tbuckley/cabot-search huggingface dataset:
Internal medicine residents' perception of cancer prognosis.
Authors: Jared David Acoba, Loni Belyea
Journal: Journal of Clinical Oncology (2017)

e18214 Background: Cancer is the second leading cause of death in the US. Many internal medicine physicians feel uncomfortable having to prognosticate, however oncology patients often ask this of them. The inability to provide an accurate prognosis could lead a patient to make a treatment decision incongruent with their true wishes. We conducted this study to assess resident and attending physicians’ knowledge of cancer prognosis. Methods: We conducted a prospective cross-sectional study to assess internal medicine resident and attending physician knowledge of median survival for seven different oncologic case scenarios. We asked participants to choose a median survival of: (a) ≤6 mo, (b) 10-12 mo, (c) 24-36 mo, or (d) 48-60 mo for each scenario. Residents were asked to identify the source(s) of information that most significantly influenced their choices. All internal medicine residents and attending physicians affiliated with the University of Hawaii Internal Medicine Residency Program were invited to participate. Results: A total of 67 of 85 surveys were completed, representing 41 residents and 26 attending physicians. Overall, the respondents correctly estimated median survival 42.6% of the time. The respondents underestimated more often than overestimated median survival (46.3% vs 14.9%, p = 0.0001). Survival in colon and pancreatic cancer were most often underestimated (61% and 53%, respectively). We found no statistically significant difference between resident and attending physician responses. Of the residents who underestimated survival, 73% sited inpatient experience as influencing their oncologic knowledge. Conclusions: Internal medicine residents and attending physicians correctly estimate median survival of cancer patients less than 50% of the time and often underestimate survival. Inpatient rotations, where residents care for the oncologic patients experiencing significant complications of their cancer and treatment, may be giving them an unbalanced perspective on cancer prognosis. Improving oncologic education to provide a more balanced perspective may be critical in improving perception of prognosis so that patients can be provided with accurate information when trying to make critical treatment decisions.
Trial in progress: Platform phase 1 study investigating the safety of stereotactic body radiotherapy with immuno-oncology agents for the treatment of multiple metastases in advanced solid tumors.
Authors: Corey Christian Foster, Gregory Kauffmann, Steven J. Chmura, Jason J. Luke
Journal: Journal of Clinical Oncology (2018)

TPS3121 Background: Stereotactic body radiotherapy (SBRT) and immuno-oncology (IO) have been associated with improved oncologic outcomes when given as monotherapy for advanced solid tumors. Furthermore, preclinical studies have suggested synergistic interactions between SBRT and IO agents with enhanced anti-tumor activity possibly mediated by the induction of CD8+ T-cells. Additionally, patients with advanced melanoma receiving dual IO therapy in the absence of SBRT experienced longer overall survival than patients receiving single-agent IO therapy. Given these findings, it is reasonable to hypothesize that dual IO therapy in combination with SBRT may be more efficacious than any of these treatments alone. However, the safety of multiple IO agents given in combination with SBRT is unknown. Methods: The study is a single-center, phase 1, open-label, two-arm, non-randomized clinical trial for patients with advanced solid tumors and at least 1 measurable site of disease after receiving ≤ 3 prior systemic therapies. Enrolled patients receive either (1) concurrent nivolumab (anti-PD-1, 240 mg IV flat dose every 2 weeks) + urelemab (anti-CD137, 8 mg flat dose IV every 4 weeks) + SBRT or (2) concurrent nivolumab (240 mg IV flat dose every 2 weeks) + cabiralizumab (anti-CSF1R, 4 mg/kg IV every 2 weeks) + SBRT. SBRT is delivered to 1-4 sites to a maximum target volume of 65 cc/site. Dual IO therapy is continued until progression or fulfilment of discontinuation criteria. We expect 42-72 patients to be enrolled on study until 5 separate organ sites receiving SBRT have accrued at least 6 participants for evaluation of dose-limiting toxicity at the starting dose and a de-escalated dose if necessary. The primary endpoint is dose-limiting toxicity defined as > 33% rate of grade ≥3 toxicity. Secondary endpoints include response rate, PFS, and OS. Exploratory analyses include investigation of candidate biomarkers (e.g., PD-L1 status, circulating tumor DNA, gut microbiome data) for treatment efficacy. Enrollment is ongoing. Clinical trial information: NCT03431948.
Treatment outcomes for patients (Pts) with metastatic castration resistant prostate cancer (mCRPC) pts and DNA damage repair gene mutations.
Authors: Steven Yip, Arkhjamil Angeles, Arshia Beigi, Evan W Warner, Daniel Khalaf, Katherine Sunderland, Gillian Rae Vandekerkhove, Matti Annala, Kasmintan A Schrader, Alexander William Wyatt, Kim N. Chi
Journal: Journal of Clinical Oncology (2018)

5069 Background: DDRm occur in 15-30% of pts with mCRPC. While BRCA2 germline mutations are linked to aggressive local disease, outcomes in pts with mCRPC and DDRm continue to be characterized. Methods: Leukocyte DNA from 631 consecutive mCRPC pts were screened for germline ATM, BRCA1/2, CDK12, and PALB2 truncating mutations using targeted sequencing. 312/631 were assessed for somatic DDRm (sDDRm) and homozygous deletions in the same genes, using matched plasma cell-free DNA. Additional pts with gDDRm were identified through our hereditary cancer program (HCP). We examined time from androgen deprivation therapy (ADT) initiation (± docetaxel) to CRPC; time to PSA progression (TTPP), PSA response (50% decline from baseline), and objective response rate (ORR) on 1st-line AR-targeted therapy, docetaxel, PARP inhibitor, platinum-based chemotherapy, and radium-223 for mCRPC; and overall survival (OS). Outcomes in pts with DDRm and pts with DDR wild-type (WT) status (with available clinical data, n = 113) were compared using the log-rank test. Results: gDDRm and sDDRm were identified in 33/631 (5.2%, BRCA2 = 25) and 35/312 (11.2%, BRCA2 = 13) pts, respectively. The HCP identified an extra 3 BRCA2 and 1 BRCA1 pts. Across 59/72 pts with available clinical data, 23/59 (39.0%) presented with de novo metastatic disease. Median time to CRPC from ADT (± docetaxel) initiation was 12.1 mo (gDDRm = 12.5 mo, sDDRm = 11.5 mo). The Table displays outcomes in pts with DDRm. All pts with DDRm had a TTPP on 1st-line AR-targeted therapy of 3.6 mo vs 7.4 mo in WT pts (p = 0.002). Median OS from the time of ADT initiation and time of CRPC was 41.5 mo (gDDRm = 41.5 mo, sDDRm = 43.5 mo) and 28.4 mo (gDDRm = 28.4 mo, sDDRm = 20.9 mo), respectively. Conclusions: In our cohort, pts with DDRm have poor AR-targeted therapy outcomes. Encouraging responses were observed with docetaxel, PARP inhibitors and platinum-based therapy. AR-Targeted Therapy Docetaxel Chemo PARP Inhibitor Radium-223 Platinum Chemo N 46 13 7 11 4 Median TTPP in mo (95% CI) 3.6 (2.7-5.8) 5.0 (2.7-6.9) 11.3 (5.5-NR) 3.0 (0.3-4.6) NR (NR-NR) PSA Response (N) 54% (25/46) 54% (7/13) 14% (1/7) 9% (1/11) 75% (3/4) ORR (N) 3% (1/32) 45% (5/11) 50% (3/6) 0% (0/6) 50% (2/4)
Safety and clinical activity of anti-programmed death-ligand 1 (PD-L1) antibody (ab) avelumab (MSB0010718C) in advanced thymic epithelial tumors (TETs).
Authors: Arun Rajan, Christopher Ryan Heery, Susan Perry, Corrine Keen, Andrew L Mammen, Arlene W. Berman, Stefania Pittaluga, Lauren Marissa Lepone, Renee Nicole Donahue, Italia Grenga, Jeffrey Schlom, Raffit Hassan, James L. Gulley
Journal: Journal of Clinical Oncology (2016)

e20106 Background: Avelumab (MSB0010718C) is a fully human, IgG1 anti-PD-L1 ab under clinical development. We report safety and clinical activity in patients (pts) with relapsed TETs enrolled in a phase I trial (NCT01772004). Methods: Eligibility criteria: > 1 prior standard therapy, no prior immune checkpoint inhibitors, no prior autoimmune disease. Treatment: Avelumab 10-20 mg/kg iv q2 wks until progression or toxicity. Responses were assessed q6 wks by RECIST 1.1. Correlative studies: PD-1, PD-L1 IHC in tumor samples and peripheral blood immune subset analysis. Results: 8 pts were treated: 7 with thymoma (T) and 1 with thymic carcinoma (TC). Median age 53 yrs (39-76). 3 pts with T (2 B3, 1 B2/B3) received Avelumab 20 mg/kg; 4 T (1 B1, 3 B2) and 1 TC received 10 mg/kg. Responses: 2 (29%) pts with T had confirmed PR (1 at 20 mg/kg, 1 at 10 mg/kg), 2 (29%) unconfirmed PR, 2 (29%) SD and 1 (14%) PD; the TC pt had SD. 3 of 4 responses occurred after 1 dose. Treatment-related adverse events (AE, all grades) in > 15% pts were potential immune-related AEs (irAEs) in 5 (63%) pts and fatigue in 4 (50%) pts. Grade > 3 AEs were irAE (G3 in 3 (38%) pts; G4 in 2 (25%) pts) and hypokalemia (G4 in 1 (13%) pt). irAEs included 1 or more of: muscle weakness, myalgia, myositis, respiratory muscle insufficiency, hoarseness, paresthesia, dysphagia, dyspnea, diarrhea and elevated creatine kinase. With oral steroids irAEs resolved rapidly and completely in 3 pts and incompletely in 1 pt. irAEs gradually resolved with additional medications (IVIG, cyclosporine A) in 1 pt. All responders experienced irAEs (myositis in 3 pts, all after 1 dose of Avelumab and enteritis in 1 pt). Response was seen before or shortly after start of steroids in 3 pts suggesting response was related to Avelumab. Decreased CTLA4+ regulatory T cells and the ratio of granulocytic vs. monocytic myeloid-derived suppressor cells was seen post-treatment at the 20mg/kg dose. Conclusions: Avelumab is active in T with 4 of 7 pts having objective responses accompanied by development of irAEs that were generally reversible with oral steroids. Understanding the mechanism of irAEs and developing treatment strategies for this spectrum of toxicity is important. Clinical trial information: NCT01772004.
Pharmacodynamic characterization of eryaspase (L-asparaginase encapsulated in red blood cells) in combination with chemotherapy in a phase 2/3 trial in patients with relapsed acute lymphoblastic leukemia (NCT01518517).
Authors: Iman El-Hariry, Karine Aguera, Frank Hoke, Kenneth Swart, Adam Hamm, Richard Kay, Philip Lorenzi
Journal: Journal of Clinical Oncology (2018)

7049 Background: L-asparaginase (ASNase) is a key drug in the treatment of ALL. ASNase therapy aims to lower serum asparagine (ASN) levels, but no critical minimum value for efficacy has yet been established. ASN levels are difficult to measure accurately due to ex vivo depletion during the time required to harvest plasma from blood samples and to quench the enzyme, even if samples are immediately processed and stored on ice. Eryaspase is an investigational product under development. Following infusion of eryaspase, ASN is actively transported into RBCs, where it is hydrolyzed by the encapsulated ASNase. Methods: This randomized Phase 2/3 study enrolled pts with relapsed ALL. The co-primary endpoints were the mean duration of ASNase activity > 100 U/L and incidence of allergic reactions during the induction phase. Secondary endpoints were safety, complete remission (CR), pharmacokinetics (PK), and pharmacodynamics (PD). Pts (n = 80, age:1-55 years) were randomized to eryaspase or native ASNase. Results: The mean duration of ASNase activity > 100 U/L measured in whole blood was significantly higher with eryaspase (18.9 ± 5.3 days) compared with native ASNase (8.5 ± 6.6 days). In both treatment arms, ASN depletion ≤2 µM was maintained for ~7 days in 75% of pts. The mean duration of ASN depletion ≤2 µM was 6.0 ± 5.0 and 11.6 ± 7.3 days with eryaspase and native ASNase, respectively. Exploratory receiver operating characteristic (ROC) analysis suggested that an optimal threshold of ≤ 7.55 µM ASN on Day 6 correlated with CR with a positive predictive value of 0.88. Conclusions: The assumed requirement for prolonged ASN depletion in patients receiving ASNase therapy is likely to be an overestimation caused by ex-vivo depletion that is observed with free ASNase. Measurement of ASN depletion in pts treated with eryaspase are less prone to such error. Accordingly, the efficacy of encapsulated ASNase cannot be accurately compared with that of free ASNase based on ASN depletion. ASN depletion ≤2 μM may not be needed with eryaspase, and a level ≤7.55 µM correlated with CR. Clinical trial information: NCT01518517.
Tyrosine kinase inhibitors to regulate the expression level of ABC transporters related to multidrug resistance.
Authors: Martin Klabusay, Vera Novakova, Jirina Medalova, Anna Konieczna
Journal: Journal of Clinical Oncology (2016)

e14112 Background: ATP-binding cassette (ABC) transporter-mediated multidrug resistance (MDR) remains a serious impediment to chemotherapy. ABC membrane transporters actively efflux various substrate molecules from the cells, which causes decreased intracellular drug accumulation. Small molecule tyrosine kinase inhibitors (TKIs) influence ABC transporters expression; however, the mechanism is not clearly understood. Methods: We aimed to investigate the interactions of three TKIs in clinical use (imatinib, nilotinib and dasatinib) with MDR-related ABC transporters (multidrug resistance protein 1 [MDR1], multidrug resistance-associated protein 1 [MRP1], and breast cancer resistance protein [BCRP]) in HL60 and HL60-MDR1, HL60-MRP1, PLB-BCRP cells (using cytotoxicity WST-1 assay), and map the changes in mRNA and surface protein expression of those transporters in A549 and HEK293 cells (using qRT-PCR and quantitative flow cytometry) after TKIs treatment. Results: We proved that all three TKIs serve as substrates to MDR1 transporter. While MDR1 is significantly down-regulated following exposure to all three TKIs both on mRNA and protein level, MRP1 mRNA is inhibited only by nilotinib and by dasatinib. On the MRP1 protein level, highest inhibition was shown three days after imatinib exposure. On the contrary we observed up-regulation of BCRP after exposure to all three TKIs. We also found that TKI-mediated down-regulation of MDR-related ABC transporters correlates with PPAR-γ/PTEN activation. Conclusions: TKIs down-regulate the expression of MDR1 and MRP1 transporters in BCR-ABL negative A549 and HEK293 cell lines via PI3K/Akt pathway inhibition, however, the expression of BCRP transporter was up-regulated.
Comparison of clinical outcomes with first-line pazopanib in clinical trial eligible and non-clinical trial eligible patients with renal cell carcinoma.
Authors: Eric Jonasch, Giuseppe Procopio, Robert E. Hawkins, Angel Rodriguez Sanchez, Sergio Vazquez, Narayanan Srihari, Haralabos Kalofonos, Aristotelis Bamias, Petri Bono, Chaitali Babanrao Pisal, Yulia Hirschberg, Luca Dezzani, Qasim Iftikhar Ahmad, Manuela Schmidinger
Journal: Journal of Clinical Oncology (2018)

4561 Background: Although pazopanib (PAZ) has been evaluated in clinical trials of patients (pts) with renal cell carcinoma (RCC), limited real-world data on the effectiveness and safety of PAZ exist. The PRINCIPAL study (NCT01649778) assessed the effectiveness and safety of first-line PAZ in a real-world setting. Methods: In this nonrandomized, prospective study, pts with advanced and/or metastatic clear cell RCC were enrolled in PRINCIPAL within 30 days of initiating first-line PAZ. Data on progression, survival, and safety were collected approximately every 3 months (mos) until death, consent withdrawal, or loss to follow-up, for up to 30 mos. Pts in PRINCIPAL were separated into two groups based on key eligibility criteria from the Phase III COMPARZ trial (Motzer et al. NEJM. 2013;369:722). Key clinical trial eligible (CTE) criteria included no prior systemic therapy, presence of measurable disease per RECIST 1.1, Karnofsky performance status ≥70, adequate organ system function, no history or clinical evidence of central nervous system metastases, and no coronary or cerebral artery disease at baseline. CTE pts were compared to non-CTE (NCTE) pts. Clinical effectiveness (ie, median overall survival [mOS], median progression-free survival [mPFS], and overall response rate [ORR]), adverse event (AE) measures, and relative dose intensity (RDI) were assessed in both pt populations. Results: Of the 657 enrolled pts who received ≥1 dose of PAZ, 97 (14.8%) were CTE and 560 (85.2%) were NCTE. RDI ≥85% was achieved in 70.1% and 56.6% in the CTE and NCTE populations, respectively. Effectiveness was similar in the CTE and the NCTE populations (mPFS, 9.6 vs 10.7 mos; ORR, 33.0% vs 29.8%; mOS, 26.3 vs 32.9 mos). Serious AEs were reported by 23.7% of CTE and 28.2% of NCTE pts. AEs led to dose adjustment/interruption in 83.5% and 95.2%, respectively, and AEs led to treatment discontinuation in 8.2% of the CTE and 15.5% NCTE pts. Conclusions: The results of the PRINCIPAL study suggest that first-line PAZ for pts with advanced or metastatic RCC remains effective and safe in a real-world setting, showing similar outcomes to those reported in large randomized clinical trials. Clinical trial information: NCT01649778.
Surveying the genomic landscape of somatic short insertions and deletions in over 2,000 cancer patients.
Authors: Shifu Chen, Tanxiao Huang, Mingyan Xu, Charles E. Melançon, Jeremy Edwards
Journal: Journal of Clinical Oncology (2018)

e24083 Background: Short insertions and deletions (indels) are frequenting found in the genomes of cancer patients. Some indels, like deletions in EGFR exon 19, have been widely studied due to their status as actionable therapeutic targets. However, many cancer-related somatic indels remain unstudied. Methods: We analyzed next-generation sequencing (NGS) data from 2,223 cancer patients whose genomes harbored at least one indel mutation. More than 80% of the samples were from cell-free DNA (cfDNA), which was target captured and sequenced using cancer gene panels. The NGS data from ~200 healthy people was used as a baseline to filter out indels found in healthy people. To further reduce false positives, only indels larger than 3bp were included in this study since indels < 3bp are often sequencing artifacts. Results: In total 25,621 indels were detected in the 2,223 samples, among which 4,759 were insertions and 20,862 were deletions. We identified 46 patients with more than 100 indels and 563 patients with only a single indel. We identified 15,384 unique indels, among which 9,062 would result in a frameshift. The four genes with most indels were KMT2D, KMT2C, EGFR and BRCA2. EGFR is a well-known oncogene, while the other three genes are tumor suppressors. Interestingly, the frameshift frequency in EGFR (147/513) is much lower than in KMT2D (492/1422), KMT2C (488/830), and BRCA2 (340/506). The most frequently detected indel is EGFR p.745_750del in exon 19. We identified 15 distinct types of exon 19 deletions, of which 4 forms are common. Conclusions: We surveyed the genomic landscape of short indels in 2,223 cancer patients. In addition to re-identifying well-known indels, we also identified hundreds of previously unreported indels. The biological significance of these indels and their relationship to cancer require further study.
What does the general population think about chemotherapy shortages?
Authors: Zachary Ak Frosch, Angel M. Cronin, Gagne J. Joshua, Maxwell P. Teschke, Stacy W. Gray, Gregory A. Abel
Journal: Journal of Clinical Oncology (2017)

6530 Background: Chemotherapy shortages have been increasingly recognized, and most oncologists report their patients have been at least intermittently affected. Despite their potential impact, little is known about the perspectives of the general population regarding shortages. Methods: In October 2016, we conducted a survey using the GfK KnowledgePanel, an online probability-based sample representative of adults in the United States. We assessed awareness of shortages, and provided vignettes in which a substitute chemotherapy drug had either a major or minor difference in side effects or effectiveness. We asked respondents whether they would want to be informed of a substitution, and, if the original drug were available elsewhere, would transfer care to receive it. We also asked if cancer centers were to publish drugs in shortage at their center, if such data would affect decisions about where to seek care. Analyses applied post-stratification sampling weights to draw national inferences. Results: Of 737 potential participants, 420 (57%) responded; 16% had heard of chemotherapy shortages. Respondents with a personal history of cancer were more likely to have heard of shortages (31% vs 14%, p = 0.03), as were those with greater education (p = 0.01) and those who reported more sources of health information (p = 0.01). Most desired to be informed about a chemotherapy substitution in the setting of both major (87%) and minor (83%) differences in side effects, as well as both major (87%) and minor (82%) differences in effectiveness. In contrast, only 61% reported they would transfer care if a substitute drug had major differences in side effects, and even fewer (40%) for minor differences. Similarly, 72% and 46% reported they would transfer care if a substitute had major or minor differences in effectiveness respectively. Finally, 57% reported that publically-reported shortage data would be a “big factor” in deciding where to be treated. Conclusions: Our data suggest that the general population is largely unaware of chemotherapy shortages. Moreover, in the setting of even minor changes in effectiveness or side effects, respondents wanted to be made aware of substitutions. With major differences, many would seek care elsewhere.