tbuckley/cabot-search huggingface dataset:
Baseline laboratory tests as predictors of early death risk in 746 elderly oncologic patients: A prospective cohort study.
Authors: Letícia Telles Sales, Jurema Telles O Lima, Maria Julia Gonçalves Mello, Leuridan Torres, maria Luiza lemos Pires, Mirella Rebello, Carolina Vanderley Menezes d'Almeida, Flavia Orange, Anke Bergmann, Luiz Claudio Santos Thuler, Flavia Orange
Journal: Journal of Clinical Oncology (2019)

e23039 Background: The elderly population is the thoroughly affected by new cases of cancer, as well as by its complications. The occurrence of early death (in the first six months after diagnosis) is one of the most important outcomes to be studied in this population. This study aims to identify if simple baseline laboratory tests can be used as predictive factors for early death in older cancer patients. Methods: Prospective cohort enrolled elderly patients ≥ 60 years with a recent cancer diagnosis admitted between 2015 -2017. Sociodemographic, tumor-related and laboratorial (leukocytes, creatinine, platelets and hemoglobin) variables were collected at admission and analyzed. Survival analysis (Kaplan-Meier) and Cox proportional hazard regression was performed. The outcome was a six-month death. Descriptive, univariate and multivariate analysis of Cox proportional hazards and Kaplan-Meier global survival were performed. Results: A total of 746 patients with an average of 71 (± 7.4) years were eligible. 16.5% died in the first six months after diagnosis. Risk factors for early death were controlled by age. Leukocytes &lt; 4,000 / mm3 or &gt; 12,000 / mm3 (HR 2.51 IC95% 1.68-3.75), Creatinine &gt; 1.7mg / dL (HR 2.14 95% CI 1.37-3.36), Platelets &lt; 150,000 / mm3 or &gt; 300,000 / mm3 (HR 1.92 CI 95% 1.31-2.80) and Hemoglobin &lt; 12 g / dL if female, or &lt; 13 g / dL, if male (HR 1.89 95% CI 1.27-2.83) were all associated with greater risk of dying in the first six months after diagnosis (log rank &lt; 0.001). Conclusions: Baseline laboratory tests performed at the hospital admission of the elderly cancer patient may be a simple way to help the clinician to identify patients at higher risk of early death.
Early results from the BRCA Founder Outreach (BFOR) Study: Population genetic screening using a medical model.
Authors: Kelly Morgan, Camila Gabriel, Heather Symecko, Jenny Lester, Jeffrey Levin, Daniella Kamara, Kelsey Spielman, Colby Jenkins, Jada G. Hamilton, Yuri Anthony Fesko, Jacob Heitler, Jeremy Block, Lydia Pace, Mark E. Robson, Katherine Nathanson, Nadine M. Tung, Susan Domchek, Beth Karlan, Judy Ellen Garber, Kenneth Offit
Journal: Journal of Clinical Oncology (2019)

1578 Background: Barriers to population screening for BRCA mutations include access, availability of counseling, and readiness of care providers to participate in this process. The BRCA Founder OutReach (BFOR) study evaluates a digital approach to genetic testing of a defined population using a medical model and risk-adapted follow-up. Methods: The BFOR study (Bforstudy.com) includes web-based enrollment open to individuals in four US cities who are age 25 or older and have at least one grandparent of Ashkenazi Jewish (AJ) ancestry. Participants receive web-based education, provide consent, complete questionnaires, and note their preference for receiving results either from their primary care provider (PCP) or BFOR staff. BRCA AJ founder mutation results are disclosed by (e)mail or phone, depending on need for additional counseling/genetic testing. Participants will be surveyed by email for up to 5 years; a subset of PCPs is also being surveyed. Results: From March 2018 to January 2019, 2562 participants enrolled: 78% female; &lt; 30 years old, 8%; 30-50 years, 39%; &gt; 50 years, 53%. At enrollment, 33% requested disclosure of results by PCP. Among 847 PCPs invited to disclose results, 45% accepted, 50% declined and 5% have yet to respond. 69 (3.2%) participants tested positive for a BRCA founder mutation, of whom 8 (12%) had no significant family history. 2087 participants tested negative, of whom 6% reported a known family mutation, 38% reported a family history of breast/ovarian cancer, and 56% no such history. The most common reason for study participation was referral by a friend. One individual with a distant history of breast cancer tested positive for a BRCA2 mutation and underwent risk reducing surgery that identified an early stage fallopian tube carcinoma. Her daughter then tested positive and underwent prophylactic surgeries. Conclusions: Population screening of individuals at higher risk for cancer-predisposing mutations is feasible and identifies individuals who would not have been tested using clinical criteria. Preliminary findings reveal challenges for engaging PCPs and at-risk individuals, particularly men. Ongoing follow-up and a second phase of the study will address these barriers to testing. Clinical trial information: NCT03351803.
Oncolytic and protective effect of strain no. 228 of a new rotavirus group in the Reoviridae family on В16/F10 melanoma growth in experiment.
Authors: Sergey A. Kolpakov, Elena P. Kolpakova, Elena Yu. Zlatnik, Anastasia O. Sitkovskaya, Oksana G. Shulgina, Ekaterina I. Zolotareva, Vladimir N. Kopyltsov
Journal: Journal of Clinical Oncology (2019)

e14210 Background: The purpose of the study was to determine the effect of a strain No. 228 of a new rotavirus group of the Reoviridae family on the growth of transplantable В16/F10 melanoma in mice and survival of animals. Methods: The study was performed using a strain No.228 of a new group of rotaviruses (working title «group K», RVK) ( http://jbks.ru/archive/issue-10/article-6 ). RVK is a live attenuated and apathogenic strain growing on the PEKC culture (pig embryo kidney cells) with 5·10 9 viral particles/mL. The dynamics of melanoma growth and survival of animals receiving RVK were studied on 25 male mice divided equally into 5 groups. RVK was administered intramuscularly and Per os once a week, respectively 0.3 mL and 25 µL to groups 1-2 21 days prior to the tumor inoculation, a total of 4 injections (“vaccination” regimen); to groups 3-4 – 7 days after tumor inoculation with the appearance of tumor nodes, a total of 3 injections (“treatment” regimen); group 5 – controls receiving saline. Groups 1 and 3 received live RVK, groups 2 and 4 - RVK inactivated by UV radiation. Results: Survival in both groups of animals with “vaccination” regimen was improved significantly, compared to controls (group 1 – 25.8±2.2 days after melanoma transplantation; group 2 – 25.4±1.1 days; controls – 14.6±3.08 days, p &lt; 0.05). In groups with “treatment” regimen, survival was 19.2±3.08 days in group 3 and 21.6±3.52 days in group 4, the latter significantly higher than in controls (p &lt; 0.05). Introduction of a live virus in the “vaccination” regimen resulted in significantly better survival compared to the “treatment” regimen (group 1 vs. group 3), while inactivated virus did not caused such a difference (groups 2 and 4). Conclusions: Improved survival of mice with B16/F10 melanoma after administration of RVK demonstrated its ability to inhibit tumor growth and confirmed our previously published data obtained on Guerin's carcinoma in rats. Administration of a live virus prior to the tumor inoculation cause stronger effect than after inoculation. Since inactivation of the virus does not eliminate its effect, apparently, it is associated with immunostimulating action, rather than with oncolytic one.
Biomarkers of outcomes in a randomized phase II trial of first-line paclitaxel, ifosfamide, and cisplatin (TIP) versus bleomycin, etoposide, and cisplatin (BEP) for intermediate- and poor-risk germ cell tumors (GCT).
Authors: Darren R. Feldman, James S Hu, Sujata Patil, Victor E. Reuter, Sandy Srinivas, Walter Michael Stadler, Brian Addis Costello, Matthew I. Milowsky, Leonard Joseph Appleman, Tanya B. Dorff, Maria Bromberg, Gabriella Joseph, Samuel Aaron Funt, Dean F. Bajorin, George J. Bosl, David I. Quinn, Robert J. Motzer
Journal: Journal of Clinical Oncology (2019)

4563 Background: We previously reported no difference in favorable response rate (FRR) or PFS for TIP vs BEP. Here we present results of a pre-planned analysis of biomarkers of outcome. Methods: HCG and AFP were drawn on days 1 and 15 of each cycle and rates of decline classified as satisfactory [S] or unsatisfactory [US] by MSK (Motzer JCO 2007) and GETUG (Fizazi Lancet Oncol 2014) methods. IHC for ERCC1, RAD51, PARP1, HER-2, and p-AKT was performed on pre-treatment tumor samples. An H-score (0 – 300) was calculated for each stain (H = stain intensity [0 – 3] x % positive cells [0-100]). H-score and marker decline category were correlated with FRR (PR + CR) and PFS. Patients (pts) who received disease-stabilizing chemotherapy were excluded from marker analyses. Results: Of 91 pts, 80 did not receive disease-stabilizing treatment with 79 having sufficient marker values for analysis by the MSK method and 75 by GETUG. By MSK, 49 had S decline vs 30 US; by GETUG, 34 S vs 41 US. FRR and PFS were improved for pts with S vs US decline by both methods and remained significant by the MSK method when stratified by IGCCCG group (Table). IHC (n=77) quality was adequate in 71 to 73 pts (varied by stain) and was positive (H &gt;0) for PARP in 68/73, ERCC1 in 54/71, RAD51 in 54/73, p-AKT in 5/72, and HER2 in 4/72. Only PARP1 was associated with outcome with worse PFS for the lowest expression tertile (H &lt; 180; p=0.013). Conclusions: PARP1 expression and tumor marker decline rates, particularly by MSK method, were significantly associated with outcome to initial chemotherapy in int/poor risk GCT. Future trials incorporating marker decline into treatment allocation and validating the prognostic effect of PARP1 expression are warranted. Clinical trial information: NCT01873326. [Table: see text]
Can high-volume surgeons achieve optimal outcomes at low-volume hospitals? Implications for the Leapfrog Initiative and regionalization of high-risk surgical oncology procedures.
Authors: Christopher Thomas Aquina, Adan Z Becerra, Zhaomin Xu, Carla Justiniano, Christian G Peyre, David Linehan, Larissa K. F. Temple, Fergal J. Fleming
Journal: Journal of Clinical Oncology (2019)

6585 Background: The Leapfrog group recently released surgeon and hospital procedure volume standards for several surgical oncology procedures. This study investigated trends in volume and whether high-volume surgeons at low-volume hospitals achieve equivalent outcomes to high-volume surgeons at high-volume hospitals. Methods: New York’s Statewide Planning and Research Cooperative System was queried for esophagectomy, lung resection, pancreatectomy, and proctectomy for cancer from 2004-2015. Mixed-effects analyses assessed the association among Leapfrog surgeon/hospital volume standards and 90-day mortality. Results: Among 55,528 cases, high-volume surgeons performed 64.7% of cases (esophagectomy = 52%; lung resection = 75.6%; pancreatectomy = 56.7%; proctectomy = 53%), and high-volume hospitals performed 59.5% of cases (esophagectomy = 55.5%; lung resection = 58.3%; pancreatectomy = 63.4%; proctectomy = 61%). After risk-adjustment, high-volume surgeons at high-volume hospitals had lower odds of 90-day mortality compared to high-volume surgeons at low-volume hospitals for each organ system except for pancreas. Despite trends toward regionalization, between 2012-2015, there were large differences in the number of hospitals and median annual case number between high-volume and low-volume centers for esophagectomy (8 vs. 56 hospitals; 31.5 vs. 3 cases), lung resection (22 vs. 89 hospitals; 69.5 vs. 7 cases), pancreatectomy (15 vs. 56 hospitals; 36 vs. 3 cases), and proctectomy (38 vs. 117 hospitals; 28 vs. 3 cases). Conclusions: This study supports the Leapfrog initiative for performance of high-risk surgical oncology procedures by high-volume surgeons at high-volume hospitals. However, it remains unclear whether full regionalization to high-volume centers is feasible. [Table: see text]
A single-arm, open phase II clinical trial of anti-programmed death-1 antibody SHR-1210 combined with nimotuzumab as second-line treatment of advanced esophageal squamous cell carcinoma.
Authors: Feng Wang, Xiangrui Meng, Qingxia Fan
Journal: Journal of Clinical Oncology (2019)

TPS4147 Background: Approximately 40% of patients (pts) with esophageal cancer are diagnosed with advanced unresectable or metastatic disease; the 5-year survival rate for advanced disease is 5%. No standard therapy is available in China for Advanced Esophageal Squamous Cell Carcinoma(ESCC) patients progressed after first-line chemotherapy.Inhibition of programmed cell death protein-1 (PD-1) has demonstrated promising antitumor activity and manageable safety in pts with advanced unresectable or metastatic ESCC. SHR-1210, a humanized IgG4 monoclonal antibody, has high affinity and specificity for PD-1 molecule. SHR-1210 was generally well tolerated and had preliminary antitumor effects in pts with solid tumors, including ESCC. Nimotuzumab, a humanized anti-epidermal growth factor receptor monoclonal antibody h-R3, has been shown to be effective and safe in the treatment of head and neck cancer,non-small cell lung cancer (NSCLC) and esophageal Cancer in several phase II studies.The purpose of this study is to observe and evaluate the efficacy and safety of anti-PD-1 antibody SHR-1210 combined with nimotuzumab as second-line therapy in patients with advanced ESCC. Methods: Patients, age 18-75, with measurable tumor lesion, failed in or progression after 1st line chemotherapy, were enrolled in this study.Patients received SHR-1210 200 mg once every 2 weeks (Q2W) combined nimotuzumab 200 mg weekly until disease progression, death or unacceptable toxicity.Assessments included response by RECIST v1.1 every 6 wks and safety (physical examination, vital signs, ECOG PS, laboratory tests).The primary endpoint is the objective response rate (ORR),and the secondary end points include the diseases control rate (DCR),duration of response (DOR),progression-free survival (PFS),and overall survival(OS). Additionally, we try to identify biomarker to predict efficacy of SHR-1210 and Nimotuzumab with target capture sequencing and gene expression profile as exploratory endpoints. Clinical trial information: NCT03766178.
Effect of smoking on the efficacy of immune checkpoint inhibitors in advanced cancers: A systematic review and meta-analysis.
Authors: Chia Ching Lee, Ivan Weng Keong Tham, Yu Yang Soon, Jeremy Chee Seong Tey
Journal: Journal of Clinical Oncology (2019)

e14109 Background: The association between smoking history and benefit from treatment with immune checkpoint inhibitors (ICIs) was unclear. We performed a meta-analysis to assess the efficacy of ICIs in advanced cancers according to smoking status (never-smokers vs ever-smokers). Methods: We searched MEDLINE and EMBASE for randomized controlled trials (RCTs) comparing immunotherapy with standard-of-care in the treatment of advanced cancers which reported overall survival (OS) as the outcome, stratified by smoking status. We calculated pooled hazard ratios (HRs) and 95% confidence interval (CIs) for OS using random-effect models and assessed the differences in OS between the two estimates (never smoker (vs) ever smoker). using a test of heterogeneity. We also performed prespecified subgroup analyses based on disease site, line of therapy, proportion of never-smokers in the trials and trial conclusion to assess the potential association of oncologic and methodologic factors in effect modification of smoking status with the efficacy of ICIs. Results: We identified ten RCTs on non-small cell lung cancer, head and neck, and urothelial cancers, including 4,245 ever-smokers and 972 never-smokers. The difference in the effects of ICIs on OS between ever-smokers (HR, 0.74; 95% CI, 0.66-0.84) and never-smokers (HR, 0.79; 95% CI, 0.61-1.02) was not statistically significant (interaction P-value = 0.69). There were no significant differences in the effects of ICIs on OS between ever-smokers and never smokers in the pre-specified subgroups. Conclusions: There was no significant association between smoking status and improved survival outcome with ICIs in the treatment of advanced cancers. Smoking status should not be used as a biomarker for guiding treatment with immunotherapy.
DNA Input, sequencing depth, and maximum somatic allele frequency may affect the concordance between blood TMB and tumor TMB.
Authors: Yuqing Huang, Qiang Liu, Xianjun Min, Yingshun Yang, Guotian Pei, Shuai Wang, Xiaoyu Wang, Hui Li, Xiaoni Zhang, Hongyue Qu, Mingxin Wen, Yaru Chen, Jeremy Edwards, Shifu Chen, Jun Wang
Journal: Journal of Clinical Oncology (2019)

e13163 Background: Tumor mutation burden (TMB) is recognized as a promising biomarker for PD-1/PD-L1 blockade therapy. However, a tissue biopsy is often not available, and hence a liquid biopsy using blood can be used to evaluate TMB (which is known as blood TMB). Unfortunately, the concordance of blood TMB (bTMB) and tissue TMB (tTMB) is not stable, and may be affected by the sample preparation methodology and sequencing depth. Therefore, e designed a study to explore the factors, which may significantly impact the concordance between bTMB and tTMB. Methods: From September 2018 to January 2019, 98 patients with pan-cancer were prospectively enrolled. For each patient, a tissue sample and paired plasma sample were collected. These samples were sequenced using a custom 605 cancer specificgene panel. Results: The data indicated that bTMB and tTMB were correlated, but the DNA input, sequencing depth and maximum somatic allele frequency (MSAF) might affect their concordance. The Spearman’s rank correlation (SRC) between bTMB and tTMB of 38 patients with &gt; = 25ng cfDNA vs. 60 patients with &lt; 25ng cfDNA was 0.77 vs. 0.15, respectively. Additionally, we explored the impact of sequencing depth and determined that the SRC (between bTMB and tTMB) of 25 patients with a sequencing depth &gt; = 2,500x vs. 73 patients with a sequencing depth &lt; 2,500x was 0.74 vs. 0.28, respectively. Finally, we showed that the allele frequency was critically important as well. We determined that the SRC (between bTMB and tTMB) of 50 patients with cfDNA MSAF &gt; = 1% vs. 48 patients with cfDNA &lt; 1% was 0.71 vs. -0.03. Conclusions: To improve concordance between bTMB and tTMB for better predicting efficacy of immunotherapy, we recommend that cfDNA input should be more than 25ng, and average effective sequencing depth should be higher than 2,500x, and the correlation hold for an allele frequency treating than 1%.
Targeting MAP2K1 mutation with trametinib in a triple wild-type melanoma patient.
Authors: Krisztian Gyuta Homicsko, Veronica Aedo, Edoardo Missiaglia, Bettina Bisig, Olivier Michielin
Journal: Journal of Clinical Oncology (2019)

e21027 Background: MAP2K1 inhibitors combined with BRAF inhibitors provide a prolonged progression-free survival for BRAF mutant patients. However, the impact of MEK inhibition of MAP2K1 mutant and BRAF/NRAS/NF1 wild type melanoma patients remains elusive. Methods: We performed next-generation sequencing using an in-house developed 400 full exon panel for one of our triple wild type (BRAF/NRAS/NF1) melanoma patient. The patient received off-label, trametinib at a dose of 2 mg o.d. We performed additional sequencing at progression. After progression, the patient was treated off-label with combined trametinib and palbociclib therapy. Furthermore, we screened the TCGA melanoma and MSK-IMPAKT databases for patients with similar mutation profiles. Results: Our patient presented with dual somatic MAP2K1 mutations at Cys121Ser and Pro124Arg with a 68% allele frequency. The tumor also harbored a minor EGFR mutant clone (11% allele frequency) and a complete loss of the CDKN2A locus. The patient received trametinib and after two months presented a partial response as per RECIST1.1. However, after two additional months, the patient progressed. A new biopsy was performed, and the treatment was modified to combine trametinib and palbociclib to co-target MAP2K1 and the loss of the CKDN2A locus. The patient progressed under dual trametinib/palbociclib therapy without any objective benefit. The on-progression biopsy showed the absence of a gatekeeper mutation of MAP2K1 and the persistence of the loss of the CDKN2A locus. We detected a large number of novel copy number variations, most notable amplification of MITF (9x), FGFR1 (10X) and of MDM2 (16x). We also detected a loss of the minor, EGFR mutant clone. The analysis of large-scale state transitions (LSTs) for deficiency in homolog recombination (HRDness) was negative in pre and post-treatment biopsies. Conclusions: Our patient provides unique evidence to target solitary MAP2K1 mutations in triple wild melanoma by MEK1 inhibitors. Resistance to MEK1 inhibition developed rapidly and likely involved FGFR1 and MDM2, which have not been previously associated with resistance to MEK inhibitor monotherapy. The addition of palbociclib could not rescue these potential resistance mechanisms.
Leeomic: A comprehensive proteomic analysis towards discovery of predictive patterns of protein expression to ribociclib sensitivity and resistance—A compLEEment-1 Canadian correlative sub-study.
Authors: Stephen K. L. Chia, Jan-Willem Henning, Ellen Warner, Xinni Song, Anil A. Joy, Nadia Califaretti, Christine Desbiens, Juan Pablo Zarate, Sina Haftchenary, Sabrina R. Perri, Gregg B. Morin
Journal: Journal of Clinical Oncology (2019)

TPS3170 Background: Despite developments in the treatment of advanced hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) breast cancer, primary or acquired resistance eventually occurs in all cases and there is still very limited understanding of the mechanisms of resistance to therapy. LEEOMIC is a sub-study of the main CompLEEment-1 ( N = 3255 patients enrolled, CLEE011A2404 v03) trial, an open-label, phase 3b study evaluating ribociclib + letrozole as first-line therapy in an expanded advanced breast cancer patient population which recruited over 250 Canadian patients. The purpose of this Canadian correlative sample collection study is to explore the mechanisms of response and resistance to ribociclib in combination with letrozole through proteomic and ctDNA analysis. Methods: The British Columbia Cancer Research Centre team developed a novel and optimized MS/MS platform called SP3-Clinical Tissue Proteomics (SP3-CTP) to perform in-depth proteome profiling ( &gt; 8,000 proteins) from formalin fixed paraffin embedded (FFPE) material (10-micron section). SP3-CTP analysis of the proteome of the study patients who did not achieve clinical benefit (primary resistance: progression within 3 months of treatment) will be compared to the proteome of the sub-group of prolonged responders (time to progression of 22 months or more) in order to identify biomarkers that can predict response or de-novo resistance to therapy. Archival tumor biopsies (primary or metastatic) collected from the study will be submitted for proteomic analysis to identify proteomic expression levels that may serve as predictor of response. It is anticipated that over 150 samples will be collected. If available, blood samples taken at time of progression or end of treatment will also be analyzed for ctDNA for genetic profiling and to study if there is any correlation between genetic mutations and response or resistance to therapy. Currently, both tissue and blood samples are being collected and no analysis has been conducted thus far. Clinical trial information: NCT03613220.