tbuckley/cabot-search huggingface dataset:
Comparison of the tumor mutation burden (TMB) analysis results between a targeted next-generation sequencing method and the conventional WES method.
Authors: Yuhang Cai, Chunli Wang, Shuang Zhou, Zhe Wang, Mao Mao, Mingzhi Ye
Journal: Journal of Clinical Oncology (2018)

e24186 Background: Tumor Mutation Burden (TMB) is an effective genomic biomarker to predict the efficacy of anti PD-L1/PD1 therapies. WES is a general method to detect the TMB in scientific studies while it is difficult to be used for clinical applications because of its cost. Targeted next-generation sequencing assay as an accurate, flexible, and cost-effective method may be able to replace WES as a TMB analytic method. Methods: In this study, we proposed Oseq-T, a comprehensive cancer panel, which can detect four types of genomic mutations including SNVs, InDels, CNV, SV of 636 genes to measure the TMB. TMB is a measure of the number of somatic protein-coding base SNV and InDel occurring in a tumor specimen. We compared the consistency of TMB measured by WES and the ones measured by Oseq-T filtered data. Then we described the distribution of TMB value of different cancer types by a 674-Chinese clinical patient cohort. Results: We used a total of 2,137 WES tumor data to examine the accuracy of the TMB value measured by targeted capture sequencing, which include 1,049 tumor data obtained from published research articles for retrospective analysis and 1,088 Chinese tumor data obtained from BGI for prospective analysis. The Pearson correlation coefficient R2of the TMB values was 0.9688 and 0.9538 for the two cohorts. For different cancer types, the R2 range from 0.3921 to 0.9862. Meanwhile, to avoid the data bias due to the selection of the targeted region, we evaluated the TMB consistency between data filtered by Oseq-T and the other 100 random targeted regions with the same size. The correlations ranged from 0.9832 to 0.9924. By the TMB detection of the 674 Chinese clinical patients, we found a subset of cancer types exhibited highly TMB, including melanoma, endometrium and bladder cancer. Conclusions: In summary, our analysis of TMB by Oseq-T cancer panel is strongly consistent with the WES result. Targeted capture sequencing can be expected as an effective TMB analysis method for clinical applications. But we also found that for the cancer types with low TMB WES/WGS analysis could still the most ideal method. More date is needed to prove this point of view.
Accessing care: Experiences and perceptions of morbidly obese women diagnosed with low-grade endometrial cancer—A qualitative study.
Authors: Andrea N Simpson, Maria Christine Cusimano, Angela Han, Robin Zoe Hayeems, Marcus Q Bernardini, Deborah Robertson, Sari Kives, Abheha Satkunaratnam, Nancy N. Baxter, Sarah E. Ferguson
Journal: Journal of Clinical Oncology (2018)

e18658 Background: Obesity is a risk factor for low-grade endometrial cancer. The surgical management of obese patients is complex, and they may experience unique barriers in accessing care. We aimed to answer the question: what are the experiences/perceptions of morbidly obese women diagnosed with low-grade endometrial cancer as they navigate the healthcare system from the onset of symptoms to surgery? Methods: Semi-structured interviews were performed with morbidly obese (body mass index (BMI) > 40kg/m2) endometrial cancer patients referred to two tertiary hospitals in Toronto, Canada. We used interpretive description and a labelling theoretical perspective to align with literature on weight-based discrimination. Interviews were transcribed verbatim, and thematic analysis was performed by two researchers. Audit trails and bracketing were used to ensure rigour. Results: Fifteen patients with a median age of 61 years (50-74) and a median BMI of 50 kg/m2 (44-70) were interviewed. Three major themes emerged: (1) There is a lack of patient and provider knowledge on red flags and risk factors for endometrial cancer, particularly in the context of obesity; (2) Both individual providers and the healthcare system are inadequately equipped to accommodate and communicate with morbidly obese patients; and (3) Universal geographic, financial, and physical barriers were identified by the participants, and may be modifiable to improve healthcare accessibility. Conclusions: Improved messaging around early identification and prevention of endometrial cancer is needed for both the public and providers. Proactive rather than reactive approaches, and dedicated care pathways for morbidly obese patients, may improve healthcare delivery to this vulnerable population.
Association of genomically unstable Ewing sarcoma tumors with HOTAIR overexpression and clinical outcome.
Authors: Jamie D. Gardiner, Xiaomeng Huang, Evangelia Lazaris, Kevin Jones, Jeffrey T. Yap, R Lor Randall, Lisa Abegglen, James Amatruda, Joshua David Schiffman
Journal: Journal of Clinical Oncology (2017)

11035 Background: Ewing sarcoma (ES) is the second most common bone cancer in children, characterized by the EWS-FLI1 fusion protein. Like most translocation-driven pediatric cancers, ES is a genomically “quiet” cancer with a low mutational burden and strong epigenetic regulation. However, recurring copy number alterations (CNAs) still arise in some ES tumors (e.g., chromosome 1q gain, 8 gain, 12 gain, and 16q loss) while other ES tumors completely lack genomic CNAs. We hypothesized that clinical, molecular, and epigenetic differences exist between these two unstable vs. stable genomic subtypes of ES. Methods: We performed CNA analysis on over 200 ES FFPE tumors. 30% of ES tumors had stable genomes while 60% had one or more CNAs across the genome. We performed gene expression and methylation microarray analyses on 24 ES FFPE tumors (11 stable, 13 unstable). Expression and methylation signatures were compared between stable vs. unstable ES and combined with clinical outcome. Results: Patients with unstable vs. stable ES tumors revealed worse 5-year overall (OS) and event-free survival (EFS) (38% vs. 67% EFS, p = 0.005; 58% vs. 84% OS, p = 0.0016). The subtypes had distinct expression and methylation signatures and clustered by methylation patterns. We identified differentially expressed and methylated genes, including upregulation (p = 0.0005) and unmethylation (p = 0.0009) of the long non-coding RNA HOTAIR in unstable vs. stable ES tumors. HOTAIR expression is higher in metastatic ES tumors compared to primary ES tumors (p = 0.02). Per the Cancer Cell Line Encyclopedia (Broad), ES cell lines have increased HOTAIR expression compared to 36 other cancers. Conclusions: ES genomic profiling through copy number, gene expression, and methylation identified at least two subtypes of ES (stable and unstable) that differ in outcome, gene expression and methylation. This data suggests HOTAIR’s involvement in ES pathogenesis, particularly in unstable tumors that have worse prognosis. Investigation is ongoing for HOTAIR expression as a prognostic and therapeutic target for ES, including a marker for LSD-inhibitor response.
An effective anti-emetic regimen for less than $2 USD: A prospective observational study.
Authors: Nikita Mehra, Prasanth Ganesan, Manikandan Dhanushkodi, Trivadi S. Ganesan, Venkatraman Radhakrishnan, Jayachandran P K, Selvaluxmy Ganesharajah, Tenali Gnana Sagar
Journal: Journal of Clinical Oncology (2018)

e22194 Background: Olanzapine is an effective agent for chemotherapy induced nausea and vomiting (CINV). The usual dose is 10 mg X 4 days when chemotherapy is given in a Q 3-4 weekly schedule. We report the efficacy of modified-dose olanzapine schedule for patients receiving weekly cisplatin. Methods: Patients of carcinoma cervix receiving 6 x weekly doses of cisplatin 40mg/m2with concurrent radiation received OPD with each dose of cisplatin (olanzapine 5mg D1,2, palonosetron 0.25mg IV bolus on D1 and dexamethasone 12mg IV D1). Patients were prospectively assessed with the help of a CINV diary. Results: Sixty-five patients [median age- 48 (23-65) years] received a median of 4 (1-6) doses of cisplatin concurrently with radiation for a total of 216 weekly OPD courses. No nausea rate was 57% (124/216) and no vomiting rate was 83% (180/216). The CR (complete response = no emetic episodes and no need for rescue medication) rate was 55% (36/65). Only 1 patient (2%) had grade 3 nausea. No patient had grade 3 or 4 vomiting. 22 patients (34%) had mild drowsiness with an average score of 1.15/10. The cost of olanzapine for all the 6 cycles in India works out to INR 18 (USD 0.24) and the cost of the OPD/course was USD 1.68. This compared favorably with the cost of aprepitant based treatment (APD) which costs INR 500–1500 (USD $ 9)/ course. Conclusions: The 2-day, low-dose, olanzapine regimen was a highly effective and very well tolerated regimen against CINV. Along with a significant cost-advantage this regimen should be considered strongly for all patients receiving concurrent chemo-radiation with weekly cisplatin.
Preclinical Evaluation of the Hsp70 Peptide Tracer TPP-PEG24-DFO[89Zr] for Tumor-Specific PET/CT Imaging
Authors: Stefan Stangl, Lorenzo Tei, Francesco De Rose, Sybille Reder, Jonathan Martinelli, Wolfgang Sievert, Maxim Shevtsov, Rupert Öllinger, Roland Rad, Markus Schwaiger, Calogero D'Alessandria, Gabriele Multhoff
Journal: Cancer Research (2018)

Abstract High precision in vivo PET/CT imaging of solid tumors improves diagnostic credibility and clinical outcome of patients. An epitope of the oligomerization domain of Hsp70 is exclusively exposed on the membrane of a large variety of tumor types, but not on normal cells, and thus provides a universal tumor-specific target. Here we developed a novel PET tracer TPP-PEG24-DFO[89Zr] based on the tumor cell–penetrating peptide probe TPP, which specifically recognizes membrane Hsp70 (mHsp70) on tumor cells. The implemented PEG24 moiety supported tracer stability and improved biodistribution characteristics in vivo. The Kd of the tracer ranged in the low nanomolar range (18.9 ± 11.3 nmol/L). Fluorescein isothiocyanate (FITC)-labeled derivatives TPP-[FITC] and TPP-PEG24-[FITC] revealed comparable and specific binding to mHsp70-positive 4T1, 4T1+, a derivative of the 4T1 cell line sorted for high Hsp70 expression, and CT26 tumor cells, but not to mHsp70-negative normal fibroblasts. The rapid internalization kinetics of mHsp70 into the cytosol and the favorable biodistribution of the peptide-based tracer TPP-PEG24-DFO[89Zr] in vivo enabled a tumor-specific accumulation with a high tumor-to-background contrast and renal body clearance. The tumor-specific enrichment of the tracer in 4T1+ (6.2 ± 1.1%ID/g), 4T1 (4.3 ± 0.7%ID/g), and CT26 (2.6 ± 0.6%ID/g) mouse tumors with very high, high, and intermediate mHsp70 densities, respectively, reflected mHsp70 expression profiles of the different tumor types, whereas benign mHsp70-negative fibroblastic hyperplasia showed no tracer accumulation (0.2 ± 0.03%ID/g). The ability of our chemically optimized peptide-based tracer TPP-PEG24-DFO[89Zr] to detect mHsp70 in vivo suggests its broad applicability in targeting and imaging with high specificity for any tumor type that exhibits surface expression of Hsp70. Significance: A novel peptide-based PET tracer against the oligomerization domain of Hsp70 has potential for universal tumor-specific imaging in vivo across many tumor type. Cancer Res; 78(21); 6268–81. ©2018 AACR.
Phase 2 trial results of DN24-02, a HER2-targeted autologous cellular immunotherapy in HER2+ urothelial cancer patients (pts).
Authors: Dean F. Bajorin, Padmanee Sharma, David I. Quinn, Elizabeth R. Plimack, Jean H. Hoffman-Censits, Peter H. O'Donnell, Arlene O. Siefker-Radtke, Nadeem Anwar Sheikh, Jennifer Susan LIll, James B. Trager, Leonard G. Gomella
Journal: Journal of Clinical Oncology (2016)

4513 Background: DN24-02 is an autologous cellular immunotherapy consisting of antigen-presenting cells (APC) cultured with BA7072, a recombinant HER2-derived antigen (HER500) linked to granulocyte macrophage colony-stimulating factor. NeuACT (NCT01353222) is an open-label, randomized, phase 2 trial of adjuvant DN24-02 or standard of care (SOC) surveillance in HER2+ urothelial cancer pts with high relapse risk after surgery. Study objectives were overall survival (OS), disease recurrence-free survival (DRFS), product potency, and immunologic response. Methods: Pts expressing HER2 were randomized 1:1 to DN24-02 or SOC (target = 180 pts). DN24-02 pts received infusions every 2 wk (for a total of 3). Product potency was assessed using CD54 upregulation as a measure of APC activation. Antigen-specific cellular response was evaluated by T cell proliferation and IFN-γ ELISPOT; humoral response was measured by ELISA. OS and DRFS were compared using Cox regression analysis. Results: In 142 enrolled pts with 13.2 mo of follow-up, OS was 37.0 (DN24-02) vs 22.2 mo (SOC) (hazard ratio [HR] 0.96; p = 0.87), and DRFS was 11.9 (DN24-02) vs 10.1 mo (SOC) (HR 0.99; p = 0.97). In subgroup OS analyses, more favorable HRs were observed in pts with lower disease burden (i.e., lack of lymph node involvement), no prior neoadjuvant chemotherapy, and lower neutrophil/lymphocyte ratios. DN24-02 increased APC activation, in vitro IL-2 and IFN-γ accumulation, serum cytokines (IL-2, IFN-γ, and TNF-α), and antigen-specific T cell responses. BA7072 and HER500 antibody titers were significantly elevated from baseline through month 16. Conclusions: No statistical differences were observed in OS or DRFS; however, interpretation of these results is restricted by limited enrollment and short follow-up. Pts with certain characteristics of lower tumor burden had the most notable HRs for OS. APC activation and cytokine patterns were consistent with an immune prime boost. DN24-02–induced immune response persisting > 1 y suggests T cell activation and immune memory generation, consistent with mobilized antitumor immune responses. Together, these results suggest that additional investigation may be warranted. Clinical trial information: NCT01353222.
A phase 2 randomized study of SHAPE Gel (SHP-141) in patients with early-stage cutaneous T-cell lymphoma: Interim results.
Authors: Madeleine Duvic, Youn H. Kim, Nicole R LeBoeuf, Pierluigi Porcu, Justin Hastings, Juri Bassuner, Laura Sowerby, Alba Posligua-Alban, Joan Guitart
Journal: Journal of Clinical Oncology (2016)

7562 Background: Cutaneous T-cell lymphoma (CTCL) is a form of extranodal lymphoma where malignant T-cells infiltrate the skin. Options for early-stage patients can be limited due to toxicity. Systemic histone deacetylase inhibitors (HDACi) can be efficacious, but may be too toxic for these patients. SHAPE Gel (SHP-141) is a topical HDACi with activity in a phase 1 study, and no systemic absorption. Objectives: To assess efficacy, safety and tolerability of SHAPE Gel in patients with early-stage CTCL, mycosis fungoides (MF)-type. Methods: Sixty-one patients with early stage (IA, IB, IIA) MF were randomized to one of three open-label arms: SHAPE Gel 0.5% BID; 1% daily; or 1% BID. Patients were assessed for response and tolerability monthly. The primary endpoint, improvement in the Composite Assessment of Index Lesion Severity (CAILS) score, and secondary endpoint, improvement in modified Severity Weighted Assessment Tool (mSWAT) score, were measured at 6 months; patients continued treatment up to one year in the absence of toxicity. A planned interim analysis was done when ~50% of the patients reached 6 months. Results: 34 patients were enrolled and assessed for CAILS and mSWAT response at this interim; 28 were available for efficacy assessment. Six discontinued prior to 6 months (4 AEs; 2 physician decision). 24% of patients had a CAILS response at the 6 month time-point; 32% for mSWAT. 35% of patients demonstrated a CAILS response at any time within 6 months; 41% of patients for mSWAT. Clinically significant reduction in itch, measured by a visual analog scale, was seen in 89% of patients with significant itch at baseline, at 1% BID. AEs attributable to SHAPE Gel were limited to skin; no related SAEs were seen, and all but one AE attributable to SHAPE Gel were CTCAE Grade ≤ 2. Conclusions: SHAPE Gel shows promising response in patients with early-stage MF-type CTCL, and may improve disease symptoms. SHAPE Gel may address an important unmet medical need by offering the clinical benefit of an HDACi with minimal local, and no systemic, toxicity. This study has now enrolled all 60 patients and final results are anticipated within the next 6 months. Clinical trial information: NCT02213861.
A randomized open label exploratory controlled trial of CLT-008 myeloid progenitor cells (MPC) to decrease infections during induction for AML.
Authors: Camille N. Abboud, Luke Paul Akard, Charalambos Andreadis, Pinkal M. Desai, James M. Foran, Olga Frankfurt, Saar Gill, Jack W. Hsu, John Lister, John M. Pagel, Gary J. Schiller, Melham M. Solh, Celalettin Ustun, Matthew Joseph Wieduwilt, Brown Janice, Alicia Wong, Lois Kellerman, Rodney Van Syoc, Rick Mamelok, Farhad Ravandi
Journal: Journal of Clinical Oncology (2018)

7043 Background: Induction chemotherapy for AML results in prolonged neutropenia and a high risk of infection. CLT-008 is a human off-the-shelf allogeneic MPC preparation manufactured by ex vivo culture expansion of CD34+ cells. Following infusion MPCs are expected to home to bone marrow (BM) and produce neutrophils. Methods: 163 subjects with de novo AML (age ≥55) and receiving HIDAC or 7+3 induction were randomized on Day 0 (first day of induction) to receive either CLT-008 (7.5x106 cells/Kg) on Day 9 + GCSF qd starting on Day 14 (treatment) or GCSF alone starting on Day 14 (control) qd until ANC recovery to 500/µL. Most endpoints were assessed from Day 9 to Day 28 and included days in a Febrile Episode (primary endpoint), microbiologically defined bacterial or fungal infections (MDI, adjudicated by a blinded independent committee), and days in hospital (to Day 42). The safety population (S-subjects) included those who received CLT-008 or GCSF. The evaluable population (E-subjects) included those who received CLT-008 or GCSF alone, were in study ≥ 28 days and did not receive additional chemotherapy before Day 28. Results: Baseline characteristics were balanced. The mean number of days in febrile episodes was 6.7 in treated and 7.1 in controls (NS) between the groups. In S-subjects, MDI was diagnosed in 14/70 treated vs 21/71 controls, a decrease of 32%. MDI with bacteremia was diagnosed in 7/70 treated vs 12/71 control subjects. MDI without bacteremia was diagnosed in 8/70 vs 11/71. In E-subjects, mean hospital stay was 3 days less in treated vs control. Remission rates and days to ANC recovery were similar in the two groups. All subjects assessed (n = 18) for chimerism had CLT-008 cells detected in peripheral blood on the day of infusion and 72% had CLT-008 detected in one or more of peripheral blood, BM or gingiva prior to ANC recovery. Infectious deaths occurred in no CLT-008 and 2 control subjects. GVHD was not observed. Antimicrobial use will be presented. Conclusions: Subjects receiving CLT-008 showed a decreased incidence of infections and days in hospital suggesting that myeloid progenitors may provide a new option to reduce infections in AML patients undergoing induction therapy. Clinical trial information: NCT02282215.
Clonal evolution in locally advanced rectal cancers in response to neoadjuvant chemoradiotherapy.
Authors: Sinead Toomey, Aoife Carr, Jillian Rebecca Gunther, Joanna Fay, Anthony O'Grady, David Weksberg, Scott W Piraino, Elaine Kay, Brian O'Neill, Sunil Krishnan, Simon J Furney, Bryan Hennessy
Journal: Journal of Clinical Oncology (2017)

3616 Background: Locally advanced rectal cancer, LARC (T3/4 and/or N+) is currently treated with neoadjuvant chemoradiotherapy (NACRT), however clinicopathological response is variable. Monitoring clonal evolution in response to NACRT may identify mutations driving therapeutic resistance or tumor growth after treatment. Methods: Fresh-frozen pre- and post-NACRT tumor and matched normal tissue from LARC patients were stratified into good (RCPath A), intermediate (RCPath B) and poor (RCPath C) responders. Following histological review, targeted exome capture was performed using an Agilent SureSelect Human all Exome V3 kit. Samples were sequenced to a minimum of 100X coverage on an Illumina HiSeq2000, and clonal evolution was assessed in matched pre- and post-NACRT tumor samples. Results: The median somatic mutation burden in pre-treatment samples was 114 (IQR 19-207). Two tumors were microsatellite (MSI) unstable and had elevated mutational burdens. The least evolution occurred in the poor responders, where there was little change in clonal composition after treatment, and driver mutations in genes including TP53 and APC were retained. On average 79% of pre-treatment mutations were retained post-treatment in poor responders and 33% of mutations were retained in intermediate responders. Many of the intermediate responders had loss of driver mutations including TP53 from the pre-treatment sample, but also shared a number of mutations in genes including PIK3CA and BRAF between pre- and post-treatment samples. There was also increased frequency in the post-treatment samples of clones that were not present in the pre-treatment samples. In one intermediate responder, all 47 mutations that were present in the pre-treatment sample including the driver mutations TP53 and APC were absent in the post-treatment sample, while 10 completely new mutations were identified. Conclusions: Dynamic mutational processes occur in LARC following selective pressures of exposure to NACRT, including changes in somatic mutation presence or frequency after treatment, owing to persistence or loss of sub-clones. As NACRT can profoundly affect the LARC genome, monitoring molecular changes during treatment may be clinically useful.