tbuckley/cabot-search huggingface dataset:
Estrogen receptor (ER) status and survival outcomes in HER2 positive (+) metastatic breast cancer (mBC).
Authors: Karen DeSouza, Rosa-Rita Zammit, Anna Haire, Rajesh Sinha, Richard Simcock, Charlotte Hannah Moss, Anca Mera, Janine Mansi, Eleni Karapanagiotou, Elinor Sawyer, Gargi Surendra Patel
Journal: Journal of Clinical Oncology (2019)

e12503 Background: The oncological management of HER2+ mBC is complicated by the development of resistance to HER2-directed therapies (HER2-DTs). This project analyses real-world clinical data to determine disease response patterns that may guide treatment sequencing decisions. Methods: This collaborative project analysed HER2+ mBC datasets held by the Sussex Cancer Centre and Guy’s Cancer Centre, UK. The datasets were generated by reviewing clinical notes, radiology and e-prescribing records to collect clinical data on patients diagnosed with HER2+ mBC between 01/01/2013 – 30/09/2018. Results: 138 patients with a median age of 59 years (30 - 89 years) were diagnosed with HER2+ mBC during this time period: 88 were ER+ (63.7%) and 50 were ER- (36.3%); the median OS is 41.1 mos. (range 0.7 - 62 mos.). Patients with HER2+ mBC were more likely to present with visceral metastases (68.1%, n = 94). A poorer median OS was identified in patients with ER+ HER2+ mBC (35.5 mos.) vs ER- HER2+ mBC (MNR). A benefit to median OS was observed with first line treatment using Docetaxel/Trastuzumab/Pertuzumab (THP) compared to other HER2-DTs ((54.5 mos. (n = 76) vs 26.7 mos. (n = 40)) 65.2% (n = 90) were previously treated for early breast cancer (EBC), evenly distributed across the 2 groups ER+ (64.7%, n = 57) vs ER- (66%, n = 33). 53.7% (n = 50) received trastuzumab with neo-adjuvant/adjuvant therapy (NACT/ACT). Patients previously treated for EBC demonstrated a poorer median OS (34 mos.) when compared to patients with de-novo mBC (MNR). When treated for EBC, ER+ disease was less likely to have a pathological complete response (pCR) with NACT (ER+ 22.2% (n = 4/18) vs ER- 50% (n = 5/10)). PFS data in response to an array of prescribed systemic therapies will be presented. Conclusions: Though, HER2 signalling is considered the dominant signalling pathway in HER2+ breast cancer, pre-clinical research indicates that the ER pathway represents an important escape mechanism influencing the development of resistance. Lack of efficacy (pCR) to NACT in ER+HER2+ EBC may translate to poorer outcomes (OS) when these patients develop MBC. Earlier targeting of the ER pathway in conjunction with HER2-DTs may contribute to improving patient outcomes.
The WNT receptor ROR2 drives the interaction of multiple myeloma cells with the microenvironment through AKT activation
Authors: M. Frenquelli, N. Caridi, E. Antonini, F. Storti, V. Viganò, M. Gaviraghi, M. Occhionorelli, S. Bianchessi, L. Bongiovanni, A. Spinelli, M. Marcatti, D. Belloni, E. Ferrero, S. Karki, P. Brambilla, F. Martinelli-Boneschi, S. Colla, M. Ponzoni, R. A. DePinho, G. Tonon
Journal: Leukemia (2019)
Real-world use and survival outcomes of immune checkpoint inhibitors in patients with non-small cell lung cancer.
Authors: Bora Youn, Nikolaos Trikalinos, Vincent Mor, Ira Wilson, Issa Dahabreh
Journal: Journal of Clinical Oncology (2019)

e14111 Background: Little is known about the real-world use and survival outcomes of immune checkpoint inhibitors among elderly patients with non-small cell lung cancer (NSCLC). Methods: Using the SEER-Medicare data, we identified 1,338 patients who were diagnosed with pathologically confirmed stage 1-4 NSCLC between 2002 and 2015 and initiated nivolumab or pembrolizumab in 2016. We examined the association of patient and disease characteristics, and treatment history with overall survival, from initiation through December 31, 2017. We estimated survival curves using the Kaplan-Meier method and identified predictors of survival using multivariable Cox proportional hazards regression. Results: The median age at immune checkpoint inhibitor initiation was 74.8 years. The majority of patients were initially diagnosed with stage 4 disease (42.7%). Median time from diagnosis to initiation were 13.9 and 19.0 months for those initially diagnosed with stage 4 and 1-3 disease, respectively. Median overall survival was 9.5 months. In multivariable analyses, multiple comorbid conditions, squamous histology, history of non-platinum doublet systemic therapy, recent radiation therapy, and shorter time from initial diagnosis to initiation were statistically significantly associated with increased hazard of death (Table). Demographics, stage at initial diagnosis, and prior oral targeted therapy were not significantly associated with the hazard of death. Conclusions: Real-world data show that factors that are generally related to poor prognosis remain predictors of survival in elderly patients treated with immune checkpoint inhibitors.[Table: see text]
Prospective head-to-head comparative phase 3 study between <sup>18</sup>F-fluciclovine and <sup>68</sup>Ga-PSMA-11 PET/CT in patients with early biochemical recurrence of prostate cancer.
Authors: Jeremie Calais, Francesco Ceci, Matthias Eiber, Tore Bach-Gansmo, Cristina Nanni, Bital Savir-Baruch, Michael Hofman, Tom Hope, Christoph Rischpler, David Elashoff, Tristan Grogan, Magnus Dahlbom, Roger Slavik, Jeannine Gartmann, Robert Evan Reiter, Matthew Rettig, Hossein Jadvar, Wolfgang P Fendler, Johannes Czernin
Journal: Journal of Clinical Oncology (2019)

5014 Background: This is a prospective single-center, single-arm, head-to-head phase 3 study of paired 18 F-fluciclovine (FACBC) and 68 Ga-PSMA-11 (PSMA) PET/CT scans for localizing early biochemical recurrence (BCR) of prostate cancer (PCa) after radical prostatectomy (RP) (NCT02940262). Methods: Fifty consecutive patients with BCR and prostate specific antigen (PSA) levels ranging from ≥0.2 to ≤2.0 ng/mL without any prior salvage therapy were included. All patients underwent FACBC and PSMA PET/CT scans within ≤15 days. PET/CT scans were each interpreted by 3 independent blinded expert readers not involved in study design and data acquisition. Region consensus interpretation (T,N,M1a,M1b,M1c) was generated based on majority rule in cases of reader disagreement (2 vs 1). PET/CT scans were considered as positive if any region was rated as positive. Detection rates per-patient and per-region served as primary study endpoint. Results: Median time interval between the 2 scans was 6 days (range 1-15). Median PSA level at the time of imaging was 0.50 ng/ml (mean 0.63; range 0.2-2.0 ng/ml). The detection rates were significantly lower with FACBC than with PSMA PET/CT per-patient (26% vs 56%; p = 0.003) and per-region for pelvic nodes (N) (8% vs 30%; p = 0.003) or any extra-pelvic lesions (M) (0% vs 16%; p = 0.008). Reader agreement for PSMA PET/CT image interpretations was significantly higher than for FACBC PET/CT (0.67 vs 0.20; p = 0.015). Conclusions: In patients with BCR and low serum PSA levels after RP, PSMA PET/CT demonstrates higher detection rates and superior reader agreement when compared with FACBC PET/CT. Therefore, PSMA PET/CT should be the imaging modality of choice in patients with early BCR. Clinical trial information: NCT03515577.
Assessment of the Clinical Benefit of Cancer Drugs Receiving Accelerated Approval
Authors: Bishal Gyawali, Spencer Phillips Hey, Aaron S. Kesselheim
Journal: JAMA Internal Medicine (2019)

The US Food and Drug Administration's (FDA's) accelerated approval pathway allows investigational cancer drugs to be approved by demonstrating a beneficial effect on a surrogate measure (eg, progression-free survival) that is expected to predict a real clinical benefit (eg, overall survival). However, these drugs must undergo postapproval confirmatory studies to evaluate their actual clinical benefits. In an assessment of the accelerated approval pathway published in 2018, the FDA concluded that this pathway was successful because only 5 (5%) of 93 accelerated drug approvals had been withdrawn or revoked over the last 25 years.To compare the end points used in preapproval trials leading to accelerated approval with the end points used in the required confirmatory trials that verified clinical benefit and to update the outcomes of accelerated approvals with confirmatory trials that were ongoing at the time of FDA's review.A review of the literature on end points used in preapproval and confirmatory trials of cancer drugs that received accelerated approval and a review of the FDA's database of postmarketing requirements and commitments focused on the outcomes of confirmatory trials that were ongoing at the time of FDA's review of cancer drug approvals published in 2018.End points used as confirmation of clinical benefit in cancer drugs that received accelerated approval, updated status of the confirmatory trials, and regulatory outcomes for cancer drugs that did not meet expectations in the confirmatory trials.The FDA published a review of 93 cancer drug indications for which accelerated approval was granted from December 11, 1992, through May 31, 2017. Of these approvals, the FDA reported that clinical benefit was adequately confirmed in 51 and confirmatory trials for 15 of these indications (16% of the main sample) accelerated approvals reported improvement in overall survival. For 19 approvals (37%), the confirmatory trials used surrogate measures that were the same as those used in the preapproval trials. In this updated review, confirmatory trials for 19 of 93 (20%) cancer drug approvals reported an improvement in overall survival, 19 (20%) reported improvement in the same surrogate used in the preapproval trial, and 20 (21%) reported improvement in a different surrogate. Five confirmatory trials were delayed, 10 were pending, and 9 were ongoing. For 3 recent approvals, the primary end points were not met in the confirmatory trials; however, 1 cancer drug indication still received full approval.Confirmatory trials for one-fifth (n = 19 of 93) of cancer drug indications approved via the FDA's accelerated approval pathway demonstrated improvements in overall patient survival. Reassessment of the requirements for confirmatory trials may be necessary to obtain more clinically meaningful information.
Regulation of Fatty Acid Oxidation by Twist 1 in the Metabolic Adaptation of T Helper Lymphocytes to Chronic Inflammation
Authors: Kristyna Hradilkova, Patrick Maschmeyer, Kerstin Westendorf, Heidi Schliemann, Olena Husak, Anne Sae Lim von Stuckrad, Tilmann Kallinich, Kirsten Minden, Pawel Durek, Joachim R. Grün, Hyun‐Dong Chang, Andreas Radbruch
Journal: Arthritis & Rheumatology (2019)

Inflamed tissue is characterized by low availability of oxygen and nutrients. Yet CD4+ T helper lymphocytes persist over time in such tissue and probably contribute to the chronicity of inflammation. This study was undertaken to analyze the metabolic adaptation of these cells to the inflamed environment.Synovial and blood CD4+ T cells isolated ex vivo from patients with juvenile idiopathic arthritis (JIA) and murine CD4+ T cells were either stimulated once or stimulated repeatedly. Their dependency on particular metabolic pathways for survival was then analyzed using pharmacologic inhibitors. The role of the transcription factor Twist 1 was investigated by determining lactate production and oxygen consumption in Twist1-sufficient and Twist1-deficient murine T cells. The dependency of these murine cells on particular metabolic pathways was analyzed using pharmacologic inhibitors.Programmed death 1 (PD-1)+ T helper cells in synovial fluid samples from patients with JIA survived via fatty acid oxidation (mean ± SEM survival of 3.4 ± 2.85% in the presence of etomoxir versus 60 ± 7.08% in the absence of etomoxir on day 4 of culture) (P < 0.0002; n = 6) and expressed the E-box-binding transcription factor TWIST1 (2-14-fold increased expression) (P = 0.0156 versus PD-1- T helper cells; n = 6). Repeatedly restimulated murine T helper cells, which expressed Twist1 as well, needed Twist1 to survive via fatty acid oxidation. In addition, Twist1 protected the cells against reactive oxygen species.Our findings indicate that TWIST1 is a master regulator of metabolic adaptation of T helper cells to chronic inflammation and a target for their selective therapeutic elimination.
Barriers to clinical trial accrual: Clinical trialists' perspectives.
Authors: Edward S. Kim, Dax Kurbegov, Patricia A. Hurley, David Michael Waterhouse
Journal: Journal of Clinical Oncology (2019)

e18156 Background: Oncology clinical trial participation rates remain at historic lows. There are many barriers that impede participation. Understanding those barriers, from the perspective of cancer clinical trialists, will help develop solutions to increase physician and site engagement, with the goal of improving accrual rates and advancing cancer treatment. Methods: Physician investigators and research staff from community-based and academic-based research sites were surveyed during ASCO’s Research Community Forum (RCF) Annual Meeting (N = 159) and through a pre-meeting survey (N = 124) in 2018. Findings and potential solutions were discussed during the meeting. Results: 84% of respondents (n = 84) reported that it took 6-8 months to open a trial and 86% (n = 81) reported that trials had unnecessary delays 70% of the time. The top 10 barriers to accrual identified were: insufficient staffing resources, restrictive eligibility criteria, physician buy-in, site access to trials, burdensome regulatory requirements, difficulty identifying patients, lack of suitable trials, sponsor and contract research organization requirements, patient barriers, and site cost-benefit. Respondents shared strategies to address these barriers. Conclusions: The current state of conducting clinical trials is not sustainable and hinders clinical trial participation. New strategies are needed to ensure patients and practices have access to trials, standardize and streamline processes, reduce inefficiencies, simplify trial activation, reduce regulatory burden, provide sufficient compensation to sites, engage the community and patients, educate the public, and increase collaborations. The ASCO RCF offers resources, available to the public, that offer practical strategies to overcome barriers to clinical trial accrual and has ongoing efforts to facilitate oncology practice participation in clinical trials.
Risk stratification and daily symptom monitoring for oncology patients.
Authors: Robert Michael Daly, Claire Perry, Yeneat O. Chiu, Lauren L. Katzen, Margarita Rozenshteyn, Gilad Kuperman, Amandeep K Dhami, Rori Salvaggio, Abigail Baldwin, Jessie C. Holland, Kimberly Chow, Chau T. Dang, Rachel N. Grisham, Stephen R. Veach, Alice Zervoudakis, Isaac Wagner, Brett A Simon, Diane Lauren Reidy, Wendy Perchick
Journal: Journal of Clinical Oncology (2019)

6535 Background: Monitoring and managing patient reported outcomes (PROs) has been recommended for oncology patients on active treatment but can be time and resource intensive. Identifying patients likely to benefit and the optimal frequency of PRO capture is still under investigation. We tested the feasibility of monitoring patients who are high-risk risk for acute care with daily PROs. Methods: Using data from our institution, we developed a model that employs over 400 clinical variables to calculate a patient’s risk of an emergency room visit within 6 months following the onset of treatment. From October 15, 2018 to January 23, 2019, we enrolled patients identified as high risk through a technology-enabled program to monitor and manage those patients’ symptoms. Enrolled patients entered PRO assessments daily via an online portal. Symptoms were monitored and managed by a centralized clinical team. Tiered notifications informed the team of concerning or escalating symptoms. We assessed how frequently patients completed symptom assessments and the frequency of symptom notifications. Results: During the pilot, 28 patients were identified as high risk and enrolled in the program (median age 65; 64% percent female). Disease types were: 15 (54%) thoracic, 7 (25%) gynecologic, 6 (21%) gastrointestinal. Median time in the program was 50 (6-98) days. Patients completed 840 of 1,350 assessments (62%). There were 328 assessments that triggered moderate alerts (39%) and 220 that triggered severe alerts (26%). The table describes the prevalence of symptoms at the patient-level. Conclusions: A model can be employed to identify high-risk patients in collaboration with clinicians. Our adherence rate with a daily symptom assessment was similar to those found in studies of less frequent PRO capture. Future work will expand to a larger patient population with other cancer types, evaluate impact on outcomes, and assess optimal frequency for PRO collection and alert thresholds. [Table: see text]
Improved hepatocellular carcinoma (HCC) outcomes in a public hospital setting with increased access to procedural-based therapy.
Authors: Elizabeth S. Ellent, Tejas V Joshi, Lee S McDaniel, Brian C. Boulmay
Journal: Journal of Clinical Oncology (2019)

e18137 Background: HCC is the 2nd most common cause of cancer death in the world. We investigate if increased access to various treatment modalities improved outcomes in a public hospital setting. Access to procedural-based treatments improved with development of an in hospital interventional radiology program that resulted from increased public hospital funding starting in 2013 at University Medical Center in New Orleans (UMC). Methods: A retrospective chart review was conducted to analyze 124 patients (pts) diagnosed with HCC from 2013 to 2018 at UMC to determine effect of treatment modality on outcome. Comparative analysis and Fisher’s exact test was performed using a previous study analyzing a similar population (n = 107) from 2007-2013. Results: Pts with HCC treated with transarterial chemoembolization (TACE) had an overall survival (OS) of 82.55% and 54.84% at 1 and 3 years (yr). Pts not treated with TACE had OS of 60.69% and 38.49% at 1 and 3 yr. OS in the 2007-2013 cohort at 1 year was 29%. Progression free survival (PFS) in pts treated with TACE was 52.99% and 22.66% at 1 and 3 yr. PFS in patients not treated with TACE was 58.36% and 50.28% at 1 and 3 yr. Treatment with Sorafenib (S) with or without TACE had OS of 75.84% and 48.43% at 1 and 3 yr. Pts not receiving S had an OS of 69.17% and 48.47% at 1 and 3 yr. PFS was 37.27% and 10.57% in pts treated with S at 1 and 3 yr. PFS for pts not treated with S was 67.00% and 47.02% over 1 and 3 yr. There were 140 total IR procedures which averages to 1.13 IR procedures per pt. Compared to 2007-2013 cohort, more HCC pts had TACE (10% to 56%, p &lt; 0.001) and received S (18% to 39%,p &lt; 0.001). Conclusions: Although PFS was not better for those pts treated with TACE (p value = 0.218), OS was statistically better with TACE (p value = 0.003). Radiologic response rates do not appear to correlate with OS benefit, perhaps due to TACE effect on image interpretation. PFS was decreased in pts treated with S (p value = &lt; 0.0001), possibly due to its use in pts who have progressed despite TACE. The 2013-2018 cohort has superior OS compared to the 2007-2013 cohort at 1 yr. Increased access to procedural- based, locoregional therapy and S positively impacts patient outcomes.
Is there a correlation between clinic-pathological features, MSI, PD-L1 and survival outcomes in resected gastric cancer? Looking for optimal biomarkers.
Authors: Margherita Ratti, Nicola Valeri, Jens Claus Hahne, Andrea Lampis, Michele Ghidini, Gianluca Tomasello, Matteo Fassan, Bianca Maria Donida, Chiara Senti, Rodolfo Passalacqua
Journal: Journal of Clinical Oncology (2019)

e15566 Background: Identification of prognostic biomarkers for gastric cancer (GC) patient selection is compelling to improve survival outcomes. Microsatellite instability (MSI) is related with a positive prognostic effect in GC, whereas perioperative chemotherapy resulted detrimental in this subgroup. In metastatic GC, immunotherapy with anti-PD1/PD-L1 drugs has shown promising results. Nevertheless, in early stages, data on the relation between MSI, clinic-pathological features, PD-L1 expression and overall survival (OS) remains sparse, especially in Western population. In our study, the prognostic role of MSI, clinic-pathological features and PD-L1 expression in a cohort of Italian GC patients was examined. Methods: CP data of 148 consecutive stage I-III GC pts resected in Cremona Institute between 2010 and 2014 (mostly chemo and/or radio-naive) were collected. MSI analysis was performed on tissue samples for all cases by polymerase chain reaction. PDL-1 expression, evaluated by immunohistochemistry, was assessed in MSI group. Differences between subgroups were evaluated with Chi-square test; Kaplan-Meier method and Long Rank test were used to calculate OS. Results: Female sex (p=0.012), earlier TNM stages (p=0.011) and limited nodal involvement (p=0.29) significantly correlated with MSI status. MSI is significantly associated with better prognosis, exhibiting an advantage of 28.6 months in OS compared with microsatellite stable subgroup (p&lt;0.001). Most MSI patients expressed PD-L1. MSI patients without PD-L1 expression showed higher percentage of clinical features correlated with better prognosis compared with PD-L1 expressing MSI patients and MSS subgroup. Conclusions: MSI is an independent prognostic biomarker in GC and identifies a subset of patients with better OS and specific clinic-pathological features, including high percentage of PD-L1 expression. MSI could represent a promising biomarker to select patients for chemotherapy versus immunotherapy in non-metastatic disease.