tbuckley/cabot-search huggingface dataset:
Biomarkers of Chinese advanced cancer patients based on real-world data: Actionable genomic alterations and tumor mutational burden.
Authors: HaiTao Wang, Huina Wang, Rongyun Guo, Mingwei Li, Yanrui Zhang, Feng Lou, Shanbo Cao
Journal: Journal of Clinical Oncology (2019)

e14280 Background: Biomarkers would enrich patients(pts) with responsiveness to both targeted treatments and immunotherapy which have become a priority. However, molecular heterogeneous in actionable gene alterations and mutational loads need to be explored. In this study, based on a real world setting, Cancer Gene Panel (CGP） analysis was performed in a series samples of Chinese pts with advanced solid tumors, to delineate the landscape of actionable mutations and tumor mutational burden (TMB). Methods: 176 advanced pts were enrolled encompassing 19 common tumor types. All tissue samples were analyzed using next-generation sequencing with Acornmed panel including 808 genes. Results: The frequencies of genetic alterations among the most common driver genes were comparable to those reported by MSK-IMPACT (2018) ( TP53: 51.7% vs 44.8%; APC: 9.7% vs 9.8%; EGFR: 12.5% vs 7.7%; KRAS: 16.5% vs 13.6%; PIK3CA: 4.6% vs 12.0%; VHL: 4.0% vs 6.7%). 58.3% of pts with refractory solid tumors had at least one actionable mutation. Among those pts, 16.7% of them including CDK4, CDK6 or CDKN2A/B could benefit from palbociclib, and 32.1% of them including mTOR, PIK3CA, PTEN or STK11 could benefit from everolimus, and 61.9% of them including BRCA2, ARID1A, MSH1/2/6 or ATM could benefit from olaparib. Across all the specimens, the top 20% of TMB was 17.23 mutations/Mb, with a range of 0-48 mutations/Mb. The top 20% of TMB for each tumor type was 21.67(Bladder cancer), 17.23(Lung cancer), 16.45(Colorectal cancer), 11.04 (Renal cell cancer), 16.25 (Prostate cancer) , 19.70 (Hepatobiliary cancer), 14.78 (Esophagogastric cancer), 7.80 (Pancreatic cancer), 25.31 (undefined tumor) mutations/Mb respectively. Conclusions: This study indicates that most of pts with advanced refractory solid tumors have at least one actionable mutation, and matched therapies may confer clinical benefit. TMB fluctuated wildly across different cancer types, illustrating the unequal objective response rate of immunotherapy across various cancer type. Furthermore, CGP analysis in advanced pan-cancer pts can provide opportunities for targeted therapies and immunotherapy, especially in those with refractory cancer.
Computer modelling in prostate anticancer therapy (COMPACT).
Authors: Mark Prentice, Kenneth Man, Yogini Jani, Heather Ann Payne, Ian Wong
Journal: Journal of Clinical Oncology (2019)

e16528 Background: Prostate cancer is the most common solid malignancy in men and despite improving radical therapies a proportion of patients will develop castrate resistant metastatic disease (mCRPC). Therapeutic options in mCRPC include abiraterone acetate and prednisolone (AA+P), enzalutamide (E) and docetaxel (D) with limited evidence to guide clinical choice between agents. COMPACT aims to collate data from multiple data sets within one hospital to assess clinical or biochemical factors that may guide therapeutic strategy. Methods: Data was collated on all patients recorded as receiving therapy with AA+P, E or D in the metastatic castrate resistant setting from the chemotherapy prescribing and dispensing systems and the pathology system at University College Hospital, London. Individual clinical notes were reviewed to determine the reason for stopping therapies. Data was collated in one dataset and analysed to present baseline demographic data. The log-rank test was used to analyse differences in the retention rate among AA+P, E and D. Results: 598 individual treatments were identified in 441 patients. 172 patients received AA+P, 119 E and 307 D with a mean age at treatment initiation of 74.1, 76.8 and 69.5 years respectively. Of the 144 patients receiving two or more treatment lines, 62% (n = 89) received D prior to either AA+P or E. E was first line therapy in 18% (n = 26) and AA+P in 20% (n = 29). 5 (3.5%) patients transferred directly from AA+P to E and 12 (8%) from E to AA+P. Kaplan Meir estimates for time to retention show no statistically significant differences when directly comparing AA+P, E and D on univariate analysis with chi squared test (AA+P vs E = 0.3609, p = 0.558 D vs E = 0.365, p = 0.5457, D vs AA+P = 0.0136 p = 0.9072). Conclusions: The COMPACT study has confirmed that it is feasible for single institutions to retrospectively review real world data from different sources, combining it into a workable database. Patient numbers were sufficient to statistically analyse the data for specific clinical factors that may correlate to a prolonged biochemical response to AA+P, E or D therapy. The failure to detect a statistically significant difference between therapies on univariate analysis may confirm that all three are acceptable treatments in mCRPC.
A global phase III multicenter, randomized, double-arm, open label trial of ASP-1929 photoimmunotherapy versus physician’s choice standard of care for the treatment of patients with locoregional, recurrent head and neck squamous cell carcinoma (rHNSCC).
Authors: Merrill A. Biel, Ann M. Gillenwater, David M. Cognetti, Jennifer Maria Johnson, Athanassios Argiris, Makoto Tahara
Journal: Journal of Clinical Oncology (2019)

TPS6094 Background: rHNSCC commonly affects local or regional sites and is associated with considerable morbidity and mortality. Outcomes of these patients remain poor with limited curative treatment options and low response rates. New modalities that are targeted, minimally invasive, and provide improved tumor response and control while having limited systemic side effects are needed. Photoimmunotherapy (PIT) is a new cancer-targeted platform technology. It is a combination drug and device treatment that utilizes monoclonal antibodies conjugated to a dye (IRDye 700DX) that is photoactivated using nonthermal red light to induce rapid and selective tumor cell death. The objective of this phase 3 study is to evaluate the efficacy and safety of ASP-1929 (EGFR-directed antibody cetuximab-IR700 conjugate) PIT treatment as a monotherapy in patients with locoregional rHNSCC. Methods: A global, multicenter phase 3, randomized, double-arm, open-label, controlled trial of ASP-1929 PIT vs physician’s choice standard of care (SOC) for the treatment of locoregional, rHNSCC in patients who have failed or progressed on or after at least two lines of therapy, of which at least one line must be systemic therapy, is currently underway. Primary endpoints of the study are PFS and OS and the key secondary endpoint is ORR. Key inclusion criteria include: disease not amenable to curative therapy; tumor(s) accessible for PIT light treatment and measurable by CT or MRI; male or female ≥ 18 yrs old with life expectancy &gt; 6 months; ECOG score of 0 to 1. Key exclusion criteria include: history of ≥ Grade 3 cetuximab infusion reaction; distant metastatic disease; tumors invading a major blood vessel unless embolized. The study will include ~275 subjects in a 2:1 randomization (ASP-1929 PIT: Physician’s choice SOC). The physician’s choice SOC arm includes cetuximab, methotrexate, or docetaxel. Tumor(s) are illuminated with 690 nm PIT light treatment 24 hrs following completion of ASP-1929 infusion (640 mg/m²). Clinical trial sites will be in the USA, EU and Asia. Clinical trial information: NCT03769506.
Tumor mutational burden and spectrum in hormone receptor-positive breast cancer patients from India.
Authors: Sachin Minhas, Sunita Bhalla, Vidya Veldore, Madhusudan Ganvir, VL Ramprasad, Shyam Aggarwal
Journal: Journal of Clinical Oncology (2019)

e12524 Background: Breast cancer is the most common type of cancer found in females in India. Moreover, more than 50% of the breast cancers in India are found to be hormone receptor positive (HR+). In this research we calculated the Tumor Mutational Burden (TMB) and studied the spectrum of mutations in HR+ breast cancer patients from India. Methods: Thirty five patients of HR+ breast cancer were enrolled in this study. Their FFPE tumor DNA was subjected to hybrid capture-based NGS assay which provided a comprehensive coverage of 170 key cancer-related genes. TMB was measured as the total number of non-synonymous coding mutations per megabase (mutations/MB). Results: Almost 50 percent (seventeen out of thirty five) of samples were found to be having either high or very high mutational burden with TMB values ranging between 148.84/MB to 734.65/MB. Nine out of thirty five samples had medium mutational burden with TMB values ranging between 59.15/MB to 137.39/MB and an equal number of samples were found to be having low mutational burden with TMB values ranging between 15.26/MB to 53.43/MB. Furthermore, we also made some interesting observations with respect to the mutational spectrum of these tumors. The most frequently mutated genes were PIK3CA and TP53. We also discovered BRCA1 and BRCA2 mutations in our study population which was a notable observation as BRCA mutations occur rarely in HR+ breast cancer in other populations of the world. The complete list of genes found to be mutated in our population is given in table. Conclusions: These preliminary results show that a substantial number of HR+ breast cancer patients could have high mutational burden. Recent clinical trials like KEYNOTE-028 suggest that such patients may get benefit from immune checkpoint inhibitor drugs. These results indicate that the Indian population has a higher TMB and a slightly different mutation spectrum compared to the other populations of the world. The study also indicates that generalizations regarding the use immunotherapy in different populations should not be made as the genetic make-up of every global population is slightly different and unique. Thus, there is a need to conduct studies like this in a much larger and different populations of the world. [Table: see text]
Circulating androgen receptor (AR) gene amplification and resistance to 177Lu-PSMA-617 in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): Results of a phase II clinical trial.
Authors: Ugo De Giorgi, Stefano Severi, Anna Sarnelli, Maddalena Sansovini, Manuela Monti, Giorgia Gurioli, Silvia Nicolini, Emanuela Scarpi, Chiara Casadei, Vincenza Conteduca, Federica Matteucci, Valentina Di Iorio, Dino Amadori, Giovanni Paganelli
Journal: Journal of Clinical Oncology (2019)

3020 Background: Plasma AR gain is associated with poor prognosis in mCRPC pts treated with abiraterone/enzalutamide, however these pts could benefit from docetaxel (Conteduca et al, Eur Urol 2019). In a phase 2 clinical trial with 177Lu-PSMA-617 in mCRPC pts who progressed after standard survival-prolonging treatments, we aimed to determine if plasma AR gene status enable early assessment of 177Lu-PSMA-617 activity for mCRPC. Methods: Between April 2017 and November 2018, 43 mCRPC pts were treated with 177Lu-PSMA-617 in a phase 2 study. Pts younger than 75 years and not heavily pretreated received 5.5 GBq of 177Lu-PSMA-617, while other pts received 4.2 GBq per cycle, for a total of 4-6 cycles, q8 weeks. We determined AR copy number by droplet digital polymerase chain reaction (ddPCR) on pretreatment plasma samples. We evaluated associations between plasma AR amplification and PSA response (≥50% PSA decline from baseline) and imaging response/progression (as measured by bone scan, CT, and PSMA PET/CT). Logistic regression was used to estimate the odds ratio (OR) and 95% confidence intervals (95% CI) in order to evaluate the independent relevance of AR status and pts without PSA response and those with early progressive disease defined as treatment interruption occurring within 4 months of the start of 177Lu-PSMA-617. Results: Forty of 43 pts (median age: 72 years, range 54-86) were fully evaluable for this analysis. A PSA response was reported in 15 (37.5%) of the 40 pts, 3 of 15 (20%) with AR gene gain, and 12 of 25 (48%) with no gain (P = 0.080). Early progressive disease was observed in 17 (42.5%) of the 40 pts, 12 of 15 (80%) with AR gene gain and 5 of 25 (20%) with no gain (P = 0.0002). The OR for pts without PSA response (decline &lt; 50%) having AR gain was 3.69, 95% CI 0.83-16.36, p = 0.085. The OR for pts with early PD having AR gain was 16.00, 95% CI 3.23-79.27, p = 0.0007. The evaluation of germline alterations in DNA damage repair (DDR) genes is ongoing (i.e., BRCA2, BRCA1, ATM). Conclusions: Plasma AR status assessment using ddPCR identifies mCRPC resistant to 177Lu-PSMA-617. These data suggest potential better activity of 177Lu-PSMA-617 in earlier phases of prostate cancer. Prospective evaluation of treatment decision making based on plasma AR status is warranted. Clinical trial information: NCT03454750.
Pharmacodynamic effect of IMCgp100 (TCR–CD3 bispecific) on peripheral cytokines and association with overall survival in patients with advanced melanoma.
Authors: Mark R. Middleton, Neil Matthew Steven, TR Jeffry Evans, Jeffrey R. Infante, Omid Hamid, Alexander Noor Shoushtari, Philippa Gail Corrie, Alan Anthoney, Avinash Gupta, Victoria K Woodcock, Cheryl McAlpine, Mario Sznol
Journal: Journal of Clinical Oncology (2019)

9523 Background: ImmTAC molecules are unique TCR–anti-CD3 bispecifics that redirect T cells against intracellular antigens. IMCgp100, an ImmTAC targeting melanocyte-expressed gp100 antigen, has demonstrated monotherapy activity in advanced melanoma and can cause rash and cytokine-mediated AEs, hypothesized to be on-target (gp100) or effector (CD3) mediated. A preclinical MoA for T cell bispecifics suggests chemokine CXCL10 redirection of CXCR3+ T cells from blood into antigen-positive tissues; this has not been clinically validated. Methods: 84 HLA-A2+ pts with advanced melanoma (n = 61 cutaneous [CM], n = 19 uveal [UM], n = 4 other) received IMCgp100 (NCT01211262). Serum (n = 40) and PBMC (n = 22) samples were taken pre- and post-infusion to analyze changes in cytokines and circulating T cells. Pre- (n = 16) and post-treatment (n = 11) tumor biopsies were analyzed by IHC for CD3, PD-L1 and gp100 expression; tumor RNA (n = 12) was analyzed for gene expression. Results: IMCgp100 induced a transient increase in IFNg-inducible cytokines, most prominently CXCL10. A greater increase in serum CXCL10 was associated with longer OS (p = 0.0002), tumor shrinkage (p = 0.003), and greater transient reduction in peripheral CXCR3+CD8+ T cells (p = 0.001). Reduction in CXCR3+ CD8+ T cells also trended with longer OS (p = 0.02), and tumor shrinkage (p = 0.03). 3/16 pre-treatment biopsies had &lt; 1% gp100 expression (all progressive disease). 8/11 biopsies post-IMCgp100 had increased CD3+ T cells compared with matched pre-treatment samples (associated with baseline gp100 but not PD-L1 expression). Based on tumor biopsy gene expression analysis, IMCgp100 increased T cell markers, IFNg-inducible and cytotoxicity-related genes. Conclusions: The association of clinical benefit with increased serum CXCL10 and decreased peripheral CXCR3+ T cells supports the MoA of IMCgp100-induced T cell redirection and activation. Tumor biopsy results support IMCgp100 redirection of T cells to antigen-positive tumor. A Phase II trial in CM (NCT02535078), a Phase I/II trial in UM (NCT02570308), and a Pivotal RCT in UM (NCT03070392) are ongoing. Clinical trial information: NCT01211262.
T cell receptor β-chain repertoire analysis to reveal potential predictive biomarker for the use of immune checkpoint blockade in patients with advanced solid tumors.
Authors: Ye Li, Shun Chang Jiao, Liang Liang Wu, Sheng Jie Sun, Hua Feng Wei, Sheng You Liao
Journal: Journal of Clinical Oncology (2019)

e14152 Background: Immune checkpoint blockade (ICB) targeted to CTLA-4, PD-1, and PD-L1 can promote antitumor T cell immunity and clinical responses. Tracking the dynamic changes of the T Cell Receptor (TCR) Immune Repertoire can reflect the evolution of the immune system in tumor immunotherapy patients, predict the immune response to ICB, and provide high-value information for clinical monitoring of immune function status of cancer patients to make effective clinical decisions. The purpose of this study was to explore the correlation between the peripheral blood TCR repertoire dynamic changes and the immune response of patients with anti-PD-1/PD-L1, and to accurately guide the individualized treatment of immunotherapy. Methods: We sequenced the TCRβ genes from T cells contained in peripheral blood mononuclear cells (PBMCs) from 24 advanced solid tumors patients (PD/7, PR/4, SD/13) treated with immune checkpoint blockade. Peripheral blood samples were collected from baseline, 8-week, and 16-week after treatment for each patient. bioinformatic analysis was used to detect the diversity and clonality changes of TCRβ-CDR3 sequence before and after treatment with ICB in patients, and provide auxiliary technology for further guiding clinical tumor immunotherapy. Results: The analysis result of Chao index showed that the TCR-CDR3 diversity in the PR group was significantly increased after treatment than SD or PD group. (pvalue = 0.001), and the number of CDR3 aa clonotypes also increased significantly (pvalue = 0.012). A total of 61 Vβ gene fragments and 15 Jβ gene fragments were uniquely identified during immunotherapy . There was a significant difference in the number of Vβ gene fragments between baseline samples and after treatment in PR group (pvalue = 0.042). Conclusions: In this project, PBMC samples was used to evaluate the changes of TCR repertoire between before and after treatment with immune checkpoint blockade in advanced solid tumor patients. The immune function status was significantly changed before and after treatment. Patients with PR had significantly increased diversity in TCR repertoire than patients with SD or PD. The results provide T cell receptor β-chain repertoire sequencing and analysis has potential to assess whether immune checkpoint blockade promotes global T cell expansion and/or loss of T cell clonotype diversity, and to identify predictive biomarker for the use of immune checkpoint blockade.
Progression and hyperprogression after anti-PD1 therapy for unresectable stage III or IV melanoma patients.
Authors: Elise Colle, Stéphane Dalle, Laurent Mortier, Bernard Guillot, Caroline Dutriaux, Marie Thérèse Leccia, Sophie Dalac, Delphine Legoupil, Julie De Quatrebarbes, Henri Montaudié, Jean-Philippe Arnault, Florence Brunet-Possenti, Philippe Saiag, Mathieu Momenzadeh, Brigitte Dreno, Raphael Porcher, Bastien Oriano, Celeste Lebbe
Journal: Journal of Clinical Oncology (2019)

e21021 Background: Primary progression (PP) and secondary progression (SP) to anti-PD1 therapy (APD) are poorly described in advanced melanoma in real life practice. Hyperprogression with a deleterious effect is reported in many cancers but is poorly assessed in advanced melanoma. Methods: Characteristics of 793 patients treated by APD (nivolumab or pembrolizumab) between July 2014 and May 2018 were collected from MelBase, a prospective French biobank (NCT02828202).We considered: group A (progressive disease as best response), group AHP (hyperprogression) within group A patients (progression/death within 3 months with normal initial LDH and ECOG at baseline, and either ECOG increased from 0 to 3-4, either LDH increased from normal to elevated or both), group B SP (response or stable disease then progression). Characteristics for all and survival for patients alive at progression (AAP) were also described. Results: Median follow-up was 11.3 months (Q1-Q3 4.8–23.6). Characteristics at baseline are in the table. In group A, 14% patients died at progression; within 262 patients AAP, 17% continue APD (the same or switch), 15.1% (CI 95 11.1-20.6) were alive 1-year after progression (1YAP); 20.5% for patients in first line and 11.5% for pretreated. In group AHP, 41% patients died at progression; within 48 patients AAP, 12% continue APD, 11.1% (CI 95 7.8-13.6) were alive 1YAP. In group B, 11% patients died at progression; within 88 patients AAP, 36% continue APD, 10.3% (CI 95 5.2-20.1) were alive 1YAP, 15.9% for patients in first line and 7.0% for pre-treated. Conclusions: Our study shows that PP and SP to APD differ at baseline, but have similar survival rates at progression, while mechanisms involved might be different, providing important landmarks to build second line trials. This study thus highlights the existence of hyperprogressors among which 41% patients died within 3 months, as well as describes their associated characteristics. [Table: see text]
Clinical outcomes of manual aspiration thrombectomy for Ilio-femoral venous thrombosis in cancer patients.
Authors: Myung Ah Lee, Eu Hyun Kim, Hae Giu Lee, Jung Suk Oh, Ho Jong Chun, Byung Gil Choi
Journal: Journal of Clinical Oncology (2019)

e23145 Background: To determine the outcomes and feasibility of manual aspiration thrombectomy (MAT) for treatment of symptomatic ilio-femoral deep vein thrombosis (IFDVT) in cancer patients. Methods: In this retrospective study, one hundred and thirty-five consecutive patients (56 men; mean age, 63 years; 149 limbs) with acute (n = 113; 83.7%), subacute (n = 14; 10.4%), and chronic (n = 8; 5.9%) symptomatic IFDVT underwent MAT-based endovascular treatment, with adjunctive balloon angioplasty and stent placement performed in 94 patients. Degree of thrombus removal on venography and symptom improvement was assessed for evaluation of technical and clinical success, respectively. Results: Technical success (thrombus removal &gt; 50%) was achieved in 90.4%, and clinical success was observed in 71.5%. The primary patency rates were 88.1%, 81.6%, 76.0%, 74.1% and 69.1% at 1, 3, 6, 12, and 30 months, respectively. Recurrent IFDVT occurred in 19.3% of patients, 0.79 cases per patients-years of follow up. According to the analysis by causes of IFDVT, recurrent rate was 19.3%, 21.2%, and 14.3% in unknown, compression/invasion of the vein by cancerous mass, and May-Thurner syndrome groups, respectively (p = 0.798). No procedure-related complication developed. Conclusions: MAT is a feasible treatment option with favorable outcomes and minimal risk of complication in cancer patients with symptomatic IFDVT.
Primary tumor location as an important predictor for survival in pulmonary adenocarcinoma.
Authors: Zhe Wang, Minghuan Li, Feifei Teng, Jinming Yu
Journal: Journal of Clinical Oncology (2019)

e20000 Background: The prognostic value of tumor location in pulmonary adenocarcinoma (ADC) is controversial. We compared the prognosis and relevant data between central-type (CT-ADC) and peripheral-type ADC (PT-ADC) in order to identify the reasons for the different outcomes between them and to improve the treatment strategy and prognosis of these two types. Methods: Data on 256 patients with pathologically diagnosed ADC were retrospectively reviewed. The prognostic factors for disease-free survival (DFS), progression-free survival (PFS) and overall survival (OS) were analyzed using univariate and multivariate analyses. Results: 124 and 132 patients had CT-ADC and PT-ADC respectively. CT-ADC was associated with an earlier age, poorer Karnofsky Performance Status (KPS), higher rates of advanced stage, bone metastasis, contralateral pulmonary metastasis and pleural effusion. Besides, CT-ADC showed a trend toward lower rate of epidermal growth factor receptor (EGFR) mutation. Patients with CT-ADC had a significantly shorter PFS/DFS and OS than did those with PT-ADC. Multivariate analysis revealed that advanced stage, central-type location, EGFR wild-type, no surgery, presence of chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD) were independent poor prognostic factors for OS. The rate of surgery was significantly lower in patients with CT-ADC. Among patients with ILD or COPD, OS is shorter in patients with central- than peripheral-type tumors. Conclusions: CT-ADC is associated with poorer survival than PT-ADC and the lower rate of surgery in patients with CT-ADC is an important reason for this. Tumor location of pulmonary adenocarcinoma plays a critical role in predicting prognosis and choosing therapeutic strategies.