tbuckley/cabot-search huggingface dataset:
Adjuvant therapy may decrease disparities in outcomes for black endometrial cancer patients.
Authors: Fan Zhu, Andrew R. Howard, Mihai Giurcanu, Christina H. Son, Yasmin Hasan
Journal: Journal of Clinical Oncology (2018)

5587 Background: Prior literature reports worse survival in Black (B) endometrial cancer patients compared to White (W) counterparts. This study compares outcomes between B and W patients after accounting for clinicopathologic (CP) factors and treatment. Methods: From 2006-2014, 305 (169 B and 136 W) patients with endometrial cancer treated at a single hospital were identified. CP features, treatment, and outcome data were collected. 201 (117 B and 84 W) with surgery and follow up were included in analysis. KM curves and log-rank test were performed to compare survival. Multivariable analysis (MVA) with Cox model was fitted for outcomes accounted for patient features, tumor details and treatment. To assess the stability of parameters and significance, an imputation analysis was performed. Results: Analysis showed that B and W patients had similar BMI, Charlson Comobidity Index (CCI), smoking history, stage, depth of invasion, and nodal involvement. B patients were older (P < 0.06) and had more non-endometrioid histology (P < 0.005) and lymphovascular invasion (LVI) (P < 0.05). Radiotherapy (RT) was used in 43% B and 30 % W (P = 0.069), and chemotherapy in 38% B and 27% W (P = 0.08), respectively. On MVA, non-endometrioid histology (HR = 10; P < 0.05), smoking (HR = 4.18; P < 0.05) and higher CCI (HR = 1.39; P < 0.05) were associated with worse OS. Race was not a predictor of OS. G3 endometrioid histology (HR = 16.14; P < 0.05), non-endometrioid histology (HR = 22.78; P < 0.005), smoking (HR = 3.32; P < 0.05) and higher CCI (HR = 1.41; P < 0.05) portended worse DFS. Early-stage improved DFS (HR = 0.16; P < 0.005). The 5-yr OS for B and W were 37% (SE 0.08) and 44% (SE 0.13) (p = 0.164) and the 2-yr DFS for B and W were 77% (SE 0.05) and 91% (SE 0.04), respectively (p = 0.215). For patients with known recurrence (N = 35), smoking (HR = 11; P < 0.005) and higher CCI (HR = 1.45; P < 0.05) portended worse OS; EBRT (HR = 0.07; P < 0.05) and W race (HR = 0.123; P < 0.05) predicted longer time to recurrence. Conclusions: While high risk CP features were associated with worse outcomes as expected, the more high risk features in B patients did not lead to worse outcomes. One explanation for this could be adjuvant therapy, which was implemented at least similarly between races in this study.
IDO1 expression in glioma molecular subtypes.
Authors: James Snyder, Tathiane M Malta, Houtan Noushmehr
Journal: Journal of Clinical Oncology (2018)

e14029 Background: Indoleamine 2,3-dioxygenase 1 (IDO1), a tryptophan catabolic enzyme is a key mediator of tumor-induced immunosuppression in multiple tumors. In gliomas, upregulation of IDO1 is associated with immune suppression and decreased survival. Inhibitors targeting IDO1 are being tested in several cancer types including malignant glioma. Methods: We aim to evaluate IDO1 expression in glioma and its associated clinical and molecular features, using 1,122 samples with molecular data across all subtypes of gliomas. Results: IDO1 gene expression was upregulated in IDH-wt gliomas compared to IDH-mutant (p < 0.05). High IDO1 expression was associated with classic, mesenchymal, and LGm6-GBM molecular subtypes, which includes low- and high- grade gliomas and presents poor outcome among all gliomas. Although in the IDH-wt macro-group, the PA-like subtype, consisting of lower grade gliomas, presented lower IDO1 expression compared to the remaining IDH-wt groups (p < 0.05). We found higher promoter methylation of IDO1 in IDH-mutant tumors compared to IDH-wt (p < 0.05). IDO1 promoter methylation was negatively correlated with IDO1 gene expression in all gliomas but G-CIMP-low which had a positive correlation with expression, suggesting an alternative epigenetic regulation of IDO1. Conclusions: Within glioma subtypes, IDO1 gene expression is negatively correlated with the percentage of CD4 T cells and positively associated with Treg, confirming its role in tumor immunity. IDH and molecular subtypes should be considered in IDO1 blockade trial design. Lower grade IDH-wt gliomas that are classified as classic- or mesenchymal-like should benefit from IDO1 inhibitors; while PA-like (IDHwt) and glioblastoma IDH-mutant (G-CIMP+) might not benefit from IDO1 blockade. IDO1 regulation in G-CIMP-low should be investigated as a potential biomarker for therapy in glioma. Further exploration of the mechanisms of tumor immunity and its epigenetic regulation in gliomas is warranted.
Prognostic factors for oligometastasis after 1<sup>st</sup> line first or second generation TKI for EGFR-mutated metastatic NSCLC.
Authors: Victor HF Lee, Cheuk-Wai Choi, Tsz-Yui Yau, Dicky Or, Tim-Shing Choy, Dennis KC Leung, Kin-Sang Lau, Ka-On Lam, To-Wai Leung
Journal: Journal of Clinical Oncology (2017)

e20521 Background: First and second generation TKI (gefitinib, erlotinib, afatinib) is the standard 1 st line therapy for EGFR-mutated metastatic NSCLC. Resistance ultimately develops despite initial durable response. Oligometastasis (OM) (defined as ≤5 newly developed metastatic lesions after TKI therapy) can be effectively treated with local ablative therapy so that the original TKI can be continued until further disseminated progressive disease. Methods: 151 patients treated with 1 st line TKI for their EGFR-mutated metastatic NSCLC recruited between 2009 and 2013 in our previous study (Lee et al, Journal of Thoracic Oncology 2013) were now included in the training set. Another 263 prospectively recruited patients treated in the same setting between 2013 and 2016 were in the validation set. The factors prognostic of OM-free survival in the training set were re-tested again in the validation set. Results: The OM-free survival for the training set did not differ from that for the validation set (mean 68.4 months vs. 56.1 months; p = 0.961, median OM-free survival were not reached for both sets). 37 (24.5%) and 56 (21.2%) patients in the training set and validation set respectively developed OM. Sex (hazard ratio 0.490, 95% confidence interval 0.257–0.936; p = 0.031) was the only significant prognostic factor of OM-free survival in the training set while it was just borderline significant in the validation set (hazard ratio 0.631, 95% confidence interval 0.366–1.088; p = 0.098). Conclusions: Male patients were more likely to develop OM after 1 st line first or second generation TKI. A more closer vigilance should be adopted for them so that effective local ablative therapy can be duly performed to procrastinate the use of 2 nd line treatment.
Serial CTC/cfDNA assessment for the identification of pathogenic mutations in patients with breast cancer.
Authors: Hanna Irie, Paul H. Schmidt, Elisa R. Port, Yayoi Kinoshita, Janis de la Iglesia, Kereeti Pisapati, Ronald Couri, Olivia Kolodka, Hanane Arib, Robert P. Sebra, Michael Joseph Donovan
Journal: Journal of Clinical Oncology (2017)

e23070 Background: Serial liquid biopsy assessment provides a unique platform for detecting existing and / or emergent resistance mutations; it may be particularly beneficial when patients begin to progress on otherwise effective therapy. We aimed to determine the utility of such an approach for detection of tumor genetic alterations at multiple points during the clinical course of patients diagnosed with breast cancer. Methods: Twenty patients diagnosed with stage I-IV breast cancer (50% with triple negative disease) receiving treatment at the Dubin Center of Mount Sinai were consented for serial CTC/cfDNA collections between October 2015 and November 2016. Circulating tumor cell (CTC)/cell-free DNA (cfDNA) were isolated using Cynvenio’s Liquid Biopsy platform and sequenced utilizing the Hotspot/Oncomine panels. DNA from corresponding patient tumors, when available, was also sequenced. Results: 25% of patients had at least one known pathogenic mutation detected in either cfDNA or CTC DNA in at least one collection; all patients had stage IV disease at collection. Pathogenic mutations detected were in p53 (15%), PIK3CA (10%) and Smad4 (5%). For those patients with available tumor tissue, the same pathogenic mutation was detected in the primary tumor. Mutations were more often detected in cfDNA rather than CTC DNA. Finally, known pathogenic mutations were more consistently detected in serial collections with clinical disease progression and resistance to treatment. Conclusions: Pathogenic mutations were identified in 25% of patients, more frequently in cfDNA and not in every collected sample, supporting serial collection studies to monitor response. Presence of same pathogenic mutations in the patient’s primary tumor suggest a role for surveillance in early stage, as well as advanced disease.
Expression of Claudin 18.2 and HER2 in gastric, gastroesophageal junction, and esophageal cancers: Results from the FAST study.
Authors: Martin H. Schuler, Salah-Eddin Al-Batran, Zanete Zvirbule, Georgy Manikhas, Florian Lordick, Andriy V. Rusyn, Ihor Vynnychenko, Assen Dudov, Igor Bazin, Bohuslav Melichar, Karl Dhaene, Kai Wiechen, Daniel Maurus, Özlem Tureci, Ugur Sahin
Journal: Journal of Clinical Oncology (2017)

4038 Background: Claudin 18.2 (CLDN18.2), a gastric mucosa tight junction protein, is aberrantly expressed in various cancers. In the FAST Phase 2 trial (NCT01630083), IMAB362, an anti-CLDN18.2 monoclonal antibody, administered in combination with EOX chemotherapy, prolonged survival compared to EOX alone in patients with advanced/recurrent gastric, gastroesophageal junction (GEJ), and esophageal cancers ineligible for trastuzumab. The aim of the present analysis was to assess tumor CLDN18.2 expression and co-expression with HER2 in the FAST population. Methods: Tumor tissue samples from patients screened for inclusion into the FAST trial were analyzed for CLDN18.2 expression using a CE-marked, validated immunohistochemistry (IHC) assay. CLDN18.2 expression was centrally scored based on staining intensity and percentage of stained tumor cells. In a subset of tissue samples with known HER2 status, overall HER2 expression and co-expression with CLDN18.2 were determined. Results: Tissue samples from 730 patients with gastric, GEJ, and esophageal cancer were screened for the FAST study. Of these 730 samples, 685 (94%) were assessed by central IHC; 49% (n=333/685) met the FAST CLDN18.2 expression criterion (≥2+ intensity in ≥40% of tumor cells) for inclusion. Across the 154 tissue samples with known HER2 status, the majority (84%; n=129/154) were HER2 – . Furthermore, 94 of these 154 samples (61%) met the FAST CLDN18.2 expression criterion, of which 14% (n=13/94) co-expressed HER2 (Table). Conclusions: In tissue samples from patients screened for the FAST trial, nearly half met CLDN18.2 expression inclusion criterion. In samples with known HER2 status, co-expression of CLDN18.2 and HER2 occurred in 14% of the samples that met study eligibility. These data suggest CLDN18.2 may serve as a non-HER2 overlapping targetable alteration in a distinct subpopulation of patients with gastric, GEJ, or esophageal cancers. Clinical trial information: NCT01630083. [Table: see text]
CALIBRATE: Intensive profiling of circulating tumour DNA (ctDNA) from patients participating in experimental therapeutics trials including mutational profiles and copy number changes.
Authors: Javier Garcia-Corbacho, Florent Mouliere, Hedley Carr, James Anthony Morris, Francesco Marrass, Davina Gillian Gale, Sanjeev Kumar, Mirela Hategan, Maricica Zabrautanu, William Dott, Elizabeth A. Harrington, Brian Andrew Dougherty, J Carl Barrett, Bristi Basu, James D. Brenton, Carlos Caldas, Duncan Ian Jodrell, Simon Pacey, Nitzan Rosenfeld, Richard D. Baird
Journal: Journal of Clinical Oncology (2016)

11530 Background: Serial analysis of plasma ctDNA with next generation sequencing could be used to identify patients for matched molecular therapies, to monitor the relative abundance of mutations over time, and to detect emergence of acquired drug resistance. Methods: Patients with solid tumours were recruited between q4 2014 and q4 2015 to early phase clinical trials of experimental drugs targeting FGFR, VEGFR, MEK, mTOR, AKT or cytotoxic agents. Plasma samples were collected according to individual trial protocols and CALIBRATE [UKCRN19138], a specific sample collection protocol. Samples were collected weekly (weeks 1-4), fortnightly (weeks 5-8), then at each cycle to progression. Intensive early sampling was performed for patients undergoing pharmacokinetic studies. Cell-free DNA (cfDNA) and ctDNA were quantified by digital PCR and analysed for mutations by tagged-amplicon deep-sequencing (TAm-Seq), using a custom panel covering regions in 28 genes of interest. On selected patients with high ctDNA content, copy number aberrations were analysed with shallow Whole Genome Sequencing (sWGS). Results: > 380 plasma samples were collected from 57 patients diagnosed with different tumour types. Gene mutations were detected in most (23/29, 79%). Notably, ESR1 gene mutations (Y537C, D538G) were detected in 6/10 patients with estrogen-receptor positive breast cancer. Preliminary results indicate a relationship between disease progression and an increase in cfDNA and ctDNA levels, also between response and decrease of cfDNA and ctDNA. Samples taken 6, 24 and 48 hours post-dose show rapid changes in total cfDNA and mutational levels. In one case, sWGS of serial plasma samples cfDNA identified a complex rearrangement between chr6 and 10. Conclusions: cfDNA, ctDNA mutational profiles may be useful to identify patients for matched molecular-targeted therapies. Preliminary results suggest that changes in ctDNA levels can be correlated with clinical outcomes. For patients who initially respond but develop progressive disease, continued molecular profiling of plasma has identified potential markers of acquired drug resistance Clinical trial information: UKCRN19138.
A transcriptome analysis of castration resistant prostate cancer metastases in a prospective cohort study reveals high expression of AKT pathway genes predictive of long term response to abiraterone acetate/prednisone.
Authors: Manish Kohli, Scott Dehm, Vipul Bhargava, Michael Gormley, Jason P. Sinnwell, Winston Tan, David W. Hillman, Ying Li, Rafael E. Jimenez, Richard M. Weinshilboum, Krishna R. Kalari, Liguo Wang, Hugues Sicotte
Journal: Journal of Clinical Oncology (2018)

5038 Background: To determine transcriptome based markers associated with long-term response to abiraterone acetate/prednisone (AA/P) in metastatic castration-resistant prostate cancer (mCRPC). Methods: RNAsequencing (RNA-seq) of metastatic biopsies were performed in a prospective cohort study of treatment naïve mCRPC patients initiating AA/P (visit1) and repeated after 12 weeks on treatment (visit2). Patients (pts) were followed for time to treatment change (TTTC), defined as time from enrollment until change of AA/P treatment due to progressive disease. The lower and upper quartiles of TTTC for the whole cohort defined short term and long term responders. Previously we published the primary analysis revealing Wnt pathway activation as markers of primary resistance to AA/P (Annals of Oncology;2017; PMID29069303). As a secondary study goal gene-set variation analysis (GSVA) of 113 prostate cancer related gene sets was performed with post treatment visit2 RNA-seq data to identify associations with long from short-term responders. RNA-seq based candidates identified as associated with long term response were also evaluated in visit1 biopsies. Results: 83/90 enrolled pts had a visit2 biopsy of which 58 biopsy specimens had good quality RNA for analysis. 18/58 had short (median 3.6 months; range 1.4-4.5) and 11/58 patients and long- (median 29 months; range 23.5-41.7) term responses. In the metastases of Visit2 biopsies, long-term responders had lowered expression of steroid-biosynthesis genes (e.g., CYP7B1, CYP39A1, AKR1D1) (p-value < 0.005) and higher expression of genes upregulated by AKT activation (e.g. GOT1, PPP4C, KRT8) (p-value < 0.02). Similar elevated expression of AKT activation was observed at Visit1 (p-value < 0.04) in long-term responders. The AKT activation signature was also negatively correlated with the steroid biosynthesis signature (Spearman correlation of -0.61, p-value < 2e-7). Conclusions: AA/P was more effective in pts with high pre-treatment AKT pathway gene expression signatures suggesting that AKT activation can be used as a predictive biomarker for AA/P. Clinical trial information: NCT# 01953640.
Quality of life analysis of Pemetrexed versus Erlotinib maintenance in EGFR mutation negative advanced non small cell lung cancer.
Authors: Vivek Agarwala, Vijay Maruti Patil, Vanita Noronha, Amit Joshi, Anuradha Chougule, Vaishakhi Trivedi, Rajiv Kumar, Sucheta More, Supriya Goud, Amit Janu, Abhishek Mahajan, Kumar Prabhash
Journal: Journal of Clinical Oncology (2018)

9024 Background: Both Pemetrexed and Erlotinib have shown survival benefit when used as maintenance therapy in advanced non small cell lung cancer (NSCLC) after platinum doublet chemotherapy. Hence this study was planned to compare the outcomes between the 2 drugs. The current abstract is focused on quality of life (QOL) results. Methods: This was a open label, randomized, phase 3 study done in adult palliatively treated EGFR-negative, NSCLC patients who had non progressive disease post administration of first line chemotherapy Pemetrexed-Carboplatin. Patients were 1:1 randomized between tablet Erlotinib 150 mg orally administered once daily versus injection Pemetrexed 500 mg/m2 administered intravenously every 3 weeks. The therapy was continued either till disease progression or development of intolerable side effects. The primary endpoint was to compare the QOL between the 2 arms at 3 months. Other secondary endpoints were to study and compare the progression free survival (PFS), overall survival (OS) and adverse event rate. We had 200 patients in this study and the sample size had 80% power, with type 1 error of 5% to detect a difference of 0.3 in effect size. Results: Total 200 patients were recruited in the study. The median follow up was 25.37 months (95%CI 21.4-29.3 months). There was no difference in global QOL between the 2 arms at 3 months (p=0.384). There was no difference in any domain of QOL except a higher score for diarrhea was seen in the Erlotinib arm (p=0.001). The PFS (HR 0.99; 95% CI 0.73-1.34, p=0.939) and OS (HR 0.88; 95%CI 0.62-1.27, p=0.493) were similar between both the arms. Conclusion: Maintenance Pemetrexed post Pemetrexed-Platinum chemotherapy fails to improve QOL or time to event outcomes (OS & PFS) over maintenance Erlotinib in EGFR mutation negative advanced NSCLC. Clinical trial information: CTRI/2014/08/004847.
Prognostic factors in HIV-positive patients with non-Hodgkin lymphoma: A Peruvian experience.
Authors: Luis Ernesto Cuellar Ponce de León, Andrea Carolina Anampa-Guzmán, Alexis Manuel Holguín Ruiz, Juan Isidro Velarde Marca, Diana Portillo Alvarez, Marco Antonio Zuñiga, Esther Luna Reyes, Jule Franve Vasquez Chavez
Journal: Journal of Clinical Oncology (2016)

e19045 Background: Non-Hodgkin lymphoma (NHL) is the most common cancer in people with HIV. The aim of this study was to determine the prognostic factors in HIV positive patients with systemic NHL. Methods: This retrospective cohort study included 47 HIV positive patients with NHL in the Infectious Diseases Unit of Instituto Nacional de Enfermedades Neoplasicas (INEN) between 2004 a 2014. The patients were divided into two groups based on their pre-treatment: HAART-naïve (n = 34) and previously treated (n = 13). These patients received chemotherapy with CHOP and HAART. The medical records, demographic data, viral load, CD4 count, serum lactate dehydrogenase, serum albumin, hemoglobin, aspartate transaminase, co-infections, ECOG score and clinical stage of the tumor were reviewed. Data were analyzed using t-test and chi-square test. Survival curves were estimated by Kaplan-Meier and comparison was done by log-rank test. Multivariate analysis for overall survival (OS) was performed with the Cox proportional hazard regression model. Results: All the previously treated patients were from the capital city (p = 0.039) and had significantly lower levels of hemoglobin compared to HAART-naïve patients (p = 0.026).The median OS time was 47.67 months, and the 5-yrs-OS was 36.1%. The median OS of HAART-naïve patients was significantly higher than previous treated patients, 57.05 and 21.09 months respectively (p = 0.018). An advanced stage, low serum albumin and previous HAART were parameters with influence on OS in both groups. The factor influencing OS of naïve patients was age > 60 and in previous treated patient was low serum albumin. Conclusions: An advanced stage, low serum albumin and previous HAART were the main prognostic factors in patients with systemic NHL and HIV infection. HAART-naïve patients live more than previous treated patients. Prognostic factors in HIV-LNH: Multivariate analysis. Total HAART-naive Previously Treated HR 95% CI P HR 95% CI P HR 95% CI P Previous HAART 5.09 1.86- 13.88 0.001 Older than 60 years 50.71 2.55- 1008.22 0.01 Stage III-IV 5.89 1.15-30.1 0.033 Serum Albumin < 3 6.04 1.83- 19.92 0.003 13.42 1.05- 171.31 0.046
Treatment of adolescents and young adults with Philadelphia negative acute lymphoblastic leukemia (AYA Ph-ALL) using a risk and response based protocol with extended intensification and high dose methotrexate: A report from a single center in Saudi Arabia.
Authors: Saleem Eldadah, Wasil Jastaniah, Ahmad Alsaeed, Mohammed Burhan Abrar, Mohamed A. Abdelaal, Zayed Alzahrani, Walaa Rajkhan, Ashraf Warsi, Enaam Alsobhi, Majed Alahmadi, Amro Ibrahim, Ahmad Higazi, Ayoub Ahmed, Ihab El-Hemaidi, Ahmed A. Absi
Journal: Journal of Clinical Oncology (2017)

e18527 Background: Studies have shown superior outcomes of AYA Ph-ALL when treated with pediatric or pediatric-inspired protocol. Since 2003 we used a modified Children’s Oncology Group (COG) protocol to treat AYA Ph-ALL aiming to improve outcomes. Methods: This study involved 67 consecutive patients aged 14-35 years with Ph-ALL diagnosed between October 2003 and March 2016. Patients with precursor B ALL, CNS1/CNS2, and negative day 29 minimal residual disease (MRD-) received single interim maintenance (IM) and delayed intensification (DI) (Arm B). While CNS3 or MRD+ patients received double IM and DI (Arm C). Patients with T cell ALL received double IM with high dose methotrexate (HDMTX) in IM#1, and double DI (Arm C+HDMTX). Dexamethasone was used in all patients but prophylactic cranial irradiation was not utilized. Results: Median age at diagnosis was 17 years with 24 (35.8%) 18 years and older. CR rate, induction death, relapse rate, 4 year event free survival (EFS) and overall survival (OS) were 93.7%, 4.5%, 19.4%, 71.4%±6.0 and 81.8%±5.0; respectively. Of the 57 patients with available MRD, 44 (77.2%) were MRD-. Day 29 MRD status significantly impacted the outcomes (EFS: 78.6%±6.8 vs. 49.2%±15.4; p = 0.007 and OS: 90.5%±4.5 vs. 49.4%±22.0; p = 0.04) for MRD- vs. MRD+ patients; respectively). Outcomes were not different for T (n = 21) vs. B (n = 46) phenotypes (EFS: 69.2%±7.6 vs. 75.6%±9.5; p = 0.57 and OS: 79.8%±6.5 vs. 85.7%±7.6; p = 0.98; respectively). Grade 3 and above toxicities were venous thromboembolism (VTE) in 9 (13.4 %), avascular necrosis (AVN) in 9 (13.4 %) and pancreatitis in 3 (4.5 %) patients. Four patients (6%) died in CR and 2 died with secondary AML. Conclusions: Improved outcomes were observed with OS rate exceeding 90% for MRD negative patients. Therapy was tolerated relatively well, however, AVN and VTE occurred frequently. This suggests that utilizing a modified COG backbone in AYA Ph-ALL patients up to 35 years of age is feasible, however, further modification is warranted to reduce toxicity and improve outcomes in MRD positive patients.