tbuckley/cabot-search huggingface dataset:
Novel risk stratification criteria of metastatic renal cell carcinoma (mRCC) patients (pts) treated with immune checkpoint inhibitors (ICI).
Authors: Dylan J Martini, Yuan Liu, Julie M. Shabto, Bradley Curtis Carthon, Greta Russler, Elise Hitron, Sarah Caulfield, Haydn Kissick, Wayne Harris, Omer Kucuk, Viraj A. Master, Mehmet Asim Bilen
Journal: Journal of Clinical Oncology (2019)

e16068 Background: IMDC risk criteria is the gold standard for predicting outcomes for mRCC pts. We developed novel risk groups for mRCC pts treated with ICI. Methods: We performed a retrospective review of 100 ICI-treated mRCC pts at Winship Cancer Institute from 2015-2018. Overall survival (OS) and progression-free survival (PFS) were used to measure outcomes; OS was the primary outcome. We obtained baseline monocyte-to-lymphocyte ratio (MLR), body mass index (BMI), and metastatic (met) sites. We created a new variable (D_met) that combines number and sites of met: 0 = &lt; 2 met sites; 1 = ≥ 2 met sites without liver metastases (mets); 2 = ≥ 2 met sites with liver mets. Cox proportional hazard model and Kaplan-Meier method were used for association with OS and PFS. Recursive partitioning and regression tree analyses were used for risk stratification. Discrimination of the risk score was measured by Uno C-statistics. Results: The pts were 66% males, 78% clear cell RCC (ccRCC), and 71% received anti-PD-1 monotherapy. Very poor risk pts (MLR ≥ 0.93 or MLR &lt; 0.93, BMI &lt; 24, and D_Met = 2) had significantly shorter OS and PFS than good risk pts (MLR &lt; 0.93, BMI ≥ 24, and D_Met = 0) in univariable and multivariable analysis (UVA and MVA, Table). The Uno C-statistic for our risk grouping criteria compared to IMDC is 0.687 vs 0.566 (p = 0.061) for OS and 0.594 vs 0.541 (p = 0.78) for PFS. Conclusions: Risk grouping using MLR, BMI, and number and sites of mets may predict survival in mRCC pts treated with ICI. These results should be validated in a larger, prospective study. [Table: see text]
Is inmunotherapy a safe treatment in bladder cancer? A retrospective study in daily practice.
Authors: Natalia Vidal Casinello, Carlos Aguado De La Rosa, Javier Puente, Jose-Luis Gonzalez-Larriba
Journal: Journal of Clinical Oncology (2019)

e14083 Background: Several checkpoint inhibitors antibodies have been approved to treat bladder cancer, and many trials are still ongoing. However, few data about their efficacy and safety outside of a clinical trial have been published. Here we report our experience in managing immune-related toxicity in our daily practice. Methods: We performed a retrospective analysis of 23 patients (pts) with metastatic bladder cancer treated with checkpoint inhibitors in Clínico San Carlos University Hospital from April 2016 to September 2018. The aim of this study is to evaluate the safety of checkpoint inhibitors in daily practice. Results: Median age was 75 years (range 53-92) and 75% were men. The performance status at the beginning of immunotherapy treatment was 0 in 4 pts (17.4%), 1 in 16 pts (69.6%) and 2 in 3 pts (13%). Thirteen pts (56.5%) received the treatment as first line, 6 (26.1%) as second line and 4 (17.4%) as third line and beyond. 18 pts (78.3%) received immunotherapy as monotherapy (15 pts Atezolizumab and 2 pts Pembrolizumab), 3 pts (13%) received an immunotherapy combination with Durvalumab plus Tremelimumab, and 2 pts (8.7%) received chemotherapy plus immunotherapy (Carboplatin plus Avelumab or Atezolizumab). Of the analyzed patients, 36% did not develop any immune related adverse event (irAE). However, 64% did present some side effect. The most common side effect was asthenia (12.5%), cutaneous (8.3%), endocrine (5.6%), gastrointestinal (4.2%) and hepatic (2.8%). Only16.6% of the events required some kind of treatment (9.7% required steroids). Three patients had grade 3 or 4 toxicity, 1 patient on Atezolizumab presented with grade 3 diarrhea and grade 3 hepatic toxicity, another patient on Atezolizumab presented two heart attacks after the two infusions and eventually died, lastly a patient on Durvalumab + Tremelimuab suffered grade 3 hypophysitis. Conclusions: Incidence and therapeutic management of irAEs occurring in our clinical setting closely resembles that reported in retrospective series even though they were mostly elderly patients and many of them were heavily pretreated. Increasing our experience and knowledge in the clinical setting will improve and optimize the use of these drugs.
MGMT status through the ages, literally.
Authors: Assad Ali, Anas Saeed Bamashmos, Addisson Barnett, Hong Li, Soumya Sagar, Gene H. Barnett, Lilyana Angelov, Alireza Mohammad Mohammadi, David M. Peereboom, Glen Stevens, John H. Suh, Erin Sennett Murphy, Jennifer S. Yu, Manmeet Singh Ahluwalia
Journal: Journal of Clinical Oncology (2019)

e13550 Background: It is known that in the setting of glioblastoma (GBM) having a methylated O6-Methylguanine Methyltransferase (MGMT) gene promoter confers a greater response to Temozolomide (TMZ) and an increased progression free survival (PFS) and overall survival (OS). Recent literature has uncovered interesting results when dichotomizing patients by demographics (i.e. age and gender) and analyzing response to the various available GBM therapies. Our primary objective is to analyze the effect of both age and MGMT status on OS and PFS in patients with newly diagnosed GBM. Understanding the role of MGMT on age in the setting of GBM can allow for a better understanding of disease course and treatment. Methods: 464 adult patients with newly diagnosed GBM and documented MGMT status were analyzed from a single major tertiary care institution between 2012 and 2018. Patients were stratified into four groups based on age (above or below 65 years) and MGMT status. A univariate Cox model was used to analyze the effect of age and MGMT status on PFS and OS, where our reference group was the group with the highest OS ( &lt; 65/methylated). Results: The median age of the whole dataset was 63.4 years, and 65.2 years for patients who were MGMT methylated. Patients less than 65 years and were MGMT methylated had the best prognosis with a PFS and an OS of 10.9 months and 18.9 (Table), respectively. Patients above the age of 65 were more likely to be MGMT methylated (p = 0.002). There was an association between IDH1-mutant status and MGMT methylation (p = 0.006). Conclusions: Using MGMT status and age of the patient, our model predicts outcomes that can vary from 7.4 months to 18.9 months (HR = 3.41 p &lt; 0.001).[Table: see text]
Fracture risk after radium-223 (Ra-223) in metastatic castration resistant prostate cancer (mCRPC).
Authors: Roberto Alonzi, Chris C. Parker, Nina Tunariu, Dow-Mu Koh, John Staffurth, Matthew D. Blackledge, Anwar R. Padhani, Alison Tree, Helen Stidwill, Jessica Finch, Peter Chatfield, Sophie Perry, Holly Tovey, Emma Hall
Journal: Journal of Clinical Oncology (2019)

e16513 Background: Ra-223 improves overall survival in patients with mCRPC, but is associated with increased risk of fracture when used in combination with abiraterone and prednisolone. We have assessed time to first new fracture in men with mCRPC receiving Ra-223 monotherapy, imaged using whole body MRI. Methods: In a prospective phase II study, patients with chemotherapy-naïve, bone mCRPC were randomised (1:1) to receive Ra-223 at 55 or 88 kBq/kg for 6 cycles, at 4-week intervals (REASURE; ISRCTN17805587). Whole body MRI was done at baseline, at cycles 2 and 4, and 1 month post-treatment. Subsequent imaging was done as clinically indicated. All scans were centrally reviewed to describe the time to first new fracture and characteristics of fractures. Time to new fracture was analysed using Kaplan Meier methods; comparisons of time to fracture between groups were based on log-rank tests. Results: 36 evaluable patients received a median of 6 cycles of Ra-223; scans were available for 35 patients. For these 35 patients, median age was 75 years (IQR: 73-80). 3 (9%) were receiving bone health agents at trial entry; 8 (23%) had received prior abiraterone or enzalutamide. 21 (60%) patients developed new fractures between randomisation and 2 years after completing treatment with radium-223. The spine was the most common location for fractures (14 patients). Median time to new fracture from randomisation was 10.8 months (95% CI: 6.2-18.2). Freedom from new fracture at 2 years post-randomisation was 21% (95% CI: 7 – 39%). Time to first new fracture was not associated with Ra-223 dose (55 kBq/kg: 10/18 patients experienced a fracture vs 88kBq/kg: 11/17; p = 0.93) or baseline use of bone health agents (3/3 vs 18/32; p = 0.09). Patients with Extent of Disease (EOD) ≥2 (defined as ≥6 metastatic sites/superscan) had earlier time to first new fracture compared to patients with EOD 1 (defined as &lt; 6 metastatic sites) (11/18 vs 10/17; hazard ratio = 2.7, 95% confidence interval = 1.0 – 6.8; p = 0.04). Conclusions: New fractures are commonly seen on imaging in men with mCRPC during and after treatment with Ra-223 monotherapy. This observation supports treatment guidelines that recommend the use of bone health agents in men with mCRPC. Clinical trial information: ISRCTN17805587.
Retrospective analysis of outcomes with different adjuvant treatments in cholangiocarcinoma: An NCDB review.
Authors: Jyothika Mamadgi, Laila Babar, Kristina Lundeen, Stephen Abel, Vivek Verma, Rodney E Wegner, Moses S. Raj
Journal: Journal of Clinical Oncology (2019)

e15677 Background: Annually approximately 5000 cases of cholangiocarcinoma are reported in the US. Of these, less than 40% are treated surgically with a curative intent. Post resection, local and distant recurrence rates are as high as 35% within two years. Positive surgical margins, with either Microscopic (R1) or Macroscopic (R2) disease, confer a higher risk of recurrence. We aim to analyze survival outcomes for different adjuvant treatment strategies in patients with R1/R2 resection. Methods: We queried the NCDB from 2004-2015 for patients with non-metastatic cholangiocarcinoma, who had an R1/R2 resection status post surgery. We then stratified these patients into three arms based on the adjuvant treatment they received: combined chemotherapy and radiation (CRT) vs chemotherapy (CTH) vs observation (OBS). Mean overall survival (OS) was compared for these three groups. OS was calculated from the date of diagnosis to the date of last contact or death using Kaplan Meier curves to present the cumulative probability of survival, with log-rank statistics to assess significance. Results: We identified 522 patients who met our inclusion criteria. Of these, 178 received CRT adjuvantly, 171 CTH, and 173 were observed. The OS in these arms was 42 vs 32 vs 30 months respectively (pooled p &lt; 0.04). As compared to CRT, the hazard ratio was 1.4 (95% CI 1.07-1.72) for CTH and 1.6 (95% CI of 1.2-2.1) for OBS arm. At one year, 83% vs 41% vs 20% of the patients were alive in the respective cohorts and at 5 years, the OS rates were 56% vs 25% vs 13% respectively. Conclusions: Our data demonstrates that combined chemotherapy and radiation is superior to either chemotherapy increase in overall survival for CRT when compared to CHT and observation alone.
Analysis of <i>EGFR</i> mutant urothelial carcinoma (UC) reveals distinct mutational landscape.
Authors: Russell Madison, Sumati Gupta, Jeffrey S. Ross, Sumanta K. Pal, Alexa Betzig Schrock, Vincent A. Miller, John Heymach, Andrea Necchi, Luke Juckett, Siraj Mahamed Ali, Jon Chung, Venkataprasanth P. Reddy
Journal: Journal of Clinical Oncology (2019)

4545 Background: Genomic alterations (GA) of EGFR, are well recognized as druggable oncogenic drivers in NSCLC, but the druggable GA EGFR L858R and exon 19 deletion (ex19del), are rarely observed in genitourinary cancer. We reviewed the genomic landscape of advanced upper tract and bladder UC (UTUC and BUC) to assess the frequencies of druggable EGFR GA. Methods: Tissue specimens from patients with UTUC (407) and BUC (2,402) were assayed using hybrid capture-based comprehensive genomic profiling (CGP). Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 95 or 114 loci. Results: EGFR alterations ( EGFR alt ) were present in 17 UTUC and 93 BUC (4.2% and 3.9%). Age distribution between the two subgroups was similar, but UTUC was more prevalent in female patients (47% v 29%). BUC had a higher median TMB (5.2mut/mb v 7.8 mut/mb; p = 0.046) and the prevalence of MSI-H cases was not significantly different. TERT (55% v 71%) and TP53 (59% v 74%) were the most frequently mutated genes in EGFR alt UTUC and BUC. Within EGFRalt, amplifications were the most common alterations in both UTUC and BUC (13/17, 76%; 57/93, 61%). Amplifications were mutually exclusive from cases with EGFR short variants (SV) in BUC (0/34, 0%), and co-occurred with EGFR SV in four UTUC cases (4/8 50%). The majority of EGFR SV were EGFR exon 20 insertions ( EGFR exon20 ), which made up a larger proportion of EGFR alt in UTUC than BUC (7/17, 41% v 13/93, 14%; p = 0.01). Compared to other EGFR alt , EGFR exon20 trended towards mutual exclusivity of GA in commonly altered UC genes: TP53 (UTUC EGFR exon20 v EGFR alt other: 0% v 100%, p = 5.1E-5; BUC EGFR exon20 v EGFR alt other: 0% v 86%, p = 2.2E-7) , PIK3CA (14% v 10%; 0% v 19%) , RAF1 (0% v 10%; 0% v 16%) , or FGFR3 (0% v 10%; 0% v 6.3%) alterations. Only 2.2% (2/93) of BUC EGFR alt were L858R mutations and none were ex19del (0/93), while neither mutation was detected in UTUC. Conclusions: EGFR exon20 defines a subset of UC cases, and is the most common non-amplification GA seen in EGFR in UC, with some enrichment in UTUC. Consideration should be given to developing a trial for EGFR exon20 UC patients given the recent investigational work on inhibitors with activity against EGFRexon20, such as poziotinib and TAK-788.
Phase II study of durvalumab following neoadjuvant chemoRT in stage II-IV rectal cancer: NSABP FR-2.
Authors: Thomas J. George, Greg Yothers, James J. Lee, Melvin Deutsch, Samuel A. Jacobs, Carmen Joseph Allegra, Norman Wolmark
Journal: Journal of Clinical Oncology (2019)

TPS3620 Background: Locally advanced rectal cancer remains a clinical challenge with few improvements noted over the past few decades. Although immunotherapy has no current clinical role in microsatellite stable (MSS) colorectal cancer, preclinical models suggest that radiotherapy (RT) can enhance neoantigen presentation, modulate the microenvironment, and improve the likelihood of anti-tumor activity with checkpoint inhibitor use. This prospective phase II trial will test that hypothesis in addition to confirming the safety of this approach using a “window-of-opportunity” study design with the anti-PD-L1 agent durvalumab (MEDI4736). Methods: This multi-center phase II trial is currently enrolling patients (pts) with rectal cancer who are undergoing standard NCCN guideline-compliant neoadjuvant chemoradiotherapy (CRT). Eligibility includes pts with MSS stage II-IV rectal cancer with adequate organ function and pre-treatment diagnostic tumor available for profiling who are undergoing CRT with intent to proceed to surgical resection. Stage IV disease must be limited such that the primary pelvic tumor requires definitive management. Standard ineligibility criteria include active infections, systemic steroid use, or other conditions making immunotherapy use unsafe. Treatment includes durvalumab (750mg IV infusion once every 2 wks) for 4 total doses beginning within 3-7 days after CRT completion. Surgery must be within 8-12 wks of the final CRT dose. Primary endpoint is a demonstrated improvement in Neoadjuvant Rectal Cancer (NAR) score compared to historical controls targeting a 20% relative risk reduction in DFS and 3-4% absolute OS improvement. Secondary endpoints include OS, DFS, toxicity, pCR, cCR, therapy completion, negative surgical margins, sphincter preservation, off-target “abscopal” effects for the subset of stage IV pts, and exploratory assessments of tumor infiltrating lymphocytes, circulating immunologic profiles, and molecular predictors of response. A safety run-in phase has completed as a precedent to full enrollment. Enrollment now continues to 47 total pts to achieve 41 surgically evaluable pts. Support: AstraZeneca-Medimmune, NSABP Foundation. Clinical trial information: NCT03102047.
Study on influencing factors and survival analysis of patients with malignant tumors treated by music therapy.
Authors: Lei Hong, Junyan Wang, Fan Zhang, Minting Ma, Da Jiang, Suju Wei
Journal: Journal of Clinical Oncology (2019)

e23144 Background: Music therapy is not easy to carry out. After carrying out music therapy propaganda, many patients still question the efficacy of it, and won’t be included in music therapy group. This study retrospectively analyzed the related factors and survival analysis of patients enrolled in music therapy, and provided reference for appropriate music therapy propaganda methods. Methods: From March 2014 to January 2016, 258 patients with malignant tumors diagnosed in Fourth Hospital of Hebei Medical University were collected. Music therapy was divided into control group and intervention group according to whether they were willing to be included in the group or not. Questionnaire survey was used to investigate the effect of factors on music therapy in the two groups. Follow-up was conducted by telephone to analyze the effect of music therapy on PFS. Single factor analysis was used to analyze the relationship between factors and music therapy. The differences of PFS between control group and intervention group was analyzed by Log-Rank test (P &lt; 0.05). Results: A total of 258 patients were enrolled in the questionnaire survey, and 240 patients completed the questionnaire effectively. Age, education level, music hobby, and knowledge of illness had significant influence on whether the patients were enrolled in music therapy group (P &lt; 0.05). Gender, occupation, type of disease, stage of disease and DT score had no significant effect on whether patients were enrolled in music therapy group (P &gt; 0.05). Age and music preference were independent influencing factors of music therapy (P = 0.025, P = 0.000). The median PFS of lung cancer patients was 8 months and 8 months, respectively (P = 0.760). The median PFS of breast cancer patients was 9 months and 8 months, respectively (P = 0.726). The median PFS of digestive tract cancer patients was 8 months and 10 months, respectively (P = 0.684). The median PFS of gynecologic tumor patients was 8 months and 8 months, respectively (P = 0.310). Conclusions: Age, education level, music hobby and condition information have significant influence on whether patients are included in music therapy group or not. Age and music hobby are independent influencing factors of music therapy. PFS of patients with malignant tumors who are willing to be included in music therapy group tends to prolong, but there is no statistical significance.
Ductal (PDC), acinar (PAC) and neuroendocrine (PNC) carcinomas of the prostate: A comparative comprehensive genomic profiling (CGP) study.
Authors: Gennady Bratslavsky, Joseph Jacob, Oleg Shapiro, Nick Liu, Elizabeth Kate Ferry, Julia Andrea Elvin, Jo-Anne Vergilio, Jonathan Keith Killian, Nhu Ngo, Shakti Ramkissoon, Eric Allan Severson, Amanda Hemmerich, Siraj Mahamed Ali, Jon Chung, Alexa Betzig Schrock, Prasanth Reddy, Sherri Z. Millis, Brian Alexander, Andrea Necchi, Jeffrey S. Ross
Journal: Journal of Clinical Oncology (2019)

5064 Background: PDC, PAC and PNC are histologic subtypes of prostate cancer (PC). We queried whether these subsets would share similar genomic alterations (GA) reflecting their disease biology and clinical features. Methods: CGP was performed using a hybrid capture-based assay on 61 PDC, 4,132 PAC and 217 PNC. Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. Results: The age, GA per tumor and TP53 GA of PDC, PAC and PNC were similar (Table). RB1 GA were predominant in PNC. TMPRSS2:ERG fusions were most frequent in PNC, intermediate in PAC and lowest in PDC. AR GA were more often identified in PAC than PDC or PNC whereas PTEN GA were most frequent in PDC than PAC or PNC. Targetable GA were identified in all 3 groups when focused on BRCA2 (PARP inhibitors) and PIK3CA (MTOR inhibitors). ATM GA (PARP inhibitors) were more common in PAC than PDC or PNC. BRAF GA (BRAF/MEK inhibitors) were more frequent in PDC and PAC than PNC. CDK12 GA potentially associated with immunotherapy (IO) benefit were similar in PDC and PAC and low in PNC. Low frequencies of MSI-High and low median TMB levels were similar in all 3 groups. Conclusions: The pathologic features of PDC, PAC and PNC have been classically maintained as representative of 3 different tumor types with potentially contrasting histogenesis. In the current CGP based study, all 3 tumor types did not display significant differences in genomic signatures other than the high RB1 GA. CGP may reveal biomarkers that could direct patients to targeted (PARP, MTOR and BRAF/MEK inhibitors) or immunotherapies ( CDK12 GA, MSI-High or high TMB status) especially in PDC and PAC. [Table: see text]
Characterization of a patient-specific T-cell and tumor cell coculture model of immuno-cytotoxicity in colorectal cancer.
Authors: Yanhui Li, Nicole Ann Gunn, Lindsay Kua, Fiona Yi Xin Lee, Si-Lin Koo, Clarinda Wei Ling Chua, Emile Tan, Ee-Lin Toh, Ronnie Mathew, Ser Yee Lee, Wah Siew Tan, Ramanuj Dasgupta, Iain B. Tan
Journal: Journal of Clinical Oncology (2019)

e14178 Background: Colorectal Cancer (CRC) is the third most commonly diagnosed cancer in the world. Yet, CRC has been difficult to treat with immunotherapy, as majority (85%) of CRC are Microsatellite stable (MSS), lowly immunogenic and do not respond well. To investigate immuno-cytotoxicity in MSS cancers, we set up an ex vivo co-culture model using patient-derived tumor epithelial cells and autologous tumor-infiltrating lymphocytes (TILs). Aims: To perform phenotypic and functional characterisation of the model, and show we are able to modulate immuno-cytotoxicity. Methods: Fresh tumor, adjacent normal and/or liver metastasis samples were collected and freshly dissociated from 29 colorectal cancer patients undergoing surgery. TILs and tumor epithelial cells were grown in culture. Weekly immunophenotyping of TILs was performed via flow cytometry and data was analysed to identify temporal changes in proportions of cell types. To modulate cytotoxicity, epithelial cell lines were co-cultured with autologous and allogeneic TILs at various effector:target ratios with and without anti-PD1 (Pembrolizumab). Caspase dye was used to detect apoptosis and measure cell death. Results: TILs from most patients were successfully expanded, with a theoretical potential of up to 10,000 times. CD4+ T cells were selectively expanded, while CD8+ T cells decreased in proportion over time. A select group of patients showed an opposite trend. Cell type proportions in metastases mirrored those of the primary tumour while NK cells expanded more in tumour samples than normal samples. Selection proceeded up to 3 weeks then decreased. In the cytotoxicity experiment, we show that cell death is increased at higher effector:target ratios in the presence of autologous TILs. Addition of Pembrolizumab further modulates cytotoxicity in vitro. Conclusions: We have developed and characterised an autologous T cell and epithelial cell co-culture system to evaluate immuno-cytotoxicity in colorectal cancer. This will allow screening of perturbations for improved immuno-cytotoxicity in colorectal cancer.