tbuckley/cabot-search huggingface dataset:
Risk of secondary hematologic malignancies and tolerability in patients with ovarian cancer treated with PARP inhibitors: A systematic review and meta-analysis of four phase III randomized controlled trials.
Authors: Kyaw Zin Thein, Somedeb Ball, Anita Sultan, Sriman Swarup, Myo Zaw, Thura WIN Htut, Pwint Phyu Hlaing, Yin Mon Myat, Rachana Yendala, Nicholas C. D'Cunha, Donald Quick, Lukman Aderoju Tijani
Journal: Journal of Clinical Oncology (2019)

e23056 Background: Poly adenosine diphosphate ribose polymerase (PARP) inhibitors have shown to improve survival in ovarian cancer (OC) through synthetic lethality with potentiation of double-strand breaks in tumor cells. Yet, there are concerns of secondary hematologic malignancies (SHM) and notable adverse events (AE) leading to treatment discontinuation (TD), interruption (TI), or dose reduction (DR). Methods: MEDLINE, EMBASE databases and meeting abstracts from inception through January 2019 were queried. Phase 3 RCTs utilizing PARP inhibitors maintenance in OC were eligible. Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI). Random effects model was applied. Results: A total of 1792 patients from four phase III RCTs were included. The study arm used olaparib or niraparib or rucaparib while the control arm utilized placebo. Almost all patients in the SOLO-2 &amp; -1 trials had a gBRCA mutation, while there were patients with and without the said mutation in the other two studies. The SHM incidence was 1.25% in PARP inhibitors group vs 0.83% in control group (RR, 1.15; 95% CI: 0.41–3.22, p = 0.79). TI due to AE was 59.71% in study group versus 11.39% in control arm (RR, 4.94; 95% CI: 2.44 – 9.96, P &lt; 0.001). DR was reported in 47.73% in PARP inhibitors arm versus 6.86% in control group (RR, 7.73; 95% CI: 4.17 – 14.31, P &lt; 0.001). TD rate was 10.97% higher in study group compared to control arm (RR, 6.63; 95% CI: 3.55 – 11.31, P &lt; 0.001). Conclusions: The risk of SHM was not significantly increased in PARP inhibitors group. However, patients on PAPR inhibitors arm experienced significant drop outs due to AE, despite showing significant improvement in PFS in studies. Proper supportive care may enhance compliance.
The value of tumor paramaters and dosimetry on prognostic nomograms for cervical cancer.
Authors: Shun Lu
Journal: Journal of Clinical Oncology (2019)

e17026 Background: A range of prognostic factors had been reported to be associated with clinical outcome of cervical cancer patients. However, most of these parameters were measured before the start of treatment but without consideration of tumor response to RT. We believed that it might be possible to provide locally advanced cervical cancer patients an opportunity to modify and guide the treatment strategies in the midway of treatment based on the early response evaluation during RT. To establish effective prognostic nomograms using clinical features including tumor volume and size mesured by MRI before treatment and after the completion of external beam radiotherapy (EBRT), and detailed dosimetry of brachytherapy dose for high-risk clinical target volume (HRCTV) D90 and Low-risk Clinical Target Volume(LR-CTV) D90 . Methods: The nomogram for local control (LC) was based on a retrospective study of 316 patients who underwent IMRT at our hospital from 2010 to 2015. The predictive accuracy and discriminative ability of our nomogram models were determined by concordance index and calibration curve, and were compared with the nomogram models combining clinical features with FIGO stage. The results were validated using bootstrap resampling and a cohort study of 141 patients. The same data cohort was used to predict the progress-free survival (PFS) of cervical cancer with 3:1 training cohort (N = 310) and validation cohort (N = 155). Results: The following factors were assembled into our prognostic survival nomogram models: Age, tumor volume and size (TV &amp; TS) before treatment, TV and TS after the completion of external beam radiotherapy (EBRT), brachytherapy dose of high-risk clinical target volume (HRCTV) D90 and Low-risk Clinical Target Volume(LR-CTV) D90. The calibration curves showed good agreement between nomogram-predicted and actual survival. Our nomogram models for LC and PFS, provided better results than the nomogram models combining clinical features with FIGO stage. Results were further confirmed in the validation set. Conclusions: Clinical features including tumor size and volume mesured before treatment and after EBRT, as well as detailed dosimetry of brachytherapy dose are able to improve the performance of prognostic nomograms for patients with cervical cancer.
A phase I multicenter study to assess the safety, tolerability, and immunogenicity of mRNA-4157 alone in patients with resected solid tumors and in combination with pembrolizumab in patients with unresectable solid tumors.
Authors: Howard A. Burris, Manish R. Patel, Daniel C. Cho, Jeffrey Melson Clarke, Martin Gutierrez, Tal Z. Zaks, Joshua Frederick, Kristen Hopson, Kinjal Mody, Alverina Binanti-Berube, Celine Robert-Tissot, Bree Goldstein, Ben Breton, Jing Sun, Shan Zhong, Scott K. Pruitt, Karen Keating, Robert S. Meehan, Justin F. Gainor
Journal: Journal of Clinical Oncology (2019)

2523 Background: T-cell targeting of mutation-derived epitopes (neoantigens) has been demonstrated to drive anti-tumor responses. Immunizing patients against such neoantigens in combination with a checkpoint inhibitor (CPI) may elicit greater anti-tumor responses than CPI alone. Mutations are rarely shared between patients, thus requiring a personalized approach to vaccine design. Methods: A phase I dose escalation study of mRNA-4157 as adjuvant monotherapy in patients with resected solid tumors (melanoma, bladder carcinoma, HPV negative HNSCC, NSCLC, SCLC, MSI-High, or TMB High cancers) and in combination with pembrolizumab in patients with advanced or metastatic cancer is being conducted to evaluate safety. mRNA-4157 is a lipid encapsulated personalized vaccine encoding multiple neoantigens selected using a proprietary algorithm designed to induce neoantigen specific T cells and associated anti-tumor responses. Patients may receive up to 9 cycles (Q3W) of mRNA-4157 by intramuscular injection (0.04 – 1 mg). In the combination arm, pembrolizumab (200 mg) is administered for two cycles prior to combination with mRNA-4157; patients may continue pembrolizumab after completion of 9 cycles of combination therapy. Primary end points include safety, tolerability, and recommended phase 2 dose. Results: 33 patients received mRNA-4157; 13 as monotherapy and 20 in combination with pembrolizumab. No DLTs were reported, and treatment related AEs have generally been of low grade and reversible, and no drug related SAEs or AEs ≥ grade 3 have been observed. Of the 13 patients on adjuvant monotherapy (3 melanoma, 8 NSCLC, 2 MSI-High), 12 patients remain disease free on study, median follow-up of 8 months. 20 patients have been treated in combination (1 TMB-high, 4 bladder, 2 HNSCC, 1 melanoma, 7 NSCLC, 2 SCLC, 3 MSI-high), 12 had progressed on prior CPI, 16 have been restaged and there are 1 CR (on pembrolizumab prior to vaccination), 2 PR, 5 SD for at least 5 combination cycles, 5 PD, 2 iuPD, and 1 patient is non-evaluable for response but remains on study. Neoantigen specific T cell responses have been detected by IFN-γ ELISpot from PBMCs. Conclusions: mRNA-4157 is safe and well tolerated at all dose levels tested. Clinical responses have been observed in combination with pembrolizumab and neoantigen-specific T cells have been induced, supporting the advancement of mRNA-4157 to phase 2. Clinical trial information: NCT03313778.
Third and successive–lines of chemotherapy in NSCLC patients without therapeutic targets: Experience of the Grupo Gallego de Cáncer de Pulmón.
Authors: Francisco Javier Afonso Afonso, Natalia Fernández Núñez, Rocio Vilchez Simo, Jose-luis Firvida, Noemi De Dios Alvarez, Begoña Campos Balea, Juan Ruiz Bañobre, Maria Carmen Areses Manrique, Sara Agraso Busto, Marta Carmona Campos, Laura María De Paz Árias, Soledad Cameselle Garcia, Diego Pereiro Corbacho, Sergio Vázquez Estévez, Jesús García Mata, Joaquin Casal Rubio, Manuel Constenla
Journal: Journal of Clinical Oncology (2019)

e20579 Background: The current treatment of advanced non-small cell lung cancer (NSCLC) is conditioned by the presence of molecular and immunohistochemical biomarkers. In the absence of these, the therapeutic option is the use of chemotherapy with or without antiangiogenic agents. The efficacy of non-target systemic treatments is not proven, beyond a second-line and the experiences in their use are limited to retrospective analyzes. We present the experience of the Grupo Gallego de Cáncer de Pulmón in patients with advanced NSCLC treated exclusively with three or more lines of chemotherapy. Methods: Retrospective analysis of patients with advanced NSCLC, treated with three or more lines of chemotherapy in standard regimen, with or without antiangiogenic agents, in Galicia´s hospitals, Spain. Results: We included 168 patients (134 male and 34 female) treated with three or more chemotherapy lines, with a median age at the time of receiving the first-line, of 60.84 years (41-83). Of these, 51 (30,35%) received a fourth-line and 18 (10,74%) a fifth-line of treatment. None received antitarget therapy or immunotherapy. The median overall survival (OS) was 18.1 months. The median OS after the third line was 6.1 months, with 73% of patients alive at three months and 44% six months after the start of that therapeutic line. We did not appreciate differences in OS between those who received three lines and those who received the largest number of subsequent treatments. Our multivariate analysis (age, gender, histology, performance status at initiation of each teatment-line, response to previous treatments) identified that the individuals who benefited the most were those under the age of 60 years, PS-ECOG 0-1 at diagnosis and those with a more durable response to the first-line. Conclusions: The third-line of chemotherapy can benefit those patients with advanced NSCLC, under 60 years of age at the time of diagnosis, with good performance status and with long-lasting responses to the first line of treatment. We did not see benefit in adding fourth or fifth-line of chemotherapy. All data will be presented in the 2019 ASCO annual meeting.
Real-world treatment patterns, survival, and cost among elderly patients with small-cell lung cancer (SCLC).
Authors: Changxia Shao, Jinghua He, Sumesh Kachroo, Fan Jin
Journal: Journal of Clinical Oncology (2019)

e20647 Background: Given a dearth of literature, this study aimed to investigate real-world use of systemic therapies, survival, and costs among elderly SCLC patients (pts) in U.S. Methods: Pts (65+ years old) with an initial diagnosis of SCLC during 2007-2013 were identified using the SEER-Medicare data. Overall survival (OS), duration of treatment (DOT) and time to next treatment (TTNT) were estimated based on the Kaplan-Meier method. Costs (2016 US dollars) were derived from Medicare claims. Results: A total of 11 812 pts were identified with 7 797 (66%) being stage IV at diagnosis. During an average of 10 months (m) follow-up post diagnosis, 6 509 (55%), 2 238 (19%) and 679 (6%) received first line (1L), 2L and 3L therapy, respectively. The median OS was 9 m from 1L start and 6 m from 2L or 3L start, suggesting existing treatment providing limited survival benefit. Majority pts (93%) received platinum-based therapy for 1L with Car + etoposide (Eto, 59%) being the most commonly used regimen, followed by Cis + Eto (18%) and Car monotherapy (8%). Car + Eto, Top and Pac were the top 3 regimens used in 2L and 3L. Median DOTs were 4-6 m, yet TTNT ranged from 7 to 18 m across lines of therapy. The average per person per month (PPPM) costs were $9.4k for 1L, $8.9k for 2L, and $8.8k for 3L. Conclusions: Advanced SCLC remains an aggressive malignancy with poor prognosis, lack of ideal therapy and high medical cost, which highlighted high unmet medical need of SCLC among elderly pts. [Table: see text]
Survival estimates for young patients with tongue cancer: An analysis of the SEER database.
Authors: Pooja Khullar, Dinesh Pendharkar, Sumant Gupta, Shivam Vatsal, Neeraj Dhingra
Journal: Journal of Clinical Oncology (2019)

e17549 Background: Carcinoma tongue is a common malignancy with increasing trend. Studies have suggested poor outcomes in young patients. To better understand ,we reviewed survival in young patients of tongue cancer from Surveillance and Epidemiologic and End Results (SEER) analysis. Methods: We identified 261 patients, aged 15 to 29 years, with squamous cell carcinoma tongue reported to SEER program between 2004 to 2015. Cases were categorized by age, sex, laterality, stage. Survival rates were compared using SPSS software. Results: The group had male to female ratio of 1.2:1, with a median age of 26 years. According to ICD-03, 85 patients (32.6%) had keratinizing variant of squamous cell carcinoma. About 40 patients (15.2%) had grade I, 161(61.7%) grade II and 46 (17%) – had grade III tumors. Out of 216 patients laterality was not paired in the majority (214-82%), while 24 (9.2%) had left side and 21 (8%) had right side primaries. According to the AJCC staging classification - 90 patients (34.5%) had stage I, 36 (13.6%)- stage II, 50 (18.9%)- stage III, and 83 (30%) as stage IV disease. Surgical procedures included- excisional biopsy in 13 patients (4.9%), 183 (69.3%) had wide local excision, 37 (14%) underwent radical excision of the tumor. Overall 193 patients were alive (73%), 40 patients (15.2%) died of cancer and 20 (7.6%) died of other causes. Average survival was 41 months (range 0-142 months). The median survival did not differ between male and female (35 vs 45, p = NS). Grade of the tumor had no impact on survival (33, 44 and 32 months-well, moderately and poorly differentiated respectively). Similarly keratinizing tumors had equal to other squamous non classified tumors ( 45 vs 31 months). The staging of the tumor was predictive of the survival(p &lt; 0.01) .Median survival as per the stage was 62, 46, 36 and 20 months for stage I,II,III and IV respectively .There was no statistical difference based on laterality of the tumor( left sided 28 months vs right sided 22 months).As per TNM staging small lesions survived better : 60, 45, 17 and 13 months respectively for T1 ,T2 ,T3 and T4 size (p &lt; 0.006). Nodal status was also strong predictor of the survival p &lt; 0.001) , 49,45,31 and 19 months respectively for N0, N1, N2 and N3 tumors. Metastatic disease also shortened survival significantly (p &lt; 0.001) , 42 month with M0, while 3 months only for M1 disease. Conclusions: In young patients with tongue cancer, stage of the disease, size of the tumor, nodal status has significant impact on survival. Other parameters like sex, histological type, grade of the tumor, laterality has no major impact.
A prospective study tracking longitudinal changes in genome-wide cell-free DNA (cfDNA) methylation to identify early nonresponders to cancer treatment.
Authors: Andrew A. Davis, Wade Thomas Iams, David Chan, Michael S Oh, Robert William Lentz, Rohith Srivas, Nicole Lambert, Alex Robertson, Neil Peterman, Abhik Shah, Timothy Wilson, Jason Close, Peter George, Haleigh Wood, Ayse Tezcan, Ram Yalamanchili, Ken Nesmith, John C Spinosa, Haluk Tezcan, Young Kwang Chae
Journal: Journal of Clinical Oncology (2019)

3042 Background: Methylation is an epigenetic modification linked to cancer pathogenesis. The aim was to determine if changes in cfDNA methylation patterns before and after initiation of treatment could predict non-response to treatment prior to routine imaging and clinical follow-up. Methods: We prospectively collected clinical data and blood from 28 patients with metastatic malignancies (13 lung, 11 breast, 4 other). Blood was drawn prior to start of a new treatment, after first cycle (median 30 days), and/or second cycle (median 57 days). We performed whole-genome (WG) bisulfite sequencing (median depth 18X) on plasma cfDNA to determine methylation levels. By tracking how methylation levels deviate from unaffected individuals, from baseline to subsequent timepoints, we classified patients as either progressors (greater deviance) or non-progressors. Treatment response at first follow-up imaging (FUI) was determined by RECIST 1.1. Study endpoints were agreement with first FUI and progression-free survival (PFS) by cfDNA classification. Results: The cohort consisted of 68% females and the median age was 70. Main treatment regimens were chemo- (N = 12), immuno- (6), endocrine (5), or targeted-therapy (5). PFS was significantly shorter (log-rank p = 8 x 10 -7 ) in patients classified as progressors by cfDNA (N = 8; median: 62 days) compared to non-progressors (N = 20, median: 263 days). For patients classified as progressors, the cfDNA assay preceded imaging and clinical evaluation by a median of 34 days. 7 out of 8 patients classified as cfDNA progressors were later confirmed to progress at first follow-up evaluation (88% positive predictive value). The one patient who was classified as progressor based on cfDNA was stable based on FUI (day 93 of treatment) but was later confirmed as progression on day 128 by FUI. For the remaining patients, 18 of 20 did not progress (90% negative predictive value). Thus, sensitivity for the assay for identifying progression was 78% and specificity was 95%. Conclusions: Our results show that WG cfDNA methylation change is a novel signature with potential to identify patients whose treatment regimen is ineffective prior to imaging.
Clinicopathologic profile and treatment outcomes of non-sensitizing <i>EGFR</i> and <i>HER2 (ERBB2)</i> activating mutations in NSCLC: Results from a single-center retrospective study.
Authors: Tejas Patil, Rao Rashid Mushtaq, Sydney Marsh, Christine Azelby, Miheer Pujara, Dara Aisner, William T. Purcell, Erin Lynn Schenk, Paul A. Bunn, Jose Maria Pacheco, D. Ross Camidge, Robert Charles Doebele
Journal: Journal of Clinical Oncology (2019)

9090 Background: The clinicopathologic characteristics and optimal treatment strategies for non-sensitizing EGFR ( ns- EGFR) and HER2 activating mutations in NSCLC remain unclear. Methods: Single-center retrospective study of patients seen at University of Colorado from 2008 – 2018 with stage IV NSCLC was performed. Clinicopathologic features and treatment outcomes of patients with ns-EGFR (Exon 18, Exon 20, L861Q) and HER2 mutations were collected. Best response to TKI was determined (RECIST v1.1). PFS was calculated using Kaplan-Meier method. Results: Among 359 patients, we identified 49 ns-EGFR (36 Exon 20, 10 Exon 18, 3 L861Q) and 28 HER2 mutations (27 Exon 20, 1 gene amplification) detected via NGS (65/77), real-time PCR (9/77), FISH (1/77) and undocumented (2/77). PDL1 &gt; 50% was seen in 44% ns- EGFR and 57% HER2. Adenocarcinoma was the most common histology (97%). Most patients were female (62%), never smokers (63%), and presented with metastatic disease (stage: I 5%, II 4%, III 6%, IV 85%). HER2+ NSCLC demonstrated a tropism for lung metastases (64%) that was significant when compared to EGFR Exon 19, EGFR L858R, ALK, ROS1, and KRAS cohorts (p &lt; 0.001). No differences were found when other metastatic sites were compared. Among evaluable patients, response rates to TKI therapy is shown. Aggregate median PFS on TKI for ns-EGFR and HER2+ NSCLC was 6 months compared to EGFR Exon 19 (15 months; p &lt; 0.01; HR 0.4; CI 0.24 – 0.67) and EGFR L858R (22 months; p &lt; 0.01; HR 0.27 and 0.8; CI 0.14 – 0.54). Aggregate median OS for ns-EGFR and HER2+ NSCLC was 28 months with no differences when compared to EGFR Exon 19 and L858R subgroups. Conclusions: HER2+ NSCLC appears to have a predisposition for lung metastases. Higher DCR was observed with newer generation TKIs, but novel targeted therapeutic approaches are needed as overall outcomes remain poor. [Table: see text]
The landscape of POLE/POLD1 mutations in Chinese solid tumor patients.
Authors: Linrong Pang, Tao Xu, Hua Tao, Gang Chen, Bin Ni, Daobing Zeng, Aodi Wang, Weiwei Shi, Kai Wang, Ming Yao
Journal: Journal of Clinical Oncology (2019)

e13050 Background: DNA polymerase epsilon and polymerase delta encoded by the POLE and POLD1 gene are the major components participating in DNA replication, which both carry a proofreading (exonuclease) domain allowing error correction during replication. In case of POLE/POLD1 mutation, a deficient DNA repair activity results in a hypermutated phenotype of cancer, which would be a promising biomarker for immune checkpoint inhibitors (ICPIs). However, the prevalence of POLE and POLD1 in Chinese patients (pts) with solid tumors remained unknown. Methods: Targeted panel sequencing of 450 cancer genes were performed on FFPE tissues and matched blood samples obtained from 6313 Chinese pts with 23 different types of solid tumors. In our cohort, 41% were female pts with a median age of 56-year-old (range: 1-91), while 59% were male with a median age of 59-year-old (range: 1-96). The major cancer types were NSCLC (29%), HCC (11%), CRC (11%), gastric cancer (GC, 7%), soft tissure sarcoma (6%), pancreatic cancer (5%), intrahepatic cholangiocarcinoma (5%), and others. Somatic genomic alterations (sGAs) including single base substitutions, short and long insertions/deletions (indels), copy number alterations (CNA), rearrangements, TMB and MSI status were assessed by NGS. Results: Clinical relevant genomic alterations (CRGAs) were defined as known loss-of-function mutations, truncations, mutations on splicing sites and confirmed somatic mutations in COSMIC. CRGAs of POLE and POLD1 accounted for 2.1% and 1.3% of Chinese solid tumors respectively. Tumors with highest frequency of POLE CRGAs in Chinese cohort were endometrial cancer (8.3%), urothelial cancer (4.8%), CRC (4.3%), GC (3.2%), breast cancer (2.9%), cancer of unknown primary (CUP, 2.5%), ovarian cancer (2.1%) and NSCLC (2.0%), which tumors with highest frequency of POLD1 CRGAs were endometrial cancer (8.3%), urothelial cancer (4.8%), GC (3.0%), CRC (2.8%), SCLC (2.1%), HCC (1.9%), cervical cancer (1.6%), CUP (1.2%) and pancreatic cancer (1.2%). In addition, 1.6% and 1.2% of Chinese solid tumors harbored variants of unknown significance of POLE and POLD1, respectively. Conclusions: For the first time, our study reported prevalence of somatic mutations of POLE and POLD1 in large samples of Chinese population. Comparing with large cohort study of western population (ESMO 2017, 1170P), more CRGAs of POLE were identified in Chinese solid tumors (2.1% vs. 0.6%, p &lt; 0.0001) indicating ethnic differences of ICPIs potential candidates between Chinese and western populations.
Abstract 16360: The Impact of a Transition of Care Program on Acute Myocardial Infarction Readmissions
Authors: Jeffrey Marbach, Scott Keith, Drew Johnson, Juergen Kloo, Amit Vira, David Whellan
Journal: Circulation (2017)

Introduction: Transitioning patient care from the inpatient to outpatient setting is a high risk time period that is often associated with miscommunication and adverse events. In order to reduce re...