tbuckley/cabot-search huggingface dataset:
Association of <i>PIK3CA</i> mutations (mut) with immune engagement and clinical benefit from immunotherapy in microsatellite stable (MSS) colorectal cancer (CRC) patients (pts).
Authors: Maliha Nusrat, Jason Roszik, Riham Katkhuda, David Menter, Kanwal Pratap Singh Raghav, Van K. Morris, Padmanee Sharma, James Patrick Allison, Jorge M. Blando, Dipen M. Maru, Gregory Lizee, Filip Janku, Michael J. Overman, Scott Kopetz
Journal: Journal of Clinical Oncology (2019)

3604 Background: PI3K pathway alterations, PIK3CA mut or PTEN loss, are known to modulate anti-tumor immune microenvironment. MSS CRC pts respond infrequently to immunotherapy, suggesting the presence of a rare MSS immunogenic subset. We investigated the immune repertoire and outcomes on immunotherapy trials in PIK3CA mut MSS CRC pts. Methods: Immune infiltrates and checkpoints were evaluated using quantitative immuno-histochemistry (IHC) on primary CRC. Mutations were assessed by next generation sequencing. PIK3CA mut neoepitopes and HLA allele affinities were predicted using NetMHC 4.0 Server. Outcomes of MSS CRC pts enrolled in 7 immunotherapy trials were assessed. Clinical benefit (CB) was defined as CR, PR or SD of 24 weeks. Time to progression (TTP) was calculated using Kaplan-Meier Method. PIK3CA mut vs wild type (wt) groups were compared using Mann-Whitney U, Fisher’s exact, or Log-Rank tests as appropriate. Results: PI3K alterations were present in 14/40 MSS CRC pts in IHC cohort (7 PIK3CA mut, 33 wt; 7 PTEN loss, 33 intact). The center of PIK3CA mut MSS CRC had higher median densities of CD3+ cells [1112 (IQ range 865-1421) vs 435 (300-744) cells/mm 3 ; P=0.037] and CD8+ cells [554 (331-1200) vs 185 (60-473) cells/mm 3 ; P=0.037] as compared to PIK3CA wt tumors. Intratumoral immune infiltrates did not differ by PTEN IHC staining in MSS CRC. PD-L1 H-scores were also higher in PIK3CA mut MSS CRC [85 (34-114) vs 29 (11-60); P=0.01]. Several activating PIK3CA mut (E542K, E545K, H1047R) were predicted to generate true neoepitopes with high binding affinity to common HLA types. Indeed, among MSS CRC pts enrolled in 7 immunotherapy trials, half (4/8) of PIK3CA mut pts derived CB as compared to 3/35 (8.6%) PIK3CA wt pts (P=0.015). PIK3CA mut pts had trend towards longer TTP (3.8 months in mut vs 2.1 months in wt; P=0.08). CB or TTP did not differ by colon sidedness, monotherapy / combination therapy, number of mut, or mut in other key genes ( APC, SMAD4, TP53, KRAS, NRAS or BRAF). Conclusions: PIK3CA mut MSS CRC are associated with increased cytotoxic T cell infiltration, higher PD-L1 expression, and greater clinical benefit from immunotherapy. Further investigation of immunotherapy outcomes in the context of neoepitope-HLA allele interaction may help identify a subset of PIK3CA mut MSS CRC pts who are likely to benefit from immunotherapy.
Clinical implications of monitoring circulating tumor DNA in early- and late-stage non-small cell lung cancer patients.
Authors: Muyun Peng, Lihan Chin, Qi Huang, Wei Yin, Sichuang Tan, Chen Chen, Wenliang Liu, Jingqun Tang, Xiang Wang, Lientu Wang, Fenglei Yu
Journal: Journal of Clinical Oncology (2019)

e20607 Background: Non-small cell lung cancer (NSCLC) accounts for about 85% of all lung cancers, and the most common types of NSCLC are squamous cell carcinoma, adenocarcinoma, and large cell carcinoma. The development of noninvasive methods to monitor circulating tumor DNA (ctDNA) continues to be a major challenge in NSCLC. Methods: We investigated if detection of ctDNA after resection of NSCLC identifies the patients with risk of relapse, and furthermore, informs about response to management.In this cohort study, high-throughput 168 target-gene capture technology and high-sensitivity circulating single molecule amplification and re-sequencing technology (cSMART) were used to detect the somatic mutations in tissues and plasma of patients with NSCLC, respectively. Moreover, ctDNA somatic mutations were used to monitor changes in minimal residual disease during a follow-up period. Results: A total of 169 patients with lung squamous cell carcinoma and adenocarcinoma were included. Detectable levels of ctDNA were present in 60.7% of patients with stage I and 68.8% of patients with late-stage. In patients not treated with adjuvant chemotherapy, ctDNA was detected preoperatively in 46 of 81 (56.8%) patients, 14 (30.4%) of whom had recurred at follow-up of 44 months; recurrence occurred in only 2 (5.7 %) of 35 patients with negative ctDNA. Serial ctDNA status changed from positive to negative during the initial phase of post operation in four patients. Then, ctDNA became positive again after 2 weeks to 3 months, all the four patients with relapse during the follow-up of 44 months. Conclusions: Detection of ctDNA supplies evidence of residual disease and identifies patients at risk of relapse. These observations have implications for the intervention of lung squamous cell carcinoma and adenocarcinoma patients.
A retrospective review of nutritional status and immunotherapy in lung cancer.
Authors: Chung-Shien Lee, Rebecca Sin, Joanna Stein Fishbein, Craig E. Devoe, Xinhua Zhu, Mee-Young Lee, Nagashree Seetharamu
Journal: Journal of Clinical Oncology (2019)

e14112 Background: Immunotherapy has transformed cancer treatment, including lung cancer. Approximately 20-25% of patients respond, therefore making it pivotal in understanding what factors may effect outcomes. There have been previous reports of obesity associated with an increased efficacy of PD-1/PD-L1 blockade and cachectic patients not responding as well. In this study, we aim to assess the association of body mass index (BMI) with outcomes of lung cancer patients being treated with immunotherapy. Methods: An IRB approved retrospective review of lung cancer patients receiving immunotherapy between 2014 and 2017 at the Monter Cancer Center, Northwell Health was conducted. Patients were categorized in underweight (BMI &lt; 18.5), normal weight (BMI of 18.5 to &lt; 25), overweight (BMI 25 to 30) or obese (BMI &gt; 30) arms. The groups were compared using the log-rank test. Kaplan-Meier was used for overall survival (OS) and progression free survival (PFS) and Cox regression models were used to adjust for potential confounders. Results: A total of 116 were included in the analysis, with a median age of 70 (95% CI, 62.5 to 75.5). Ten (8.6%) were underweight, 44 (37.9%) were normal weight, 32 (27.6%) were overweight, and 30 (25.9%) were obese. BMI classification were not found to be a significant predictor of survival, after adjusting for therapy duration (p = 0.44). PFS was 6.6, 6.0, and 6.9 months for patients in the underweight, normal weight, and overweight/obese groups, respectively. Of 116 subjects, 46 (40%) died within the follow up period: 3 (30%), 17 (39%), 11 (34%), and 15 (50%) respectively. Additional post hoc analysis showed that patients with low nutritional status as defined by either a BMI &lt; 18.5 and/or baseline albumin &lt; 3.5 mg/dL had a median PFS of 2.2 months compared to those who did not of 5.2 months (p &lt; 0.00032). Conclusions: In this single institution retrospective review, BMI or albumin as solitary factors did not have a significant effect on outcomes receiving immunotherapy in lung cancer patients. However, a more comprehensive nutritional assessment using a composite endpoint of BMI and serum albumin predicted response to checkpoint inhibitors. Additional studies are needed to validate these findings.
Personalized peptide vaccination for castration-resistant prostate cancer progressing after docetaxel chemotherapy: A randomized, double-blind, placebo-controlled, phase III trial.
Authors: Masanori Noguchi, Kiyohide Fujimoto, Gaku Arai, Hiroji Uemura, Katsuyoshi Hashine, Hiroaki Matsumoto, Satoshi Fukasawa, Hideomi Nakatsu, Atsushi Takenaka, Masato Fujisawa, Hirotsugu Uemura, Seiji Naito, Shin Egawa, Hiroyuki Fujimoto, Shiro Hinotsu, Kyogo Itoh, Yasuo Kohjimoto
Journal: Journal of Clinical Oncology (2019)

5033 Background: To develop a new treatment modality, we conducted a phase III randomized trial of personalized peptide vaccination (PPV) for human leukocyte antigen (HLA) -A24 positive patients with castration-resistant prostate cancer (CRPC) who failed docetaxel chemotherapy. Methods: Patients were randomly assigned in a 2:1 ratio to receive PPV or placebo. Four of 12 warehouse peptides selected based on preexisting peptide-specific immunoglobulin G levels or the corresponding placebo were subcutaneously injected 6 doses weekly followed the maximum of 30 doses bi-weekly until disease progression. The primary end point was overall survival (OS), and secondary end points were progression-free survival (PFS) and immune responses. Results: From August 2013 to April 2016, 310 patients were randomly assigned (207 to PPV and 103 to placebo), and 306 patients were analyzed by the full analysis set (204 to PPV and 102 to placebo). Baseline characteristics were balanced between groups. Estimated median OS was 16.1 months (95% CI, 13 to 18.2) with PPV and 16.9 months (95% CI, 13.1 to 20.4) with placebo (HR, 1.04; 95%CI, 0.79 to 1.37; P = 0.77). Median PFS was also not significantly different among them. Median Grade ≥ 3 adverse events were observed in 41% in both groups. The analysis of treatment arm effects among various subgroups revealed a lower HR for OS in favor of the PPV arm in patients with a &lt; 64% neutrophil proportion (HR, 0.55; 95%CI, 0.33 to 0.93), with a significant interaction test ( P = 0.003). Conclusions: PPV did not prolong either OS or PFS in HLA-A24 positive patients with CRPC progressing after docetaxel chemotherapy. Clinical trial information: 0000113088.
Abstract 20512: Metabolic Reprogramming of Cardiac Progenitor Cells by Lin28 Enhances Cardiac Repair Potential
Authors: Priya Zaveri, Daria Harlamova, Sadia Mohsin, Steven R Houser, Mohsin Khan
Journal: Circulation (2017)

Introduction: Cardiac progenitor cells (CPCs) possess incredible repair properties in the neonatal heart but are prone to disease and age diminishing their efficacy. Interestingly, CPCs stemness is...
Real-world treatment patterns and outcomes in ER+/PR+/HER2+ metastatic breast cancer (MBC) patients: A National Cancer Database analysis.
Authors: Abby Statler, Zeina A. Nahleh, Brian Hobbs, Wei (Auston) Wei, Annie Gupta, Cassann N. Blake
Journal: Journal of Clinical Oncology (2019)

1033 Background: Treatment patterns and clinical outcomes are unclear for MBC patients diagnosed with estrogen receptor-positive (ER+) and/or progesterone receptor-positive (PR+) human epidermal growth factor 2 positive (HER2+) disease (i.e. triple positive). This study aimed to: 1) examine the utilization of first-line therapy among ER+/PR+/HER2+ MBC patients and 2) compare overall survival (OS) between the identified regimens. Methods: We analyzed triple positive MBC patients included in the National Cancer Database who were treated with endocrine therapy (ET) or chemotherapy (chemo) between 2010 and 2015. Kaplan-Meier method was used to estimate distributions of OS, which were compared among patient cohorts using the log-rank test. Results: A total of 6,234 patients were included in the analysis; of these, 3770 (60%) received ET and 2464 (40%) received chemo. Of those with complete survival data, there was no difference in median OS between patients treated with chemo vs. ET; however, those who received anti-HER2 therapy had significantly better OS than those who did not (median OS 49.4 vs. 41.0 months, p &lt; 0.0001). Median OS stratified by ET or chemo with and without anti-HER2 further supported these findings, revealing the addition of anit-HER2 therapy to chemotherapy and ET resulted in superior median OS (Table). Conclusions: This is the first study to evaluate treatment utilization and OS among real-world triple positive MBC patients treated with ET or chemo. Our results suggest the majority of patients in the United States are treated with first-line ET; furthermore, the reported OS outcomes support the consideration of ET plus anti-HER2 therapy as a first-line treatment option for ER+/PR+/HER2+ MBC. Prospective trials evaluating de-escalation of systemic therapy in this subgroup of patients and future research to identify biomarkers to determine which patients can avoid chemotherapy are warranted. [Table: see text]
A large retrospective analysis of CDK 4/6 inhibitor retreatment in ER+ metastatic breast cancer (MBC).
Authors: Carlos Henrique dos Anjos, Pedram Razavi, Joshua Herbert, Jodecy Colon, Kaitlyn Gill, Shanu Modi, Jacqueline Bromberg, Chau T. Dang, Dazhi Liu, Larry Norton, Sarat Chandarlapaty, Mark E. Robson, Komal L. Jhaveri
Journal: Journal of Clinical Oncology (2019)

1053 Background: Sequential retreatment with endocrine therapy (ET) has been the clinical paradigm for ER+ MBC due to persistent dependence on hormone signaling. Recently CDK4/6i + ET have improved PFS and are routinely utilized in the first/second- line setting. Whether this paradigm of sequential retreatment holds for CDK 4/6i is unknown. To evaluate the potential benefit of CDK4/6i re-treatment we conducted this retrospective analysis. Methods: We identified ER+/HER2- MBC pts treated with ≥ 2 lines of CDK4/6i at our institution between 2015-2018. We categorized pts based on reason for discontinuation of their first CDK4/6i: cohort 1 – switch to alternate CDK4/6i due to toxicity; cohort 2 – retreatment with same CDK4/6i beyond progression with change of ET and cohort 3- switch to alternate CDK4/6i as monotherapy or with same or another ET. We analyzed pt demographics, imaging reports and time to subsequent therapy (TTST) for every CDK4/6i line for each cohort. If a pt received &gt; 2 lines of CDK4/6i, then that pt was evaluated for every CDK4/6i exposure. Results: 135 pts received ≥ 2 lines of CDK4/6i treatment (Tx). Cohorts 1, 2 and 3 had 23, 43 pts and 84 pts respectively. In Cohort 2, 95% of pts received 2 subsequent CDK 4/6i + ET Tx; 56% had the second CDK4/6i in second-line met setting. TTST1 (1st CDK4/6i Tx) was 9.6m (95% CI 4.9 - 11 m), TTST2 (second CDK4/6i Tx) was 4.5m (95% CI 3.3 – 7.6 m) and 35% had TTST2 ≥ 24 weeks. For Cohort 3, 48% were retreated with a different CDK 4/6i in ≥ fifth-line. 51% received 2 subsequent CDK 4/6i Tx with 18% in second-line met setting. TTST1 was 9.6 m (95% CI 5.9 – 12 m), TTST2 was 4.4 m (95% CI 3.8 – 5.9 m) and 29% had TTST2 ≥ 24 weeks. In cohort 3, 29% (n=24) pts had PD as best response at the time of first CDK4/6i exposure but 29% (7/24) achieved a radiologic response to their second CDK4/6i Tx. Pts had tumor sequencing using MSK-IMPACT which will be correlated with TTST. Conclusions: This large single institution retrospective analysis suggests that retreatment with a CDK4/6i regimen should be evaluated in prospective trials. Additionally, despite PD as best response with the first CDK4/6i (palbociclib/ribociclib) regimen, a subset of pts had radiologic response to a subsequent abemaciclib-containing regimen, which is an hypothesis generating observation.
David Oliver: The CQC, hierarchies, and hospital safety
Authors: David Oliver
Journal: BMJ (2019)

Last month Ted Baker, chief inspector of hospitals at the Care Quality Commission, said that safety in many NHS hospitals wasn’t improving quickly enough.1 Although performance had improved in recent years, 40% of services still received ratings of “requires improvement” or “inadequate” for safety.

In the same speech he compared hospitals with other sectors, including the aviation industry. I’m sure he was right to say that a focus on safety first, as an overarching priority and mission, isn’t so well ingrained in the NHS. But he also mentioned pilots not leaving the stand if a flight wasn’t safe, however much trouble they got into for missing schedules, and an “elastic attitude to safety” among …
Consistent efficacy of nivolumab plus ipilimumab across number of International Metastatic Database Consortium (IMDC) risk factors in CheckMate 214.
Authors: Bernard Escudier, Robert J. Motzer, Nizar M. Tannir, Camillo Porta, Yoshihiko Tomita, Sabeen Fatima Mekan, M. Brent McHenry, Brian I. Rini
Journal: Journal of Clinical Oncology (2019)

4575 Background: The IMDC prognostic model was created based on anti-VEGF treatments for advanced renal cell carcinoma (aRCC), and may not be relevant for immunotherapy. Methods: In a post hoc analysis of CheckMate 214, we compared efficacy with nivolumab + ipilimumab (N+I) vs sunitinib (S) by number of IMDC risk factors present. Results: Among 1096 intent-to-treat (ITT) patients (pts) in both arms, 21%, 61%, and 18% had favorable, intermediate (int), or poor-risk, respectively. Of int-risk pts, 58% had 1 factor (most commonly &lt;1 y from diagnosis [Dx], 52%; Hb &lt; LLN, 27%; or KPS ≤70%, 10%); and 42% had 2 factors (of these pts, the most common combination of 2 factors was &lt;1 y from Dx and Hb &lt; LLN, 59%). Of poor-risk pts, 58% had 3 factors, 29% had 4 factors, and few had 5 (10%) or 6 (3%) factors. Due to small numbers, pts with 4–6 factors were pooled. At 30-mo minimum follow-up, RECIST v1.1-confirmed objective response rate (ORR) and complete response (CR) rate per investigator remained consistently higher with N+I vs S across pts with 1–4 factors, although with S, ORR decreased with increasing number of factors (Table). Improved progression-free survival (PFS) and overall survival (OS) were seen with N+I over S irrespective of the number of factors present, including in pts with only 1 risk factor (Table). Conclusions: N+I showed consistent efficacy across number of IMDC risk factors, while S decreased in efficacy with increasing number of factors. Efficacy of N+I was superior to S in all int- and poor risk pts. These CheckMate 214 results along with prior CheckMate 025 data showing consistent OS benefit with N monotherapy across IMDC risk categories show a need for improved prognostic models for immunotherapies in aRCC. Clinical trial information: NCT02231749. [Table: see text]
Patient controlled analgesia (PCA) versus non-PCA intravenous hydromorphone titration for severe cancer pain: A randomized, controlled, multicenter, phase III trial, HMORCT09-1.
Authors: Rongbo Lin, Jinfeng Zhu, Shuitu Feng, Sunzhi Lin, Jianqian Fu, Yongzhi Yao, Lixia Hong, Min Xin, Zhangshu Chen, Zhenyu Cai, Chunxiang Li, Shen Zhao, Qingyi Wu, Shangwang Yang, Cheng Huang
Journal: Journal of Clinical Oncology (2019)

TPS11635 Background: The opioid dose for an individual with cancer pain to provide adequate relief of pain with an acceptable degree of side effects is variable. Opioid titration is a process to obtain the tailored dose. Conventional titration is administered by a clinician or nurse. PCA is that patients control cancer pain by self-administration of intravenous opioids using programmable pump. The aim of our study is to evaluate the efficacy of PCA titration versus conventional titration intravenously for severe cancer pain (10-point numerical rating scale, NRS ≥ 7). Injectable Hydromorphone was selected as pharmaceutical analgesics, which works as well as morphine and oxycodone and had similar side effects. Methods: This is currently enrolling patients (n=230) with severe cancer pain during previous 24 hours. Patients are randomized 1:1 and stratified by opioid intolerance or opioid tolerance into PCA or non-PCA titration. PCA titration using programmable pump: bolus hydromorphone at 0.5mg (for opioid intolerance) or hydromorphone dose equivalent to 10% to 20% of the total opioid taken in the previous 24 hours with a lockout time 15 minutes (for opioid tolerance) was administered by the patients educated. No basal infusion was set in the pump. Non-PCA titration administered by a nurse or clinician: Initial hydromorphone doses were same with PCA titration. Reassess pain at 15 minutes. Increased dose of hydromorphone by 50%-100% if pain unchanged or increased, or repeat same dose if pain decreased to NRS 4-6, or continue at current effective dose as needed over initial 24 hours. The primary endpoint is the time needed to successful titration was defined the time from the first dose of hydromorphone after randomization to achieve satisfied pain control. The satisfied pain control was defined NRS pain score ≤ 3 at rest in at least 2 consecutive assessment (15 minutes interval). The time needed to successful titration was extended to achieve satisfied pain control again if NRS pain score ≥ 7 after satisfied pain control within 24 hours. The failure of successful titration was defined that satisfied pain control does not achieve within 24 hours. Secondary endpoints include the percentage of patients titrated successfully, the mean NRS pain score of 24 hours, the total dose of hydromorphone titrated, and adverse events. Clinical trial information: NCT03375515.
Combination of tissues analysis and immune infiltrate in localized colon cancer using artificial intelligence in PETACC8 study.
Authors: Cynthia Reichling, Julien Taieb, Valentin Derangere, Karine Le Malicot, Jean Francois Emile, Jean Marc Gornet, Hakim Becheur, Francine Fein, Oana Cojocarasu, Marie-Christine Kaminsky, Jean-Paul Lagasse, Dominique Luet, Suzanne Nguyen, Pierre-Luc Etienne, Mohamed Gasmi, Andr Vanoli, Herve Perrier, Quentin Klopfenstein, Come Lepage, Francois Ghiringhelli
Journal: Journal of Clinical Oncology (2019)

3574 Background: We used artificial intelligence to perform tissue classification and count CD3 and CD8 in each subclass and determined their role in outcome prediction in PETACC8 cohort of stage III colon cancer treated with FOLFOX or FOLFOX plus cetuximab. Methods: We developed artificial intelligence aimed to detect tumor, healthy mucosa, stroma and immune cells on whole slide of CD3 and CD8 staining. The invasive margin (IM) was also automatically determined. Using a lasso algorithm, the software was able to detect digital parameters within the tumor core (TC) which were related to patients’ outcome (variable called DGMate for DiGital tuMor pArameTErs). CD3 and CD8 lymphocytes density were also quantified automatically by the software in TC and at IM. Associations with disease-free survival (DFS) were evaluated by multivariable Cox regression adjusting for age, T/N stage, sidedness, KRAS/BRAF, DNA mismatch repair (MMR). Results: On 1220 samples collected, data could be generated for 1018 patients. We observed that a high IM stromal area and a high DGMate were associated with a poorer DFS [HR 5.65 (95% CI, 2.34, 13.67), p &lt; 0.0001; HR 2.72 (95% IC, 1.92, 3.85), p&lt;0.001 respectively for the continuous variable]. A higher density of CD3 + TC, CD3 + IM and CD8 + TC were significantly associated with a longer DFS (HR 0.75 (95% IC, .66, .87), p&lt;0.0001; HR 0.78 (95% IC, .68, .88), p&lt;0.0001; HR 0.83 (95% IC, .71, .96), p=0.01). All these immune variables were significantly correlated with each other. ANOVA test demonstrated that CD3 + TC gave a similar prognostic value compared to the classical CD3/CD8 immunoscore (p=0.44). The combination of IM stromal area, DGMate and CD3 outperformed the classical CD3/CD8 immunoscore to estimate patients’ prognosis (C-index= 0.601 vs 0.578, p-value=0.04). Adding this new variable to classical clinical prognostic parameters we generated a nomogram which predicted the risk of relapse of stage III colon cancer with a stronger predictive value compared to clinical parameters or the immunoscore. Conclusions: We propose a new fully automated method of whole slide analysis using a software based on artificial intelligence which classify tissue and determine tumor and immune parameters on one single slide stained with CD3 antibody. This valuable strategy outperforms immunoscore and clinical outcome prediction models.