tbuckley/cabot-search huggingface dataset:
Analysis of the EF-14 phase III trial reveals that tumor treating fields alter progression patterns in glioblastoma.
Authors: Suriya A. Jeyapalan, Steven A Toms, Andreas Felix Hottinger, Lawrence Kleinberg, Erqi Pollom, Scott G. Soltys, Martin Glas
Journal: Journal of Clinical Oncology (2019)

2055 Background: The EF-14 [NCT00916409] trial showed that addition of alternating electric fields (Tumor Treating Fields, TTFields) to Temozolomide (TMZ) resulted in improved survival in newly diagnosed Glioblastoma (GBM) patients with supratentorial tumors treated compared to TMZ alone. TTFields delivery is planned to optimize dose at the tumor bed, leading to the hypothesis that TTFields treated patients are more likely to exhibit distal progressions, including progression to the infratentorial brain where TTFields dose is minimal when targeting the supratentorium. Here we present analysis of the EF-14 trial testing this hypothesis. Methods: Patients on treatment for more than two months who had an MRI that exhibited progression were included in the study (treatment: N=280/466, control: N=122/229). Regions of enhancing tumor, necrosis and resection were contoured on T1 contrast MRIs acquired at baseline and at the date of first progression. New lesions at progression were classified as distal if they appeared outside of a Proximal Boundary Zone (PBZ) of 20 mm surrounding the lesions identified in the baseline MRI. The rate of occurrence of distal progressions in the TTFields-treated arm was compared to the rate observed in the control arm. Patients with (distal) infratentorial progression were identified. Results: Distal progressions were more common in the treatment arm (49/280 (18%) vs. 10/122 (8%) P&lt;0.02; chi-squared). Infratentorial progression were observed in 4% (10 patients) of the treatment arm vs. 0 patients in the control (P&lt;0.002 t-test). Distal lesions at progression were more distant from the original lesion in the TTFields treated arm (58.57 + 28.12 mm vs 46.61 + 20.48 mm, P&lt;0.02; Wilcoxon rank sum test. The relative tumor growth rates in TTFields treated patients were significantly slower than those observed in the control arm (0.036+ 0.126 ml/day vs. 0.036+ 0.183 ml/day P&lt;0.03; t-test). Conclusions: This analysis indicates that adding TTFields to TMZ could impact GBM growth patterns. The results suggest that TTFields increases local control of tumor growth, emphasizing the need for adaptive treatment after progression to control progressing disease. Clinical trial information: NCT00916409.
A multicenter prospective observational study of nutritional status on survival in locally advanced nasopharynx cancer treated by induction chemotherapy and chemoradiotherapy.
Authors: Jingjing Miao, Lin Wang, Chaosu Hu, Shaojun Lin, Sze Huey Tan, Enya Ong, Xiaozhong Chen, Yuan yuan Chen, Yahua Zhong, Feng Jin, Qin Lin, Shaomin Lin, Xuefeng Hu, Ning Zhang, Rensheng Wang, Cong Wang, Hanping Shi, Melvin Lee Kiang Chua, Conghua Xie, Chong Zhao
Journal: Journal of Clinical Oncology (2019)

6036 Background: We conducted a multicenter prospective study (NCT02575547) to investigate the association between longitudinal nutritional status and survival in locally advanced nasopharynx cancer (LA-NPC) treated with induction chemotherapy and concurrent chemoradiotherapy (IC-CCRT). Methods: All patients with biopsy-proven LA-NPC and planned for IC-CCRT were recruited from ten institutions. IC entailed 2 cycles of docetaxel 75mg/m 2 /3w and cisplatin 75mg/m 2 /3w; CCRT entailed 2-3 cycles cisplatin 100mg/m 2 /3w and IMRT (70-72Gy/30-32fr). Study parameters included weight loss (WL), % of ideal body weight (%IBW), body mass index (BMI), nutrition risk screening 2002 (NRS2002), patient-generated subjective global assessment (PG-SGA), and EORTC QLQ-C30 that were collected at the following time-points: baseline (T1), 1 w pre-2 nd IC (T2), 1 w pre-CCRT (T3), 4 w mid-CCRT (T4), end-CCRT (T5), 3 mo post-CCRT (T6), 1 y post-CCRT (T7), 2 y post-CCRT (T8). Results: 186 patients were recruited; 171 were eligible for analysis. Median follow-up was 35.8 mo (range 12.3-46.1 mo). Compliance rates were 97.7% (167/171) and 87.7% (150/171) for IC and CCRT, respectively; all except one completed RT. Longitudinal assessment indicated the worst nutritional status at T5, followed by recovery at T8: 27.1% with %IBW &lt;90%; 69.2% with WL ≥5%, which was also associated with a worsened QOL (OR = 6.23 for QOL change ≥25.0, P = 0.012). Interestingly, T1 nutritional status was not associated with prognosis (P &gt;0.05 for all). However, nutritional parameters at T5 were significantly associated with survival; %IBW &lt;90% was the strongest predictor for inferior DMFS (HR = 2.669) and OS (HR = 4.661) among all parameters (multivariable-adjusted P &lt;0.05). Subgroup analyses revealed that %IBW &lt;90%, WL ≥10% at T5 represented the most adverse subset of patients (Table). Conclusions: Here, we show that poor nutrition despite systemic intensification leads to inferior QOL and disease control in LA-NPC patients. This is counter-intuitive and highlights the crucial importance of paracrine factors in optimising treatment efficacy. Clinical trial information: NCT02575547. [Table: see text]
Optimizing chemotherapy for frail and elderly patients (pts) with advanced gastroesophageal cancer (aGOAC): The GO2 phase III trial.
Authors: Peter S Hall, Daniel Swinson, Justin S. Waters, Jonathan Wadsley, Stephen Falk, Rajarshi Roy, Tania Tillett, Jonathan Nicoll, Sebastian Cummings, Simon Aird Grumett, Konstantinos Kamposioras, Angel Garcia, Christine Allmark, Helen Marshall, Sharon Ruddock, Eszter Katona, Galina Velikova, Russell D. Petty, Heike I. Grabsch, Matthew T. Seymour
Journal: Journal of Clinical Oncology (2019)

4006 Background: Many pts with aGOAC are elderly and/or frail. We previously compared epirubin/ oxaliplatin/ capecitabine (EOCap) vs OCap vs Cap in a pick-the-winner study and found OCap best. GO2 was designed to find the optimum dose of OCap and to explore the use of an objective baseline geriatric assessment to individualize doses for maximum Overall Treatment Utility (OTU), a composite of clinical benefit, tolerability, QL and patient value. Methods: Pts with aGOAC were eligible if unsuitable for full-dose EOCap due to age or frailty, but fit for OCap; GFR ≥ 30, bili &lt;2x ULN. Baseline assessment included global QL; symptoms; functional scales; comorbidity; frailty. Randomization was 1:1:1 to dose Level A (Ox 130 mg/m 2 d1, Cap 625 mg/m 2 bd d1-21, q21d), B (80% Level A doses) or C (60% Level A doses). Pts with GFR 30-50 ml/min or bili 1.5-2.0 xULN received 75% of the allocated dose of Cap. At 9 wks, pts were scored for OTU. Continuation thereafter was based on clinical judgement. Non-inferiority (vs A) was assessed using PFS censored at 12 months, with boundary HR 1.34 (based on discussion with pts and clinicians), needing 284 PFS events per 2-way comparison. Baseline fitness was assessed as predictive of OTU, overall and by interaction with dose level. Results: 514 pts were randomised, 2014-17, at 61 UK centres. Clinical trial information: 44687907. Non-inferiority of PFS is confirmed for Level B vs A (HR 1.09, CI 0.89-1.32) and for Level C vs A (HR 1.10, CI 0.90-1.33). Level C pts had less toxicity and better OTU outcomes than A or B. When analysed by baseline age, frailty and PS, Level C produced the best OTU even in younger, less frail and better PS patients; no group was identified who benefit more from the higher dose levels. Conclusions: This is the largest RCT to date specifically investigating frail and/or elderly aGOAC pts, and should guide future treatment. The lowest dose tested was non-inferior in terms of PFS and produced less toxicity and better overall treatment utility.[Table: see text]
Gls-010, a novel anti-PD-1 mAb in Chinese patients with relapsed or refractory classical Hodgkin lymphoma: Preliminary impressive result of a phase II clinical trial.
Authors: Yuqin Song, Jun Zhu, Ningjing Lin, Mingzhi Zhang, Hai Bai, Hui Liu, Jie Cui, Xiaoyan Ke, Huilai Zhang, Lihong Liu, Dongmei Yan, Yongsheng Jiang, Aimin Zang, Junyuan Qi, Li Wang, Zhuogang Liu, Bing Xu, Ying Zhang, Zhihui Zhang, Haijin Meng
Journal: Journal of Clinical Oncology (2020)

8033 Background: classical Hodgkin lymphoma (cHL) are characterized by genetic alterations at the 9p24·1 locus and PD-L1 ligand overexpression. GLS-010 is a novel fully human anti-PD-1 mAb and exhibited favorable result in previous Phase I study. This multi-center, single-arm Phase II clinical trial is aimed to further evaluate the safety and efficacy profile of GLS-010 in Chinese patients (pts) with relapsed or refractory cHL. Methods: All pts enrolled received GLS-010 240mg every 2 weeks until disease progression, death, unacceptable toxicity or withdraw from the study. The primary endpoint was objective response rate (ORR) by independent review committee (IRC) per Lugona 2014. Adverse events (AEs) were graded by NCI CTCAE v4.03. Results: 85 pts with relapsed or refractory cHL who had received at least 2 lines of prior systemic chemotherapies were enrolled and treated. As of August 2 2019, data cutoff, pts received a median of 8 treatment cycles (1 cycle include 2 injections), with 12 pts discontinued and 73 pts were still in treatment. At a median follow-up of 6.57 months, an ORR was reported in 78 of 85 patients (91.76%, 95%CI, 83.77-96.62), by an IRC assessment, including 30(35.3%) pts with a complete response (CR) and 48 pts (56.5%) with a partial response (PR). Median duration of response (DoR) and progression free survival (PFS) were not reached yet. Treatment-related adverse events (TRAEs) of any grade occurred in 77 (90.6%) of 85 patients, most of which were Grade 1-2.The most common TRAEs were fever (26/85, 30.6%), neutrophil count decreased (16/85, 18.82%), white blood cell count decreased (15/85, 17.65%). ≥ Grade 3 TRAEs occurred in 23 (27.06%) pts, most commonly, hepatic function abnormal (5/85, 5.88%), hyperuricaemia (4/85, 4.71%). Conclusions: GLS-010 showed impressive anti-tumor activity (ORR = 91.96%) and manageable safety profile in Chinese patients with relapsed or refractory cHL, which could be a new safe and effective treatment option in this setting. Clinical trial information: NCT03655483 .
Cell-specific upregulation of lung “cancer signature genes” in the small airway epithelium of asymptomatic smokers.
Authors: Mahboubeh Rostami, Wu-Lin Zuo, Ronald G. Crystal, Jason G. Mezey
Journal: Journal of Clinical Oncology (2019)

3109 Background: Most lung cancers are derived from the small airway (6 th -23 rd generations) epithelium (SAE). While a pathogenic mutation in a driver gene is critical to transform a SAE cell to a malignant cell, single cell analysis of lung cancers has demonstrated that individual cancer cells have transcriptional alterations in many “cancer signature genes” (Lambrechts D et al, Nature Med 2018; 24:1277) that are not driver genes, but likely support the malignant state. Based on the concept that dysregulation of many of these genes facilitate the malignant state, we hypothesized that, with the stress of smoking, some of these cancer-supporting transcriptional modifications occur long before the random hit with a driver mutation, providing a soil for the driver mutation. Methods: To assess this hypothesis, we applied drop-seq single cell transcriptome analysis to assess SAE recovered by fiberoptic bronchoscopy and brushing of n = 3 healthy non-smokers and n = 3 healthy smokers. Using unsupervised clustering, 11 cell types were identified including major SAE cell types (basal, intermediate, club, mucous and ciliated), rare epithelial cells (ionocyte, neuroendocrine and undefined NCL hi ) and rare immune/inflammatory cell (Tcell, mast, antigen presenting). Results: Comparison of smokers and nonsmokers showed that smoking significantly altered the transcriptome (n = 426 genes upregulated, n = 572 genes downregulated) in different SAE cell types; 21% -56% of smoking-upregulated genes in the major SAE cell population are identified as “cancer signature genes”, where a number have cell-specific smoking regulated patterns within individual cell types including HSPB1 in mucous cells, ADH7 in ciliated, LAMB3 in basal and intermediate cells, MIF intermediate and club cells, ALDH3A1 in all main SAE cell types. Conclusions: These data support the concept that cigarette smoking, long before the development of cancer, reprograms specific SAE cells to provide the biological soil to support driver genes to function.
Rationale and preclinical development of LEAF-1401 and LEAF-1701: A novel class of potent next generation antifolates.
Authors: Victor M. Moyo, Zhenghong Xu, Kaniz Khalifa, Nishant Gandhi, Bolin Geng, Navreet Dhindsa, Clet Niyikiza
Journal: Journal of Clinical Oncology (2019)

e14515 Background: Polyglutamation of antifolates by folylpolyglutamate synthase (FPGS) greatly enhances their activity, e.g. pentaglutamated pemetrexed is 80-fold more potent at inhibiting thymidylate synthase than pemetrexed. Polyglutamated antifolates however, do not readily cross the cell membrane, due to high negative charge and molecular mass. The resulting poor intracellular bioavailability greatly limits their therapeutic potential. Gamma glutamyl hydrolase (GGH) enzyme removes the glutamate residues from polyglutamates, which then are subject to efflux pumps. Resistance to pemetrexed has been linked to downregulation of both FPGS and folate transporters and upregulation of both GGH and the efflux pumps. We have been developing a novel class of nanoliposomal polyglutamated-antifolates including: LEAF-1401; nanoliposomal gamma-L pentaglutamated antifolate LEAF-1701; nanoliposomal alpha-L pentaglutamated antifolate These were designed to address key challenges of currently used antifolates namely: Bypassing the need for intracellular endogenous FPGS Direct delivery of the much more active polyglutamates through nanoliposome technology Minimizing toxicity to normal cells Mitigating against key antifolate resistance mechanisms such as downregulation of FPGS and folate transporters, and upregulation of GGH and efflux pumps Methods: In vitro testing in cell lines and in vivo testing in mice were performed using LEAF-1701 and LEAF-1401 in various tumor types. Results: Compared to pemetrexed: In vitro, LEAF-1701 and LEAF-1401 were more potent, in various cell lines while sparing normal neutrophils, colon and liver cells. In vivo, in H292 lung cancer xenografts, treatment with LEAF-1701 improved survival to 59 days vs 39 days for pemetrexed. In A549 lung cancer mouse orthotopic models, treatment with LEAF-1401 reduced metastatic tumor burden and prevented new metastases. In vivo, in mice doses of up to 80 mg/kg IV weekly were tolerated with little impact on blood counts and chemistry. Conclusions: LEAF-1701 and LEAF-1401 are innovative new chemical entities with promising preclinical activity and improved safety profiles and are now advancing to the clinic.
Prognostic values of cell free DNA, CA 15.3, and ESR1 circulating mutations variations in hormone receptor (HR)-positive metastatic breast cancer (MBC) patients under aromatase inhibitor (AI).
Authors: Laetitia Augusto, Ludivine Beaussire, Justine Lequesne, Anne Perdrix, David Sefrioui, Maxime Fontanilles, Marianne Leheurteur, Frédéric Di Fiore, Nasrin Sarafan-Vasseur, Florian Clatot
Journal: Journal of Clinical Oncology (2019)

e12534 Background: Circulating cell free DNA (cfDNA), CA 15.3 and circulating tumor DNA (ctDNA) have been associated with survival in MBC. These 3 biomarkers have never been compared. Methods: We retrospectively included all patients treated in our center between 2010 and 2012 for a HR+ MBC, who had clinical progression during the first line of aromatase inhibitor (AI) and available plasma samples. CfDNA level (ng/mL), CA 15.3 level (U/mL) and ESR1 circulating mutation level (Y537N, Y537S, Y537C and D538G, identified by ddPCR) were determined at time of clinical progression (Tp) and 3 months before (Tp-3). Biomarkers values at Tp and Tp-3 as well as their variations were analyzed according to clinical progression and overall survival (OS). Results: 91 patients were analyzed. CA 15.3 was elevated ( &gt; 30 U/mL) in 71/91 (78%) at Tp and 62/91 (68%) at Tp-3. Higher CA 15.3 was associated with worse OS, especially at Tp (HR = 1.0006/unit at both times, p = 0.009 at Tp; p = 0.08 at Tp-3). Higher cfDNA was associated with worse OS, both at Tp and Tp-3 (HR = 1.006/unit, p &lt; 0.0001 and HR = 1.007/unit, p = 0.02, respectively). An ESR1 mutation was detected in 14/91 at Tp-3 (15%) and 28/91 at Tp (31%). ESR1 mutation detection was strongly correlated with OS both at Tp and Tp-3 (HR = 2.4, p = 0.0005 and HR = 1.97, p = 0.03, respectively). Between Tp-3 and Tp, overall median CA 15.3 and ESR1 mutation level increased (p &lt; 0.0001 and p = 0.007, respectively) and were related to poorer OS (HR = 1.007/unit, p = 0.0002 and HR = 3.1, p = 0.05). In contrast, CfDNA was not correlated at all with clinical progression (36/91 increase, 36/91 decrease, and 19/91 stable cfDNA). ROC curve analysis identified a 59% CA 15.3 increase as the best cut-off for predicting progression, but with poor performance (AUC = 0.64). Multivariate analysis showed that CA 15.3 at Tp (HR = 1.0006/unit, p = 0.006), cfDNA at Tp (HR = 1.005/unit, p = 0.01), ESR1 detection at Tp (HR = 2.7, p = 0.0002) and CA 15.3 increase between Tp-3 and Tp (HR = 1.006/unit, p = 0.003) were associated with poor OS. Conclusions: All 3 biomarkers are correlated with OS in MBC treated with AI. CfDNA variation is poorly related to clinical progression while CA 15.3 variation or ESR1 mutation detection are much more reliable. Overall the better performance is observed with ESR1 mutation detection.
Insight into the brain metastasis journey: Initial survey results from patients and caregivers.
Authors: Nicole Willmarth, Scott Elder, Avery Fine, Manmeet Singh Ahluwalia, Jill Barnholtz-Sloan, Priscilla Kaliopi Brastianos, Daniel Brat, Minesh P. Mehta, Robin Page, Ralph DeVitto, Debbie Robins
Journal: Journal of Clinical Oncology (2019)

2069 Background: Brain metastases (BM) are the most common central nervous system tumors in the US. Though the exact incidence is unknown, BM are estimated to occur in up to 10-20% of all cancers. Despite the high frequency, there is little systematic knowledge about how BM are typically diagnosed and treated. The American Brain Tumor Association (ABTA) seeks to understand the BM journey: symptoms, diagnosis, treatment, and end of life, through a survey of BM patients and caregivers. Methods: Two surveys were developed by the ABTA with vendor, PSB Research, after careful literature review. The surveys were reviewed by a panel of clinicians who treat BM patients. Online survey research was conducted between 8/13-9/16/18, with one survey for adults with BM (N = 237) and another for caregivers (N = 211). Respondents came from PSB’s panels and ABTA collaborators: LUNGevity, Melanoma Research Foundation and the Kidney Cancer Association. Results: Ninety percent of patients, and a similar number of caregivers, were surprised by the diagnosis, with only 20% of patients knowing about BM before diagnosis. Most caregivers were the adult child of a patient. The impact of the diagnosis was primarily emotional. Top concerns after diagnosis, for both patients and caregivers, were likelihood of treatment success and impact on quality of life. Although a majority of patients were happy with the quality of information given, they stated a need to receive a greater quantity of information about treatment success and options. Only 30% of patients were referred to a patient advocacy organization. When referred, information on treatment success rates and options was most sought. Conclusions: Direct patient and caregiver feedback provides valuable insight towards understanding the BM journey and resources needed to support patients and caregivers. A subsequent survey among oncologists and other clinicians, planned for spring of 2019, will add to these findings.
Breast radiotherapy among <i>ATM</i>-mutation carriers.
Authors: Leslie A. Modlin, Jessica Flynn, Zhigang Zhang, Boris Mueller, Atif J. Khan, Erin F. Gillespie, Oren Cahlon, Beryl McCormick, Mark E. Robson, Simon N. Powell, Lior Zvi Braunstein
Journal: Journal of Clinical Oncology (2019)

1504 Background: Syndromes of DNA repair deficiency may confer both cancer predisposition and increased sensitivity to DNA damaging agents, such as ionizing radiation. Whereas homozygous deficiency of ATM causes the ataxia telangiectasia syndrome, heterozygous ATM mutation carriers exhibit increased rates of breast, pancreas and prostate cancers. ATM repairs DNA double-strand breaks; consequently, mutation carriers may exhibit excessive radiotherapeutic (RT) toxicity. We evaluated the tolerability of adjuvant breast radiation in ATM mutation carriers. Methods: We identified 167 ATM mutation carriers presenting to our institution with breast cancer; of these, 91 received RT and records were reviewed for RT-related morbidity. Toxicities were graded per CTCAE v5. Associations of clinicopathologic features with toxicity were evaluated by multivariate regression. Results: Of 91 ATM mutation carriers receiving breast RT, 31% (n = 28) harbored a pathogenic mutation whereas 69% (n = 63) harbored variants of uncertain significance (VUS). 71% (n = 65) underwent lumpectomy and adjuvant whole-breast RT; 29% (n = 26) had mastectomy and PMRT. Nine patients underwent bilateral RT for a total of 100 RT courses. 86% of RT courses comprised whole-breast/chest-wall tangents; 14% were VMAT or protons. Median tangent dose was 50Gy; 62% included an additional boost (median 10Gy) and 48% used a bolus (median thickness 0.3cm). Lymph nodes were treated in 43% (n = 39). At last on-treatment visit, 31% had grade 2 dermatitis, 4% had other grade 2 events (fatigue, seroma, decreased range of motion, or pain), and 1% had grade 3 dermatitis. At 1 year, 13% had grade ≥2 toxicity: grade 2a lymphedema (n = 3), and grade 2 (n = 1) or 3 (n = 2) capsular contracture. At last follow-up, 4 PMRT patients had capsular contracture (3 with grade 2, 1 with grade 3); 1 patient had grade 2b lymphedema. Overall, no patients had significant (grade ≥2) telangiectasias, fibrosis, or fat necrosis; no grade 4 or 5 toxicities were seen. Neither pathogenic ATM mutations nor VUS were associated with acute or late RT toxicities. Conclusions: We found no evidence of excess breast radiation toxicity among ATM mutation carriers, either pathogenic or VUS. Breast conserving therapy can be safely considered in this population.