tbuckley/cabot-search huggingface dataset:
The role of m6A RNA methylation in human cancer
Authors: Xiao-Yu Chen, Jing Zhang, Jin-Shui Zhu
Journal: Molecular Cancer (2019)

N6-methyladenosine (m6A) is identified as the most common, abundant and conserved internal transcriptional modification, especially within eukaryotic messenger RNAs (mRNAs). M6A modification is installed by the m6A methyltransferases (METTL3/14, WTAP, RBM15/15B and KIAA1429, termed as "writers"), reverted by the demethylases (FTO and ALKBH5, termed as "erasers") and recognized by m6A binding proteins (YTHDF1/2/3, IGF2BP1 and HNRNPA2B1, termed as "readers"). Acumulating evidence shows that, m6A RNA methylation has an outsize effect on RNA production/metabolism and participates in the pathogenesis of multiple diseases including cancers. Until now, the molecular mechanisms underlying m6A RNA methylation in various tumors have not been comprehensively clarified. In this review, we mainly summarize the recent advances in biological function of m6A modifications in human cancer and discuss the potential therapeutic strategies.
Systemic therapy for advanced clear cell renal cell carcinoma (ccRCC) after progression on immune-oncology plus VEGF targeted therapy combinations (IO-VEGF).
Authors: Yasser Ged, Ruby Gupta, Cihan Duzgol, Natalie Shapnik, Almedina Redzematovic, Ritesh Kotecha, Martin Henner Voss, Darren R. Feldman, Oguz Akin, Sujata Patil, Robert J. Motzer, Brian I. Rini, Chung-Han Lee
Journal: Journal of Clinical Oncology (2019)

4576 Background: IO-VEGF combinations are the backbone for current and future therapeutic developments in RCC with several IO-VEGF regimens reporting positive results in phase 3 trials. However, limited data exists on outcomes to subsequent therapy in patients progressing on IO-VEGF regimens. Methods: A retrospective analysis was performed on patients with ccRCC at the Memorial Sloan Kettering Cancer Center and Cleveland Clinic Cancer Institute who initiated systemic therapy post IO-VEGF regimens including combinations with VEGFR tyrosine kinase inhibitors (IO-TKI) and combinations with anti-VEGF monoclonal antibodies (IO-mAB). Patients treated on unreported clinical trials were excluded from the outcomes analysis. The primary objective was to evaluate the overall survival (OS) post IO-VEGF. The secondary objectives included objective response rate (ORR) and progression-free survival (PFS) according to RECIST v1.1. Kaplan-Meier methods and the log-rank test were used to evaluate time from start of systemic therapy post IO-VEGF to the event of interest. Results: Fifty-nine patients were treated after discontinuation of IO-VEGF regimens. Prior IO-VEGF regimens included IO-mAB (n = 35, 59%) and IO-TKI (n = 24, 41%). IMDC scores at the start of next line of therapy were favorable in 20%, intermediate in 60% and poor in 20%. Next line of therapy included VEGFR-TKI monotherapy (n = 45, 76%), VEGFR-TKI based combinations (n = 6, 10%), mTOR inhibitors (n = 3, 5%), and unreported clinical trials (n = 5, 9%). VEGFR-TKI containing regimens (n = 51) included cabozantinib (n = 22), axitinib (n = 17), lenvatinib/everolimus (n = 4), pazopanib (n = 4), and others (n = 4). Median OS was 24.5 months (95% CI 12-NE) with a 12 months OS rate of 63%. The ORR was 27% (14/51) and the median PFS was 6.8 months (95% CI 4.8-11). No difference in post IO-VEGF OS was observed when comparing IO- TKI vs IO-mAB (log rank p = 0.7). Conclusions: Post combination IO-VEGF treatment, most patients received VEGFR-TKIs. In this setting, VEGFR-TKIs continue to show clinical activity similar to historic experiences of patients post VEGF monotherapy.
Empowering lung cancer survivors and family members to “breathe easier”: Adaptation and evaluation of a m-health intervention.
Authors: Karen Kane McDonnell, Otis L Owens, Jenay M Beer, Kasey Smith, Taylor Kennedy, Dane Acena, David Gallerani
Journal: Journal of Clinical Oncology (2019)

e23046 Background: Survivors of lung cancer often experience a myriad of symptoms that have devastating effects on their physical and psychological functioning such as dyspnea, fatigue, and stress. To combat these symptoms, the American College of Chest Physicians has recommended the use of complementary therapies. Mindfulness-based Cancer Recovery (MBCR) can empower survivors, and caregivers who often cope with their own health problems and the stress related to caring for a survivor. Our goal is to deliver a tailored, culturally sensitive, MBCR intervention to survivors and family members via a mHealth app. Methods: This research was comprised of four phases. Phase I was the development and testing of an 8-week in-person intervention called Breathe Easier with survivors and family members (dyads). Phase II adapted Breathe Easier into a mHealth app prototype utilizing user-centered design. Phase III was a focus-group evaluation of the usability and acceptance of the mHealth app prototype by survivors and family members. Phase IV was comprised of additional interviews with an African-American subset of survivors and family members to assess the cultural sensitivity of the mHealth app. Results: Findings from the in-person intervention (n = 62) showed that all agreed the intervention materials were acceptable, different levels of yoga, breathing exercises, and meditations helped them, and involving a family member was important. Preliminary analyses showed survivors had less dyspnea and perceived stress over time (T1 vs T2). Both groups had improved fatigue and sleep scores. Findings from the mHealth app design and acceptance evaluation were organized into two primary categories: usefulness and ease of use. User-friendly design recommendations included aesthetic appeal, navigation layout, and display of content. Furthermore, potential health outcomes, privacy concerns, and comparison to in-person interventions also influenced app usefulness and acceptance. Lastly, findings from our cultural sensitivity assessment demonstrated that the mHealth app was culturally sensitive for African-Americans, but some changes were recommended. Conclusions: MBCR interventions hold great promise for improving the lives of racially diverse survivors of lung cancer and family members. An mHealth app will increase accessibility. However, special consideration of app design is needed to ensure future acceptance and longer-term usage.
Clinical and safety outcomes of TALAPRO-2: A two-part phase III study of talazoparib (TALA) in combination with enzalutamide (ENZA) in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Neeraj Agarwal, Neal D. Shore, Curtis Dunshee, Lawrence Ivan Karsh, Beth Sullivan, Nicola Di Santo, Mohamed Elmeliegy, Xun Lin, Akos Gabor Czibere, Karim Fizazi
Journal: Journal of Clinical Oncology (2019)

5076 Background: TALA is a dual-mechanism PARP inhibitor that inhibits PARP catalytic activity and traps PARP on DNA. ENZA is a novel hormonal therapy approved to treat castration resistant prostate cancer. TALA + ENZA may improve clinical outcomes for men with mCRPC. However, TALA, is a substrate for efflux drug transporters P-gp and BCRP. Prior to the initiation of TALAPRO-2 part 1, the in vivo effect of ENZA on exposure of P-gp and BCRP substrates, such as TALA, had not been evaluated. Methods: TALAPRO-2 part 1 was designed to determine TALA starting dose based on safety and pharmacokinetics (PK) evaluation of TALA + ENZA. Pts were ≥18 yrs of age, had ECOG PS ≤1, with no prior systemic treatment for mCRPC. The starting dose of TALA in the first 13 pts was 1 mg once daily (QD) + ENZA 160 mg QD (1 mg QD cohort). Based on safety review of prespecified target safety events and PK data, TALA dose was reduced to 0.5 mg QD; additional pts were treated with a starting dose of TALA 0.5 mg QD + ENZA 160 mg QD (0.5 mg QD cohort). Results: 19 pts were enrolled in part 1 (1 mg QD cohort, 13; 0.5 mg QD cohort, 6). The median (range) age was 71 yrs (52-82). As of the analysis cutoff date, the median treatment duration was 25 and 11 wks for the 1 mg QD and 0.5 mg QD cohorts, respectively. Treatment-emergent adverse events (TEAEs) occurred in 19 pts. The most common TEAE, anemia, occurred in 76.9% and 33.3% of pts in the 1 mg QD and 0.5 mg QD cohorts, respectively. TEAEs that led to TALA dose reduction occurred in 6 pts (46.2%) and 0 pts in the 1 mg QD and 0.5 mg QD cohorts, respectively. In the 1 mg QD cohort, target safety events were reported for 7 pts (53.8%) vs 0 in the 0.5 mg QD cohort. 92% and 100% of pts had a 50% decline from baseline in PSA in the 1 mg QD and 0.5 mg cohorts, respectively, demonstrating preliminary anti-tumor activity. PK data showed that ENZA increased TALA exposure and that TALA 0.5 mg QD + ENZA maintained similar TALA exposure to that achieved with 1 mg QD monotherapy. Conclusions: TALA 0.5 mg QD + ENZA 160 mg QD had a manageable safety profile in pts with mCRPC and will be the starting dose for the randomized portion of TALAPRO-2. Clinical trial information: NCT03395197.
Quality of life assessment in dose escalating head and neck radiation therapy.
Authors: Riham H. Hany, Ehab Saad, Samy Al sirafy, Yasser A. Kader, Mohamed Abdulla Hassan Aly, Eman Abdelhady
Journal: Journal of Clinical Oncology (2019)

e17511 Background: Both Dose escalation and acceleration can achieve higher tumor control rates with uncertain role of addition of concurrent chemotherapy. We aimed at developing a protocol for patients unable to receive the standard CCRT with little toxicity profile. Toxicity and Quality of life assessment were our primary end points in this pilot phase II trial. It is known from literature that pre-treatment QOL affects survival. Also, changes in QOL after treatment predict survival in cancer patients. Methods: 63 locally advanced HNC patients were randomized to receive (Arm A) 70Gy/35fr/7wks at 2Gy/fx concurrently with weekly Cisplatin 40mg/m 2 or to receive (Arm B) 74Gy/33fx/6.5wks at 2.24Gy/fx with calculation of the Biological equivalent doses. CTCEA v4.3 was used to assess toxicity and Functional Assessment Cancer Therapy-Head &amp; Neck (FACT-H&amp;N) questionnaire (39-item) was used to assess QOL. The Questionnaires were collected and their scorings were calculated to get the FACT-H&amp;N Trial outcome index (TOI), FACT-G and FACT-H&amp;N total score pre-radiotherapy, 3 and 6 months post-radiotherapy for each patient. Results: There were 33 patients in arm A vs. 30 patients in arm B with median follow up 24.2 months. Our results showed statistical significant decrease of chemotherapy related toxicities (nausea, vomiting, neutropenia and anemia), acute (mucositis, oral pain, voice alteration, fatigue and acute dysphagia) and some late toxicities (late xerostomia) in the investigational arm vs. the CCRT arm. Regarding the FACT QOL assessment and scorings of the different parameters, there was no statistical difference between both arms in all FACT-H&amp;N TOI, FACT-G and FACT-H&amp;N total scores at pre-treatment, 3 and 6 months post treatment. Also when analyzing the mean change with time across the two groups pre-radiotherapy, 3 and 6 months post radiotherapy, it was not statistically significant. Our results did not demonstrate any significant differences in 2-year disease local control, PFS and OS between both arms, with comparable patterns of relapse. Conclusions: Slightly dose escalated hypofractionated regimen could be an option in LA-HNC treatment without affecting QOL, which needs confirmation in prospective large multi-centric trials. Clinical trial information: NCT03699969.
Impact of KRAS mutations in clinical features and survival in pancreatic cancer patients: A single institution experience.
Authors: Elizabeth Inga Saavedra, Maria Auxiliadora Gomez, Maria Teresa Cano, Eduardo Perdomo, Marta Toledano, Enrique Aranda
Journal: Journal of Clinical Oncology (2019)

e15779 Background: Pancreatic cancer (PC) is currently one of the most lethal tumors. In recent years, although improvements have been developed in the detection and treatment of this disease, the 5-year survival is less than 10%. KRAS plays a key role in ras/mitogen-activated protein kinase signaling. Somatic mutation in KRAS mutations have been shown to be early events in the carcinogenesis of PC. KRAS mutations as a prognostic factor for PC remains inconclusive. Methods: We performed a retrospective study of our patients (pts) to demonstrate the impact of KRAS mutations in clinical features and survival in real-life clinical practice. This was an observational study of all patients with histological confirmed PC referred to Medical Oncology between April 2017 to December 2018 and followed until February 2019. KRAS mutations were analyzed by sequencing codons 12, 13, and 61 in diagnostic tumor tissues from formalin fixed paraffin embedded tissue using PCR and liquid biopsy test (BEAMing technology). Categorical variables were statistically analyzed with Fisher’s exact test and continuous variables with T-student for differences between both groups. Survival was analyzed by Kaplan–Meier estimation and log-rank testing while Cox regression was used to estimed hazard ratios. Results: Our study cohort was 64 pts. 43% of pts died, the most die at home (25%). Median follow-up was 552 days (18 months). Metastatic pts had an expected overall survival (OS) of 376 days, locally advanced 525 days and localized stage 592 days but not statistically significant difference (p = 0.11). Wild-type pts had an expected OS of 559 days and KRAS mutated 389 days with statistically significant difference. (p = 0.032). Conclusions: KRAS mutations are associated with a poorer survival in patients with pancreatic cancer in all stages. These results suggest that KRAS mutations may be an important biomarker in determining response and prognosis in patients with high risk and in developing specific treatments for these patients in clinical applications.[Table: see text]
A phase I, open label, perioperative study of AG-120 and AG-881 in recurrent IDH1 mutant, low-grade glioma: Results from cohort 1.
Authors: Ingo K. Mellinghoff, Timothy Francis Cloughesy, Patrick Y. Wen, Jennie Webster Taylor, Elizabeth A. Maher, Isabel Arrillaga, Katherine B. Peters, Changho Choi, Benjamin M. Ellingson, Alexander P. Lin, Sunitha B Thakur, Brandon Nicolay, Min Lu, Kha Le, Feng Yin, Feng Tai, Steven Schoenfeld, Lori Steelman, Shuchi Sumant Pandya, Jennifer Leigh Clarke
Journal: Journal of Clinical Oncology (2019)

2003 Background: AG-120 (ivosidenib [IVO]) is a first-in-class oral inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1) evaluated in 66 glioma patients (pts) in an ongoing phase 1 study. AG-881 (vorasidenib [VOR]) is an oral, potent, brain-penetrant inhibitor of mIDH1/2 evaluated in 52 glioma pts in an ongoing phase 1 study. In an orthotopic glioma model, IVO and VOR reduced 2-hydroxyglutarate (2-HG) by 85% and 98%, respectively, despite different brain:plasma ratios (&lt;0.04 vs 1.33). Methods: Primary endpoint: brain tumor 2-HG concentration with IVO or VOR treatment in mIDH1 low-grade glioma. Pts with recurrent non-enhancing WHO-2016 Grade (Gr) 2 or 3 mIDH1-R132H oligodendroglioma or astrocytoma undergoing craniotomy were randomized 2:2:1 to IVO 500mg QD, VOR 50mg QD, or no treatment for 4 wks preoperatively in Cohort 1. Post-operatively, pts continued to receive IVO or VOR and control pts were randomized 1:1 to IVO or VOR. Tumors were assessed for mIDH1 status, cellularity, 2-HG, and drug concentration. Treated samples were compared to control pts and mIDH1 and wild type (WT) banked reference (ref) samples. Plasma and CSF 2-HG were assessed. Pts with non-evaluable tissue were replaced. Results: As of 29 Nov 2018, 26 pts (17M, 9F; 25 Gr 2, 1 Gr 3) were randomized preoperatively (IVO 10, VOR 11, control 5), 25 received drug (IVO 12, VOR 13). At the data cut, 19 tumors were analyzed with 16 evaluable. Common (&gt;10%) TEAEs (all grade 1/2): diarrhea (36%), hypocalcemia and constipation (each 20%), anemia, hyperglycemia, pruritus, headache and nausea (each 16%), and hypokalemia and fatigue (each 12%). Mean brain:plasma ratio: 0.16 for IVO, 2.4 for VOR. Tumor 2-HG results are shown in Table. Updated data from Cohort 1 will be presented. Conclusions: In Cohort 1 of this phase 1 perioperative study, IVO and VOR were CNS penetrant and lowered 2-HG compared to untreated samples. Cohort 2 is open and will evaluate IVO 250mg BID and VOR 10mg QD. Brain tumor 2-HG concentration. Clinical trial information: NCT03343197. [Table: see text]
Closed-loop digital meditation improves sustained attention in young adults
Authors: David A. Ziegler, Alexander J. Simon, Courtney L. Gallen, Sasha Skinner, Jacqueline R. Janowich, Joshua J. Volponi, Camarin E. Rolle, Jyoti Mishra, Jack Kornfield, Joaquin A. Anguera, Adam Gazzaley
Journal: Nature Human Behaviour (2019)
Menopausal Hormone Therapy
Authors: Jan L. Shifren, Carolyn J. Crandall, JoAnn E. Manson
Journal: JAMA (2019)

This JAMA Insights Clinical Update reviews the use of hormonal therapy to manage menopausal vasomotor symptoms and proposes an algorithm for deciding if therapy should be initiated or continued based on a woman’s age, duration since onset of menopause, and risk factors for adverse outcomes.
Incidental atypical hyperplasia/LCIS in mammoplasty specimens and subsequent risk of breast cancer.
Authors: Francisco Acevedo, Victor Diego Armengol, Zhengyi Deng, Rong Tang, Suzanne Coopey, Emanuele Mazzola, Conor Lanahan, Danielle Braun, Adam Yala, Regina Barzilay, Clara Li, Enrico Santus, Amy Colwell, Anthony Guidi, Curt Cetrulo, Judy Ellen Garber, Barbara L. Smith, Tari A. King, Kevin S. Hughes
Journal: Journal of Clinical Oncology (2019)

1561 Background: Proliferative breast lesions with atypia (atypical hyperplasia and lobular carcinoma in-situ (LCIS)) increase the risk of breast cancer (BC). Most cases are diagnosed in the context of an abnormal mammogram. Little is known about BC risk for patients with these lesions who are asymptomatic. Mammoplasty specimens allow us to study breast tissue in asymptomatic healthy women. We previously published the rate of atypia in the largest reported mammoplasty cohort. The aim of this study is to examine the risk of BC in the atypia cohort. Methods: Breast pathology reports were retrospectively reviewed for evidence of atypical ductal hyperplasia (ADH), atypical lobular hyperplasia (ALH) or LCIS in bilateral reduction mammoplasty specimens from five institutions within a single healthcare system between 1990 to 2017. Patients with prior or concurrent BC or prior atypia were excluded. Data was extracted from electronic medical records using natural language processing and manual review to assess subsequent risk of BC. Results: From our mammoplasty cohort of 4771 patients, 295 patients were found to have atypia (6.2%) at baseline. 40 of these patients were lost to follow-up and excluded from the study. For the remaining 255 patients, 13 had severe ADH bordering on ductal carcinoma in situ, 52 had LCIS, 119 had ALH, and 71 had ADH at baseline. The median age at baseline was 52.1 (range 17.9 – 74.3). With a median follow-up of 7.7 years, of the 255 patients 9 patients developed BC (8 invasive carcinomas, 1 ductal carcinoma in situ). 81.3% of the cohort did not receive chemoprevention. Only one patient out of the nine who developed BC received chemoprevention. The risk of developing BC among women with atypia at baseline was 0.5%, 2.9% and 4.1%, at 3, 5 and 10 years respectively. Conclusions: Patients with asymptomatic atypias found in reduction mammoplasty specimens appear to be at lower risk of developing BC than those diagnosed with atypia in the context of an abnormal mammogram. These results may provide guidance on how to manage this group of patients related to future screening and/or chemoprevention.
First-in-human, dose-escalation, phase (ph) I trial to evaluate safety of anti-Axl antibody-drug conjugate (ADC) enapotamab vedotin (EnaV) in solid tumors.
Authors: Malaka Ameratunga, R Donald Harvey, Morten Mau-Sørensen, Fiona Thistlethwaite, Ulf Forssmann, Manish Gupta, Hrefna Johannsdottir, Terrie Ramirez-Andersen, Mika Linette Bohlbro, Nedjad Losic, Annette L. Ervin-Haynes, Juanita Suzanne Lopez, Ignace Vergote
Journal: Journal of Clinical Oncology (2019)

2525 Background: Axl, a transmembrane receptor tyrosine kinase, is aberrantly overexpressed in various human cancers and associated with poor prognosis and treatment resistance. EnaV, a novel ADC of anti-Axl human IgG1 and monomethyl auristatin E, demonstrated potent anti-tumor activity in xenograft models. Methods: In a ph1 trial (NCT02988817), patients (pts) with relapsed/refractory cancer received single agent EnaV, 0.3–2.8 mg/kg once every 3 wks (1Q3W) or 0.45–1.4 mg/kg 3 times over 4 wks (3Q4W). Endpoints included dose-limiting toxicities (DLTs), adverse events (AEs) and pharmacokinetics (PK). DLTs were classed as hematological (e.g. Grade [G] 3/4 febrile neutropenia; G4 neutropenia or anemia) or non-hematological (e.g. severe skin toxicities; G3/4 neuropathy or infusion reactions; ≥G3 treatment-related AEs in first treatment cycle). Upon determining maximum tolerated dose (MTD) per arm and recommended ph2 dose (RP2D), ph2a (dose expansion) will enroll ≤297 pre-treated pts with advanced/metastatic cancer in 7 cohorts. Results: 47 pts with NSCLC (n=8), melanoma (n=9), ovarian (n=22), cervical (n=3) and endometrial (n=5) cancer enrolled in ph1 (1Q3W n=32; 3Q4W n=15). Most pts were female (87%), White (94%) and aged &lt;65 y (66%). MTD was 2.2 mg/kg in 1Q3W arm and 1.0 mg/kg in 3Q4W arm; RP2D was 2.2 mg/kg 1Q3W. EnaV median elimination half-life: 0.9–2.2 d across doses/schedules. In 47 enrolled pts, there were 6 DLTs (Table). Most common AEs (any G; ≥40% pts) were fatigue (64%), nausea (57%), constipation (57%), diarrhea (47%), vomiting (45%) and decreased appetite (43%). 3 pts (1Q3W arm) had partial response (1 NSCLC [2.2 mg/kg dose]; 2 ovarian [1.5 and 2.4 mg/kg dose levels]). Conclusions: The RP2D of single agent EnaV in pre-treated pts with solid tumors was 2.2 mg/kg 1Q3W. EnaV had encouraging preliminary anti-tumor activity and will be evaluated in 7 ph2a expansion cohorts to further assess safety, tolerability, PK, anti-tumor activity and Axl expression. Funding: Genmab A/S. Clinical trial information: NCT02988817. [Table: see text]