of BCs within TCGA/METABRIC/MSK (5511 samples), but did not show differences in frequency between histology, grade, or estrogen receptor (ER)/HER2 receptor status. MSK metastatic tissue samples had higher incidence of ARID1a mutation compared to primary tumor samples (7.6% vs 4.4%, χ 2 P = 0.0073). Analysis of ARID1a in KMPLOT showed that lower gene expression was associated with worse relapse-free survival and overall survival across all BCs, but the difference was primarily in molecularly classified luminal A tumors. Mutations in ARID1a did not show an association with outcomes in TCGA/METABRIC/MSK datasets. Pathway analysis of ARID1a showed it is involved in regulating ER ligand driven signaling and interacts with targets regulated by CDK4 and mTOR activity. CancerRxgene drug sensitivity analyses on BC cell lines revealed that ARID1a mutated BC cell lines were significantly more sensitive to palbociclib, SHP1/2, and mTOR1/2 inhibitors compared to ARID1a wildtype cell lines. Conclusions: Reduced activity of ARID1a in luminal BC cells may negatively affect prognosis by altering ER signaling leading to activation of druggable resistance mechanisms, particularly in metastatic tissue. Loss of function ARID1a mutations may sensitize cancer cells to CDK4/6, mTOR1/2, and SHP1/2 inhibitors in vitro. Further research in ARID1a mutated ER+ BCs using combinations of these inhibitors is warranted.
A phase II study of anti–PD-1 antibody camrelizumab plus FOLFOX4 or GEMOX systemic chemotherapy as first-line therapy for advanced hepatocellular carcinoma or biliary tract cancer.
Authors: Shukui Qin, Zhendong Chen, Ying Liu, Jianping Xiong, Zhenggang Ren, Zhiqiang Meng, ShanZhi Gu, Linna Wang, Jianjun Zou
Journal: Journal of Clinical Oncology (2019)

4074 Background: Advanced hepatocellular carcinoma (HCC) and biliary tract cancer (BTC) patients (pts) have very limited treatment options. Considering the immunogenic effects of oxaliplatin, combination of camrelizumab with oxaliplatin-based chemotherapy might bring a better clinical benefit. Methods: That was an ongoing single-arm, multicenter phase 2 trial. Advanced HCC or BTC pts naive to systemic treatment were given camrelizumab (3 mg/kg i.v., every 2 weeks) plus typical FOLFOX4 (infusional fluorouracil, leucovorin and oxaliplatin) or GEMOX (gemcitabine and oxaliplatin) regimen. Primary endpoints were confirmed objective response rate (ORR) per RECIST v1.1 and safety per CTC AE 4.03. Results: From Apr 27, 2017 to Oct 31, 2018, 34 Chinese HCC and 47 BTC pts were treated, in which 27 (79.4%) HCC and 17 (36.2%) BTC pts were HBV-infected. In the 34 evaluable HCC pts, confirmed ORR was 26.5% and disease control rate (DCR) was 79.4%. Median time to response (TTR) was 2.0 mo (range 1.5–5.7). Six of the 9 responses were still ongoing, and median duration of response (DoR) was not reached (range 3.3–11.5 + mo). Median progression-free survival (PFS) was 5.5 mo. At data cutoff, 61.7% BTC pts were still receiving study drug. In the 43 evaluable BTC pts, with a median duration of exposure of 2.9 mo, confirmed ORR was 7.0% and DCR was 67.4%. Median TTR was 1.9 mo (range 1.8–2.1). Median DoR was 5.3 mo (range 3.7–7.0). Median PFS was not reached yet. Median estimates for overall survival in both HCC and BTC were also not reached. Grade ≥3 treatment-related adverse events (TRAEs) occurred in 85.3% of HCC and 57.4% of BTC pts, most commonly neutrophil count decreased (HCC: 55.9%; BTC: 29.8%), white blood cell decreased (HCC: 38.2%; BTC: 21.3%), platelet count decreased (HCC: 17.6%; BTC: 12.8%), and anaphylaxis (BTC: 19.1%). Only one BTC pt stopped treatment due to a TRAE (recurrent Grade 2 anemia related to FOLFOX4). Grade ≥3 immune-related AEs occurred only in 5.9% of HCC (lipase increased) and 3.8% of BTC pts (anaphylaxis). Conclusions: Camrelizumab plus FOLFOX4 or GEMOX chemotherapy was tolerable and might offer a new promising choice for advanced HCC and BTC pts. Clinical trial information: NCT03092895.
Phase II COLET study: Atezolizumab (A) + cobimetinib (C) + paclitaxel (P)/nab-paclitaxel (nP) as first-line (1L) treatment (tx) for patients (pts) with locally advanced or metastatic triple-negative breast cancer (mTNBC).
Authors: Adam Brufsky, Sung-Bae Kim, Zanete Zvirbule, Luc Yves Dirix, Alexandru E. Eniu, Francisco Carabantes, Yann Izarzugaza, Jeroen Mebis, Joohyuk Sohn, Matthew Wongchenko, Saibah Chohan, Reena Amin, V. A. McNally, David Miles, Sherene Loi
Journal: Journal of Clinical Oncology (2019)

1013 Background: COLET showed that the addition of C (MEK1/2 inhibitor) to P resulted in an increased ORR (38%; Brufsky, SABCS 2017); IMpassion130 demonstrated clinical benefit with the combination of PD-L1 inhibitor A and nP as 1L tx for pts with mTNBC (Schmid, N Engl J Med, 2018). We investigated the efficacy and safety of A + C + P/nP in pts with mTNBC, as this combination may target multiple cancer immune escape mechanisms simultaneously. Methods: In the multi-stage, multi-cohort Phase II COLET study, pts with histologically confirmed mTNBC were randomized 1:1 to receive 1L tx with A 840 mg IV (d1, d15) + C 60 mg qd (d3-d23) + P 80 mg/m 2 IV (d1, d8, d15; cohort 2) or + nP 100 mg/m 2 (d1, d8, d15; cohort 3) in 28-day cycles until progression or toxicity. The primary endpoint (EP) was confirmed ORR per investigator-assessed RECIST 1.1. Additional EPs were DOR, PFS, OS, safety and exploratory efficacy by PD-L1 status. Results: As of 10 Aug 2018 (6.5-mo median follow-up), 63 and 62 pts were evaluable for efficacy and safety, respectively. In cohorts 2 and 3, 21 pts (66%) and 20 pts (65%) had received neo/adjuvant taxane tx, 9 pts (28%) and 6 pts (19%) had a disease-free interval of ≤12 mo, respectively. All pts had ≥1 AE; 69% and 70% had Gr 3-5 AEs and 47% and 43% had serious AEs in cohorts 2 and 3, respectively. Efficacy data for all pts and by PD-L1 expression on tumor-infiltrating immune cells (IC ≥1%; PD-L1+) are summarized in the Table. Conclusions: ORRs were similar between the A + C + P arm and A + C + nP arm. Numerically higher ORR and PFS were observed in pts with PD-L1+ disease. The combination’s safety profile was consistent with the known individual safety profiles, and A did not increase toxicity. Clinical trial information: NCT02322814. [Table: see text]
Learnings from a pragmatic study to evaluate benefit of performing reflex clinical trial matching and providing clinical decision support to physicians.
Authors: Neha M Jain, Alison Culley, Travis John Osterman, Mia Alyce Levy
Journal: Journal of Clinical Oncology (2019)

e18006 Background: Clinical trial enrollment is an assiduous process and requires active initiation and maintenance efforts by providers, patients, trial investigators, or other clinical staff. Setting up automated process triggers to perform a reflex clinical trial matching can kick-start the process without requiring human intervention. Methods: Using a clinical trial matching service developed in collaboration with GenomOncology, we used the receipt of sequencing test results as a process trigger to perform reflex clinical trial matching on oncology patients. A research nurse performed additional refinements to these results using multi-faceted filtering and an initial manual prescreening. In this pragmatic study, providers were randomized to receive results of prescreening events. EMR messages were sent to the intervention cohort of providers with recommendations for clinical trials for their patients and suggested next steps. Provider responses and prescreening outcomes were recorded in a REDCap project. To iteratively refine the trial results, matching algorithm updates were deployed throughout the study. Results: In the pilot deployment of this trial, we performed prescreening on 60 patients. At the time of prescreening vital status of 17% of the patients was outdated. We observed that trial cohort related recruiting statuses were the highest contributors to false matches (44%) and provider response rate was 94%. Conclusions: It is not possible to make substantial improvements to the outcome of clinical trial enrollment events without investing in reliable publicly available resources that host updated recruiting status for trials at the arm/cohort level. Uptake of such efforts by NCI or NLM has the potential to radically change the accuracy of clinical trial matching services and thereby improve enrollment efficiencies.[Table: see text]
Investigating racial differences in treatment responses through analysis of real-world data (RWD).
Authors: Zongzhi Liu, Meng Ma, Kartikey Grover, Li Li, Howard Goldsweig, Kamlesh Yadav, Xiang Zhou, Tommy Mullaney, Arielle Redfern, Whitney Jappe, Michelle Zimmerman, Tony Prentice, Qi Pan, William K. Oh, Eric E. Schadt, Dan Li, Rong Chen
Journal: Journal of Clinical Oncology (2019)

e18141 Background: Clinical trials remain the most reliable means to evaluate drug efficacy and safety for evidence-based cancer care. However, there is a significant racial disparity among participants in clinical trials. For example, only 1-3% of the participants in registration trials of immune checkpoint inhibitors (CPIs) in advanced non-small cell lung cancers (aNSCLCs) were Black. RWD data enable assessment of whether clinical trial results can be generalized to broader populations. Methods: We analyzed clinical records of &gt; 145,000 cancer patients treated at Mount Sinai hospitals. Therapeutic agents approved by FDA in recent years were assessed for responses across various race groups. Time to treatment discontinuation (TTD) was used as a surrogate clinical endpoint for outcomes. Results: Overall we did not observe significant differences in TTD among different race groups for the following drugs and indications we examined: palbociclib in metastatic breast cancer (mBC), EGFR tyrosine kinase inhibitors in aNSCLC, EGFR antibody cetuximab and panitumumab in metastatic colorectal cancer with wild type KRAS, abiraterone in metastatic castration-resistant prostate cancer (mCRPC), enzalutamide in mCRPC, sorafenib in unresectable hepatocellular carcinoma (HCC), CPIs in metastatic melanoma. For example, the median TTD of palbociclib in combination with fulvestrant or letrozole in post-menopausal women with HR+HER2- mBC was 181, 261, and 160 days in White (n = 114), Black (n = 55), other (n = 48) race groups, respectively (P = 0.61, log-rank test). Among patients with unresectable HCC treated with sorafenib, the median TTD was 64, 49, and 67 days in the White (n = 201), Black (n = 127) and other (n = 243) race groups, respectively (P = 0.70). However, when CPIs in aNSCLC were examined, we observed a significantly longer TTD in the Black group (median TTD not reached; n = 77) compare to the non-Black group (169 days, 95% CI 133-331; n = 211), P = 0.0049, median follow up 194 days. Conclusions: RWD showed there are no apparent differences of treatment response in various race groups for most new therapeutic agents. Preliminary results of CPIs in aNSCLC suggested a favorable response in the Black than the non-Black population.
Protein phosphatase 2A as a therapeutic target in inflammation and neurodegeneration
Authors: Andrew R. Clark, Michael Ohlmeyer
Journal: Pharmacology & Therapeutics (2019)

Protein phosphatase 2A (PP2A) is a highly complex heterotrimeric enzyme that catalyzes the selective removal of phosphate groups from protein serine and threonine residues. Emerging evidence suggests that it functions as a tumor suppressor by constraining phosphorylation-dependent signalling pathways that regulate cellular transformation and metastasis. Therefore, PP2A-activating drugs (PADs) are being actively sought and investigated as potential novel anti-cancer treatments. Here we explore the concept that PP2A also constrains inflammatory responses through its inhibitory effects on various signalling pathways, suggesting that PADs may be effective in the treatment of inflammation-mediated pathologies.
A double-blind, placebo-controlled randomized phase II study: Evaluating the effect of curcumin for treatment of cancer anorexia-cachexia syndrome in solid cancer patients.
Authors: Naiyarat Prasongsook, Kasarn Sitalarom, Siriwimon Saichaemchan, Khunthong Peechatanan, Aornchuma Chaiworramukkul
Journal: Journal of Clinical Oncology (2019)

e23151 Background: Cancer anorexia–cachexia syndrome (CACS) is common among patients with advanced solid cancer and associated with poor prognosis. CACS is a hypercatabolic state, which comprises adipose tissue and skeletal muscle loss, which is characterized by negative protein and energy balance, loss of lean body mass and adipose tissue. Also, CACS increase systemic inflammation. The treatment of CACS is still unclear. Curcumin has been shown anti-cancer and anti-inflammatory effects, including attenuation of CACS in animal models. Therefore, clinical study of curcumin for CACS is required. Methods: This is randomized, double-blind, placebo-controlled phase ll study, 52 patients with CACS in solid malignancy were enrolled and randomized in 1:1 to receive oral curcumin (at a dose of 400 mg twice daily) or placebo for 8 weeks. The primary end point was body tissue composition and the secondary end points were body weight and body mass index, Hand grip muscle strengthening, safety and toxicity. Results: All parameters of body compositions were not statistically significant different between two groups: curcumin group and placebo group, which were consist body fat mass -0.9, SEM = 0.94 versus –1.65, SEM = 1 ( p-value = 0.58), skeletal muscle mass -0.17, SEM = 0.49 versus +0.4, SEM = 0.52 ( p-value = 0.42) and percent body fat –1.0, SEM = 0.65 versus -0.1, SEM = 0.68 ( p-value = 0.3) including with basal metabolic rate -5.3, SEM = 18 versus +18.3, SEM = 19 ( p-value = 0.37). The average of weight loss was also not statistically significant different between two groups, -1.04, SEM = 0.63 in curcumin group versus –1.15, SEM = 0.61 in placebo group, ( p-value = 0.9). Notably, patient with curcumin had less reduction of hand-grip muscle strength on both hands [right hand: -2.09 in curcumin versus -3.68 in placebo; p = 0.46], [left hand: -1.24 versus -5.04; p-value = 0.12], and basal metabolic rate than placebo group. Most adverse events were grade 1 on both groups similarly. Conclusions: Curcumin was not shown to be superior to placebo with regard to increasing the body composition in cancer patients with CACS. However, curcumin might show some clinical benefits, including slow progression of hand-grip muscle strength loss and basal metabolic rate. Further investigations should be explored.
Cost of prochlorperazine rose 700% after drug companies colluded, alleges watchdog
Authors: Clare Dyer
Journal: BMJ (2019)

The UK’s competition watchdog has accused four drug companies of unlawfully colluding in an agreement that increased the price of a prescription-only medicine used to treat nausea and dizziness by 700% over four years.

The Competition and Markets Authority (CMA) has provisionally concluded that Alliance, Focus, Lexon, and Medreich agreed not to compete for the supply of prochlorperazine 3 mg buccal or dissolvable tablets to the NHS. The price of a 50 tablet pack rose from £6.49 (€7.36; $8.22) in December 2013 to £51.68 …
THU0152 SARCOPENIA IS ASSOCIATED WITH PERSISTENT DISEASE ACTIVITY DURING FOLLOW-UP OF RHEUMATOID ARTHRITIS
Authors: Dong-Jin Park, Ji-Hyoun Kang, Haimuzi Xu, Kyung-Eun Lee, Shin-Seok Lee
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Objectives</h3> This study investigated the prevalence and impact of sarcopenia on clinical outcomes during follow-up in patients with rheumatoid arthritis (RA). <h3>Methods</h3> We enrolled 294 RA patients from a single tertiary center. Data were collected at the time of enrollment and annually thereafter for 3 consecutive years. Sarcopenia was assessed by bioelectrical impedance analysis and defined as a relative skeletal mass index (RSMI) &lt; 5.14 kg/m<sup>2</sup> in women and &lt; 7.40 kg/m<sup>2</sup> in men. Univariate and multivariate analyses were performed to identify the association between sarcopenia and clinical outcome. <h3>Results</h3> Of the 294 RA patients, 8.2% had sarcopenia at the time of enrollment. Patients with sarcopenia were more likely to be older (<i>P</i>=0.001), male (<i>P</i>=0.001), and smokers (<i>P</i>=0.001), and to have a higher body fat mass (<i>P</i>=0.034) and body fat percentage (<i>P</i>=0.039), and a lower basal metabolic rate (<i>P</i>=0.013), than non-sarcopenic patients. Biologic agents were more commonly prescribed to sarcopenic patients than to non-sarcopenic patients (<i>P</i>=0.048). The sarcopenic patients had higher Physician Global Assessment (PGA) (<i>P</i>=0.015), higher mean and delta tender joints (<i>P</i>=0.007), higher mean and delta swollen joints (<i>P</i>=0.007), and higher mean DAS28-ESR (<i>P</i>=0.014) and DAS28-CRP (<i>P</i>=0.020) scores than the non-sarcopenic patients. In the multivariate analysis, sarcopenia was significantly associated with male gender (OR = 0.112, 95% CI: 0.041–0.304, P &lt;0.001), mean PGA score (OR = 1.680, 95% CI: 1.067–2.646, <i>P</i>=0.025), and mean DAS28-ESR score (OR = 4.477, 95% CI: 1.661–12.067, <i>P</i>=0.003). <h3>Conclusion</h3> Sarcopenia at baseline was an independent predictor of disease activity during follow-up in Korean patients with RA. Our results provide a rationale for lifestyle interventions designed to maintain normal weight in RA patients and thus help control disease activity. <h3>Disclosure of Interests</h3> None declared
The international collaboration of active surveillance trials for low-risk DCIS (LORIS, LORD, COMET, LORETTA).
Authors: Chizuko Kanbayashi, Alastair Mark Thompson, Eun-Sil Shelley Hwang, Ann H. Partridge, Daniel William Rea, Jelle Wesseling, Tadahiko Shien, Tomonori Mizutani, Taro Shibata, Hiroji Iwata
Journal: Journal of Clinical Oncology (2019)

TPS603 Background: Retrospective data suggest breast cancer-specific survival rates with versus without surgery in patients with low-grade ductal carcinoma in situ (DCIS) are similar. Some DCIS patients have a low likelihood of progression to invasive cancer, but predicting who is at risk has not been established. Thus, treatment with a well-balanced risk / benefit ratio has not been achieved. Four active surveillance clinical trials for low risk DCIS have commenced in the United Kingdom (LORIS), Europe (LORD), United States (COMET), and Japan (LORETTA). We aim to examine the effectiveness &amp; safety of active surveillance compared with surgical based treatment approaches for low-risk DCIS patients. Methods: Non surgical approaches are of the two types; active surveillance (AS) alone and AS + endocrine therapy (ET). In the randomized trials LORIS and LORD, the study arms are AS only, but while ET is an option in COMET, ET is mandatory in the single arm trial LORETTA. COMET and LORETTA have broader inclusion criteria as compared to LORIS and LORD. In COMET, comedo necrosis is eligible. In LORETTA, findings other than calcification on mammography (MMG) are also eligible (e.g. low echo area on breast ultrasound). Leaders of the four trials hold regular meetings to foster international DCIS trials collaboration to share information. LORIS Clinical trial information: ISRCTN27544579, LORD Clinical trial information: NCT02492607, COMET Clinical trial information: NCT02926911, LORETTA Clinical trial information: UMIN000028298 [JCOG1505]. Clinical trial information: UMIN000028298, NCT02492607, NCT02926911, ISRCTN27544579. [Table: see text]