tbuckley/cabot-search huggingface dataset:
Population health impact of genome-driven oncology by race and ethnicity.
Authors: Fabrice Smieliauskas, Hari Sharma, Daniel V.T. Catenacci, Dezheng Huo
Journal: Journal of Clinical Oncology (2019)

e18229 Background: The magnitude of clinical benefit from genome-driven oncology is the subject of controversy. Past estimates of the population health gains from genomic therapies have not explored differences by race and ethnicity (R/E) nor accounted for the lack of representativeness of commonly used tumor genomics databases. We assessed the attainable population health gains by R/E from cancer drugs with genomic biomarker indications for use. Methods: We used all patient (pt) samples of solid tumors from the AACR Project GENIE v3.0.0 tumor genomics data sharing initiative that met criteria for comprehensiveness of sequencing. We categorized biomarker-tumor site indications as actionable if FDA-approved or considered standard of care in the OncoKB Knowledge Base as of 1/25/19, and estimated actionability rates from genomic therapies. We modelled attainable median overall or progression free-survival gains for actionable pts and all pts from these therapies using results from registrational trials in pts with metastatic cancer. Analyses were performed for all pts and for Black, Asian, Hispanic, and non-Hispanic White R/E groups. To test for disparities in actionability rates (survival gains), we estimated logistic regression (least squares regression) models of having a clinically actionable gene abnormality (survival gains) regressed on minority R/E indicator variables and performed overall Chi-squared tests (F-tests) of whether the R/E coefficients were jointly equal to zero. All analyses were weighted to be representative of the U.S. cancer incident pt population by demographic and tumor site subgroup. Results: Data for 24,255 adult cancer patients met our criteria, including over 900 patients of each of the three minority R/E. Population-weighting showed that the Black and Hispanic pts were heavily underrepresented in the original sample. Weighted actionability rates were 18.2%, with disparities across R/E groups (p &lt; 0.01) and Asians having the highest rates (24.0%). Median survival gains were 10.3 months among actionable pts (disparities test p &lt; 0.10) and 1.9 months among all pts (disparities p &lt; 0.01). Conclusions: Attainable population health gains from genome-guided oncology are modest with disparities across R/E groups.
Inactivation of <i>Bap1</i> Cooperates with Losses of <i>Nf2</i> and <i>Cdkn2a</i> to Drive the Development of Pleural Malignant Mesothelioma in Conditional Mouse Models
Authors: Anna-Mariya Kukuyan, Eleonora Sementino, Yuwaraj Kadariya, Craig W. Menges, Mitchell Cheung, Yinfei Tan, Kathy Q. Cai, Michael J. Slifker, Suraj Peri, Andres J. Klein-Szanto, Frank J. Rauscher, Joseph R. Testa
Journal: Cancer Research (2019)

Abstract Pleural malignant mesothelioma is a therapy-resistant cancer affecting the serosal lining of the thoracic cavity. Mutations/deletions of BAP1, CDKN2A, and NF2 are the most frequent genetic lesions in human malignant mesothelioma. We introduced various combinations of these deletions in the pleura of conditional knockout (CKO) mice, focusing on the contribution of Bap1 loss. While homozygous CKO of Bap1, Cdkn2a, or Nf2 alone gave rise to few or no malignant mesotheliomas, inactivation of Bap1 cooperated with loss of either Nf2 or Cdkn2a to drive development of malignant mesothelioma in approximately 20% of double-CKO mice, and a high incidence (22/26, 85%) of malignant mesotheliomas was observed in Bap1;Nf2;Cdkn2a (triple)-CKO mice. Malignant mesothelioma onset was rapid in triple-CKO mice, with a median survival of only 12 weeks, and malignant mesotheliomas from these mice were consistently high-grade and invasive. Adenoviral-Cre treatment of normal mesothelial cells from Bap1;Nf2;Cdkn2a CKO mice, but not from mice with knockout of one or any two of these genes, resulted in robust spheroid formation in vitro, suggesting that mesothelial cells from Bap1;Nf2;Cdkn2a mice have stem cell–like potential. RNA-seq analysis of malignant mesotheliomas from triple-CKO mice revealed enrichment of genes transcriptionally regulated by the polycomb repressive complex 2 (PRC2) and others previously implicated in known Bap1-related cellular processes. These data demonstrate that somatic inactivation of Bap1, Nf2, and Cdkn2a results in rapid, aggressive malignant mesotheliomas, and that deletion of Bap1 contributes to tumor development, in part, by loss of PRC2-mediated repression of tumorigenic target genes and by acquisition of stem cell potential, suggesting a potential avenue for therapeutic intervention. Significance: Combinatorial deletions of Bap1, Nf2, and Cdkn2a result in aggressive mesotheliomas, with Bap1 loss contributing to tumorigenesis by circumventing PRC2-mediated repression of oncogenic target genes.
Health-related quality of life in the Swedish PREDIX HER2 trial, evaluating docetaxel, trastuzumab, pertuzumab versus trastuzumab emtansine as neoadjuvant treatment of HER2-positive breast cancer.
Authors: Yvonne Brandberg, Anne Andersson, Judith Bjohle, Ana Bosch, Lena Carlsson, Ann Charlotte Dreifaldt, Zakaria Einbeigi, Hanna Fredholm, Erika Isaksson-Friman, Theodoros Foukakis, Ellinor Elinder, Mats Hellstrom, Hemming Johansson, Tobias Lekberg, Henrik Lindman, Jonas C. S. Bergh, Thomas Hatschek
Journal: Journal of Clinical Oncology (2019)

583 Background: Neoadjuvant therapy combining docetaxel, trastuzumab and pertuzumab (DTP) was compared to trastuzumab emtansine (T-DM1) in the randomized phase 2 PREDIX HER2 trial. Patients, ≥18 years with HER2 positive breast cancer, ≥20mm or with verified lymph node metastases, were randomized to six courses of DTP (Standard arm) or T-DM1 (Experimental arm). Primary endpoint was pathological objective response to primary medical therapy at post-treatment surgery. Health related quality of life (HRQoL) was a secondary outcome, and is of specific interest as there was no difference between the randomization groups regarding the main endpoint (results presented in a separate abstract sent to ASCO 2019, Bergh et al.). Methods: Of 202 randomized patients, 190 are available for evaluation at this point. HRQoL was measured, using EORTC QLQ-C30 + EORTC QLQ-BR23, at baseline before randomization and after six courses. Results: No differences between the randomization arms were found at baseline. Results after six courses, based on 163 patients (86%) and adjusted to baseline values, revealed statistical significant differences (p≤0.01), favoring the experimental T-DM1 arm on 7 out of 15 of the EORTC QLQ-C30 variables (Physical functioning, Role functioning, Social functioning, Global quality of Life, Fatigue, Dyspnea, and Diarrhea). For the breast cancer specific questionnaire (EORTC-BR23), the experimental arm scored statistically significantly better on 5 out of 7 subscales (Body image, Sexual functioning, Sexual enjoyment, Systemic therapy side effects and Upset by hair loss). All of the statistical significant differences were of moderate or large clinical significance (≥10 scale scores). No differences between the randomization arms were found for the remaining HRQoL variables. Conclusions: The experimental arm reported better HRQoL than the control arm after six courses. Trastuzumab emtansine may be a useful treatment alternative due to better HRQoL and lower toxicity. Clinical trial information: NCT02568839.
Benefit of combining local treatment and systemic therapy for stage IV NSCLC: Results from the National Cancer Database.
Authors: Meaghan Dendy Case, Johannes Uhlig, Justin Blasberg, Daniel J. Boffa, Anne C. Chiang, Scott N. Gettinger, Hyun S. Kim
Journal: Journal of Clinical Oncology (2019)

8545 Background: To determine the potential benefit of combining local and systemic therapy in stage IV non-small cell lung cancer (NSCLC). Methods: Data from stage IV NSCLC patients receiving systemic therapy alone, surgical resection and systemic therapy, or external beam radiation therapy/thermal ablation (EBRT/TA) and systemic therapy were acquired from the 2010-2015 National Cancer Database (NCDB). EBRT and TA patients were combined to enhance the power of the study. Overall survival (OS) was evaluated via multivariable Cox proportional hazards models. Comparison was made between EBRT/TA and systemic therapy alone utilizing 1:1 propensity matching analysis. A multivariable logistic regression model was used to determine variables predictive of lung cancer treatment. Significant variables (p &lt; 0.05) were used to calculate the propensity score, and patients receiving EBRT/TA and systemic therapy were 1:1 matched using a greedy (nearest-neighbor) approach. Results: 46,964 patients from the NCDB database fulfilled inclusion criteria (surgical resection n = 1,235; EBRT/TA n = 12,456; systemic therapy alone n = 33,273.) Treatment differed across patient demographics and disease characteristics. Surgical resection demonstrated superior OS compared to EBRT/TA and systemic therapy alone, even after multivariable adjustment (compared to systemic therapy alone HR = 0.54, 95% CI: 0.50-0.58, p &lt; 0.001; compared to EBRT/TA HR = 0.56, 95% CI: 0.52-0.60, p &lt; 0.001). EBRT/TA treatment demonstrated superior survival compared to systemic therapy alone after accounting for confounders via propensity score matching (HR = 0.95, 95% CI: 0.93-0.98, p = 0.002). Interaction analyses indicated heterogeneous effectiveness of EBRT/TA according to patient demographics and cancer factors: the survival benefit of EBRT/TA over systemic therapy alone was especially pronounced in stage IV squamous cell carcinoma patients with limited nodal and metastatic disease (HR = 0.78, 95% CI: 0.71-0.85, p &lt; 0.001 compared to systemic therapy alone; OS rates at 1-year = 50.9% vs. 42.4%; 2-years = 26.6% vs. 19.8%; 3-years = 17.2% vs. 10.1%). Conclusions: Stage IV NSCLC patients who received EBRT/TA or surgical resection in addition to systemic therapy demonstrated prolonged survival. EBRT/TA in combination with systemic therapy should be preferred in selected patients that are ineligible surgical candidates.
Gliomas in the context of Li-Fraumeni syndrome: An international cohort.
Authors: Orli Michaeli, Uri Tabori, Joshua David Schiffman, Anne Naumer, Wendy Kohlmann, D. Gareth Evans, Claire Forde, Lindsey Marie Hoffman, Surya P Rednam, Kara Noelle Maxwell, Miriam Bornhorst, Allison Frances O'Neill, Kim Nichols, Anita Villani, Thomas Paul Slavin, Shani Caspi, Shayna M. Zelcer, Sarah Leary, Shannon M Stasi, David Malkin
Journal: Journal of Clinical Oncology (2019)

1517 Background: Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome associated with germline mutation in the TP53 tumor suppressor gene. As a result of increased awareness and surveillance imaging, more asymptomatic low-grade brain lesions are being identified, raising important questions regarding the management of those patients. Sporadic low-grade gliomas (LGG) in the pediatric age rarely transform to malignant lesions, whereas the prognosis of high-grade gliomas (HGG) is grim in all age groups. Although HGG is a hallmark of LFS, little is known of the natural history of these lesions in this syndrome. Methods: For this multi-institutional retrospective study, anonymized clinicopathologic data from TP53 mutation carriers with gliomas were collected and analysed. Results: Our cohort included 61 patients, of whom 71% (n = 45) were children or young adults (age &lt; 25 years). 39% of patients with known family history of cancer had a close relative with a brain tumor. Of 31 patients with low grade lesions at presentation, 83% (n = 26) were identified through surveillance. Five-year progression free survival (PFS) for these patients was 48%, though two patients progressed later. Furthermore, at 5 years 25% of these patients had biopsy proven malignant transformation to HGG. This “transformation free survival” rate did not plateau, as at 7 years 56% of patients transformed. When considering death from a brain tumor, the 5- and 10- year overall survival (OS) for the LGG group was 100% and 83%, respectively. Additional 3 patients succumbed to other LFS related malignancies. For the HGG group, consisting of 30 patients, the 5 year OS was 35% (median follow-up 19.5 months), comparing favorably with the sporadic HGG population as reported in the literature. Almost all of these patients presented with clinical symptoms. Notably, 12 (40%) of them had a prior malignancy. Conclusions: Our analysis suggests that the risk of transformation of LGG in the setting of LFS is high and warrants ongoing surveillance. Interestingly, there are a considerable number of long- term survivors in our HGG group, although the median follow up is still short. Further study to examine potential genotype- phenotype correlations in germline TP53 mutation carriers will inform strategies to identify those patients at highest risk of glioma progression.
Somatic mutations in triple-negative breast carcinoma and high-grade serous ovarian carcinoma from young women.
Authors: Pedro Adolpho MP Serio, Glaucia Fernanda Lima Pereira, Maria Lucia Hirata Katayama, Simone Maistro, Rossana Veronica Mendoza Lopez, Rosimeire Aparecida Roela, Livia Munhoz Rodrigues, Maria A. A. Koike Folgueira
Journal: Journal of Clinical Oncology (2019)

e12561 Background: High grade serous ovarian carcinoma (HGSOvCa) and triple negative breast cancer (TNBC) share characteristics, such as poor prognosis, BRCA1 germline mutations and TP53 somatic mutations. Our aim was to analyze somatic mutations from HGS-OvCa and TNBC from young patients aged ≤ 40 years. Methods: Whole genome or exome sequencing data for TNBC (n = 83) or HGS-OvCa (n = 21) was recovered from COSMIC or cBioPortal. Data was searched for cancer driver genes catalogued in Cancer Gene Census (CGC) or Candidate Cancer Gene Database rank A or B (CCGD) and for DNA repair genes. Results: TNBC mainly consisted of ductal carcinomas (78/83). A median of two cancer causing genes was affected in both TNBC and HGS-OvCa and TP53 was mutated in at least 2/3 of the samples. Only 7/83 and 2/19 of TNBC and HGS-OvCa samples, respectively, did not present variants in known cancer causing genes. C &gt; T substitutions were the most frequent events in both TNBC and HGS-OvCa, however transversions were more frequently detected in TNBC. Besides TP53, another 33 genes were mutated in both tumor types, including PIK3CA, RYR2, TARBP1, CSMD3, DNAH11, MYO3A, NF1, TNRC6A, CACNA1E, HCMN1, PRKDC. Conclusions: Although many similarities were detected, TNBC in young patients presents a higher number of transversions and almost 25% of HGSOvCa present somatic mutations in HR genes. [Table: see text]
The prognostic value of KRAS mutation in locally advanced rectal cancer.
Authors: Veli Bakalov, Shaakir Hasan, Stephen Abel, Laila Babar, Hira Shaikh, Moses S. Raj, Gene Grant Finley, Dulabh K. Monga, Alexander V. Kirichenko, Rodney E Wegner
Journal: Journal of Clinical Oncology (2019)

e15090 Background: The prognostic value and prognostic value of the KRAS proto-oncogene mutation in colorectal cancer has been debated. Herein, we analyzed the National Cancer Database (NCDB) to assess the role of KRAS mutation as a prognostic marker in patients with locally advanced rectal cancer (LARC). Methods: We identified LARC patients treated with neoadjuvant chemoradiation from 2004-2015 excluding those with stage I/IV disease and unknown KRAS status.Multivariable logistic regression identified variables associated with KRAS positivity. Propensity adjusted univariable and multivariable analyses identified predictors of survival. Results: Of the 784 eligible patients, 506 and 278 were KRAS negative (KRAS-) and KRAS positive (KRAS+). Median survival was 63.6 months and 76.3 months for KRAS+ and KRAS-patients, with propensity adjusted 3 and 5-year survival of (79.9% vs. 83.6%) and (56.7% vs 61.9%) respectively (HR 1.56, p 1.074-2.272). Male sex, no insurance, and KRAS+ disease was associated with poorer survival on unadjusted and propensity adjusted multivariable analyses (Table). Conclusions: Our analysis of KRAS+ LARC suggest that KRAS+ disease is associated with poorer overall survival. Given the inherent limitations of retrospective data, prospective validation is warranted. [Table: see text]
Epigenomic profiling of plasma cell-free DNA (cfDNA) to predict bladder cancer recurrence after radical cystectomy.
Authors: Yi-Tsung Lu, Gerald C Gooden, Ben Yi Tew, David Buckley, Kimberly Siegmund, Siamak Daneshmand, Bodour Salhia, Amir Goldkorn
Journal: Journal of Clinical Oncology (2019)

e14525 Background: Muscle invasive bladder cancer (MIBC) frequently recurs despite radical cystectomy, and new biomarkers are needed to guide treatment. DNA methylation plays a key regulatory role in cancer initiation and progression and has been correlated with prognosis in multiple cancer types. We hypothesized that methylation patterns in cfDNA can predict recurrence after curative cystectomy. Methods: Using a clinically annotated USC bladder cancer tissue archive under an IRB approved protocol, we selected 40 patients whose cancer relapsed within 3 years of radical cystectomy, as well as 46 age-matched and stage-matched patients who did not recur after 3 years of follow-up. cfDNA was extracted from the archival plasma, and samples were pooled for whole genome bisulfite sequencing (WGBS) based on pathologic stage and recurrence status. Differentially methylated regions (DMRs) was identified between recurrence and non-recurrence groups in each stage. Results: Pooled analysis across stages yielded 729 DMRs, of which 487 (67%) were hypomethylated in the pooled recurrence group. Of the 729 DMRs from the pooled analysis, 63.5% were in gene bodies, 17.1% were in promoter regions and 47.9% were at CPG islands. Unsupervised clustering of these DMRs accurately distinguished the recurrence groups. Stage-specific analysis yielded DMR sets ranging from 6412 to 9532 DMRs per stage, with a similar trend of global hypomethylation in the recurrence groups. Basespace Correlation Engine analysis revealed that methylation in our recurrence groups (pooled and by stage) was correlated with bladder cancer methylation in publicly available data and also correlated with expression in the TCGA bladder cancer dataset. Conclusions: WGBS was successfully performed in MIBC using cfDNA extracted from clinically annotated archival plasma. Methylation patterns were correlated with publicly available methylation and expression datasets, and cfDNA hypomethylation pre-cystectomy in our cohort was associated with cancer recurrence. A subset of maximally discriminatory DMRs has been selected to define a methylation signature that is currently undergoing validation as a biomarker predictive of recurrence in MIBC.
Concomitant Use of Blinatumomab and Donor Lymphocyte Infusion for Post-Transplant Relapsed CD19 Positive Acute Lymphoblastic Leukemia: Systematic Review
Authors: Ceren Durer, Seren Durer, Madeeha Shafqat, Zunairah Shah, Maryam Sadiq, Muhammad Asad Fraz, Malik Qistas Ahmad, Hafiz Muhammad Fazeel, Sharoon Samuel, Mustafa Nadeem Malik, Midhat Lakhani, Chaudhry Saad Sohail, Anum Qureshi, Faiz Anwer
Journal: Blood (2018)
A prospective, open label, multicenter, randomized phase II trial: Sequential therapy with bevacizumab, RAd001 (everolimus) and axitinib in metastatic renal cell carcinoma (mRCC) (BERAT study).
Authors: Viktor Grünwald, Lothar Bergmann, Peter J. Goebell, Arne Strauss, Johannes Meiler, Arndt Hartmann, Jens Bedke
Journal: Journal of Clinical Oncology (2019)

e16097 Background: Inhibitors of the vascular endothelial growth factor (VEGF), its receptor (Ri) or mammalian target of rapamycin (mTORi) are components of systemic treatment in metastatic renal cell carcinoma (mRCC) and are applied in sequence. We compared the efficacy of VEGFRi and mTORi in 2 nd line after failure of bevacizumab/interferon in a phase II trial. Methods: Key inclusion criteria were: measurable mRCC (all histologies), ECOG 0-1, IMDC risk: good or intermediate, adequate organ function. Tumor status was assessed in week 11 and q12 wks., thereafter. Measures of Health-related quality of life (HR-QoL) utilized FKSI-10 and was assessed in week 4, 10 and q12 wks., thereafter. 1 st line consisted of bevacizumab 10mg/kg q2wks. + interferon 9*10 6 IE 3x/week (BEV/IFN). Upon progression or intolerance, patients were re-screened and randomized between VEGFRi (axitinib 5 mg BID, dose-escalation permitted; sunitinib 50 mg OD, 4-2 regimen) and everolimus (EVE) treatment (10 mg OD). Cross-over occurred at time of progression or intolerance. Improvement of 2 nd line PFS-rate at 6 mo. from 50% to 65% was the primary endpoint. Secondary endpoints were PFS, total PFS, ORR, OS, safety and HR-QoL. Results: Between November 2012 and June 2015 a total of 22 of 100 patients were included and at that time stopped for poor accrual. 10 pts. (46%) were randomized to receive 2 nd line treatment with everolimus (n = 5) or VEGFRi (n = 5). At study entry (2/10) 20% had nephrectomy. ECOG 0 was recorded in 20% (EVE) and 60% (VEGFRi), respectively. Objective response rate (ORR) to 1 st line BEV/IFN was 20%. In 2 nd line treatment all patients experienced adverse events (AE). Grade ≥3 AEs occurred in 2/5 (40%) (EVE) and 4/5 (80%) (VEGFRi) pts., respectively. SAEs occurred in 3/5 (60%) in each arm. ORR was 1/5 (20%) for axitinib and 0/5 (0%) for EVE. PFS rate at 180 days was 20% in each arm. Median PFS was 3.7 (EVE) and 2.2 mo. (VEGFRi) HR 1.0 (95%CI 0.26-3.85; p = 0.997). OS was comparable between arms HR 1.12 (95%CI 0.27-4.61; P = 0.872). 7 pts. crossed over to 3 rd line treatment. Conclusions: The small number of pts. randomized to EVE or VEGFRi is a major limitation of our trial, but may mirror the current change of treatment reality. However, no significant difference was detected for the PFS rate at 6 mo., indicating the limited activity of EVE or VEGFRi in 2 nd line treatment. Clinical trial information: NCT01731158.
Case 3-1988
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, William F. McNeely, Betty U. McNeely, Barry W. Levine, Eugene J. Mark
Journal: New England Journal of Medicine (1988)

Presentation of CaseA 56-year-old man was admitted to the hospital because of a question of interstitial lung disease.He was well until two years earlier, when arthralgia and swelling of the ankles and knees developed, persisted for about a week, and then resolved. Thereafter he experienced occasional morning stiffness in the metacarpophalangeal joints, without swelling. Eight months before admission he began to have exertional dyspnea while hiking. Three months before entry he became dyspneic while walking from his parking space to his office. A chronic morning cough occurred and worsened during the month before admission, with the production of . . .