tbuckley/cabot-search huggingface dataset:
Molecular profiling by circulating tumor DNA (ctDNA) and benefit from anti-PD-1 in HCC.
Authors: Roberto Carmagnani Pestana, Yehia I. Abugabal, Lianchun Xiao, Manal Hassan, Reham Abdel wahab Hassan, Lauren Girard, Kanwal Pratap Singh Raghav, Jeffrey Morris, Asif Rashid, Aliya Qayyum, Funda Meric-Bernstam, Robert A. Wolff, James C. Yao, Hesham M. Amin, Ahmed Omar Kaseb
Journal: Journal of Clinical Oncology (2019)

e15679 Background: Molecular profiling has defined actionable mutations in HCC, and has the potential to be used for selection of targeted therapies, as well as for the characterization of predictive biomarkers from approved treatments. Noninvasive strategies are critical to HCC given the challenge of obtaining liver biopsies. We investigated whether profiling by ctDNA could provide predictive and/or prognostic information for HCC patients (pt) treated with immune checkpoint inhibitors. Methods: We analyzed blood samples from 22 HCC pt who underwent treatment with anti-PD-1 using comprehensive genomic testing of ctDNA with a commercially-available platform (Guardant Health, CA). Demographic and treatment data were retrospectively collected with the goal of correlating treatment outcomes and drug response (by imaging and/or AFP) with molecular abnormalities. Results: 17/22 (77.3%) were men; median age was 66 years. 21 patients received nivolumab and 1 received pembrolizumab. 9 were HCV positive and 5 were HBV positive. 15/22 patients had &gt; 1 alteration identified. The median number of alterations/pt was 3 (range, 1-8). TP53 was the common altered gene (n = 11) followed by CTNBB1 (n = 8) , TERT (n = 5) KRAS (n = 3) , GNAS (n = 2). Mutations were also seen (n = 1) in KIT, PIK3CA, PTEN, EGFR, NTRK, FGFR2 among others. 6 pt (27.3%) had AFP response and 8 (36.4%) achieved disease control &gt; 12 weeks. Mutations involving KIT, PIK3CA and PTEN were associated with shorter progression-free (PFS) (p &lt; .001 for all) and overall survival (OS) (p = .028 for all), whereas GNAS mutation was associated with shorter PFS (p = 0.019) but not OS. No differences in OS or PFS was observed for other alterations, including the presence of CTNNB1 mutation. There were no correlations between specific alterations and objective tumor response (either by imaging or AFP). 32% of pt were progression-free at 6 months. Median OS was not reached, and 62% were alive after 1 year. Conclusions: Identifying non-invasive predictive biomarkers of benefit to immunotherapy is a priority in HCC. Our data suggest that specific ctDNA alterations can provide predictive information for survival (OS and PFS) on immune checkpoint inhibitors. Further larger studies are warranted for confirmation.
Molecular circulating tumor DNA response to identify long-term survival in patients receiving immunotherapy with initial radiologic stable disease.
Authors: Matthew David Hellmann, Qu Zhang, Shaad Essa Abdullah, Jamie E. Chaft, Neil Howard Segal, Chen Gao, Phillip A. Dennis, Brandon W. Higgs
Journal: Journal of Clinical Oncology (2019)

2546 Background: Early on-treatment changes in ctDNA may identify responders to immunotherapy and complement radiologic assessment of benefit. Here we investigate how early changes in ctDNA associate with long-term survival following treatment with immunotherapy, and if differential patterns in molecular ctDNA response (MCR) among patients with radiologic stable disease (SD) at first on-treatment scan could identify patients deriving benefit from treatment. Methods: Paired pre- and on-treatment (week 6-8) plasma samples from 3 cohorts of patients treated with durvalumab (D) +/- tremelimumab (D+T) were evaluated (NCT01693562, NCT02087423, NCT02261220). CtDNA was profiled with the 73-gene Guardant 360 assay. Nonsynonymous variants were summarized per patient to calculate variant allelic frequency changes (dVAF) and on-treatment variant allele frequency (pVAF). A combination of dVAF and pVAF was used to define MCR. Results: The reduction of ctDNA (dVAF&lt;0) and undetectable on-treatment ctDNA (pVAF=0) were each associated with improved OS and PFS. An optimal threshold for MCR was determined from one cohort, then applied to the other cohorts. MCR associated with significantly improved PFS and OS across all three cohorts (Table). MCR was then applied to a pooled subgroup of patients with initial radiologic SD from all three cohorts (n=78). Patients with radiologic SD and MCR were significantly more likely than those without MCR to achieve radiologic CR or PR (pooled Odds ratio 12.7, p&lt;0.001), had improved PFS (stratified pooled HR 0.36, p&lt;0.001), and improved OS (stratified pooled HR 0.38, p=0.005). Conclusions: MCR is an early on-treatment tool that may identify patients with improved long-term survival and patients with radiologic SD who derive clinical benefit from immunotherapy. MCR may be a supportive endpoint in prospective clinical trials. MCR and survival benefit. [Table: see text]
Procancerous immune cells in primary tumor is associated with breast cancer recurrence.
Authors: Takashi Takeshita, Li Yan, Kazuaki Takabe
Journal: Journal of Clinical Oncology (2019)

e13042 Background: Breast cancer (BC) recurrence is largely determined by cancer factors as well as host factors. It has been implicated that infiltrating immune cells play critical roles in long term survival. We hypothesize that immune cell infiltration profile rather than clinical characteristics or gene expression signatures of the primary tumors associate with the timing of cancer recurrence. Methods: 308 primary BCs in TCGA with cancer recurrence data was divided into; recurrence &lt; 2 years (Early, n = 103), 2-5 years (Late, n = 20), and no recurrence &gt; 5 years (Control, n = 185). 1410 primary BCs in METABRIC with BC specific death data was divided into; death &lt; 10 years (Early Death, n = 499), death &gt; 10 years (Late Death, n = 123), and survived &gt; 10 years (Survivors, n = 788). Results: We found that Early tumors demonstrated more aggressive clinical characteristics such as larger tumor, more lymph node metastases, higher pathological grades, higher Stages, and negative estrogen and progesterone receptors, compared with Control tumors. On the other hand, no clinical characteristics of Late tumors were significantly different from Control tumors, which implicate that clinical characteristics cannot distinguish late recurrence from Control. Gene set enrichment analyses revealed that there was no significant gene sets that enriched with Early nor Late recurrence compared with Control, which implicate that gene expression signatures cannot distinguish recurrent tumor from Control. Utilizing CIBERSORT algorithm, we found that M1 was low and M2 was high macrophages in Early compared from Control. Further, anti-cancer lymphocytes, memory CD4 T cells and gamma delta T cells, were significantly lower, and pro-cancerous regulatory T cells were significantly higher in Early and Late compared from Control. In agreement, cytolytic activity score that assess immune cell killing were significantly lower in Early and Late compared from Control. Interestingly, only elevation of regulatory T cells was similar in METABRIC cohort when Early Death and Late Death were compared with Survivors. Conclusions: We found that not clinical characteristics or gene expression signatures, but pro-cancerous immune cells in primary BC associate with cancer recurrence and breast specific death.
The effect of guideline-concordant novel therapy use on meeting cost targets in OCM: Results from a large community oncology network.
Authors: Stephen Matthew Schleicher, Basit Chaudhry, Christopher A. Waynick, Cheryl A. Crouse, Johnathan D. Shipley, Natalie R. Dickson, Jeffrey Patton, Susanna N. Supalla, Daniel Soudek, Aaron J. Lyss
Journal: Journal of Clinical Oncology (2019)

6635 Background: The Oncology Care Model (OCM) is intended to incentivize physicians to improve the quality and reduce the cost of cancer care. In OCM, providers are accountable for all costs during six month episodes of care relative to target costs (TC) derived from a baseline spending period (BSP; 2013-2015). This accountability is intended to foster care coordination to reduce preventable emergency department visits and hospitalizations (EDH). Benefits of reducing EDH may be diluted when new treatment indications for costly immunotherapies (IO) are introduced into clinical practice after BSP. Methods: We identified all non-small cell lung cancer (NSCLC) and bladder cancer (BC) OCM episodes attributed to Tennessee Oncology (TO), a large community oncology network of over 90 oncologists, during performance period 2 (PP2; the most recent PP with available data). We selected NSCLC and BC because both diseases have IO indications that became standard of care after BSP. Using claims data analytics software, we identified all NSCLC and BC episodes with spending above TC, and found a subset of these above target episodes (ATEs) without any EDH that remained above TC due to IO use. Two medical oncologists reviewed these cases in duplicate to assess guideline concordance of IO. Results: During PP2 there were 2,623 OCM episodes attributed to TO, including 240 NSCLC and 31 BC episodes. Spending was above TC in 118 (49%) and 13 (42%) of NSCLC and BC episodes, respectively. For these NSCLC and BC ATEs, EDH was prevented in 62 (53%) and 5 (38%) of cases, respectively. In NSCLC and BC ATEs without EDH, 43 (69%) and 5 (100%) of episodes included IO, respectively. Clinician review in duplicate (S.M.S.; C.A.W.) found that the use of IO was NCCN guideline concordant in 33 (77%) and 4 (80%) of these NSCLC and BC cases, respectively (K = 0.87). Conclusions: Guideline-concordant use of expensive IO as its treatment indications expand poses substantial challenges to meeting cost targets in OCM, even when practices prevent EDH. [Table: see text]
Predictors of poor outcome for transarterial chemoembolization (TACE) in hepatocellular carcinoma (HCC).
Authors: Petra Prins, Bhavana P Singh, Samantha Ann Armstrong, Aiwu Ruth He
Journal: Journal of Clinical Oncology (2019)

4100 Background: The use of TACE in select patients with BCLC stage B HCC has been shown to improve survival. Despite this, it remains unclear which patients will benefit from repeated TACE versus switching to systemic therapy upon disease progression. The purpose of this study is to identify prognostic factors that predict poor outcomes in patients who receive TACE. Methods: In this single-institutional retrospective analysis, patients with unresectable HCC were treated with TACE between 2007-2016. Relevant factors such as staging by BCLC stage B, Child-Pugh score, vascular invasion (VI), tumor thrombus (TT), AFP levels, and number of TACE treatments within six months from the initiation of TACE were analyzed using either Pearson’s chi-square test or the student's t-test. The Kaplan-Meier method was used for survival analysis. Results: Patients (n = 176) underwent TACE; 45% had stage I-II disease, 42% were BCLC stage B prior to TACE, 71% were Child-Pugh A, 21% had extrahepatic spread, 34.7% had VI, and 26% had TT. The median number of TACE treatments was 2 (range, 1- 6). The median overall survival (mOS) was 43 months (m) (95% CI 31.3-54.7) and mOS from start of TACE was 34m (95% CI 26.2-41.8). Elevated AFP (&gt;400) correlated with decreased mOS (25m vs. 35m, p=0.041). Similarly, the presence of TT correlated with poor outcomes (25m vs. 37m, p=0.015). The mOS was also negatively impacted by having 3 or more TACE treatments within a 6 m period (25m vs. 38m, p = 0.09). AFP &gt;400, TT, and interval between TACE were all independent factors in this multivariate analysis, resulting in a shorter mOS of approx. 2 years compared to 3 years in patients without these negative prognostic factors. There was a strong association with both elevated AFP and TT (Chi square p=0.009). Conclusions: Elevated AFP (&gt;400), the presence of TT, and a need for 3 or more TACE treatments within 6 months appear to be independent predictors for shorter mOS in patients receiving TACE. Patients with these poor prognostic factors tend to have more aggressive HCC, and earlier initiation of systemic therapy might provide benefit to these patients. A larger study is needed for confirmation of these findings.
Stereotactic radiotherapy combined with immunotherapy is safe and effective: Results from a phase I clinical trial.
Authors: Gishan Ratnayake, Simone Reinwald, Mark J. Shackleton, Maggie A. Moore, Mark Voskoboynik, Jeremy Ruben, Menno Van Zelm, Di Yu, Rachel Ward, Robin Smith, Andrew Mark Haydon, Sashendra Senthi
Journal: Journal of Clinical Oncology (2019)

9557 Background: There is growing evidence to suggest synergism between stereotactic ablative radiotherapy (SABR) and immunotherapy (IO) against metastatic melanoma. The optimal timing and dosing of SABR for this purpose has not been established. Here, we report results from a Phase I trial, finding the best outcomes with low dose SABR delivered late. Methods: Metastatic melanoma pts with at least two metastases received SABR to a single metastatic site. All pts had standard dose IO with anti-PD1 and/or anti-CTLA4. Following a standard 3+3 design, pts were escalated through three SABR doses (10Gy, 15Gy and 20Gy) delivered at three different time points (Cycle 1, 2, or 3 of IO). Dose limiting toxicity (DLT) were defined as Grade 3 or higher toxicity within 3 months of first treatment and assessed by an independent data safety monitoring committee (IDSMC). Logistic or cox regressions were used to assess the impact of SABR dose, timing and use of combination IO on toxicity, progression-free (PFS) and overall survival (OS) while controlling age, gender and baseline performance status. Results: Between April 2016 and August 2018, 24 pts were enrolled. The median age was 66 years and most were ECOG 0-1 (92%). The median follow-up was 10 months. Three pts (12.5%) developed DLTs (enterocolitis, hepatitis and liver function derangement). None occurred at SABR treated sites and all were in pts receiving 15Gy. DLTs were not associated with SABR timing (p = 0.44) or use of combination IO (p = 0.72). On this basis the IDSMC recommended stopping the trial and maximum tolerated SABR dose was defined at 10 Gy. The median PFS and OS were respectively 5.4m (95% CI 2.1m-NR) and 16.9m (95% CI 7.1m-NR). The median PFS for those receiving 10Gy was numerically higher than those receiving 15Gy (11.8m vs 2.6 m, p = 0.42). The only treatment related factor associated with improved PFS (HR = 0.14, p = 0.02) and OS (HR = 0.09, p = 0.04) was receiving SABR with Cycle 3. SABR dose (PFS p = 0.75, OS p = 0.67) and IO type (PFS p = 0.13, OS p = 0.06) were not significant. Conclusions: SABR combined with IO is generally safe overall. We found the optimal therapeutic index may be achieved with 10Gy delivered with the third cycle of IO; a strategy that warrants further testing. Clinical trial information: ACTRN12616001064493.
Understanding contribution and independence of multiple biomarkers for predicting response to atezolizumab.
Authors: Parantu K. Shah, Jan Kaczmarczyk, Alexander Myronov, Katarzyna Gruba, Piotr Stępniak, P. Alexander Rolfe
Journal: Journal of Clinical Oncology (2019)

2567 Background: No biomarker satisfactorily predict response to anti-PD-L1 therapies. Biomarker studies suffer from small sample size, presence of disease subtypes, and lack of simultaneous measurement of multiple biomarkers. The IMvigor210 dataset (Mariathasan et al., Nature 2018) provides baseline measurements for multiple biomarkers of response to atezolizumab (n range: 105-298) coupled with genomewide RNAseq profiles. We examined predictive performance of individual biomarkers and combined information from multiple biomarkers to measure changes in predictive performance. Methods: We built classification models (PR/CR vs. PD/SD) using genes and gene sets that provide information on pathways (mSigDB), immune components (xCell, Cibersort), and predictors of response (IMPRES, Immunophenoscore, and TIDE). Prognostic features were removed based on survival association in TCGA. All experiments were done with repeated five-fold double cross validation. Predictions from the gene sets model were used as a single biomarker. PD-L1 expression by IHC in tumor core and immune cells, tumor mutation burden(TMB), neo-antigen burden (NB), location of metastatic disease, immune phenotype and genomic subtypes were then systematically merged with the gene set based model. Results: NB was the best predictor of response (AUC 0.77), while a model combining NB, TMB, ECOG and expression signatures was marginally better (AUC 0.81) with a chance of over fitting. Chi-square tests for independence suggested that examined biomarkers do not provide independent information explaining lack of increase in AUC. Signatures for TP53 mutations, M1 macrophages, CD8+ T effector cell and DNA repair, among others, were present frequently in classification using gene expression information (AUC 0.71), suggesting their independent contributions to response. Adding gene expression information to NB didn’t improve AUC for response but provided better survival stratification. Conclusions: Integration of examined biomarkers with machine learning did not improve response prediction significantly. We are now examining sizes of subgroups defined by combination of low NB/TMB with these biomarkers.
Prognostic factors associated with short-term survival (STS) in advanced pancreatic cancer (APC): A multicenter analysis from the CHORD consortium.
Authors: Sakshi Mehta, Miguel Cardoso, Christina Kim, Dawn Elizabeth Armstrong, Ravi Ramjeesingh, Daniel John Renouf, Shahid Ahmed, Yoo-Joung Ko, Mohammed Harb, Shiying Kong, Winson Y. Cheung, Brandon M. Meyers
Journal: Journal of Clinical Oncology (2020)

650 Background: The survival of patients (pts) with APC (locally advanced/metastatic) is slowly improving; however, in some pts it remains extremely short. Few studies have evaluated the clinical, pathologic and treatment characteristics associated with STS in APC. Methods: Pts with APC (between 2011-2017) were included in the analysis. Descriptive analyses were conducted for demographic, tumor and treatment characteristics between pts who survived ≤ and &gt; 90 days using Wilcoxon rank-sum test and Chi-square test for continuous and categorical variables respectively. Multivariable logistic regression was performed to identify association between pts’ characteristics and STS. Results: A total of 580 pts were included in the analysis: median age 68, 53% male, 92% metastatic and 53% ECOG 0/1. STS ≤90 days occurred in 152 pts (26.2%), with 65.1% not receiving any chemotherapy. Median overall survival for STS was 49 days vs. 276 for non-STS. At least 1 cycle of chemotherapy was administered to 358 pts; mean duration of first-line chemotherapy for pts with STS ≤90 was 1.5(SD 2.5) cycles (N=53), compared to 7.6(SD 11.1) cycles (N=305) for pts surviving &gt; 90 days. Prognostic factors associated with STS &lt;90 days were neutrophil:lymphocyte ratio, LDH, metastatic disease, ECOG and not receiving chemotherapy (Table). Other clinical factors (BMI, smoking history, diabetes) and laboratory values (platelet, baseline CA19-9, estimated GFR) were not prognostic. Conclusions: In a multicenter database of Canadian academic centers, &lt;2/3 of pts received at least 1 cycle of chemotherapy. Prognostic factors associated with STS include routine laboratory values, not receiving chemotherapy, ECOG and the presence of metastatic disease. Further evaluation of factors related to not receiving chemotherapy, and why chemotherapy is discontinued could improve the outcomes of pts with STS. [Table: see text]
Phase II trial of palbociclib in recurrent RB-positive anaplastic oligodendroglioma: A Spanish group for research in neurooncology (GEINO) trial.
Authors: Juan Manuel Sepulveda-Sanchez, Miguel J. Gil Gil, Miriam Alonso, María Ángeles Vaz Salgado, Elena Vicente, Carlos Mesia Barroso, Angel Rodriguez Sanchez, Gema Durán, Ramon De Las Penas, José Muñoz-Langa, Guillermo de Velasco, Aurelio Hernandez-Lain, Amaya Hilario, L Miguel Navarro, Manuel Benavides, Laura Oleaga, Diana Cantero, Yolanda Ruano, Pilar Sanchez-Gomez, Estela Pineda
Journal: Journal of Clinical Oncology (2019)

2038 Background: The pRB-dependent cell cycle checkpoint is altered in the vast majority of anaplastic oligodendrogliomas (AO), either by homozygous deletion or by hypermethylation of CDKN2A and/or CDKN2B, or by amplification and/or overexpression of CDK4. Palbociclib is an oral inhibitor of CDK4 and 6 that has already been shown to be highly active in breast cancer. Methods: We conducted a multicenter, open-label, phase II trial evaluating efficacy and safety of Palbociclib in patients with AO that progressed to radiotherapy and more than one chemotherapy regimen containing Temozolomide and/or Lomustine. Inclusion criteria included: histologically and molecularly confirmed grade III oligodendroglioma (WHO 2016 classification, IDH1/2 mutation and 1p/19 codeletion were mandatory), recurrence after radiotherapy and 1 or 2 chemotherapy regimens and conserved RB protein expression by immunohistochemistry (IHC). Patients were treated with Palbociclib 125 mg/daily 3 weeks on/1off. The primary objective of the study was progression-free survival at 6 months (6M-PFS). Results: Between October 2015 and September 2018, 34 patients were enrolled across ten hospitals. The study was stopped early secondary to lack of efficacy, with 74% of evaluable patients progressing within 6 months. Number of patients alive and free from progression at 6 months after the enrollment was 9 (26%) out of the first 34 patients, below the minimum number required (18 out of 40) to consider Palbociclib as an active drug in this population. With a median follow-up of 11.2 months, the median PFS was 3 months (95% CI: 2.5-3.5 months). Median overall survival (OS) was 23.1 months (95% CI: 17.2-25 months). There were no partial or complete responses and only 11 patients (32%) achieved stable disease as best response. Palbociclib was well tolerated with neutropenia (Grade 3 or 4: 40%) and thrombocytopenia (Grade 3 or 4: 15%) as the most common adverse effects (AEs). Both AEs had no significant impact since there were no episodes of febrile neutropenia or bleeding. Conclusions: Despite the good tolerance and drug exposure, Palbociclib monotherapy did not show favorable activity in recurrent AO. Clinical trial information: NCT02530320.