tbuckley/cabot-search huggingface dataset:
PI3K mutation and effect of aspirin use in breast cancer.
Authors: Shou-Ching Tang, Priyanka Raval, Mohamad Bassam Sonbol, Josh David Simmons, Rohini Chintalapally, Natasha Savage, Ravindra B. Kolhe, Eiko Kitamura, Chang-Sheng Chang, Mark Robert Keaton, Nita J. Maihle, Sangmi Kim
Journal: Journal of Clinical Oncology (2017)

e23209 Background: Increasing literature suggests a protective role of aspirin in breast cancer. PI3K mutation is prevalent in 30% of estrogen receptor positive and 50% of HER2 receptor positive breast cancers. Aspirin inhibits prostaglandin-endoperoxide synthase 2 (PTGS2) through down-regulation of phosphatidylinositol 3-kinase (PI3K). A study in colorectal cancer demonstrated that regular use of aspirin was associated with superior survival among patients with PI3K mutated tumors. The aim of this study was to retrospectively examine the presence of PI3K mutation in breast cancer tissue in patients who used aspirin during treatment, and compare survival between those with and without PI3K mutations. Methods: Among 1259 patients diagnosed with breast cancer between year 2002 to 2013 at Augusta University (AU), 47 patients who used at least 81 mg of aspirin daily during cancer treatment were identified, and their breast cancer tissue blocks were analyzed for PI3K mutation by gene sequencing technique. Genomic DNAs were extracted from formalin fixed paraffin-embedded tissues using GeneRead DNA FFPE kit (Qiagen) and sequenced on Miseq sequencer (Illumina). We selectively analyzed five genes involved in the PI3K pathway, including PIK3CA, AKT, PIK3R1, PTEN, and TP53. The presence of mutation was correlated to overall survival, using Kaplan-Meier and Cox Regression analyses. Results: Of the 47 patients, 53% were Caucasian and 47% were African American. 70% were early stage (TNM stage I, II) and 30% were late stage (TNM stage III, IV). 69% were never smokers, 31% were current or former smokers. ER, PR and HER2 were expressed in 84%, 79%, and 86% patients respectively. 66% had PI3K mutation, and 34% were PI3K wild type. There was no significant difference (log-rank test p = 0.28) in overall survival (OS) of patients with PI3K mutation versus those without, although the former group had longer survival numerically. The multivariable-adjusted hazard ratio (HR) for PI3K mutation was 0.53 (p = 0.29). Conclusions: Our project supports justification for a larger study to explore the role of aspirin in prevention, treatment and prognosis of breast cancer, and to validate biomarkers such as PI3K and related genes mediating the aspirin effect.
Evaluation of value in non-inferiority trials by ASCO’s conceptual framework.
Authors: Kenichi Miyamoto, Junki Mizusawa, Taro Shibata, Kenichi Nakamura, Junko Eba, Hiroshi Katayama, Haruhiko Fukuda
Journal: Journal of Clinical Oncology (2016)

e18276 Background: ASCO released a conceptual framework assessing the value of cancer treatment options in 2015 to evaluate clinical benefit and toxicity of clinical trials. In this framework the number of adverse event (AE) items of which at least one patient develops G3-5 is counted but the frequency of AE is not considered. On the other hand, evaluation of the frequency of AE is important in non-inferiority trials; because test treatments are generally considered less toxic than standard treatments when the frequency of AE is lower. We investigated whether the ASCO framework can identify reasonable difference between the arms in toxicity evaluation of non-inferiority trials. Methods: A systematic literature search of randomized non-inferiority trials for cancer reported from 2009 to 2015 was conducted using PubMed. Inclusion criteria were English, a full-length article, available toxicity data, non-inferiority trial with a positive result, and chemotherapy. We calculated clinical benefit, toxicity score, bonus points, and net health benefit in ASCO’s framework. We also calculated the ratio of the total frequency of G3-5 AEs and estimated toxicity scores using ASCO’s framework. Results: We found 17 non-inferiority trials. Median sample size was 412 pts. The common cancer types included colorectal (5 trials), lung (4), and hematologic (2), and breast (2). Of 17 trials, 6 were conducted internationally, 4 in Germany, and 3 in Japan. In the ASCO framework, the toxicity scores of 16 trials (94%) were calculated as zero, which means toxicities between the arms are same, including 5 trials adopted in the NCCN guidelines. One trial scored -10 points, which means the test treatment was less well tolerated. Even when we calculated toxicity score based on the frequency of G3-5 AEs, only 2 trials showed difference between the arms (scored -10 points, -20 points, which means the test treatment was substantially less well tolerated). Conclusions: In the ASCO framework, toxicity difference was not identified even in the trials adopted in the NCCN guidelines, which reflect clinically meaningful less-toxicity evaluated by oncology communities. Establishing a better method to assess the risk balance in non-inferiority trials is desirable.
Comparison of treatment-related fatigue and tolerability between PD-1 immune checkpoint inhibitors and chemotherapy: A meta-analysis.
Authors: Tomohiro F. Nishijima, Shlomit S. Shachar, Hyman B. Muss
Journal: Journal of Clinical Oncology (2016)

10114 Background: Programmed death receptor-1 (PD-1) inhibitors nivolumab and pembrolizumab have been approved by the FDA for metastatic melanoma, non-small cell lung cancer (NSCLC) and renal cell carcinoma. Although fatigue has been described with these agents, the overall risk remains unclear. Fatigue is one of the most distressing adverse events (AEs) and negatively affects patients’ quality of life. We performed a systematic review and meta-analysis to compare treatment-related fatigue and tolerability between PD-1 inhibitors and standard-of-care chemotherapy. Methods: Studies were identified using PubMed, and ASCO abstract databases up to September 2015. The primary outcome was fatigue. Treatment discontinuation and any all (1-4) or high (3-4) grade AEs were secondary outcomes. Eligible studies included phase II/III randomized controlled trials (RCTs) comparing single agent PD-1 inhibitor with chemotherapy in cancer patients that reported adequate safety data for the primary and secondary outcomes. The summary incidence, relative risk (RR), and 95% confidence intervals (CIs) were calculated (comprehensive meta-analysis program Ver. 2, Englewood, NJ). Results: A total of 2,124 patients from five RCTs were included in the analysis with four nivolumab phase III trials and one pembrolizumab phase II trial. The underlying malignancies included were melanoma (3 trials) and NSCLC (2 trials). The incidence of all-grade and high-grade fatigue was respectively 20.7% and 0.8% for PD-1 inhibitor arm and 28.6% and 4.5% for chemotherapy arm. The risk of fatigue, treatment discontinuation and any AEs was significantly lower with PD-1 inhibitor compared with chemotherapy (Table). Conclusions: PD-1 inhibitors are associated with a significantly lower risk of developing treatment-related fatigue and better tolerability than chemotherapy. Our results provide further evidence supporting the favorable risk-benefit ratio for PD-1 inhibitors. RR (95% CI) P value Fatigue (G1-4) 0.71 (0.53-0.96) 0.024 Fatigue (G3-4) 0.18 (0.09-0.37) < 0.001 Treatment Discontinuation 0.46 (0.33-0.65) < 0.001 Any AEs (G1-4) 0.84 (0.74-0.95) 0.005 Any AEs (G3-4) 0.32 (0.16-0.65) 0.002
Strategies to embed palliative care into a culture of cancer care.
Authors: Angela Marie Taber, Susan F. Korber, Edward Martin, Anthony E. Mega
Journal: Journal of Clinical Oncology (2017)

e21678 Background: In 2012, the 3 hospital Lifespan Health System launched a palliative care initiative. The hospitals and medical oncologists knew this was critical for patient centered and value-based cancer care, but recognized many barriers: physician practice patterns, lack of dedicated resources and systems, patient and family education gaps, and limited return on investment in the current environment. A multi-level inpatient and outpatient strategy was implemented and tracked over four years. Methods: External benchmarking data from a Medicare claims analysis of Vizient (academic health system consortium) member organizations and from ASCO QOPI data were used in the analysis. Internal data analysis included a study on symptom management for lung cancer patients, hospital reports on palliative care service utilization, ED visits and hospital admission trends for cancer patients. Multi-level interventions were employed: hospital investment in staff and systems, partnership with a community-based hospice and palliative care provider, a medical oncology physician champion with Board certification in palliative care, a palliative care inpatient consult service and daily ICU rounds, an oncology medical home, medical oncologist Saturday hours, electronic prompts for consults, and a cancer call triage center. Results: A Medicare claims analysis for 2012 to 2014 on cancer decedents with ICU stays in the last 30 days in the Vizient national study of health systems showed that Lifespan was at the 11th percentile, making them the 4th lowest (days in ICU) in performance (pre/post data requested). QOPI data on appropriate referrals to hospice or palliative care prior to death improved from 58% in 2010, which was below the QOPI benchmark of 61%, to 94% in 2016 which is above the QOPI benchmark of 74%. Other QOPI and hospital data will be included in the presentation. Conclusions: Palliative care, a crucial tool for the delivery of future cancer care, is challenging to implement effectively. This study shows that a hospital/medical oncology partnership can drive change to embed palliative care into the culture of cancer care and these strategies offer a roadmap for others to follow as they strive to offer patient centered and value-based cancer care.
Risk of breast cancer in patients exposed to insulin glargine compared to human NPH insulin.
Authors: Peter Boyle, Chuntao Wu, Kristen Sharma, Stephen Lin, Juhaeri Juhaeri
Journal: Journal of Clinical Oncology (2018)

e13592 Background: Diabetes and breast cancer are common diseases in women. Studies of the association have been heterogeneous. The objective of this study was to compare the risks of breast cancer in women treated with insulin glargine and NPH using claims data. We set out to provide more information regarding this potential association from real world studies. Methods: The MarketScan and Clinformatics databases were used to identify patients prescribed glargine or NPH in the study periods of January 2007 to March 2016 and July 2005 to June 2016, respectively. The risks of breast cancer in patients prescribed glargine relative to NPH were compared using three approaches: (1) on-treatment, (2) intent-to-treat and (3) time-dependent analysis. The overall and follow-up period stratified adjusted hazard ratios (aHRs) for breast cancer for glargine compared to NPH were obtained using Cox proportional hazards modelling controlling for potential confounders. Results: In the MarketScan database, 75,422 glargine and 21,491 NPH patients were identified, of which 42,491 glargine and 7,826 NPH patients were new users. Using the Clinformatics database, 65,648 glargine and 16,194 NPH patients were identified, including 47,118 and 10,560 new users, respectively. The overall aHRs for breast cancer for glargine compared to NPH ranged from 0.90 (95% CI: 0.76 – 1.07) in the time-dependent analysis for all users in the Clinformatics database to 1.30 (95% CI: 0.76 – 2.25) in the on-treatment analysis for new users in the MarketScan database. In the MarketScan database, the aHRs stratified by the follow-up period ( < 1, 1 - < 3, 3 - < 5 and ≥ 5 Years) ranged from 0.67 to 1.63. In the Clinformatics database the corresponding aHRs ranged from 0.85 to 1.40. All 95% confidence intervals (CIs) included the null value of 1. Conclusions: The risks of breast cancer were not different between patients prescribed glargine and NPH. Additionally, no association between glargine and breast cancer was observed with follow-up longer than 5 years. Taken on their own, these findings suggest that the risk of breast cancer in patients prescribed glargine was not different from that in NPH patients and they also contribute to the growing body of evidence.
Implementing and analyzing a distress screening tool (DST) in a community oncology setting: Breaking down barriers to comprehensive medical and psychosocial (PS) care—The Kaiser Permanente Lone Tree, CO (KP-LT) experience.
Authors: Scott Arthur Kono, Jammie Reichel, Alex R. Menter, Stephen Armond Mayer, Lillian Klancar, Keren Sturtz, Vignesh Narayanan, Rebecca Crank, Brenda Elliot, William G Grimes, Jeromie Barden, Kylee Virdi
Journal: Journal of Clinical Oncology (2017)

e21553 Background: PS distress (D) in cancer patients is an underestimated barrier to optimal care. The NCCN recommends D screening and intervention for D scores (DS) ≥4. KP is an ideal environment for large-scale screening. We sought to identify barriers in DST compliance, find a successful standardized workflow (SWF), and understand sources of D to elevate the standard of PS care. Methods: The DST was administered by the physician at completion of initial encounter to all new patients. Compliance recorded before and after implementing a SWF in 2/2016. Our DST utilizes 4 Major Categories of Distress (MCD) [Practical (P), Social (S), Health (H), Emotional (E)] to identify specific areas of D, and stratify DS by diagnosis [Benign (BH)-, Malignant- (MH) Hematology, Solid Tumor (ST)]. Clinic outreached any patient with a 4+ DS. DST was modified (mDST) 9/2016 to provide a DS for each MCD rather than 1 overall DS to improve practicality. Results: 936 DSTs completed from 6/2015-1/2017 (304/632 were mDST). DST compliance increased from 51% to 78% after the SWF. 289/632 (46%) scored 4+ (avg. DS 6.15). 153/304 (54%) mDSTs scored 4+ in ³ 1category. The avg. DS was 3.9 (n=936). Avg. DS for: BH= 3.67 (50% scored 4+, avg. 6.0), MH=3.79 (49% score 4+, avg. 6.14), and ST=4.02 (54% score 4+, avg. 6.18). The 3 most common concerns in each MCD are reported in Table 1. Most frequent outreach requests: Dietitian (n=88, 9%), LCSW (n=70, 7%), and Financial Counselor (n=50, 5%). Conclusions: Sources of D are a patient reported metric, not provider-assumed. DST use is feasible and essential to comprehensive cancer care. A SWF is crucial for success and led to a 27% increase in compliance. 4+ DS is frequent and was higher than expected in BH. Identifying specific stressors allows early intervention and improved resource utilization. [Table: see text]
Distress management in lung cancer patients undergoing prehabilitation.
Authors: Leonard Gonzalez, Philip Glynn, Gale Mason, Mariellen Counter, Jack Jury, Erica Gaeta, Neal Chuang, Laki Rousou, Rachel Sapelli
Journal: Journal of Clinical Oncology (2016)

e21539 Background: Recent emphasis has been given to preoperative care in lung cancer patients. The best practices for rehabilitation during this time (prehabilitation) have not been established. At Sister Caritas Cancer Center, we performed an exploratory pilot to address several domains of a lung cancer patient's life and care before surgery. This report calls attention to the importance of including interventions for the physical and psychosocial health of these patients. Methods: Lung cancer patients seen at Sister Caritas enrolled in a prehabilitation (time from diagnosis to possible surgery) pilot for the STAR (Survivorship Training and Rehabilitation) Program. Patients received an individualized multi-modal program requiring targeted respiratory and routine exercises, education on smoking cessation, and nutrition counseling. Educational materials regarding coping strategies were given to every patient and an appointment with a counselor to discuss these strategies was recommended but optional. At the initial and final prehabilitation visit before surgery, patients were assessed with the Visual Analog Scales (VAS) for pain, fatigue and distress, Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), Timed Up and Go Test (TUG), and the 6-min Walk Test. Results: 11 patients (6 females, 5 males) followed during their prehabilitation period (Avg 13 days) participated in the required activities. All 11 patients declined the optional counseling visit to address coping strategies. The Avg levels of distress increased from 3.0 to 4.0 on the Distress VAS. The Avg Worst Distress VAS changed from a 3.2 to 6.4 across the prehabilitation period. Other functional and performance measures improved during the same period (to be presented at the meeting). Conclusions: As a cancer patient nears surgery, it appears to be an increasingly anxious and stressful period of their care continuum. Although the functional and performance measures are closely monitored during prehabilitation, more research and awareness of distress is needed to effectively guide patients to appropriate counseling and better care for their psychological status.
Oncology drug approval: Questioning efficacy evidence.
Authors: Amina B. Taleb
Journal: Journal of Clinical Oncology (2018)

e18888 Background: In the last decade, drug approval was based on surrogate endpoints, often with no OS or QOL benefit. On the grounds of « faster access to innovative therapies », the conventional development phases are skipped and approval process rely on small studies or seamless approach which are expanded phase I trials, lowering the evidence of efficacy. This led to a huge number of molecules on the market with uncertain benefit. In addition, once a first-in-class is approved, similar agents or « me-too » drugs are following. Although adding new options to existing treatments, small gains rather than meaningful clinical outcomes are accepted. With lack of efficacy evidence and rising costs, this is unlikely to be sustainable. Methods: Search for registration trials leading to approval, publications, ASCO abstracts, Pubmed, regulatory documents. Results: From 2008 to 2012, FDA approvals were based on surrogate markers, with no OS benefit and no improved QOL for 67 % (36/54). At a median follow-up 4.4 years, only 5/36 drugs improved OS in randomized controlled trials. From 2009 to 2013, EMA approved 48 cancer drugs for 68 indications in which 39 (57%) on surrogate endpoints, with absence of OS benefit or improvement QOL. In post-marketing with median follow of 5.4 years, only 35 (51%) drugs showed a significant improvement in OS or QOL. Data from 2010 to 2017, reported the rising use of seamless approach which are combined studies, instead of conventional clinical development. Of 1786 phase I/II trials, 51 were seamless trials. FDA granted accelerated approval for 8 drugs (16%) using seamless design. In France, CAV (clinical added value) assessment is performed on a 5-point scale, ranging from major to no CAV. In a retrospective analysis, from 2010 to 2015, 78 new cancer indications reported, 32 (41%) had a minor CAV and 26 (33%) no CAV. Conclusions: Lowering the efficacy evidence could be harmful for the patients and the healthcare systems, hence the need to question the current approval process and make a concerted effort sharing the different stakeholders goals.
A pediatric phase 1 study of LOXO-101, a highly selective inhibitor of the tropomyosin receptor kinase (TRK) family.
Authors: Ramamoorthy Nagasubramanian, Steven G. DuBois, Theodore Willis Laetsch, Leo Mascarenhas, Steven Smith, Mark Reynolds, Scott Cruickshank, Lia Donahue, Alberto S. Pappo, Michael Craig Cox
Journal: Journal of Clinical Oncology (2016)

TPS10583 Background: The TRK family of neurotrophin receptors, TRKA, TRKB, and TRKC (encoded by NTRK1, NTRK2, and NTRK3 genes, respectively) and their neurotrophin ligands regulate growth, differentiation and survival of neurons. Translocations involving the NTRK1/2/3 kinase domain, mutations involving the TRK ligand-binding site, amplifications of NTRK, TRK splice variants, and autocrine/paracrine signaling have been described in many tumor types and may contribute to tumorigenesis. In pediatric tumors, the ETV6-NTRK3 fusion is the hallmark genetic abnormality of infantile fibrosarcoma (IF) and cellular congenital mesoblastic nephroma (CMN). TRK over-expression is common in neuroblastoma. LOXO-101 is a potent, oral, ATP-competitive pan-TRK inhibitor with IC50 values in the low nanomolar range for inhibition of TRK family members, with 100x selectivity over other kinases. LOXO-101 is the only selective pan-TRK inhibitor in development and has demonstrated tumor inhibition in preclinical models and meaningful responses in an adult phase 1 trial. Methods: This study (NCT02637687) is an ongoing phase I dose escalation and expansion multicenter trial in pediatric patients with advanced solid and primary CNS tumors. Dose escalation uses a Rolling 6 design. Eligible patients include those with solid or CNS tumors refractory to standard therapy between 1 and 21 years of age with adequate hematopoietic and major organ function are eligible for study. Patients ≥ 1 month of age with a primary diagnosis of IF or CMN and a documented NTRK fusion are also eligible. LOXO-101 is administered orally BID for continuous 28-day cycles. Capsule and liquid solution dosage forms will be used. This component of the trial will determine the MTD. For the dose expansion component, patients must have a demonstrated alteration in one of the three NTRK genes or TRK proteins. The number of expansion cohorts will be determined by the molecular characteristics of the tumors in the patients enrolled. Data will provide initial evidence of tumor activity of LOXO-101as well as further elucidation of the safety profile of LOXO-101 in pediatric patients. Archival tissue will be used to further characterize molecular abnormalities. Clinical trial information: NCT02637687.