tbuckley/cabot-search huggingface dataset:
MUC16 germline mutations may predispose inherited cancer family members to lung adenocarcinomas.
Authors: Tao Wang, Hong Liu, Shanshan Xiao, Ruifang Mao, Rui Lin
Journal: Journal of Clinical Oncology (2019)

e13039 Background: Familial lung cancer is rare. Previous studies have identified random EGFR mutations associated with the inherited lung cancer. Reports also show that TP53 and CDKN2A mutations may predispose individuals to lung cancer, and MUC16 plays important roles in tumorigenesis and metastasis of lung cancer cells through regulating TP53. However, the molecular findings of familial lung cancer are still few. Methods: We have identified an extremely rare family, four siblings diagnosed with lung adenocarcinomas and one with bladder cancer; all lung cancer patients had multiple synchronous nodules. Their father was also lung cancer patient and deceased. We extracted tumor tissue DNA, genomic DNA (gDNA) and circulating cell-free DNA (ctDNA) from the 5 patients and analyzed the DNA samples using a 500-gene next generation sequencing (NGS) panel. Results: TP53 P72R and other 3 CDKN2B-AS1 germline mutations were identified in all the 5 patients. Although the 3 CDKN2B-AS1 mutations are commonly occurred in population according to dbSNP, these observations are consistent with a hypothesis that TP53 P72R and the CDKN2B-AS1 germline mutants may synergize in predisposing the family members to cancer. Interestingly, 3 MUC16 mutations ((rs754254000, rs754856910, and rs746152510) were all identified in the four lung cancer patients, but none were identified in the bladder cancer patient. All of the 3 MUC16 mutants had very low population allele frequency (all below 0.1%,) suggesting that the MUC16 germline mutations may play roles in the familial lung cancer, which is consistent with previous reports demonstrating the involvement of MUC16 in lung cancer cell growth. Moreover, all the four lung cancer patients had somatic mutations of EGFR L858R/exon 19 deletion prior to treatment with EGFR tyrosine kinase inhibitor (TKI), including one patient with L858R and exon 19 deletion in different tumor nodules, which is consistent with molecular characteristics in synchronous primary lung cancer. Conclusions: We have demonstrated in this study that germline MUC16 mutations may predispose the inherited cancer family members to lung adenocarcinomas. This study provides a clue of the cause of familial lung cancer and also warrants further mechanistic study of MUC16 gene in lung cancer.
Different classes of anti-modified protein antibodies are induced on exposure to antigens expressing only one type of modification
Authors: Arieke Suzanna Berendina Kampstra, Jacqueline Stephanie Dekkers, Mikhail Volkov, Annemarie L Dorjée, Lise Hafkenscheid, Ayla C Kempers, Myrthe van Delft, Theresa Kissel, Sanne Reijm, George M C Janssen, Peter A van Veelen, Holger Bang, Tom W J Huizinga, Leendert A Trouw, Diane van der Woude, René E M Toes
Journal: Annals of the Rheumatic Diseases (2019)

Autoantibodies against post-translationally modified proteins (anti-modified protein antibodies or AMPAs) are a hallmark of rheumatoid arthritis (RA). A variety of classes of AMPAs against different modifications on proteins, such as citrullination, carbamylation and acetylation, have now been described in RA. At present, there is no conceptual framework explaining the concurrent presence or mutual relationship of different AMPA responses in RA. Here, we aimed to gain understanding of the co-occurrence of AMPA by postulating that the AMPA response shares a common 'background' that can evolve into different classes of AMPAs.Mice were immunised with modified antigens and analysed for AMPA responses. In addition, reactivity of AMPA purified from patients with RA towards differently modified antigens was determined.Immunisation with carbamylated proteins induced AMPAs recognising carbamylated proteins and also acetylated proteins. Similarly, acetylated proteins generated (autoreactive) AMPAs against other modifications as well. Analysis of anti-citrullinated protein antibodies from patients with RA revealed that these also display reactivity to acetylated and carbamylated antigens. Similarly, anti-carbamylated protein antibodies showed cross-reactivity against all three post-translational modifications.Different AMPA responses can emerge from exposure to only a single type of modified protein. These findings indicate that different AMPA responses can originate from a common B-cell response that diversifies into multiple distinct AMPA responses and explain the presence of multiple AMPAs in RA, one of the hallmarks of the disease.
Efficacy of apalutamide (APA) plus ongoing androgen deprivation therapy (ADT) in patients (pts) with nonmetastatic castration-resistant prostate cancer (nmCRPC) and baseline (BL) comorbidities (CM).
Authors: Eric Jay Small, Fred Saad, Simon Chowdhury, Stephane Oudard, Boris A. Hadaschik, Julie Nicole Graff, David Olmos, Paul N. Mainwaring, Ji Youl Lee, Hiroji Uemura, Angela Lopez-Gitlitz, Anil Londhe, Amitabha Bhaumik, Shinta Cheng, Oliver Brendan Rooney, Matthew Raymond Smith
Journal: Journal of Clinical Oncology (2019)

5023 Background: The addition of APA to ongoing ADT in pts with nmCRPC significantly prolonged metastasis-free survival (MFS), time to symptomatic progression (SymProg), and second progression-free survival (PFS2) in SPARTAN. We assessed the impact of APA on these end points in pts with or without BL CM. Methods: Using Cox proportional hazards models, treatment effect of APA was evaluated in SPARTAN pts with CM at BL, stratifying by the presence of BL diabetes/hyperglycemia (D/H), cardiovascular disease (CVD), hypertension (HTN), and renal insufficiency (RI). Results: Of 1207 SPARTAN pts, 1062 (88%) had ≥ 1 BL CM, including 703/806 (87%) APA pts and 359/401 (90%) PBO pts. A total of 226 (19%), 398 (33%), 798 (66%), and 774 (64%) pts had D/H, CVD, HTN, and RI, respectively; 323 (27%), 412 (34%), 259 (21%), and 68 (6%) pts had 1, 2, 3, and 4 CM, respectively. Incidence of CM was balanced between arms. Pts with CM were older than pts with no CM (median age, 75 vs 69 yrs, APA; 74 vs 69 yrs, PBO). MFS, SymProg, and PFS2 benefit with APA was significant in all CM subgroups, except PFS2 for pts with D/H (Table) and regardless of the number of CM. The incidence of any treatment-emergent AE was balanced between pts with and without CM. AEs with APA were not affected by any CM. Clinical trial information: NCT01946204. Conclusions: The benefit of APA + ongoing ADT in pts with nmCRPC was maintained in pts with D/H, CVD, HTN, and RI. The safety profile of APA was not affected by any CM.[Table: see text]
Germline mutation PTCH2 1172-1173delCT in Chinese population with early-onset breast cancer.
Authors: Lixi Li, Chunxiao Li, Fei Ma, Haili Qian, Xiuwen Guan, Zongbi Yi, Binliang Liu, Jingtong Zhai, Yanchen Li, Ying Suo, Hongnan Mo, Binghe Xu
Journal: Journal of Clinical Oncology (2019)

e13049 Background: Early-onset breast cancer has more aggressive clinicopathological characteristics and worse prognosis. The peak age of breast cancer in China is about 40 years old, 10 years ahead of that in Europe and the United States. PTCH2 was characterized as susceptibility gene in early-onset breast cancer by whole exons sequencing in preliminary work. PTCH2 performs as a tumor suppressor in the Hedgehog signaling pathway, but it has never been reported in breast cancer. Methods: 259 women with early-onset breast cancer and 571 women with non-early-onset breast cancer with peripheral blood samples were included for genetic testing. According to the ACMG guidlines, PTCH2 1172-1173delCT was defined as likely pathogenic mutation. To make an in-depth exploration of the function and molecular mechanism of PTCH2 gene, we performed experiments at molcular, cellular and animal level. Results: The frequency 2.3%(6/259)of PTCH2 germline mutation in early-onset breast cancer was significantly higher than that(2/571) in non-early-onset breast cancer( P ＜ 0.05), and increased with the age at diagnosis younger. Bioinformatics analysis showed that the patients with lower expression of PTCH2 had worse prognosis. PTCH2 knockout cells lines promoted the cell proliferation and enhanced the ability of colony formation and tumorigenic ability of nude mice. Furthermore, the expression level of pten in the PTCH2 knockout cell lines was significantly downregulated. Conclusions: Patients with PTCH2 1172-1173delCT mutation had aggressive clinicopathological characteristics and worse prognosis. As a tumor suppressor gene, PTCH2 may promote the incidence of early-onset breast cancer by downregulating the expression of pten and cross-regulating Hedgehog and PI3K/AKT signaling pathways. PTCH2 could be acted as a diagnostic and prognostic biomarker for early-onset breast cancer.
Lenvatinib (len) plus pembrolizumab (pembro) in patients (pts) with advanced melanoma previously exposed to anti–PD-1/PD-L1 agents: Phase 2 LEAP-004 study.
Authors: ANA Maria Arance Fernandez, Paolo Antonio Ascierto, Matteo S. Carlino, Adil Daud, Alexander M. Eggermont, Axel Hauschild, Harriet M. Kluger, Matthew H. Taylor, Alan Smith, Ke Chen, Clemens Krepler, Scott J. Diede, Steven O'Day
Journal: Journal of Clinical Oncology (2019)

TPS9594 Background: Pembro, a PD-1 inhibitor, has shown effective antitumor activity, deep and durable responses, and survival benefit in treatment-naive pts and those with previously treated metastatic melanoma. Len, a potent inhibitor of VEGF receptors 1-3, FGF receptors 1-4, PDGF receptor α, RET, and KIT, combined with a PD-1 inhibitor showed antitumor activity superior to either agent alone in preclinical models of colorectal and lung cancer. Additionally, len plus pembro showed anti-tumor activity and was well-tolerated (24-wk ORR, 47.6%; TRAE: gr 3/4, 67%; gr 5, 0%) in pts with advanced melanoma previously treated with 0-2 therapies in the phase 1b/2 KEYNOTE-146 trial. The efficacy and safety of len plus pembro combination therapy will be evaluated in an open-label, phase 2 trial of pts with advanced melanoma that progressed on PD-1/PD-L1 inhibitor therapy (NCT03776136). Methods: Key inclusion criteria: age ≥18 years, histologically/cytologically confirmed unresectable stage III-IV melanoma that progressed (per iRECIST) within 12 weeks of last dose of an approved PD-1/PD-L1 inhibitor therapy (≥2 doses as monotherapy or combined with other therapies), measurable disease, ECOG PS 0/1, no active autoimmune disease, and adequate organ function. Pts must provide a baseline tumor sample. Pts will receive len 20 mg/day orally plus pembro 200 mg IV Q3W for approximately 2 years (35 doses of pembro), after which they may receive len alone until PD or unacceptable toxicity. Response will be assessed per RECIST v1.1 based on blinded independent central review (BICR) Q9W until week 54, Q12W until week 102, and Q24W thereafter. Pts with CR may discontinue treatment after ≥24 weeks of therapy; eligible pts may continue treatment beyond initial RECIST- or iRECIST-defined PD. AEs will be assessed throughout treatment and for 90 days (120 days for serious AEs) after last dose and graded per NCI CTCAE v4.0. Pts will be followed-up for survival status Q12W. The primary efficacy end point is ORR per modified RECIST v1.1 (BICR). Key secondary end points are PFS and DOR per modified RECIST v1.1 (BICR), OS, and safety; an exploratory biomarker analysis is planned. Clinical trial information: NCT03776136.
Real-world clinical and economic outcomes among newly-diagnosed merkel cell carcinoma (MCC) patients initiating first-line (1L) checkpoint inhibitors (CPIs) or chemotherapy (CT) in the veterans health administration (VHA).
Authors: Hemant Phatak, Shivani Pandya, Ting Yu, Mairead Kearney, Li Wang, Ruth Kim, Ying Zheng
Journal: Journal of Clinical Oncology (2019)

e21002 Background: The use of CPIs among patients (pts) with metastatic MCC, a rare and aggressive skin cancer, has increased since the US FDA approval of avelumab and the National Cancer Comprehensive Network (NCCN) recommendation of CPIs in 2017. Given the growing interest in understanding real-world clinical and economic outcomes associated with CPI use, this study assessed time to treatment failure (TTF), overall survival (OS), healthcare resource utilization (HRU), and costs among MCC pts receiving NCCN-recommended 1L regimens including CPIs and CT in the VHA. Methods: This is a retrospective analysis of pts with newly-diagnosed MCC who initiated 1L treatment between October 2013 and January 2018 (index date = 1L therapy start date) and had continuous enrollment from ≥6 months pre-initial MCC diagnosis date until ≥2 months post-index date (follow-up). The index date to earliest of death or subsequent line of therapy start was used as a proxy for TTF. TTF and OS were estimated using Kaplan Meier method. All-cause HRU and costs (2018 USD) per patient per month (PPPM) were evaluated during TTF or until end of follow-up, whichever occurred first. Results: Of 120 MCC pts (72% pre-2017) initiating 1L therapy, 62% received NCCN-recommended regimens, including 17% and 45% treated with CPIs and CTs. Pts receiving CPIs were on average older with higher baseline comorbidity burden. The clinical and economic outcomes of these two pt groups are summarized in the table below. Conclusions: The current descriptive non-comparative analyses provide new information on the trends in clinical and economic outcomes of MCC pts treated in the VHA. Despite higher costs, the utilization of newly-approved CPIs in 1L setting showed delayed treatment failure and reduced all-cause HRU vs. CTs. These findings require further validation in studies with larger patient cohorts and longer follow-up. [Table: see text]
Nemesis: Non-inferiority meta-analysis of selective internal radiation therapy with yttrium-90 resin microspheres versus sorafenib in advanced hepatocellular carcinoma: A preliminary analysis.
Authors: Marino Venerito, Maciej Pech, Ali Canbay, Rossella Donghia, Vito Guerra, Gilles Chatellier, Helena Pereira, Mihir Gandhi, Pierce K. H. Chow, Valérie Vilgrain, Jens Ricke, Gioacchino Leandro
Journal: Journal of Clinical Oncology (2019)

e15604 Background: No survival benefit has been observed for selective internal radiation therapy (SIRT) with yttrium-90 resin microspheres versus (vs.) sorafenib in patients with advanced hepatocellular carcinoma (HCC). In NEMESIS, we assessed by an individual patient data meta-analysis whether SIRT, either as monotherapy or followed by sorafenib, is non-inferior to sorafenib and compared safety profiles. Here we present preliminary data. Methods: A systematic search of MEDLINE, EMBASE, and the Cochrane Library, up to 6 December 2018, found three randomized trials comparing SIRT as monotherapy, or followed by sorafenib, to sorafenib monotherapy among patients with advanced HCC. The main outcomes were overall survival (OS) and frequency of adverse events (AEs). Survival data were pooled (fixed effect analysis). The primary population for non-inferiority analysis was the per-protocol (PP) population. The non-inferiority margin for the hazard ratio (HR) upper boundary was set at 1.08 as specified in EASL guidelines. Results: The three included trials compared sorafenib to SIRT (SIRveNIB and SARAH) or to SIRT followed by sorafenib (SORAMIC) in 1243 patients. After randomization, 23.3% vs. 7.1% of patients (p &lt; 0.0001) did not receive the allocated intervention, and 542/608 (89.1%) vs. 418/635 (65.8%), (odds ratio [OR] 4.3, 95% CI: 3.2-5.8, p &lt; 0.0001) completed the study without major protocol deviations (PP population), in the SIRT and sorafenib arms, respectively. Baseline characteristics of the PP population did not differ between the two comparison groups. Median OS with SIRT followed or not by sorafenib was non-inferior to sorafenib (HR 0.90, 95% CI 0.78–1.02). Treatment-related AEs grades ≥3 were reported in 109/356 (30.6%) patients who received SIRT and 197/378 (52.1%) patients in the sorafenib arm (SIRveNIB and SARAH only, p = 0.0002). Conclusions: SIRT as initial therapy for advanced HCC is non-inferior to sorafenib in OS, and offers a better safety profile.
Efficacy and safety of selinexor in recurrent glioblastoma.
Authors: Andrew B. Lassman, Patrick Y. Wen, Martin J. Van Den Bent, Scott Randall Plotkin, Anna Maria Elisabeth Walenkamp, Xiu Huang, Karla Rodriguez-Lopez, Michael G. Kauffman, Sharon Shacham, Morten Mau-Sørensen
Journal: Journal of Clinical Oncology (2019)

2005 Background: New treatment modalities are needed for recurrent glioblastoma (rGBM). Selinexor (SEL) is a novel, oral selective inhibitor of nuclear export which forces nuclear retention of tumor suppressor proteins including p53 and p27, leading to apoptosis. We previously reported interim results showing tolerability, preliminary efficacy, and blood-brain barrier penetration in a surgical cohort (N = 8). We now report updated results following completion of accrual to non-surgical cohorts (N = 68). Methods: This is an open-label, multicenter, phase 2 study of SEL monotherapy. Patients (pts) not undergoing surgery for measurable rGBM (per RANO) were enrolled in one of 3 arms encompassing different dosing schedules. Treatment was continuous, although cycles were defined as 28 days and response was assessed every other cycle by MRI. Prior treatment with radiotherapy and temozolomide was required and prior bevacizumab was exclusionary. The primary endpoint was 6-month progression free survival (6mPFS) rate, calculated by the Kaplan Meier method. Results: A total of 76 pts were enrolled. Median age was 56 years (range 21-78). Median number of prior treatments was 2 (range 1-7). At the end of the 6 cycles, 30.2% patients on 80 mg QW were free from progression. The 6mPFS rate on 80 mg QW was 15.1%. Best RANO-defined responses (assessed locally) among 26 evaluable pts on 80 mg QW included 1 complete response, 2 partial responses, 7 stable disease, and 16 with progressive disease. Median duration of response was 10.8 months. The most common related adverse events in pts on ~85 mg BIW/60 mg BIW/80 mg QW were nausea (42%/64%/60%), leukopenia (38%/7%/43%), fatigue (71%/71%/43%), neutropenia (29%/14%/33%), decreased appetite (46%/71%/27%), and thrombocytopenia (67%/29%/23%). Conclusions: SEL demonstrated efficacy, with durable responses and disease stabilization in rGBM. Based on the favorable efficacy and safety profile, SEL at a dose of 80 mg QW is recommended for further development in rGBM. Clinical trial information: NCT01986348. [Table: see text]
Innovative Practice, Clinical Research, and the Ethical Advancement of Medicine
Authors: Jake Earl
Journal: The American Journal of Bioethics (2019)

Innovative practice occurs when a clinician provides something new, untested, or nonstandard to a patient in the course of clinical care, rather than as part of a research study. Commentators have noted that patients engaged in innovative practice are at significant risk of suffering harm, exploitation, or autonomy violations. By creating a pathway for harmful or nonbeneficial interventions to spread within medical practice without being subjected to rigorous scientific evaluation, innovative practice poses similar risks to the wider community of patients and society as a whole. Given these concerns, how should we control and oversee innovative practice, and in particular, how should we coordinate innovative practice and clinical research? In this article, I argue that an ethical approach overseeing innovative practice must encourage the early transition to rigorous clinical research without delaying or deferring the development of beneficial innovations or violating the autonomy rights of clinicians and their patients.
A phase ib trial to evaluate the safety and efficacy of quinacrine plus capecitabine in patients with refractory metastatic colorectal cancer.
Authors: Arthur Winer, Namrata Vijayvergia, Steven J. Cohen, Crystal S. Denlinger, Igor A. Astsaturov, Efrat Dotan, Jean-Nicolas Gallant, Edward W Wang, Miriam Kunkel, Bora Lim, Harold A. Harvey, Jeffrey Michael Sivik, Lanlan Zhou, Kenneth Korzekwa, Karen Ruth, Eric A. Ross, Wafik S. El-Deiry
Journal: Journal of Clinical Oncology (2019)

e15020 Background: Acridines emerged from a cell-based screen for p53-pathway restoring compounds. Quinacrine, an acridine demonstrating p53 pathway restoration properties, displayed preclinical anti-tumor effects when used as monotherapy in colorectal cancer (CRC) cell culture and in vivo xenografts. Quinacrine suppresses survival pathways by inhibiting Mcl-1 expression, NFkB, STAT3, and angiogenesis. The combination of quinacrine plus 5-FU showed in-vivo preclinical efficacy against CRC with mutant KRAS, BRAF, or p53. Capecitabine, an oral 5-FU prodrug, is FDA-approved to treat metastatic (m)CRC. This phase I trial evaluated the safety and efficacy of quinacrine plus capecitabine in patients with refractory mCRC. Methods: Patients ≥18 years old with histologically confirmed mCRC refractory to standard therapy or with no standard therapy options available were eligible for the study. Using a modified 4B Simon’s accelerated titration design, patients were treated with a fixed dose of capecitabine 1000 mg/m 2 twice daily (bid) for 14 days of a 21-day cycle, and escalating doses of quinacrine 100 mg daily, 100 mg bid, and 200 mg bid for 21 days. The primary endpoint was to identify the maximum tolerated dose (MTD) of quinacrine in combination with capecitabine and to determine their tolerability and safety. Results: Ten patients were enrolled, median age 60-years old (range: 56-79). Quinacrine 100 mg daily and 100 mg bid were well tolerated by the first two patients. Dose Limiting Toxicities (DLTs) were seen in 3 patients treated with quinacrine 200 mg bid and included hyperbilirubinemia, transaminitis, increased alkaline phosphatase, hypokalemia, diarrhea, vomiting, and dehydration. No grade 4 or 5 toxicities were seen. 5 additional patients tolerated treatment with quinacrine 100 mg bid and capecitabine without further DLTs making this the MTD. The median time on treatment was 63 days. Three patients came off study prior to their first response evaluation. In 7 patients evaluable for response, 4 had stable disease (57%), while 3 (43%) had disease progression. Median overall survival was 196.5 days. Conclusions: Capecitabine and quinacrine can be safely administered at the MTD of capecitabine 1000 mg/m 2 PO bid D1-14 and quinacrine 100 mg PO bid D1-21 of a 21-day cycle for patients with mCRC. A phase II study is ongoing. Clinical trial information: NCT01844076.