tbuckley/cabot-search huggingface dataset:
A prognostic 10-miRNA risk score (10-miRNA RS) in predicting neoadjuvant chemotherapy sensitivity of luminal breast cancer.
Authors: Chang Gong, Luyuan Tan, Na You, Kai Chen, Weige Tan, Zhenluan Tian, Wenjing Zhong, Wanyi Lin, Zhigang Yu, Zhihua Li, Wenbo Zheng, Qiang Liu, Erwei Song
Journal: Journal of Clinical Oncology (2019)

3139 Background: The 10-miRNA risk score is a prognostic 10-gene expression signature specifically developed in luminal breast cancer associated with relapse-free survival. Since high-risk patients identified by10-miRNA RS had worse prognosis but better outcome with chemotherapy than low-risk patients (Gong C et al, EBioMedicine. 2016), this model may facilitate personalized therapy-decision making for luminal breast cancer patients. Therefore, we seek to validate whether high-risk group are more sensitive to chemotherapy than low-risk group by assessing the predictive value of 10-miRNA RS for pathological complete response (pCR) in patients receiving neoadjuvant chemotherapy (NAC). Methods: The 10-miRNA gene expression and clinicopathological data were prospectively gathered from 251 pretreated biopsy-diagnosed luminal breast cancer patients from 4 breast cancer centers. Formalin-fixed paraffin-embedded tissues from basal line biopsy were used for the detection of 10-miRNA expression to calculate the RS. The correlation between pCR and the 10-miRNA RS classification were identified. Results: In this prospective, multicenter study, the overall pCR rate was 13.6% (34/251). The 10-miRNA RS of the pCR group was significantly higher than the non-pCR group ( P = 0.015). Fifty-one percent of patients were classified as low-risk according to the 10-miRNA RS classification and 49% as high-risk with a RS cut-off point of 2.144. The 10-miRNA RS classification was associated with a pCR rate of 9.4% in the low-risk group and 17.8% in the high-risk group ( P = 0.041). The correlation between the pCR and the 10-miRNA RS classification was significant in subgroup analysis stratified by molecular subtypes (8% vs. 13.2% in luminal B 1 ; 14.7% vs. 30.1% in luminal B 2 ; no pCR was observed in all 13 luminal A subtype). In multivariate analysis, the 10-miRNA RS remained significantly associated with pCR and independent from subtype, ki67 and other clinicopathological characteristics. Conclusions: 10-miRNA RS clearly defined that high-risk patients are more sensitive to chemotherapy which leads to a higher pCR rate in NAC patients. Thus, 10-miRNA RS is not only a prognostic factor but an effective method in determining whether a patient would undergo surgery or receive NAC prior to surgery. Clinical trial information: ChiCTR-DDD-17013651.
Loss of SRSF3 in Cardiomyocytes Leads to Decapping of Contraction-Related mRNAs and Severe Systolic Dysfunction
Authors: Paula Ortiz-Sánchez, María Villalba-Orero, Marina M. López-Olañeta, Javier Larrasa-Alonso, Fátima Sánchez-Cabo, Carlos Martí-Gómez, Emilio Camafeita, Jesús M. Gómez-Salinero, Laura Ramos-Hernández, Peter J. Nielsen, Jesús Vázquez, Michaela Müller-McNicoll, Pablo García-Pavía, Enrique Lara-Pezzi
Journal: Circulation Research (2019)

RBPs (RNA binding proteins) play critical roles in the cell by regulating mRNA transport, splicing, editing, and stability. The RBP SRSF3 (serine/arginine-rich splicing factor 3) is essential for blastocyst formation and for proper liver development and function. However, its role in the heart has not been explored.To investigate the role of SRSF3 in cardiac function.Cardiac SRSF3 expression was high at mid gestation and decreased during late embryonic development. Mice lacking SRSF3 in the embryonic heart showed impaired cardiomyocyte proliferation and died in utero. In the adult heart, SRSF3 expression was reduced after myocardial infarction, suggesting a possible role in cardiac homeostasis. To determine the role of this RBP in the adult heart, we used an inducible, cardiomyocyte-specific SRSF3 knockout mouse model. After SRSF3 depletion in cardiomyocytes, mice developed severe systolic dysfunction that resulted in death within 8 days. RNA-Seq analysis revealed downregulation of mRNAs encoding sarcomeric and calcium handling proteins. Cardiomyocyte-specific SRSF3 knockout mice also showed evidence of alternative splicing of mTOR (mammalian target of rapamycin) mRNA, generating a shorter protein isoform lacking catalytic activity. This was associated with decreased phosphorylation of 4E-BP1 (eIF4E-binding protein 1), a protein that binds to eIF4E (eukaryotic translation initiation factor 4E) and prevents mRNA decapping. Consequently, we found increased decapping of mRNAs encoding proteins involved in cardiac contraction. Decapping was partially reversed by mTOR activation.We show that cardiomyocyte-specific loss of SRSF3 expression results in decapping of critical mRNAs involved in cardiac contraction. The molecular mechanism underlying this effect likely involves the generation of a short mTOR isoform by alternative splicing, resulting in reduced 4E-BP1 phosphorylation. The identification of mRNA decapping as a mechanism of systolic heart failure may open the way to the development of urgently needed therapeutic tools.
Targeting checkpoint kinases in prostate cancer cells resistant to poly ADP-ribose polymerase inhibitors.
Authors: Mohammad Omar Atiq, Goutam Chakraborty, Subhiksha Nandakumar, Ying Zhang Mazzu, Konrad Hermann Stopsack, Lina E. Jehane, Yuki Yoshikawa, Nabeela Khan, Gwo-Shu Mary Lee, Philip W. Kantoff
Journal: Journal of Clinical Oncology (2019)

e16543 Background: The identification of DNA damage response (DDR) gene abnormalities in various cancers has provided potential therapeutic targets including the poly ADP-ribose polymerase enzyme (PARP). PARP inhibitors are now approved for use in ovarian, breast, and prostate cancer (PC). Olaparib and rucaparib have been given Breakthrough Therapy designation by the FDA for use in patients with metastatic castration-resistant prostate cancer and germline BRCA1/2 or ATM mutations. However, drug resistance limits the efficacy of PARPi. Somatic reversion mutations of BRCA1/2 have been described as one potential mechanism of resistance to PARPi in patients with germline BRCA1/2 mutations. However, in PC, the BRCA2 gene is frequently deleted, in contrast to other cancers, where it is mutated. Thus, we hypothesize that resistance to PARPi in PC may involve alternative molecular mechanisms. Methods: We performed cell viability assays to determine the inhibitory growth (IG) concentrations of olaparib and talazoparib on human castration-resistant PC cell lines (PC-3 and LNCaP-Abl) that have heterozygous genomic deletions of BRCA2. Parental PC-3 cells were cultured in sublethal concentrations (IG 50% and IG 90%) of talazoparib-supplemented media for approximately 2 months to develop talazoparib-resistant cells. We then performed an analysis of phosphorylation status in untreated and treated parental PC-3 and talazoparib-resistant clones with a phosphokinase array. We confirmed this with Western blot. Results: Talazoparib-resistant PC-3 clones showed significantly enhanced cell growth compared to parental cells when cultured in media supplemented with the IG 90% concentration of talazoparib or olaparib. The phosphokinase array revealed a significant increase in the phosphorylation of CHEK2 in talazoparib-resistant clones compared to parental PC-3 cells. Interestingly, a similar increase was seen after 72 hours of treatment with talazoparib, indicating an early connection between PARP inhibition and CHEK2 phosphorylation in PC cells. Moreover, a pan-CHEK inhibitor, prexasertib, led to significant cell growth inhibition in talazoparib-resistant PC-3 clones and a significantly lower IG 50% concentration compared to parental PC-3 cells. Conclusions: We speculate that early activation of CHEK2 may be a primary mechanism of resistance to PARPi in PC cells with deletion of BRCA2. Furthermore, our preliminary data showed that CHEK inhibition can overcome PARPi resistance, indicating a potential for CHEK inhibitor-based therapy for PC patients.
Cost-effectiveness (CE) of regorafenib dose optimization schedule in metastatic colorectal cancer.
Authors: Afsaneh Barzi, Sang K Cho, Joel W Hay, Heinz-Josef Lenz, Fang-Shu Ou, Axel Grothey, Tanios S. Bekaii-Saab
Journal: Journal of Clinical Oncology (2019)

e18367 Background: Regorafenib at 160mg daily 21/28 days is a standard therapeutic option in patients with metastatic colorectal cancer. However, the cost of treatment and management of its side-effects is more than the cost-effectiveness threshold for oncology drugs in US and many countries around the world. ReDOS (Regorafenib Dose Optimization Study), is a randomized phase II trial in refractory mCRC and established that weekly dose escalation of regorafenib over the conventional dosing is superior in the composite endpoint of safety and efficacy. We explored the impact of the new dosing strategy on CE of regorafenib. Methods: A Markov model was constructed to compare costs and effectiveness of regorafenib (standard), regorafenib (ReDOS), and best supportive care (BSC). Model inputs for clinical efficacy and safety were from the CORRECT trial for regorafenib (standard) and BSC, and the ReDOS study for regorafenib (ReDOS). The incremental cost-effectiveness ratios (ICERs) were reported to compare treatments. Model robustness was checked with univariate and probabilistic sensitivity analyses. The model used a US payer’s perspective with 5% annual discount rate, and all costs were measured in 2018 US dollars. Results: Regorafenib (ReDOS) dominated regorafenib (standard), producing higher quality-adjusted life years at a lower cost. When compared to BSC, regorafenib (ReDOS) resulted in the ICER of $112,705 while regorafenib (standard) resulted in the ICER of $384,687. The most influential parameters on the ICERs were efficacy and health state utility parameters under univariate sensitivity analysis. In probabilistic sensitivity analysis using cost-effectiveness acceptability curves, regorafenib (ReDOS) was more cost-effective than regorafenib (standard) and BSC in 70% of repetition at the willingness-to-pay threshold of $120,000 per QALY (Quality-Adjusted Life Year) and 98% at a WTP threshold of $150,000. Conclusions: Based on the outcomes demonstrated in the ReDOS study, the dose optimization strategy of regorafenib results in favorable cost-effectiveness under a typical US willingness-to-pay threshold of $150,000 per QALY.
Real-world outcomes of patients with advanced non-small cell lung cancer (aNSCLC) and autoimmune disease (AD) receiving immune checkpoint inhibitors (ICIs).
Authors: Sean Khozin, Mark S. Walker, Monika Jun, Li Chen, Edward Stepanski, Wendy S. Rubinstein, George Anthony Komatsoulis, Jeremy Roberts, Jizu Zhi, Robert S. Miller, Ryan Fukushima, Denise Lau, Brigham Hyde
Journal: Journal of Clinical Oncology (2019)

110 Background: Anecdotal and early evidence suggest ICIs are being used in patients with advanced malignancies and history of AD, despite such patients being typically excluded from traditional clinical trials. We compared the outcomes of patients with or without AD, all of whom had ICI treatment for aNSCLC. Methods: We conducted a retrospective, observational cohort study using de-identified, curated data in ASCO’s CancerLinQ. Patients with Stage III or IV NSCLC who received ≥1 dose of an ICI and had ≥2 visits from Jan 2011 to Nov 2018 were included. AD status prior to ICI treatment was identified using ICD-9/ICD-10 codes or AD medications (including steroids). Symphony claims data were linked via tokenization to build cohorts. Time to treatment discontinuation (TTD), time to next treatment (TTNT), real-world progression-free survival (rwPFS) and overall survival (OS) were compared across the two cohorts using the log-rank test. Cox Proportional Hazards Model was used to adjust for covariates. Adverse events (AEs) were compared using Chi-Square and Fisher’s Exact Test. Active AD was defined as evidence of autoimmune disease in the year prior to starting ICIs. Results: Among 2425 patients with aNSCLC treated with ICIs, AD was present in 22% (N=538). Median OS in all patients was 12.4 months (95% CI 11.3-13.5). TTD, TTNT, rwPFS and OS did not differ between the two cohorts (Table). There was no association between AD status and outcomes. There was no increased incidence of AEs in the AD group; however a sub-analysis among patients with active AD showed higher rates of select AEs including endocrine, GI and blood disorders. Conclusions: This analysis demonstrates that patients with evidence of AD prior to receiving ICI have similar outcomes compared to patients with no evidence of AD. Further research is needed to better understand the impact of active AD on the risk of AEs and patient outcomes. [Table: see text]
Some characteristics of cancer-testis gene expression regulation in colorectal cancer.
Authors: Kristina I. Soldatova, Oleg Ivanovich Kit, Roman E. Tolmakh, Denis S. Kutilin
Journal: Journal of Clinical Oncology (2019)

e14233 Background: Cancer-testis antigens (CTA) can be used in immunotherapy and for early detection of cancer. Despite numerous studies of the CTA expression in different tumors, their transcriptional activity and its regulation in colorectal cancer (CRC) remain poorly understood. The purpose of the study was to analyze the expression of cancer-testis genes (CT-genes) and mechanisms of its regulation in CRC. Methods: Tumor and intact tissues of the colon were studied in 60 patients. RNAs were isolated using the method described by Chomczynski and Sacchi (2006). The REVERTA-L reagent kit was used for the cDNA synthesis. Expression of 16 CT-genes (MAGE-A1, -A2, -A3, -A4, MAGE-B1, -B2, GAGE-1, -3, -4, MAGEC1, BAGE, XAGE3, NYESO1, SSX2, SCP1, PRAME1) and expression and copy number of 3 DNA methyltransferase genes (DNMT1, DNMT3A, DNMT3B) were determined by Real-Time qPCR (GAPDH and GUSB - reference genes). For the cluster analysis, we used our R scripts. Differences were assessed by the Mann-Whitney test, and correlations – by the Spearman's rank correlation coefficient (r). Results: The expression of 2 CT genes, SSX2 and PRAME1, was increased (p &lt; 0.05) by 1.8 and 2.9 times, respectively, and the BAGE expression was decreased by 2.4 times in tumor tissues, compared to the normal tissues. The expression and copy number of DNMT3A in tumor tissues was 1.5 and 2 times higher (p &lt; 0.05), and that of DNMT3B – 2 times lower (p &lt; 0.005), compared to normal tissues. The copy number and expression of the DNMT1 gene did not change. A strong positive correlation (r = 0.996) between the expression and copy number of DNA methyltransferase genes was observed. Using cluster analysis (Hierarchical Clustering, Euclidean distance), we detected two clusters of CRC samples different in the expression of CT-genes and methyltransferases. Cluster 1 showed increased expression of DNMT1, DNMT3A and DNMT3B and decreased expression of BAGE, SSX2 and PRAME1; cluster 2 – decreased expression of DNMT1, DNMT3A and DNMT3B and increased expression of BAGE, SSX2 and PRAME1. Conclusions: The detected aberrant expression of the CT-genes BAGE, SSX2, PRAME1 in CRC depends on the expression of DNMT1, DNMT3A, DNMT3B, which in its turn depends on the copy number of the corresponding DNA methyltransferase genes.
An estimate of premature deaths averted with immunotherapy in treating Brazilian patients with advanced clear cell renal cell carcinoma.
Authors: Gabriel Lenz, Nicolas Peruzzo, Cecília Arraes, Gilberto Lopes
Journal: Journal of Clinical Oncology (2019)

e16114 Background: Clear cell renal cell carcinoma (RCC) accounts for 3% of all cancers in Brazil, and the majority of these patients (pts) are treated in our public health system, SUS. Sunitinib and Pazopanib were incorporated into SUS in early 2019 for use in metastatic RCC (mRCC). Although Nivolumab plus Ipilimumab (NI) is the standard first-line systemic therapy for intermediate- and poor-risk pts with mRCC, these drugs are not yet available. We aimed to estimate the number of premature deaths that could be averted with incorporation of NI for mRCC pts treated in SUS. Methods: We used incidence rates reported by GLOBOCAN to estimate the annual number of pts with mRCC due to receive first-line systemic therapy in Brazil. Privately insured patients were excluded. A review (Lalani et al., 2018) and CheckMate 214 Trial were used to estimate stage distribution at diagnosis and overall survival (OS) in 12 months, respectively. We explored differences in the number of deaths between different therapeutic strategies. Results: GLOBOCAN estimates 9,619 new cases of RCC per year in Brazil, of which 72.1% are to be treated in SUS. Twenty-five percent are de novo metastatic. Among patients with mRCC, 75% have intermediate- or poor-risk disease. That is, 1,300 pts with intermediate- or poor-risk mRCC are to be treated each year in SUS. We estimated that 9,360 pts are expected to be alive over a 10 year period with sunitinib and 10,400 pts with NI. Conclusions: In the Brazilian public health system, it can take more than a decade for novel therapies to be incorporated. Over a ten-year period, approximately 1,040 pts with mRCC will die prematurely due to the lack of access to immunotherapy (NI) in the public health system. Studies to evaluate the cost-effectiveness of NI for Brazilian pts with mRCC are urgently needed.
Differences in clinical outcomes in young-onset colorectal cancer based on ethnicity in an NCI designated comprehensive cancer center.
Authors: Benjamin David Fangman, Stephen Haff, Shannon Scielzo, Aravind Sanjeevaiah, Udit N. Verma, John Vernon Cox, Radhika Kainthla, Muhammad Shaalan Beg, Syed Mohammad Ali Kazmi
Journal: Journal of Clinical Oncology (2019)

3605 Background: Ethnic disparities can impact clinical outcomes of young-onset colorectal cancer (CRC) patients. We aimed to determine if differences in outcomes based on ethnicity exist in young–onset CRC treated at an NCI-designated comprehensive cancer center program. Methods: A retrospective chart review for stage II – IV young-onset CRC patients ≤45 years old diagnosed between 04/2011 and 11/2015. Patients had to undergo treatment at safety-net Parkland Hospital (PH) or at the Simmons Comprehensive Cancer Center (SCCC) in Dallas, TX. Demographic data, dates of surgery, adjuvant chemotherapy, recurrence or death were obtained. Results: Of 123 patients that met inclusion criteria, 15 were excluded due to incomplete information. Of the remaining 108 patients, 36 (33%) and 72 patients (67%) were treated at SCCC and PH, respectively. Sixty (55%) were non-Hispanic vs 48 (44.4%) Hispanic. There were more Stage IV patients at SCCC vs Parkland (58.3% vs 30.6%, p &lt; 0.01) but there was no difference regarding ethnicity. Also, no significant difference was seen between non-Hispanic White (NHW), Hispanic, and Black patients in median days to colectomy (1 vs 13 vs 0; p = .402) or adjuvant chemotherapy (55.5 vs 53.0 vs 64.0 days, p = .820). Hispanic patients had significantly better overall survival (OS) than Black or NHW patients (p = 0.025). The OS benefit was driven by improved 5-year OS in stage II/III Hispanic vs NHW vs Black patients (95% vs 62% vs 60%; p = 0.06). Multivariate Cox Regression analysis showed stage II/III (p &lt; 0.001) and Hispanic ethnicity (p &lt; 0.001) were independently associated with improved outcomes. Conclusions: In young-onset CRC treated at an NCI-designated comprehensive cancer center, Hispanic ethnicity had better OS than other ethnicities and this was largely due to better outcomes in stage II and III CRC. The causes for these ethnic differences in young-onset CRC patients needs further exploration. [Table: see text]
Correlation of the tumor mutational burden with the composition of the immune cell subpopulations in peripheral blood of triple-negative breast cancer patients undergoing neoadjuvant therapy with durvalumab: Results from the prospectively randomized GeparNuevo trial.
Authors: Barbara Seliger, Thomas Karn, Carsten Denkert, Andreas Schneeweiss, Claus Hanusch, Jens Uwe Blohmer, Christian Jackisch, Marion van Mackelenbergh, Frederik Marme, Volkmar Mueller, Jens Bodo Huober, Michael Untch, Sibylle Loibl, Anja Mueller, Katharina Biehl, Karsten Ernst Weber, Chiara Massa
Journal: Journal of Clinical Oncology (2019)

588 Background: The GeparNuevo trial is a randomized, double-blind, multi-center phase II trial of neoadjuvant therapy in patients with early-stage triple negative breast cancer (TNBC) investigating the role of durvalumab, an anti-PD-L1 antibody, which blocks PD-L1 binding to PD1 and CD80, in addition to standard chemotherapy with nab-Paclitaxel (nab-Pac) followed by Epirubicin plus Cyclophosphamid (EC; Loibl S et al. ASCO 2018). Since the tumor mutational burden (TMB) has been suggested to be associated with a better outcome of patients undergoing immunotherapy and an increased T cell response, we determined whether there exists a link between TMB and immune cell composition, frequency and function in patients of the GeparNuevo trial. Methods: In order to determine possible predictive and / or prognostic biomarkers, tumor biopsies taken at recruitment from 149 patients out of the 174 enrolled patients underwent deep sequencing in order to determine the TMB. In addition, for 120 patients blood samples were taken at recruitment and during different time points of treatment (after durvalumab pre-treatment, after Nab-Pac and at surgery after EC) and evaluated using multicolor flow cytometry by monitoring the absolute cell counts of T cells, B cells and NK cells as well as the frequency, composition and functionality of different immune cell populations. Results: The TMB of the GeparNuevo cohort was in line with published data with a mean of 1.8 mutations/MB (range 0.02 – 7.65), respectively. Preliminary evaluation demonstrated a significant correlation of TMB with blood parameters, in particular with subsets of CD8+ T cells. Interestingly, the data suggest a negative correlation of TMB with the frequency of effector cells while a positive correlation exists with the effector memory cells at recruitment. In depth analyses of a correlation with treatment arm and clinical responses are currently performed. Conclusions: Using this approach we hope to identify biomarkers, which will allow a better selection of TNBC patients undergoing specific immunotherapies. Clinical trial information: NCT02685059.