tbuckley/cabot-search huggingface dataset:
Patient-derived organoid (PDO), a new personalized therapy selection tool for prompt clinical decision making in metastatic gastrointestinal (mGI) cancer patients.
Authors: Hao Xie, Tara L Hogenson, Isaac P Horn, Luciana Almada, David Marks, Amanda Koenig, Ezequiel Tolosa, Michael T. Barrett, James H Boyum, Amit Mahipal, Joleen Marie Hubbard, Temperance J Scheffler Hanson, Jun Yin, Gloria M. Petersen, Alexander Revzin, Daniel D. Billadeau, Tanios S. Bekaii-Saab, Alex A. Adjei, Wen Wee Ma, Martin Fernandez-Zapico
Journal: Journal of Clinical Oncology (2019)

3101 Background: PDO is a promising translational tool that recapitulates the biology and drug response of donor cancer patient. However, an unmet need is to have PDO drug-screening data available for treatment decision making in clinic. We conducted a pilot study to determine whether PDO testing results will be available at critical treatment decision points in metastatic GI cancer patients. Methods: Metastatic GI cancer patients undergoing core-needle biopsy were eligible. Tumor cells isolated from ≤4 fresh biopsy tissues were grown in a Matrigel-based culture. PDO response to anti-cancer drugs were evaluated; and when available, correlated with donors’ clinical response to the same agent(s). PDO response was defined as IC50 &lt; 0.1 × published Cmax of the drug clinically; stable as IC50 between 0.1 to 10 × Cmax. Radiographic response was per RECIST criteria. Results: We enrolled 27 refractory metastatic GI cancer patients (9 colorectal [CRC], 9 pancreas, and 9 biliary tract). Median lines of therapy were 4, 2, and 2; the success rate of organoid establishment was 89%, 44%, and 55%, respectively. The median time from biopsy to availability of drug-testing data was 64 days (range: 24 to 93 days). The median time from biopsy to next CT re-staging in donors was 64 days. The established PDOs shared histological and genomic features with donor clinical tissue. PDO and clinical responses to the same agent(s) were correlated in 2 CRC donors including (1) BRAF V600E -mutated PDO responded to vemurafenib + panitumumab, as did the donor who had partial response (PDO drug-testing data were available 55 days post-biopsy, 23 days prior to restaging scan); (2) KRAS/FGF-dual amplified PDO had stable disease status to regorafenib, as did the biopsied lesion from the donor (73 days post-biopsy, 5 days post-scan). Conclusions: We showed the feasibility of completing PDO drug sensitivity testing in metastatic GI cancer patients within a short time that could impact clinical decision making, particularly in CRC. PDO drug response showed correlation with clinical response. With further refinement, PDO can be a powerful tool for personalizing cancer therapy in metastatic GI cancer patients.
Single agent immunotherapy for relapsed or refractory small cell lung cancer (rrSCLC).
Authors: Ankur Singh, Tamjeed Ahmed, Andy Dothard, Stefan C. Grant, Jimmy Ruiz, Michael Farris, William J. Petty, Thomas Lycan
Journal: Journal of Clinical Oncology (2019)

e20094 Background: There are limited effective treatment options for rrSCLC. Based on results from CheckMate 032 (n = 98) and KEYNOTE-158 (n = 107), both of which were limited to performance status (PS) 0-1, guidelines recommend consideration of single agent PD-1 immunotherapy (IO) for patients (pts) with PS 0-2. Methods: All rrSCLC pts receiving single agent IO at our institution from May 2016 – April 2018 were retrospectively analyzed with IRB approval. Primary endpoints were overall survival (OS) and end-of-life outcomes. Results: 48 rrSCLC pts who were predominantly PS 2-3 (56%), female (63%), and Caucasian (90%) received single agent IO with either nivolumab (94%) or pembrolizumab (6%) for either relapsed (81%) or refractory (19%; defined as initial diagnosis &lt; 180 days) SCLC. They received median 3 cycles (IQR 2-5). 32 deaths occurred during the analysis period. 6 and 12 month (mo) OS were 31% and 18%, as compared to 45% and 33% reported in CheckMate, respectively. Adverse events (AEs) leading to treatment discontinuation occurred in 5 (10%) and serious AEs (pneumonitis and posterior reversible encephalopathy syndrome) occurred in 2 (4%). For end-of-life outcomes, 18 (38%) were referred to hospice at any point, 8 (17%) began IO within 30 days of death, and 7 (15%) received a dose of IO within 14 days of death. The subgroup of pts who received ≥2 prior lines of therapy appear to have had greater benefit. Conclusions: Although tolerable, salvage single agent IO for rrSCLC in these unselected pts had poor efficacy and may have led to under-utilization of end-of-life resources. It may still be beneficial among pts with more indolent, treatment-responsive disease, as indicated by multiple lines of prior therapy. But overall, these results support the combination of IO with chemotherapy or novel agent as part of a clinical trial. Further investigation is warranted to better define its use in this setting. [Table: see text]
Abstract 11340: In vitro Evaluation Model of Allogeneic Immune Rejection Could Predict In Vivo Immune Response of Allogenic Induced Pluripotent Stem Cells
Authors: Emiko Ito, Shigeru Miyagawa, Maki Takeda, Yuhki Nakamura, Noriko Mochizuki-Oda, Yoshiki Sawa
Journal: Circulation (2018)

Background: Although allogeneic human induced pluripotent stem cells (hiPSCs) with homozygous human leukocyte antigen (HLA) haplotypes are used for the purpose of immunotolerance in clinical applic...
Association between gene fusions and anti-EGFR resistance signature in colorectal cancer.
Authors: Thereasa A. Rich, Katherine Clifton, Victoria M. Raymond, Arvind Dasari, Kanwal Pratap Singh Raghav, Christine Megerdichian Parseghian, Richard B. Lanman, Scott Kopetz, Van K. Morris
Journal: Journal of Clinical Oncology (2019)

3564 Background: Acquired resistance to anti-EGFR therapy in metastatic colorectal cancer (mCRC) has been characterized by a circulating tumor DNA (ctDNA) signature including any sub-clonal RAS mutation, co-existing RAS mutations, or co-existing EGFR mutations. Here, we investigated if fusions in ctDNA are associated with this anti-EGFR signature for CRC patients (pts). Methods: 4289 advanced stage CRC pts underwent molecular profiling using a plasma-based NGS assay that included FGFR2, FGFR3, RET, ALK, NTRK1, and ROS1 fusions. Available clinical histories were reviewed. Correlations between fusions and clinicopathological features were measured with a Fischer exact test. Relative frequencies of genomic alterations were compared between fusion-present vs -absent cases with an unpaired t-test. Clonality for a given alteration was called for a relative variant allele frequency (rVAF) &gt; 50 %, while subclonal was defined as &lt; 50% rVAF. Results: 44 unique fusions were detected in 40 (1.1%) of the 3808 pts with alterations present: RET (N = 16), FGFR3 (N = 12), ALK (N = 10), NTRK1 (N = 3), ROS1 (N = 2), and FGFR2 (N = 1). Relative to non-fusion variants detected, fusions were more likely to be subclonal (OR 8.2, p &lt; 0.0001). Mutations associated with a previously reported anti-EGFR resistance were found in FGFR3 (7/12 pts), RET (7/15 pts) and ALK (5/10 pts). In fusion-present cases, co-existing RAS mutations were more likely to be subclonal than non-fusion cases (OR 14, p &lt; 0.0001). EGFR mutations were more common in fusion present cases (OR 3.7, p = 0.0001) and predominantly subclonal (97%). EGFR mutations aggregated to ectodomain sites (85%) previously linked to acquired anti-EGFR resistance. For 27 pts with available clinical histories, 21 (78%) received anti-EGFR treatment prior to ctDNA testing. Conclusions: Actionable fusions using a ctDNA NGS assay were predominantly subclonal and co-existed with subclonal RAS and EGFR mutations. These clinicopathologic features are consistent with a previously validated signature linked to resistance to anti-EGFR therapies in CRC. We hypothesize that fusions may arise as a previously undescribed mechanism of acquired resistance to anti-EGFR therapies in CRC pts.
Progression-free survival as a predictor of overall survival in patients with advanced breast cancer: A real-world study from the China National Cancer Center.
Authors: Hongnan Mo, Binghe Xu, Fei Ma, Qing Li, Pin Zhang, Peng Yuan, Jiayu Wang, Yang Luo, Ruigang Cai, Qiao Li, Yiqun Li, Xiuwen Guan, Shaoyan Lin, Yimeng Chen, Zijing Wang
Journal: Journal of Clinical Oncology (2019)

e12590 Background: Use of progression-free survival (PFS) as a clinical trial endpoint in first-line treatment of patients with advanced breast cancer is attractive, but would be enhanced by establishing a correlation between PFS and overall survival (OS). Methods: From January 2003 to December 2012, 1851 patients with advanced breast cancer at start of first-line therapy were enrolled in this real-world study. An independent cohort of patients hospitalized in 2013 was used for external validation. All data were collected from the Database of China National Cancer Cancer. Results: The correlation coefficient (Pearson’s r) between PFS and OS was 0.807 in patients only receiving endocrine therapy as first-line treatment, 0.643 in those treated with chemotherapy, and 0.642 in the whole cohort. Receiver operating characteristic curve indicated that PFS = 12 months was the optimal cutoff value for predicting patient’s survival. The median OS was 30.0 months (95% CI 27.8-32.2) in the PFS &lt; 12 months group, and 69.0 months (95% CI 60.8-77.2) in the other group (P &lt; 0.0001). Multivariate analysis revealed that compared with patients who did not progress at 12 months, the adjusted hazard ratio (HR) for death was 2.681 (95% CI, 2.301-3.124; P &lt; 0.0001) for patients with PFS &lt; 12 months. Subgroup analysis based on patient’s age, molecular subtype, visceral metastasis and types of first-line treatment further confirmed that PFS &lt; 12 months was associated with significant poor prognosis in all these subgroups. In patients with luminal type of breast cancer, the HR for death was 2.567 (95%CI 2.147-3.069; P &lt; 0.0001) for patients with PFS &lt; 12 months. Notably, for these patients with luminal type breast cancer who had progressed within 12 months after first-line treatment, addition of chemotherapy in the second-line therapy would surprisingly have adverse effects on patients’ survival when compared with endocrine therapy alone (HR = 1.627, 95%CI 1.016-2.604, P = 0.043). The findings were externally validated in the independent cohort. Conclusions: To our knowledge, this is the first real-world study revealed that PFS at 12 months in first-line therapy predict OS of patients with advanced breast cancer.
Emergence of Hybrid Models of Genetic Testing Beyond Direct-to-Consumer or Traditional Labs
Authors: Kathryn A. Phillips, Julia R. Trosman, Michael P. Douglas
Journal: JAMA (2019)

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Case 47-1986
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, Betty U. McNeely, Fred H. Hochberg, Nancy L. Harris
Journal: New England Journal of Medicine (1986)

Presentation of CaseA 64-year-old man was admitted to the hospital because of a gait disorder and unilateral exophthalmos.There was a history of a partial thyroidectomy 32 years earlier because of a multinodular goiter; no evidence of cancer was found, and the patient took levothyroxine thereafter. He was well in other respects until eight years before admission, when unstable angina pectoris developed, and a double coronary-artery-bypass graft was inserted with the use of a left saphenous-vein graft. The angina disappeared completely after the operation; he was able to walk 4 miles and to swim 60 laps daily. Two years . . .
Pembrolizumab (P) in patients (Pts) with colorectal cancer (CRC) with high tumor mutational burden (HTMB): Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) Study.
Authors: Eyal Meiri, Elizabeth Garrett-Mayer, Susan Halabi, Pam K. Mangat, Sagun Shrestha, Eugene R. Ahn, Olufunlayo Osayameh, Venu Perla, Richard L. Schilsky
Journal: Journal of Clinical Oncology (2020)

133 Background: TAPUR is a phase II basket study evaluating anti-tumor activity of commercially available targeted agents in pts with advanced cancers with genomic alterations. Results in a cohort of CRC pts with HTMB treated with P are reported. Methods: Eligible pts had advanced CRC, no standard treatment (tx) options, measurable disease, ECOG PS 0-1, and adequate organ function. Genomic testing was performed in CLIA-certified, CAP-accredited site selected labs. Pts had HTMB, defined as ≥9 mutations/megabase (Muts/Mb) by a FoundationOne test (n=26) or other tests (n=2) approved by the Molecular Tumor Board. Pts with MSI-H tumors were ineligible. Dosing of P was 2 mg/kg (n=8) or 200 mg (n=20) IV over 30 mins, every 3 wks. Simon two-stage design was used to test a null rate of 15% vs. 35% (power = 0.85; α = 0.10). If ≥2 of 10 pts in stage 1 have disease control (DC) (objective response (OR) or stable disease at 16+ wks according to RECIST (SD16+)), 18 more pts enrolled. If ≥7 of 28 pts have DC, the tx is worthy of further study. Secondary endpoints are progression-free survival (PFS), overall survival (OS) and safety. Results: Twenty-eight pts enrolled from June 2017 to November 2018; 1 pt was ineligible and excluded. HTMB ranged from 9 to 54 Muts/Mb. Table (N=27) summarizes demographics and outcomes. Tumor MS status was reported stable for 25 pts, ambiguous for 1 pt, and not available for 1 pt. One PR (MS stable and 10 Muts/Mb) and 7 SD16+ were observed for DC and OR rates of 28% (90% CI, 16% to 45%) and 4% (95% CI, 0% to 19%), respectively. 2 pts each had grade 3 AEs at least possibly related to P including abdominal infection, anorexia, colitis, diarrhea, fatigue, nausea, and vomiting; 1 also had SAE of acute kidney injury. Conclusions: Monotherapy with P showed anti-tumor activity in heavily pre-treated CRC pts with HTMB . Additional study is warranted to confirm the efficacy of P in this population. Clinical trial information: NCT02693535. [Table: see text]
Lgr5-mediated p53 Repression through PDCD5 leads to doxorubicin resistance in Hepatocellular Carcinoma
Authors: Zhili Ma, Deliang Guo, Quanxiong Wang, Pengpeng Liu, Yushao Xiao, Ping Wu, Yitao Wang, Baiyang Chen, Zhisu Liu, Quanyan Liu
Journal: Theranostics (2019)

The devastating prognosis of hepatocellular carcinoma (HCC) is partially attributed to chemotherapy resistance.Accumulating evidence suggests that the epithelial-mesenchymal transition (EMT) is a key driving force of carcinoma metastasis and chemoresistance in solid tumors.Leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5), as an EMT inducer, is involved in the potentiation of Wnt signaling in HCC.This study proposes uncovering the roles of Lgr5 in Doxorubicin (Dox) resistance of HCC to improve treatment efficacy for HCC.Methods: We investigated the expression and significance of Lgr5 in HCC tissue and different cell lines.The effect of Lgr5 in EMT and Dox resistance was analyzed in HCC cells and implanted HCC tumor models.A two-hybrid analysis, using the Lgr5 gene as the bait and a HCC cDNA library, was used to screen targeted proteins that interact with Lgr5.The positive clones were identified by coimmunoprecipitation (Co-IP) and Glutathione-S-transferase (GST) pull-down.The impact of the interaction on Dox resistance was investigated by a series of assays in vitro and in vivo .Result: We found that Lgr5 was upregulated and positively correlated with poor prognosis in HCC.Additionally, it functioned as a tumor promoter to increase cell migration and induce EMT in HCC cells and increase the resistance to Dox.We identified programmed cell death protein 5 (PDCD5) as a target gene of Lgr5 and we found that PDCD5 was responsible for Lgr5-mediated Dox resistance.Further analysis with Co-IP and GST pull-down assays showed that the N-terminal extracellular domain of Lgr5 could directly bind to PDCD5.Lgr5 induced p53 degradation by blocking the nuclear translocation of PDCD5 and leading to the loss of p53 stabilization.Lgr5 showed a protection against the inhibition of Dox on the growth of tumor subcutaneously injected.Moreover, Lgr5 suppressed Dox-induced apoptosis via the p53 pathway and attenuated the cytotoxicity of Dox to HCC.Conclusion: Lgr5 induces the EMT and inhibits apoptosis, thus promoting chemoresistance by regulating the PDCD5/p53 signaling axis.Furthermore, Lgr5 may be a potential target gene for overcoming Dox resistance.
Development and characterization of a theranostic multimodal anti-PSMA targeting agent for imaging, surgical guidance, and targeted photodynamic therapy of PSMA-expressing tumors
Authors: Susanne Lütje, Sandra Heskamp, Gerben M. Franssen, Cathelijne Frielink, Annemarie Kip, Marlène Hekman, Giulio Fracasso, Marco Colombatti, Ken Herrmann, Otto C. Boerman, Martin Gotthardt, Mark Rijpkema
Journal: Theranostics (2019)

Rationale: Prostate cancer (PCa) recurrences after surgery frequently occur. To improve the outcome after surgical resection of the tumor, the theranostic multimodal anti-PSMA targeting agent 111In-DTPA-D2B-IRDye700DX was developed and characterized for both pre- and intra-operative tumor localization and eradication of (residual) tumor tissue by PSMA-targeted photodynamic therapy (tPDT), which is a highly selective cancer treatment based on targeting molecules conjugated to photosensitizers that can induce cell destruction upon exposure to near-infrared (NIR) light. Methods: The anti-PSMA monoclonal antibody D2B was conjugated with IRDye700DX and DTPA and subsequently radiolabeled with 111In. To determine the optimal dose and time point for tPDT, BALB/c nude mice with PSMA-expressing (PSMA+) s.c. LS174T-PSMA xenografts received the conjugate (24-240 µg/mouse) intravenously (8 MBq/mouse) followed by µSPECT/CT, near-infrared fluorescence imaging, and ex vivo biodistribution at 24, 48, 72 and 168 h p.i. Tumor growth of LS174T-PSMA xenografts and overall survival of mice treated with 1-3 times of NIR light irradiation (50, 100, 150 J/cm2) 24 h after injection of 80 µg of DTPA-D2B-IRDye700DX was compared to control conditions. Results: Highest specific tumor uptake was observed at conjugate doses of 80 µg/mouse. Biodistribution revealed no significant difference in tumor uptake in mice at 24, 48, 72 and 168 h p.i. PSMA+ tumors were clearly visualized with both µSPECT/CT and NIR fluorescence imaging. Overall survival in mice treated with 80 µg of DTPA-D2B-IRDye700DX and 1x 150 J/cm2 of NIR light at 24 h p.i. was significantly improved compared to the control group receiving neither conjugate nor NIR light (73 days vs. 16 days, respectively, p=0.0453). Treatment with 3x 150 J/cm2 resulted in significantly prolonged survival compared to treatment with 3x 100 J/cm2 (p = 0.0067) and 3x 50 J/cm2 (p = 0.0338). Principal conclusions:111In-DTPA-D2B-IRDye700DX can be used for pre- and intra-operative detection of PSMA+ tumors with radionuclide and NIR fluorescence imaging and PSMA-targeted PDT. PSMA-tPDT using this multimodal agent resulted in significant prolongation of survival and shows great potential for treatment of (metastasized) prostate cancer.
The Children’s Oncology Group (COG) Adolescent and Young Adult (AYA) Responsible Investigator (RI) Network: An initiative for advancing AYA cancer research in the National Clinical Trials Network (NCTN).
Authors: Nupur Mittal, Aniket Saha, David Robert Freyer, Michael Roth
Journal: Journal of Clinical Oncology (2019)

e18016 Background: The COG has previously developed a successful model in which institutional RIs are identified to champion site-level research activities and trial enrollment. In response to low participation of AYAs in COG clinical trials, the COG AYA RI Network was developed. Methods: In January 2018, the COG AYA Committee solicited nominations of AYA RIs by site Principal Investigators. The AYA RI role is focused on the following site-level activities: 1. Working with the local IRB to prioritize AYA relevant studies; 2. Developing systems for screening AYAs for enrollment; 3. Serving as a liaison with medical oncology; 4. Educating staff on disparities in AYA outcomes. Increased site-level interaction with adult NCTN groups is a goal of this initiative. Results: The network was launched in February 2018. Subsequently, 144 RIs (physicians, research staff, psychologists, administrators) from 118 demographically and geographically diverse sites have joined the initiative. To date, there have been 9 interactive webinars, with 18 presenters from diverse institutions, each attended by 60-90 RIs. Two symposia on addressing barriers to enrollment were held at COG meetings. Shared site-level barriers and facilitators to enrollment have been identified. The most common recommendations for improving AYA accrual are: 1. Increase the number and diversity of AYA trials; 2. Increase collaboration between pediatric and medical oncology; 3. Increase support and resources from institutional leadership; and 4. Overcome logistical constraints to accruing AYAs to COG trials. Recently, the COG AYA RI Network joined with the SWOG AYA Committee to identify site-level dyads involving an AYA RI representing each group. Conclusions: To our knowledge, the COG AYA RI network is a novel model for enhancing AYA-focused cooperative group research at the site level, including enrollment on clinical trials. Next steps include conducting a formal survey to gather site-level data and establishing metrics to assess impact of this initiative, as well as continuing to work closely with SWOG to improve cross-group trial enrollment of AYAs.