tbuckley/cabot-search huggingface dataset:
Standard-dose pembrolizumab (pembro) plus alternate-dose ipilimumab (ipi) in advanced melanoma: Initial analysis of KEYNOTE-029 cohort 1C.
Authors: Georgina V. Long, Caroline Robert, Marcus O. Butler, Felix Couture, Matteo S. Carlino, Steven O'Day, Victoria Atkinson, Jonathan S. Cebon, Michael Paul Brown, Stéphane Dalle, Andrew Graham Hill, Geoffrey Thomas Gibney, Steven L. McCune, Alexander M. Menzies, Cuizhen Niu, Nageatte Ibrahim, Blanca Homet Moreno, Adi Diab
Journal: Journal of Clinical Oncology (2019)

9514 Background: KEYNOTE-029 cohort 1B showed substantial efficacy for standard-dose pembro + 4 doses of ipi 1 mg/kg with lower rate of grade 3-5 toxicity than reported for standard-dose nivolumab + ipi in patients (pts) with advanced melanoma. In KEYNOTE-029 cohort 1C, we assessed the toxicity and antitumor activity of standard-dose pembro plus 2 alternate ipi doses (NCT02089685). Methods: Eligible pts with previously untreated stage III/IV melanoma, ECOG PS 0-1, and no active CNS metastases were randomized 1:1 to pembro 200 mg Q3W for 24 mo + 4 doses of ipi 50 mg Q6W (arm A) or pembro 200 mg Q3W for 24 mo + 4 doses of ipi 100 mg Q12W (arm B). Primary endpoints were the grade 3-5 treatment-related AE (TRAE) rate and ORR (RECIST v1.1, central review). With 50 pts per arm and compared with other anti–PD-1 + ipi regimens, a grade 3-5 TRAE rate ≤26% would suggest a meaningful reduction in toxicity and an ORR ≥48% would suggest no decrease in efficacy. Data cutoff date was Jul 17, 2018, and will be updated. Results: 102 pts were randomized: 51 to each arm. Median age was 63.5 y, 70% were male, 15% had ECOG PS 1, 34% had BRAF mutation, and 30% had elevated LDH at baseline. With 9.4 mo median follow-up, 69% of pts in arm A and 71% in arm B remained on treatment. All pts in arm A and 96.1% in arm B had ≥1 TRAE; grade 3-5 TRAE rates were 22% in arm A and 33% in arm B. 1 pt had a grade 5 TRAE (autoimmune myocarditis; arm A). ORR was 49% (95% CI 35-63) in arm A, including 7 CRs and 18 PRs, and 53% (95% CI 39-67) in arm B, including 6 CRs and 21 PRs. An additional 16 pts in each arm had SD or non-CR/non-PD, leading to a DCR of 80% and 84%, respectively. Median response duration was not reached in either arm (range 1.4+ to 9.6+ in arm A, 1.4+ to 9.8+ in arm B). Updated data based on longer follow-up will be presented. Conclusions: Standard-dose pembro + ipi 50 mg Q6W and standard-dose pembro + ipi 100 mg Q12W showed robust antitumor activity in this initial analysis. Both regimens appeared to have a lower rate of grade 3-5 TRAEs than previously observed. Longer follow-up and randomized studies are needed to confirm that these regimens reduce toxicity without compromising efficacy compared with other anti–PD-1 and ipi combinations. Clinical trial information: NCT02089685.
Nivolumab (NIVO) + low-dose ipilimumab (IPI) as first-line (1L) therapy in microsatellite instability-high/DNA mismatch repair deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC): Clinical update.
Authors: Heinz-Josef Lenz, Sara Lonardi, Vittorina Zagonel, Eric Van Cutsem, M. Luisa Limon, Ka Yeung Mark Wong, Alain Hendlisz, Massimo Aglietta, Pilar Garcia-Alfonso, Bart Neyns, Dana Backlund Cardin, Andrea Spallanzani, Tomislav Dragovich, Usman Shah, Ajlan Atasoy, Jean-Marie Ledeine, Michael J. Overman
Journal: Journal of Clinical Oncology (2019)

3521 Background: In the phase 2 CheckMate 142 trial, NIVO + low-dose IPI provided robust and durable clinical benefit and was well tolerated as 1L therapy for MSI-H/dMMR mCRC (Lenz et al. Ann Oncol 2018;29:LBA18). Longer follow-up data will be presented. Methods: Patients with MSI-H/dMMR mCRC and no prior treatment for metastatic disease received NIVO 3 mg/kg every 2 weeks + low-dose IPI 1 mg/kg every 6 weeks until disease progression or discontinuation. The primary endpoint was investigator-assessed objective response rate (ORR). Results: For all 45 patients (median follow-up was 13.8 months), ORR was 60% (95% CI 44.3–74.3). Responses were consistent with the overall population across subgroups including age, Eastern Cooperative Oncology Group (ECOG) performance status, prior adjuvant/neoadjuvant therapy, and mutation status (Table). Seven patients (16%) had grade 3–4 treatment-related adverse events (TRAEs); 3 (7%) had any grade TRAEs leading to discontinuation. Updated response, survival, and safety data after a longer follow-up (median 19.9 months) will be presented. Conclusions: NIVO + low-dose IPI demonstrated robust and durable clinical benefit and was well tolerated. Evaluated subgroups had responses consistent with the overall population. NIVO + low-dose IPI may represent a new 1L treatment option for patients with MSI-H/dMMR mCRC. Clinical trial information: NCT02060188. [Table: see text]
Measuring parameters of the cancer ecosystem for cancer ecological staging.
Authors: James R. Cunningham, Jon Rittenbach, Mitch Clemens, Cheryl Dodd, Ashley Wilson, Kaikuihala Roberson
Journal: Journal of Clinical Oncology (2019)

e14684 Background: Cancer progression through clonal evolution and emergent phenotypic heterogeneity is thought to reflect stochastic events such as genetic drift. This divergence over time in the character of a neoplasm might also reflect genetic selection, analogous to other populations in nature, to maximize niche resource utilization. We hypothesized that selection pressures operate in patients with cancer to drive cancer evolution, are clinically identifiable, their influence measurable. Methods: To develop a system for cancer ecology staging, a feasibility study recruited 15 patients with active cancer from any site, with expected survival of more than 6 months and providing informed consent. A set of clinical parameters obtained from a patient questionnaire, physical exam and laboratory testing was used to generate eight separate ecological profiles of tumor microenvironment, chronic inflammation, energy balance, psychosocial stress, GI microbiome, endocrine environment, skeletal remodeling and environmental mutagenesis. A scoring system, based on evidence of positive selection was designed to quantitate the individual profiles. Profile scores were then aggregated using a 2-D radar plot to generate a polygon, an ‘ecogram’, whose area, it is hypothesized, corresponds to the net level of selection pressure influencing tumor evolution. Results: Ecological profiles were obtained from each of 15 patients allowing determination of the ecogram area (EA) bounded by the polygon. EA determinations ranged widely among the 15 patient, from 0-12.7 arbitrary units (au, mean 5.01± 0.80). Ecograms from individual patients demonstrated unique shapes suggesting specificity for individual patient ecology. EA measurements were then used to inform an ecological staging system based on a simplified dichotomization, low/high, of ecosystem resources and threats. Of 15 patients, 6 were considered to have high resources (EA &gt; 5au) available to support tumor evolution. High anti-tumor threat, measured by CD3 lymphocyte immunohistochemical scoring, was detected in 11 patients. Conclusions: An ecological assessment of patients with active cancer appears feasible. Inter-patient variation in ecogram area and morphology suggests there are potential important differences in genetic selection found between patients and should be correlated with survival outcomes in future studies, validation offering a target for ecosystem ‘restoration’.
Use of remote symptom monitoring with breast cancer survivors using patient-reported outcome (PRO) measures in MyChart.
Authors: Shelby A. Terstriep, James Wacker, Charissa Quinlan, Kiara Pochardt, Ethan M. Basch
Journal: Journal of Clinical Oncology (2019)

e23125 Background: Electronic patient-reported outcome monitoring has been found to improve quality of life and overall survival when used with metastatic cancer patients during treatment (Basch, et al., 2017). There has been limited data on using PROs to enhance clinical outcomes in cancer survivorship. This pilot study of breast cancer survivors assessed utilization and satisfaction of electronic proactive symptom and adherence monitoring. Methods: Eighty breast cancer survivors who had completed surgery, chemotherapy, and/or radiation and had received their survivorship care plan were randomized to either usual care or to the PRO monitoring group. The PRO group received questions from the NIH PROMIS toolkit through their patient portal (EPIC) monthly for 6 months. The triage nurse received an alert if the survivor reported on the questionnaire that they had moderate to severe symptoms, had not taken their medication, or would like to speak to a nurse. Participants in the control arm were assessed for sadness, anxiety and satisfaction with provider communication at their usual follow-up visits. Results: Response rates for surveys ranged from 47to 75%. Patients in the PRO monitoring group exhibited no difference in satisfaction at 3 months but had significantly higher scores at 6 months for communication (P=0.005) and monitoring (P= 0.002). Anxiety scores were not significantly different among the usual care group versus the frequent remote monitoring group. Conclusions: Electronic PROs monitoring between clinic visits improved satisfaction with communication and follow-up without increasing anxiety in breast cancer survivors. The pilot data indicate continued development of efficient PROs monitoring can be an important tool to transform the survivorship care plan from a document to an active process of proactively monitoring symptoms and adherence. Support: UG1CA189823. Reference: Basch, E., Deal, A. M., Dueck, A.C., et al. (2017). Overall Survival Results of a Trial Assessing Patient-Reported Outcomes for Symptom Monitoring During Routine Cancer Treatment. Jama, 318 (2), 197. Study Number: A23_Pilot2
An Overview of Cancer Drugs Approved by the US Food and Drug Administration Based on the Surrogate End Point of Response Rate
Authors: Emerson Y. Chen, Vikram Raghunathan, Vinay Prasad
Journal: JAMA Internal Medicine (2019)

Approximately one-third of cancer drugs are approved based on response rate (RR)-the percentage of patients whose tumors shrink beyond an arbitrary threshold-typically assessed in a single-arm study.To characterize RR end points used by the US Food and Drug Administration (FDA) for cancer drug approval.A retrospective review of FDA-approved drug indications in oncology from 2006 to 2018.Data related to cancer type, line of therapy (first-line, second-line, or third-or-later-line treatment for advanced/metastatic disease), type of FDA approval pathway, trial design, sample size, and level of innovation were extracted.The primary outcome was the RR used as the basis for FDA approval. The secondary outcome was rate of complete response.Eighty-five indications for 59 cancer drugs were identified, 32 (38%) received regular approval, and 53 (62%) were granted accelerated approval. Twenty-nine (55%) accelerated approvals were later converted to regular approval. Of these, 6 (21%) approvals showed overall survival benefit, 16 (55%) later established progression-free survival benefit, and 7 (24%) continued to use RR but gained regular approval. The median RR among the 85 indications was 41% (interquartile range [IQR], 27%-58%). Among them, 14 of 85 (16%) had an RR less than 20%, 28 of 85 (33%) had an RR less than 30%, and 40 of 85 (47%) had an RR less than 40%. The median complete RR for 81 participants was 6% (IQR, 2%-22%). The median sample size among studies leading to approval was 117 (IQR, 76-182; range, 18-1052 participants). Drugs with accelerated approval pending confirmatory data had lower RR compared with drugs that have completed most postmarketing efficacy requirements (median, 28%; IQR, 15%-50% vs median, 42%; IQR, 31%-58%; P = .02).Many cancer drugs approved on the basis of response rate offer numerically low or modest response rates. Most premarket studies accrue more than 100 patients. Some of these drugs could potentially be tested in premarket randomized clinical trials measuring directly end points that demonstrate clinical benefit.
Detect and visualize tumor microsatellite instability status from next-generation sequencing data by simulating PCR techniques.
Authors: Shifu Chen, Hongyue Qu, Bo Yang, Tanxiao Huang, Xiaoni Zhang, Yuanyuan Liu, Yanqing Zhou, Qin You, Kamen Ivanov, Jia Gu
Journal: Journal of Clinical Oncology (2019)

e13052 Background: Although multiplex PCR is still the golden standard technology for detecting microsatellite instability (MSI), it has some disadvantages. Firstly, its results are not quantized, and the interpretation of results can be varying for different operators. Secondly, PCR requires extra sample amount and may affect the sample amount for next-generation sequencing (NGS). So we developed a method to detect MSI status from NGS data. Methods: We developed a tool called VisualMSI, which simulates the PCR behaviors to detect the instability level of microsatellite loci. For each microsatellite locus, a pair of PCR primers are simulated by extracting the sequence from reference genome. The read pairs covering this microsatellite locus will be merged first, and then the simulated PCR primers will be mapped to the merged sequences to evaluate the inserted length. For paired tumor/normal samples, VisualMSI evaluates the earth mover's distance (EMD) between the inserted length distributions of tumor and normal. MSI status is determined by the EMD value, and is also visualized on a HTML page for manual validation. As a comparison, the MSI was also evaluated using a multiplex PCR comprising 5 loci (NR27, NR21, NR24, BAT25, and BAT26). Results: To evaluate the concordance of VisualMSI results and PCR-based results, we enrolled a group of 92 patients (39 lung cancers, 33 colorectal cancers and 20 others). For each patient, a tumor tissue sample and a blood sample were collected. White blood cells from the blood samples were also sequenced as normal control. For each patient, the 5 major MSI loci, including BAT-25, BAT-26, NR-21, NR-24 and NR-27 were evaluated by VisualMSI from NGS data, and by PCR. MSI status was categorized as MSI-H or MSI-L for each MSI locus. Finally, for the total 460 MSI loci, the VisualMSI and PCR results were concordant for 425 of them (92.39%), and were not concordant for the rest 35 (7.61%). The sensitivity is 89% (95% CI) and the specificity is 95% (95% CI), indicating that they were highly consistent. Conclusions: We developed a tool for detecting and visualizing MSI status from NGS data. The data shows that results of VisualMSI and PCR are highly concordant. This tool is now open-sourced at: https://github.com/OpenGene/VisualMSI.
Nonclinical endpoint assessment utilizing a digital vivarium cloud platform in an ovarian cancer xenograft model.
Authors: Chibueze Dominic Nwagwu, Erwin Defensor, Laura Schaevitz, Shawn Carbonell
Journal: Journal of Clinical Oncology (2019)

e14690 Background: Translation of preclinical data is highly dependent on the validity of the metrics for assessing disease progression and endpoint in mouse oncology models. A digital cloud platform would provide an objective and non-invasive technology allowing real-time assessment of several parameters including motion, breathing, and activity. Here, we hypothesize digital metrics can serve to predict endpoint in an ovarian cancer xenograft model with ascites, thereby improving analysis and interpretation of therapeutic efficacy data and improved adherence to the Three Rs. Methods: Six groups of athymic mice were intraperitoneally inoculated with increasing numbers of ES-2 ovarian cancer cells or control and housed in the Vium Digital Vivarium. Leveraging Vium’s readily accessible videographic and electronic records we retrospectively analyzed night time motion data using the ROC curve on GraphPad Prism and R programming. The following parameters were defined: motion loss post induction (MLPI) and motion loss from endpoint (MLFE). These were in turn compared to the conventional parameters (ie, number of tumor nodules, tumor weight, volume of ascites, and clinical signs) in terms of predicting disease and endpoint. Results: MLPI showed significantly high correlation with endpoint when graphed on a linear regression plot (R 2 = 0.8671; p&lt; 0.0001), while the conventional metrics showed low correlations with endpoint: number of tumor nodules (R 2 = 0.1334; p= 0.1133); volume of ascites (R 2 = 0.2524; p= 0.0240); tumor weight (R 2 = 0.1162; p= 0.1413). We also showed that MLFE was significantly higher than the days from onset of first clinical sign to endpoint. Analysis of additional digital metrics are underway. Conclusions: The results support the improved ability of a digital platform to predict endpoint over conventional metrics, and earlier than manually-recorded clinical signs. These results are important as they not only provide an objective parameter to enhance study interpretation, but they also reduce the time to humane endpoint. Additionally, the continuously recorded digital metrics increase statistical power, which can be leveraged to potentially reduce the number of animals required per study.
The landscape of palliative systemic therapy and overall survival of 2,063 advanced breast cancer patients in the China National Cancer Center.
Authors: Xiuwen Guan, Binghe Xu, Fei Ma, Qing Li, Pin Zhang, Peng Yuan, Jiayu Wang, Yang Luo, Ruigang Cai, Qiao Li, Hongnan Mo, Yiqun Li, Shaoyan Lin, Yimeng Chen, Zijing Wang
Journal: Journal of Clinical Oncology (2019)

e12583 Background: Despite novel therapeutic options evolved rapidly, advanced breast cancer (ABC) remains an incurable disease with a median overall survival (OS) of 24-30 months. However, real-world data on the treatment and outcome of ABC in routine practice was rare, especially in Chinese cohort. Methods: We summarized the clinicopathological characteristics, therapeutic regimens and survival outcome of 2063 females with ABC who were hospitalized between January 2003 and December 2013 from the Database in China National Cancer Center. Results: The median OS of enrolled population was 42.6 months (95% CI 39.6 to 45.5). Significantly prolonged OS was observed since 2011 ( P= 0.041), with a median OS of 41.0 months (95% CI 37.5 to 44.4) in patients diagnosed with ABC in 2003-2010 and 44.6 months (95% CI 37.9 to 51.2) in 2011-2013, respectively. Between these two periods, Luminal-like, HER2-positive, and Triple-negative patients had an improved median OS of 45.9 to 56.2 months ( P= 0.001), 38.3 to 43.1 months ( P= 0.414), and 28.6 to 28.7 months ( P= 0.364), respectively. As for the analysis of therapeutic mode alteration, the proportion of multidisciplinary care for recurrent disease raised significantly over the years (χ 2 = 8.2, P= 0.004), from 39.6% in 2003-2010 to 47.7% in 2011-2013. In Luminal-like patients, the application of endocrine therapy increased significantly from 64.4% in 2003-2010 to 77.6% in 2011-2013 during the palliative systemic therapy (χ 2 = 17.7, P &lt; 0.001). Among HER2-positive patients, significantly increased application of HER2-targeted therapy were observed in both adjuvant therapy (χ 2 = 4.7, P= 0.030) and palliative therapy (χ 2 = 10.3, P= 0.001) between these two periods. For patients receiving the first-line chemotherapy, the use of maintenance treatment ascended dramatically from 37.1% in 2003-2010 to 58.8% in 2011-2013 (χ 2 = 50.5, P &lt; 0.001). The percentage of participating clinical trials was 14.3%, slightly increased in 2011-2013, when compared with the proportion of 11.6% in 2003-2010 (χ 2 = 2.0, P= 0.160). Conclusions: Real-world data revealed that significantly prolonged OS in China was achieved since 2011 due to the increased use of multidisciplinary care, endocrine therapy, HER2-targeted therapy and maintenance treatment.
Case 40-1987
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, William F. McNeely, Betty U. McNeely, Peter E. Newburger, Nancy L. Harris
Journal: New England Journal of Medicine (1987)

Presentation of CaseA seven-year-old boy with acute lymphocytic leukemia was admitted to the hospital because of cough, lethargy, and fever.The child was born of an uncomplicated full-term pregnancy and vaginal delivery, with a birth weight of 3.0 kg. There were no perinatal problems, and he was discharged home with his mother at the age of two days. The boy was breast-fed. He was slower than older siblings in that he walked at 17 months and was toilet-trained at 2 1/2 years; his speech function was delayed, and he attended a special school. From the age of two years . . .
A systematic review of the characteristics of thyroid metastases from clear cell renal cell carcinoma.
Authors: Karam Khaddour, Nadiia Marenych, Jerry X. Liu, Wendy Ward, Theodora Pappa
Journal: Journal of Clinical Oncology (2019)

e16113 Background: Thyroid gland is an uncommon site for metastases from clear cell renal cell carcinoma (CCRCC) and literature is scarce. Due to the variable and often long lag time before development of metastases in patients with CCRCC, thyroid nodules may be misdiagnosed initially as benign. This systematic review aims at a better understanding of the nature of these metastases. Methods: A bibliographic search was performed using PubMed (1990-2019), key words being “renal cell carcinoma, thyroid, kidney cancer, clear cell.” 147 cases were analyzed. The patient’s characteristics assessed were: age, sex, stage, size of metastases, lag time, diagnostic modality, initial symptoms, treatment and outcome in last documented follow up. Binary logistic regression, spearman and ANOVA were performed to identify differences between the existing variables. Results: The mean age (±SE) was 64± (10) years in males and 64 (±11) in females. The mean lag time to diagnosis of thyroid metastasis was 8.7 (±6.3) years. Gender distribution of the patients was 46.3% male, 52.4% female. There was a weak correlation between lag time and size of metastases, not statistically significant. Size of metastases was significantly higher in symptomatic patients (6.06±3.51cm) compared to those with painless mass (4.6±0.29cm) and asymptomatic ones (3.93±1.99cm) (p = 0.03). Fine Needle Aspiration (FNA) was diagnostic in 29.4% of cases, 47.1% were non diagnostic. Most patients (80.3%) underwent thyroid surgery. At 1 year follow up, 55.6% of patients operated were alive versus 35.3% who did not have surgery, though this was not statistically significant (p = 0.1). Conclusions: A larger size of thyroid metastasis was more likely to present with symptomatology. A high index of suspicion is warranted when evaluating thyroid nodules in CCRCC patients. There was no significant difference in outcome between patients who underwent surgery and those who did not. With the wider use of immune check-point and tyrosine kinase inhibitors in metastatic CCRCC, surgery may eventually be reserved only for palliative purposes.