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Rxivist combines biology preprints from bioRxiv and medRxiv with data from Twitter to help you find the papers being discussed in your field. Currently indexing 173,468 papers from 716,134 authors.

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in category oncology

645 results found. For more information, click each entry to expand.

41: The contribution of evolutionary game theory to understanding and treating cancer
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Posted 04 Dec 2020

The contribution of evolutionary game theory to understanding and treating cancer
1,002 downloads medRxiv oncology

Benjamin Woelfl, Hedy te Rietmole, Monica Salvioli, Artem Kaznatcheev, Frank Thuijsman, Joel S Brown, Boudewijn Burgering, Katerina Stankova

Evolutionary game theory mathematically conceptualizes and analyzes biological interactions where one's fitness not only depends on one's own traits, but also on the traits of others. Typically, the individuals are not overtly rational and do not select, but rather, inherit their traits. Cancer can be framed as such an evolutionary game, as it is composed of cells of heterogeneous types undergoing frequency-dependent selection. In this article, we first summarize existing works where evolutionary game theory has been employed in modeling cancer and improving its treatment. Some of these game-theoretic models suggest how one could anticipate and steer cancer's eco-evolutionary dynamics into states more desirable for the patient via evolutionary therapies. Such therapies offer great promise for increasing patient survival and decreasing drug toxicity, as demonstrated by some recent studies and clinical trials. We discuss clinical relevance of the existing game-theoretic models of cancer and its treatment, and opportunities for future applications. We discuss the developments in cancer biology that are needed to better utilize the full potential of game-theoretic models. Ultimately, we demonstrate that viewing tumors with an evolutionary game theory approach has medically useful implications that can inform and create a lockstep between empirical findings, and mathematical modeling. We suggest that cancer progression is an evolutionary game and needs to be viewed as such.

42: Polygenic risk, susceptibility genes, and breast cancer over the life course
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Posted 22 Apr 2020

Polygenic risk, susceptibility genes, and breast cancer over the life course
994 downloads medRxiv oncology

Nina Mars, Elisabeth Widen, Sini Kerminen, Tuomo Meretoja, Matti Pirinen, Priit Palta, FinnGen, Aarno Palotie, Jaakko Kaprio, Heikki Joensuu, Mark J Daly, Samuli Ripatti

Polygenic risk scores (PRS) for breast cancer have potential to improve risk prediction, but there is limited information on their clinical applicability. We set out to study how PRS could help in clinical decision making. Among 99,969 women in the FinnGen study with 6,879 breast cancer cases, the PRS was associated not only with breast cancer incidence but also with a range of breast cancer-related endpoints. Women with a breast cancer PRS above the 90th percentile had both higher breast cancer mortality (HR 2.40, 95%CI 1.82-3.17) and higher risk for non-localized disease at diagnosis (HR 2.94, 95%CI 2.63-3.28), compared to those with PRS <80th percentile. The PRS modified the breast cancer risk of two high-impact frameshift risk variants. Women with the c.1592delT variant in PALB2 (242-fold enrichment in Finland, 263 carriers) and an average PRS (20-80th percentile) had a lifetime risk of breast cancer at 58% (95%CI 50-66%), which increased to 85% (70-100%) with a high PRS (>90th percentile), and decreased to 27% (15-39%) with a low PRS (<20th percentile). Similarly, for c.1100delC in CHEK2 (3.7-fold enrichment; 1,543 carriers), the respective lifetime risks were 27% (95%CI 25-30%), 59% (52-67%), and 18% (13-22%). Among breast cancer cases, a PRS >90th percentile was associated with risk of contralateral breast cancer with HR 1.66 (95%CI 1.24-2.22). Finally, the PRS significantly refined the risk assessment of women with first-degree relatives diagnosed with breast cancer, i.e. the combination of high PRS (>90th percentile) and a positive family-history was associated with a 2.33-fold elevated risk (95%CI 1.57-3.46) compared to a positive family history alone. These findings demonstrate opportunities for a comprehensive way of assessing genetic risk in the general population, in breast cancer patients, and in unaffected family members.

43: Leveraging sequences missing from the human genome to diagnose cancer
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Posted 17 Aug 2021

Leveraging sequences missing from the human genome to diagnose cancer
992 downloads medRxiv oncology

Ilias Georgakopoulos-Soares, Ofer Yizhar Barnea, Ioannis Mouratidis, Rachael Bradley, Ryder Easterlin, Candace Chan, Emmalyn Chen, John S. Witte, Martin Hemberg, Nadav Ahituv

Cancer diagnosis using cell-free DNA (cfDNA) can significantly improve treatment and survival but has several technical limitations. Here, we show that tumor-associated mutations create neomers, DNA sequences 11-18bp in length that are absent in the human genome, that can accurately detect cancer subtypes and features. We show that we can detect twenty-one different tumor-types with higher accuracy than state-of-the-art methods using a neomer-based classifier. Refinement of this classifier via supervised learning identified additional cancer features with even greater precision. We also demonstrate that neomers can precisely diagnose cancer from cfDNA in liquid biopsy samples. Finally, we show that neomers can be used to detect cancer-associated non-coding mutations affecting gene regulatory activity. Combined, our results identify a novel, sensitive, specific and straightforward cancer diagnostic tool.

44: ACE2 and TMPRSS2 expression by clinical, HLA, immune, and microbial correlates across 34 human cancers and matched normal tissues: implications for SARS-COV-2 COVID-19
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Posted 30 Apr 2020

ACE2 and TMPRSS2 expression by clinical, HLA, immune, and microbial correlates across 34 human cancers and matched normal tissues: implications for SARS-COV-2 COVID-19
972 downloads medRxiv oncology

Riyue Bao, Kyle Hernandez, Lei Huang, Jason J Luke

Background: Pandemic COVID-19 by SARS-COV-2 infection is facilitated by the ACE2 receptor and protease TMPRSS2. Modestly sized case series have described clinical factors associated with COVID-19, while ACE2 and TMPRSS2 expression analyses have been described in some cell types. Cancer patients may have worse outcomes to COVID-19. Methods: We performed an integrated study of ACE2 and TMPRSS2 gene expression across and within organ systems, by normal versus tumor, across several existing databases (The Cancer Genome Atlas, Census of Immune Single Cell Expression Atlas, The Human Cell Landscape, and more). We correlated gene expression with clinical factors (including but not limited to age, gender, race, BMI and smoking history), HLA genotype, immune gene expression patterns, cell subsets, and single-cell sequencing as well as commensal microbiome. Results: Matched normal tissues generally display higher ACE2 and TMPRSS2 expression compared with cancer, with normal and tumor from digestive organs expressing the highest levels. No clinical factors were consistently identified to be significantly associated with gene expression levels though outlier organ systems were observed for some factors. Similarly, no HLA genotypes were consistently associated with gene expression levels. Strong correlations were observed between ACE2 expression levels and multiple immune gene signatures including interferon-stimulated genes and the T cell-inflamed phenotype as well as inverse associations with angiogenesis and transforming growth factor-{beta} signatures. ACE2 positively correlated with macrophage subsets across tumor types. TMPRSS2 was less associated with immune gene expression but was strongly associated with epithelial cell abundance. Single-cell sequencing analysis across nine independent studies demonstrated little to no ACE2 or TMPRSS2 expression in lymphocytes or macrophages. ACE2 and TMPRSS2 gene expression associated with commensal microbiota in matched normal tissues particularly from colorectal cancers, with distinct bacterial populations showing strong associations. Conclusions: We performed a large-scale integration of ACE2 and TMPRSS2 gene expression across clinical, genetic, and microbiome domains. We identify novel associations with the microbiota and confirm host immunity associations with gene expression. We suggest caution in interpretation regarding genetic associations with ACE2 expression suggested from smaller case series.

45: Cystic Glioblastoma Presentation as a Beneficial Prognostic Indicator for Overall Survival
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Posted 09 Dec 2019

Cystic Glioblastoma Presentation as a Beneficial Prognostic Indicator for Overall Survival
953 downloads medRxiv oncology

Lee Curtin, Paula Whitmire, Cassandra R Rickertsen, Gina L Mazza, Peter Canoll, Sandra K Johnston, Maciej M Mrugala, Kristin R Swanson, Leland S Hu

PurposeGlioblastoma (GBM) is the most aggressive primary brain tumor with a median overall survival of 15 months with standard-of-care treatment. GBM can have a cystic component, identifiable through magnetic resonance imaging (MRI). Previous studies suggest that cysts occur in 7-23% of GBMs and report mixed results regarding its prognostic impact. Using our large retrospective cohort of 493 patients with first-diagnosis GBM, we aim to elucidate this link between cystic GBM and survival. MethodsUsing pretreatment MRIs, we manually identified 88 patients with GBM that had a significant cystic component at presentation. ResultsCompared to patients with noncystic GBM (N=405), patients with cystic GBM had significantly longer overall survival and were significantly younger at presentation. However, among patients who received the current standard-of-care treatment, cystic GBM (N=40) was not significant for outcome. We also did not observe a significant survival benefit when comparing this standard-of-care cystic cohort to patients with cystic GBM diagnosed before the standard was established (N=19), but the analogous result for patients with noncystic GBM gives a sizeable benefit, as expected (N=144, N=111, respectively). We also report differences in the absolute and relative sizes of imaging abnormalities on MRI and the prognostic implication of cysts based on sex. ConclusionTogether, these results may explain later studies that note no significant survival benefit for patients with cystic GBM receiving current standard-of-care. We discuss hypotheses for these observed differences, including the possibility that the presence of a cyst could indicate a less aggressive tumor. Compliance with ethical standardsO_ST_ABSFundingC_ST_ABSThe authors would gratefully like to acknowledge the funding that made this research possible from the National Institutes of Health (R01NS060752, R01CA164371, U54CA143970, U54CA193489, U01CA220378, U54CA210180), the Arizona Biomedical Research Commission (ADHS16-162514), the James S. McDonnell Foundation (220020400TT), and the Ben and Catherine Ivy Foundation. Ethical ApprovalAll procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. For this type of study formal consent is not required. Conflict of InterestThe authors declare that they have no conflict of interest.

46: Quantifying and mitigating the impact of the COVID-19 pandemic on outcomes in colorectal cancer
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Posted 05 May 2020

Quantifying and mitigating the impact of the COVID-19 pandemic on outcomes in colorectal cancer
951 downloads medRxiv oncology

Amit Sud, Michael Jones, John Broggio, Stephen Scott, Chey Loveday, Bethany Torr, Alice Garrett, David L. Nicol, Shaman Jhanji, Stephen A. Boyce, Matthew Williams, Georgios Lyratzopoulos, Claire Barry, Elio Riboli, Emma Kipps, Ethna McFerran, Mark Lawler, David C. Muller, Muti Abulafi, Richard Houlston, Clare Ann Turnbull

Background: The COVID-19 pandemic has caused disruption across cancer pathways for diagnosis and treatment. In England, 32% of colorectal cancer (CRC) is diagnosed via urgent symptomatic referral from primary care, the "2-week-wait" (2WW) pathway. Access to routine endoscopy is likely to be a critical bottleneck causing delays in CRC management due to chronic limitation in capacity, acute competition for physician time, and safety concerns. Methods: We used age-specific, stage-specific 10 year CRC survival for England 2007-2017 and 2WW CRC cases volumes. We used per-day hazard ratios of CRC survival generated from observational studies of CRC diagnosis-to-treatment interval to model the effect of different durations of per-patient delay. We utilised data from a large London observational study of faecal immunochemical testing (FIT) in symptomatic patients to model FIT-triage to mitigate delay to colonoscopy. Findings: Modest delays result in significant reduction in survival from CRC with a 4-month delay resulting across age groups in [&ge;]20% reduction in survival in Stage 3 disease and in total over a year, 1,419 attributable deaths across the 11,266 CRC patients diagnosed via the 2WW pathway. FIT triage of >10 ug Hb/g would salvage 1,292/1,419 of the attributable deaths and reduce colonoscopy requirements by >80%. Diagnostic colonoscopy offers net survival in all age groups, providing nosocomial COVID-19 infection rates are kept low (<2.5%). Interpretation To avoid significant numbers of avoidable deaths from CRC, normal diagnostic and surgical throughput must be maintained. An accrued backlog of cases will present to primary care following release of lockdown, supranormal endoscopy capacity will be required to manage this without undue delays. FIT-triage of symptomatic cases provides a rational approach by which to avoid patient delay and mitigate pressure on capacity in endoscopy. This would also reduce exposure to nosocomial COVID-19 infection, relevant in particular to older patient groups. Funding: Breast Cancer Now, Cancer Research UK, Bobby Moore Fund for Cancer Research, National Institute for Health Research (NIHR).

47: Genomic profiling reveals heterogeneous populations of ductal carcinoma in situ of the breast
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Posted 25 Jun 2020

Genomic profiling reveals heterogeneous populations of ductal carcinoma in situ of the breast
947 downloads medRxiv oncology

Satoi Nagasawa, Yuta Kuze, Ichiro Maeda, Yasuyuki Kojima, Ai Motoyoshi, Tatsuya Onishi, Tsuguo Iwatani, Takamichi Yokoe, Junki Koike, Motohiro Chosokabe, Manabu Kubota, Hibiki Seino, Ayako Suzuki, Masahide Seki, Katsuya Tsuchihara, Eisuke Inoue, Koichiro Tsugawa, Tomohiko Ohta, Yutaka Suzuki

A substantial number of cases of ductal carcinoma in situ (DCIS) of the breast will never progress to invasive ductal carcinoma (IDC), indicating they are overtreated under the current criteria. Although various candidate markers are available, the relevant markers for delineating the risk categories have not been established. In this study, we analyzed of the integrated clinical features of 431 cases of DCIS followed by deep sequence analyses in a 21-case discovery cohort and a 72-case validation cohort. We identified the five most critical markers of the aggressiveness of DCIS: age <45 years, HER2 amplification, GATA3 mutation positivity, PIK3CA mutation negativity, and PgR protein negativity. Spatial transcriptome and single-cell DNA sequencing further revealed that GATA3 dysfunction, but not PIK3CA mutation, upregulates EMT, invasion, and angiogenic pathways followed by PgR downregulation. These results reveal the existence of heterogeneous populations of DCIS and provide predictive markers for classifying DCIS and optimizing treatment.

48: Convalescent Plasma and Improved Survival in Patients with Hematologic Malignancies and COVID-19
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Posted 05 Feb 2021

Convalescent Plasma and Improved Survival in Patients with Hematologic Malignancies and COVID-19
910 downloads medRxiv oncology

Michael A. Thompson, Jeffrey P. Henderson, Pankil K Shah, Samuel M Rubinstein, Michael J Joyner, Toni K Choueiri, Daniel B Flora, Elizabeth A Griffiths, Anthony P Gulati, Clara Hwang, Vadim S Koshkin, Esperanza B Papadopoulos, Elizabeth V. Robilotti, Christopher T Su, Elizabeth M Wulff-Burchfield, Zoey Xie, Peter Paul Yu, Sanjay Mishra, Jonathon Senefeld, Dimpy P Shah, Jeremy L Warner, COVID-19 and Cancer Consortium

Convalescent plasma may benefit immunocompromised individuals with COVID-19, including those with hematologic malignancy. We evaluated the association of convalescent plasma treatment with 30-day mortality in hospitalized adults with hematologic malignancy and COVID-19 from a multi-institutional cohort. 143 treated patients were compared to 823 untreated controls. After adjustment for potential confounding factors, convalescent plasma treatment was associated with improved 30-day mortality (hazard ratio, 0.60; 95% CI, 0.37-0.97). This association remained significant after propensity-score matching (hazard ratio, 0.52; 95% CI, 0.29-0.92). These findings suggest a potential survival benefit in the administration of convalescent plasma to patients with hematologic malignancy and COVID-19.

49: Utility of circulating tumor DNA for detection and monitoring of endometrial cancer recurrence and progression
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Posted 06 Mar 2020

Utility of circulating tumor DNA for detection and monitoring of endometrial cancer recurrence and progression
894 downloads medRxiv oncology

Esther Moss, Diviya Gorsia, Anna Collins, Pavandeep Sandhu, Nalini Foreman, Anu Gore, Joey Wood, Christopher Kent, Lee Silcock, David S. Guttery

Despite the increasing incidence of endometrial cancer (EC) worldwide and the poor overall survival of patients who recur, no reliable biomarker exists for detecting and monitoring EC recurrence and progression during routine follow-up. Circulating tumor DNA (ctDNA), the tumor-derived fraction of cell-free DNA (cfDNA) holds promise as a sensitive method for monitoring cancer activity and stratifying patients that are likely to respond to chemotherapy. Here, we investigated the utility of ctDNA for detecting and monitoring EC recurrence and progression in 13 patients using a combination of highly-sensitive digital droplet PCR (ddPCR), targeted next-generation sequencing (tNGS) and personalized ctDNA assays. Using the Oncomine Pan-cancer cfDNA tNGS panel, at least 1 somatic mutation at a variant allele frequency (VAF) >20% was detected in 69% (9/13) of patient tumors. The four patients with no detectable tumor mutations at >20% VAF were whole exome sequenced, with all four harbouring mutations in genes not analyzed by the Oncomine Pan-cancer cfDNA panel. Analysis of matched and longitudinal plasma DNA revealed earlier detection of EC recurrence and progression compared to standard clinical imaging techniques and dynamic kinetics of ctDNA levels reflecting treatment response. We also detected, for the first time to our knowledge, acquired high microsatellite instability (MSI-H) in ctDNA from one patient whose primary tumor was MSI stable. Overall, our study suggests that ctDNA analysis, and in particular MSI analysis in ctDNA could become a useful biomarker for early detection and monitoring of EC recurrence and progression.

50: Optimizing Clinical Outcome and Toxicity in Lung Cancer Using a Genomic Marker of Radiosensitivity
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Posted 13 Jan 2020

Optimizing Clinical Outcome and Toxicity in Lung Cancer Using a Genomic Marker of Radiosensitivity
891 downloads medRxiv oncology

Jacob G Scott, Geoffrey Sedor, Michael W Kattan, Jeffrey Peacock, G. Daniel Grass, Eric A Mellon, Ram Thapa, Michael Schell, Anthony Waller, Sean Poppen, George Andl, Steven Eschrich, Thomas Dilling, William Dalton, Louis Harrison, Tim Fox, Javier Torres-Roca

While radiation therapy serves as the backbone for nearly 40% of all cancer cures, and is received by nearly 70% of all cancer patients at some point in their cancer journey, it has yet to enter the modern era of personalized medicine. While field shape and size is personalized anatomically for all patients, the dose of radiation is still prescribed in a one-size-fits-all manner. Given the reality of inter-tumoral heterogeneity demonstrated by cancer sequencing efforts, we propose that we are working under an outdated null hypothesis in our field: that all patients should respond the same to the same dose of radiation. We have previously developed a method by which to predict optimal dosing for a given patient, which we term the Genomically Adjusted Radiation Dose, given the a priori knowledge of a patients tumor genomics. Knowing how much dose a patients tumor requires for biological optimization provides the first opportunity to characterize the inefficienies of one-size-fits-all dosing schemes, that result in both over- and under-dosing for the majority of patients. To elucidate this inefficiency, and therefore the opportunity to improvement using a personalized dosing scheme, we develop a competing hazards-style mathematical model combining the canonical equations for tumor control and normal tissue complication probabilities. Using data from two prospectively collected cohorts of patients with non-small-cell lung cancer, we show how the results of a recent uniform dose escalation study can be explained by the biological innefficiency of empiric uniform dose escalation, and highlight the opportunities for improvement in radiation outcomes available today, without need for new technology or equipment.

51: The utility of homologous recombination deficiency biomarkers across cancer types
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Posted 20 Feb 2021

The utility of homologous recombination deficiency biomarkers across cancer types
886 downloads medRxiv oncology

Shiro Takamatsu, J.B. Brown, Ken Yamaguchi, Junzo Hamanishi, Koji Yamanoi, Hisamitsu Takaya, Tomoko Kaneyasu, Seiichi Mori, Masaki Mandai, Noriomi Matsumura

BackgroundGenomic alterations in BRCA1/2 and genomic scar signatures are associated with homologous recombination DNA repair deficiency (HRD) and serve as therapeutic biomarkers for platinum and PARP inhibitors in breast and ovarian cancers. However, the clinical significance of these biomarkers in other homologous recombination repair-related genes or other cancer types is not fully understood. ResultsWe analyzed the datasets of all solid cancers from The Cancer Genome Atlas and Cancer Cell Line Encyclopedia, and found that the association between biallelic alterations in the homologous recombination pathway genes and genomic scar signatures differed greatly depending on gender and the presence of somatic TP53 mutation. Additionally, HRD cases identified by a combination of these indicators showed higher sensitivity to DNA-damaging drugs than non-HRD cases both in clinical samples and cell lines. ConclusionOur work provides novel proof of the utility of HRD analysis for all cancer types and will improve the precision and efficacy of chemotherapy selection in clinical oncology.

52: New Role of Red Blood Cells in Absorption of DNA Bearing Tumorigenic Mutations from Lung Cancer Tissue
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Posted 24 Jan 2021

New Role of Red Blood Cells in Absorption of DNA Bearing Tumorigenic Mutations from Lung Cancer Tissue
883 downloads medRxiv oncology

Nai-Xin Liang, Tao Wang, Cong Zhang, Zichen Jiao, Tianqiang Song, Hongwei Liang, Qihan Chen

Red blood cells (RBC) are commonly assumed to be vehicles for oxygen, carbon dioxide, and cells' metabolic byproducts. In this study, we investigated whether RBC may contain cancer-cell derived DNA and whether such cargo may be used as a biomarker for detecting cancer. Using an in vitro co-culture system, we showed that RBC could absorb DNA bearing tumorigenic mutations from cancer cell lines. Next, we demonstrated that we could detect common genetic mutations, including EGFR 19 deletion, L858R, and KRAS G12 in RBC collected from early-stage non-small cell lung cancer patients. We were able to repeat our finding using both next-generation sequencing and droplet digital PCR. Our study highlights a new biological phenomenon involving RBC and their translational potential as a novel liquid biopsy technology platform that can be used for early cancer screening.

53: HLA allele-specific expression loss in tumors can shorten survival and hinder immunotherapy
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Posted 04 Oct 2020

HLA allele-specific expression loss in tumors can shorten survival and hinder immunotherapy
867 downloads medRxiv oncology

Ioan Filip, Rose Orenbuch, Junfei Zhao, Gulam A. Manji, Evangelina López de Maturana, Núria Malats, Kenneth Olive, Raul Rabadan

Efficient presentation of aberrant peptide fragments by the human leukocyte antigen class I (HLA-I) genes is necessary for immune detection and killing of cancer cells. Patient HLA-I genotypes are known to impact the efficacy of cancer immunotherapy, and the somatic loss of HLA-I heterozygosity has been established as a factor in immune evasion. While global deregulated expression of HLA-I has been reported in different tumor types, the role of HLA-I allele-specific expression loss - that is, the preferential RNA expression loss of specific HLA-I alleles - has not been fully characterized in cancer. In the present study, we quantified HLA-I allele-specific expression (ASE) across eleven TCGA tumor types using a novel method from input RNA and whole-exome sequencing data. Allele-specific loss in at least one of the three HLA-I genes (ASE loss) was pervasive and associated to worse overall survival across tumor types, including pancreatic adenocarcinomas, prostate carcinomas and glioblastomas, among others. In particular, our analysis shows that detection of neoantigens with binding affinity to the specific HLA-I genes subject to ASE loss was a top prognostic indicator of overall survival. Additionally, we found that ASE loss hindered immunotherapy in retrospective analyses. Together, these results highlight the prevalence of HLA-I ASE loss - a previously uncharacterized phenomenon in cancer - and provide initial evidence of its clinical significance in cancer prognosis and immunotherapy treatment.

54: GARD is a pan-cancer predictor of radiation therapy benefit
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Posted 22 Dec 2020

GARD is a pan-cancer predictor of radiation therapy benefit
864 downloads medRxiv oncology

Jacob G Scott, Geoffrey Sedor, Patrick Ellsworth, Jessica A Scarborough, Kamran Ahmed, Daniel E Oliver, Steven A Eschrich, Javier Torres-Roca, Michael W Kattan

Purpose/ObjectivesDespite advances in cancer genomics, radiation therapy (RT) is still prescribed based on an empiric one-size-fits-all paradigm. Previously, we proposed a novel algorithm using the genomic adjusted radiation dose (GARD) to personalize RT prescription dose based on the biological effect of a given physical RT dose, calculated using individual tumor genomics - hypothesizing that the extra genomic dimension would reveal differences in clinical outcome not apparent with standard physical RT dose alone. To test this hypothesis, and the GARD-based RT dosing paradigm, we performed a pooled pan-cancer analysis in 9 separate clinical cohorts of 1,574 unique patients that represent all available cohorts with the data required to calculate GARD, together with clinical outcome. Materials/MethodsWe collected 9 previously-published datasets for which all information to calculate GARD was available. Two clinical endpoints were defined: (i) time to first recurrence and (ii) overall survival. The recurrence and survival analysis included a total of 1,257 (972 +RT, 285 -RT) and 636 patients (414 +RT, 222 -RT), respectively. A stratified Cox proportional hazard regression analysis model was constructed for each disease site and each outcome using GARD as the covariate, and a common GARD effect was estimated. Secondary Cox models were constructed similarly using total RT dose and sham-GARD (for -RT patients) as the covariates for comparison. Restricted cubic splines with 3-5 knots were included to allow for possible nonlinear associations. Interaction tests between GARD and whether patients received RT were performed using the Wald statistic for all cohorts. ResultsPooled analysis of all available data reveal that GARD is a continuous predictor of recurrence (HR = 0.984, CI [0.982, 0.996], p= 0.004) and survival (HR = 0.975, CI [0.958, 0.993], p= 0.005) in RT treated patients. There was no significant relationship between physical RT dose or sham-GARD and survival or recurrence in any group, or in the pooled analysis. The interaction test revealed the effect of GARD on survival depends on whether or not that patient received RT (Wald statistic: p=0.026), as is the effect of GARD on first recurrence for all but those patients treated to the lowest GARD (for patients with GARD > 19.2Gy, Wald statistic: p=0.04). ConclusionsBiologic effect, as quantified by GARD, is significantly associated with recurrence and survival in a continuous manner in RT treated patients, and physical RT dose is not. We propose that genomics should be integrated into radiation dosing decisions, using a GARD-based framework as the new paradigm for personalizing RT treatment.

55: Determinants of anti-PD1 response and resistance in clear cell renal cell carcinoma
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Posted 24 Mar 2021

Determinants of anti-PD1 response and resistance in clear cell renal cell carcinoma
854 downloads medRxiv oncology

Lewis Au, Emine Hatipoglu, Marc Robert de Massy, Kevin Litchfield, Andrew Rowan, Rachael Thompson, Desiree Schnidrig, Fiona Byrne, Gordon Beattie, Stuart Horswell, Nicos Fotiadis, Steve Hazell, David Nicol, Scott Thomas Colville Shepherd, Annika Fendler, Robert Mason, Jan Attig, Kroopa Joshi, Imran Uddin, Pablo Becker, Mariana Werner Sunderland, Ayse Akarca, Ignazio Puccio, Tom Lund, Kim Dhillon, Marcos Duran Vasquez, Ehsan Ghorani, Hang Xu, Jose Ignacio Lopez, Anna Green, Ula Mahadeva, Elaine Borg, Miriam Mitchison, David Moore, Ian Proctor, Mary Falzon, Andrew Furness, Lisa Pickering, James L Reading, Roberto Salgado, Teresa Marafioti, Mariam Jamal-Hanjani, George Kassiotis, Benny Chain, James Larkin, Charles Swanton, Sergio A. Quezada, Samra Turajlic

Antigen recognition and T-cell mediated cytotoxicity in clear-cell renal cell carcinoma (ccRCC) remains incompletely understood. To address this knowledge gap, we analysed 115 multiregion tumour samples collected from 15 treatment-naive patients pre- and post-nivolumab therapy, and at autopsy in three patients. We performed whole-exome sequencing, RNAseq, TCRseq, multiplex immunofluorescence and flow cytometry analyses and correlated with clinical response. We observed pre-treatment intratumoural TCR clonal expansions suggesting pre-existing immunity. Nivolumab maintained pre-treatment expanded, clustered TCR clones in responders, suggesting ongoing antigen-driven stimulation of T-cells. T-cells in responders were enriched for expanded TCF7+CD8+ T-cells and upregulated GZMK/B upon nivolumab-binding. By contrast, nivolumab promoted accumulation of new TCR clones in non-responders, replacing pre-treatment expanded clonotypes. In this dataset, mutational features did not correlate with response to nivolumab and human endogenous retrovirus expression correlated indirectly. Our data suggests that nivolumab potentiates clinical responses in ccRCC by binding pre-existing expanded CD8+ T-cells to enhance cytotoxicity.

56: STK11 and KEAP1 Mutations as Prognostic Biomarkers in an Observational Real-World Lung Adenocarcinoma Cohort
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Posted 27 Jan 2020

STK11 and KEAP1 Mutations as Prognostic Biomarkers in an Observational Real-World Lung Adenocarcinoma Cohort
851 downloads medRxiv oncology

Simon Papillon-Cavanagh, Parul Doshi, Radu Dobrin, Joseph Szustakowski, Alice M Walsh

ImportanceUnderstanding the mechanisms of primary resistance to immune checkpoint blockade therapy is of paramount importance for treatment selection. Somatic mutations in STK11 and KEAP1, frequently co-mutated in nonsquamous non-small cell lung cancer, have been associated with poor response to immune checkpoint blockade. However, previous reports lack non-immune checkpoint blockade controls needed to properly ascertain the predictive nature of those biomarkers. ObjectiveTo evaluate the predictive vs prognostic effect of STK11 or KEAP1 mutations across different treatment classes in nonsquamous non-small cell lung cancer. DesignA retrospective, real-world data cohort from the Flatiron Health network linked with genetic testing from Foundation Medicine, from January 1, 2011, through December 31, 2018. SettingMulticenter, including academic and community practices. ParticipantsPatients diagnosed with stage IIIB, IIIC, IVA, or IVB nonsquamous non-small cell lung cancer who initiated first-line treatment within 90 days after diagnosis. Main Outcomes and MeasuresReal-world, progression-free survival and overall survival calculated from time of initiation of first-line treatment. ResultsWe analyzed clinical and mutational data for 2276 patients with advanced, nonsquamous non-small cell lung cancer (mean age at advanced diagnosis, 66.3 years [SD 10.3], 54.4% female, 80.1% with a history of smoking), including patients treated with anti-programmed death-1/anti-programmed death ligand 1 inhibitors at first line (n = 574). Mutations in STK11 or KEAP1 were associated with poor outcomes across multiple therapeutic classes and were not specifically associated with poor outcomes in immune checkpoint blockade cohorts. There was no observable interaction between STK11 mutations and anti-programmed death-1/anti-programmed death ligand 1 treatment on real-world, progression-free survival (HR, 1.05; 95% CI, 0.76-1.44; P = .785) or overall survival (HR, 1.13; 95% CI, 0.76-1.67; P = .540). Similarly, there was no observable interaction between KEAP1 on real-world, progression-free survival (HR, 0.93; 95% CI, 0.67-1.28; P = .653) or overall survival (HR, 0.98; 95% CI, 0.66-1.45; P = .913). Results were consistent in KRAS-mutated patients. Conclusion and RelevanceOur results show that STK11-KEAP1 mutations are prognostic, not predictive, biomarkers for anti-programmed death-1/anti-programmed death ligand 1 therapy. Key PointsO_ST_ABSQuestionC_ST_ABSAre loss-of-function somatic mutations in STK11 and KEAP1 predictive of response to immune checkpoint blockade or simply prognostic? FindingsIn this observational real-world cohort totaling 2276 patients, including 574 treated with immune checkpoint blockade, we find that mutations in STK11 and KEAP1 are associated with poor prognosis across multiple first-line treatment classes. MeaningMutations in STK11 and KEAP1 are prognostic biomarkers of poor response to both immune checkpoint blockade and chemotherapy.

57: Molecular characterization of non-small cell lung cancer tumors in Latin American patients from Brazil, Chile and Peru uncovers novel potentially driver mutations
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Posted 13 Sep 2020

Molecular characterization of non-small cell lung cancer tumors in Latin American patients from Brazil, Chile and Peru uncovers novel potentially driver mutations
817 downloads medRxiv oncology

Gonzalo Sepulveda, Alejandro Blanco, Matias Freire, Rodrigo Lizana, Javier Caceres-Molina, Diego Ampuero, Paola Perez, Liliana Ramos, Osvaldo Aren, Sara Chernilo, Maria Loreto Spencer, Jacqueline Flores, Giuliano Bernal, Monica Ahumada Olea, German Rasse, Carolina Sanchez, Katherine Marcelain, Solange Rivas, Maria Galli de Amorim, Gabriela Branco, Diana Noronha Nunes, Emmanuel Dias-Neto, Helano C. Freitas, Cristina Fernandez, Rodrigo Assar, Ricardo Armisen

Introduction Therapies that target activating Egfr, Alk, Ros1 and other mutations have become first-line treatments that improve NSCLC patient life expectancy. Latin-American patients are poorly represented in clinical trials and in genomic databases, thus little is known about the prevalence of actionable mutations in this population. This study characterizes, for the first time, the somatic mutations found in 52 actionable genes, and describe a novel set of potentially actionable mutations, in NSCLC patients from Chile, Brazil and Peru, while correlating these genomic occurrences with relevant clinical, demographic and pathology aspects. Methods 1732 subjects diagnosed with NSCLC were analyzed. DNA and RNA were sequenced using a 52 genes NGS panel. Mutations were annotated using the Variant Effect Predictor, COSMIC, OncoKB and the Cancer Genome Interpreter to categorize somatic mutations. Results We found a total of 1713 mutations with 626 (36.5%) novel, potentially driver mutations. 66.1% of these novel mutations were predicted as Tier 1 driver mutations. Actionable mutations for Ret and Alk were more prevalent in Brazil than in Chile, whereas Met exon-14 skipping was significantly enriched in Chile. In Peru, Egfr is higher while Kras is lower. A high number of novels potentially driver mutations in know NSCLC actionable genes, such as Alk, Erbb2, Ret, Met, and Ros1, was found. Conclusions The analysis of many Latin America subjects revealed a significant number of clinically actionable but also novel somatic mutations in cancer genes highlighting the importance of including less-represented populations in clinical trials and molecular studies.

58: Evaluating the utility of tumour mutational signatures for identifying hereditary colorectal cancer and polyposis syndrome carriers
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Posted 15 Dec 2019

Evaluating the utility of tumour mutational signatures for identifying hereditary colorectal cancer and polyposis syndrome carriers
804 downloads medRxiv oncology

Peter Georgeson, Bernard Pope, Christophe Rosty, Mark Clendenning, Khalid Mahmood, Jihoon E Joo, Ryan A. Hutchinson, Romy Walker, Susan Preston, Julia Como, Sharelle Joseland, Aung Ko Win, Finlay A. Macrae, John L Hopper, Dmitry Mouradov, Peter Gibbs, Oliver M Sieber, Dylan E O'Sullivan, Darren R Brenner, Steve Gallinger, Mark A. Jenkins, Ingrid M. Winship, Daniel Buchanan

Objective: Germline pathogenic variants (PVs) in the DNA mismatch repair (MMR) genes and in the base excision repair gene MUTYH underlie hereditary colorectal cancer (CRC) and polyposis syndromes. We evaluated the robustness and discriminatory potential of tumour mutational signatures in CRCs for identifying germline PV carriers. Design: Whole exome sequencing of formalin-fixed paraffin embedded (FFPE) CRC tissue was performed on 33 MMR germline PV carriers, 12 biallelic MUTYH germline PV carriers, 25 sporadic MLH1 methylated MMR-deficient CRCs (MMRd controls) and 160 sporadic MMR-proficient CRCs (MMRp controls) and included 498 TCGA CRC tumours. COSMIC V3 single base substitution (SBS) and indel (ID) mutational signatures were assessed for their ability to differentiate CRCs that developed in carriers from non-carriers. Results: The combination of mutational signatures SBS18 and SBS36 contributing >30% of a CRC's signature profile was able to discriminate biallelic MUTYH carriers from all other non-carrier control CRCs with 100% accuracy (area under the curve (AUC) 1.0). SBS18 and SBS36 were associated with specific MUTYH variants p.Gly396Asp (p=0.025) and p.Tyr179Cys (p=5x10-5), respectively. The combination of ID2 and ID7 could discriminate the 33 MMR PV carrier CRCs from the MMRp control CRCs (AUC 0.99), however, SBS and ID signatures, alone or in combination, could not provide complete discrimination (AUC 0.79) between CRCs from MMR PV carriers and sporadic MMRd controls. Conclusion: Assessment of SBS and ID signatures can discriminate CRCs from biallelic MUTYH carriers and MMR PV carriers from non-carriers with high accuracy, demonstrating utility as a potential diagnostic and variant classification tool.

59: Comprehensive genomic profiling of 30,000 consecutive solid tumors
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Posted 22 Nov 2020

Comprehensive genomic profiling of 30,000 consecutive solid tumors
784 downloads medRxiv oncology

Scott A. Tomlins, Daniel H. Hovelson, Jennifer M. Suga, Daniel M. Anderson, Han A. Koh, Elizabeth C. Dees, Brendan McNulty, Mark E Burkard, Michael Guarino, Jamil Khatri, Malek M. Safa, Marc R. Matrana, Eddy S Yang, Alex R. Menter, Benjamin M. Parsons, Jennifer N. Slim, Michael A. Thompson, Leon Hwang, William J. Edenfield, Suresh Nair, Adedayo Onitilo, Robert Siegel, Alan Miller, Timothy Wassenaar, William J. Irvin, William Schulz, Arvinda Padmanabhan, Vallathucherry Harish, Anneliese Gonzalez, Abdul Hai Mansoor, Andrew Kellum, Paul Harms, Stephanie Drewery, Jayson Falkner, Andrew Fischer, Jennifer Hipp, Kat Kwiatkowski, Lorena Lazo de la Vega, Khalis Mitchell, Travis Reeder, Javed Siddiqui, Hana Vakil, D. Bryan Johnson, Daniel R. Rhodes

PurposeTissue-based comprehensive genomic profiling (CGP) is increasingly utilized for treatment selection in patients with advanced solid tumors, however real-world tissue availability may limit widespread implementation. Here we established real-world CGP tissue availability and assessed CGP performance on consecutively received samples. Patients and MethodPost-hoc, non-prespecified analysis of 32,048 consecutive tumor tissue samples received for StrataNGS, a multiplex PCR based-CGP (PCR-CGP) test, as part of an ongoing observational trial (NCT03061305). Tumor tissue sample characteristics and PCR-CGP performance were assessed across all tested tumor samples, including exception samples not meeting minimum input requirements (<20% tumor content [TC], <2mm2 tumor surface area [TSA], DNA or RNA yield <1ng/ul, or specimen age >5yrs). Tests reporting at least one prioritized alteration or meeting all sequencing QC metrics (and [&ge;]20% TC) were considered successful. For prostate carcinoma and lung adenocarcinoma, tests reporting at least one actionable/informative alteration or those meeting all sequencing QC metrics (and [&ge;]20% TC) were considered actionable. ResultsPCR-CGP was attempted in 31,165 of 32,048 (97.2%) consecutively received solid tumor tissue samples. Among the 31,165 tested samples, 10.7% had low (<20%) tumor content (TC) and 58.4% were small (<25mm2 TSA), highlighting the challenging nature of samples received for CGP. Of the 31,101 samples evaluable for input requirements, 8,079 (26.0%) were exceptions not meeting requirements. However, 94.2% of the 31,101 tested samples were successfully reported, including 80.6% of exception samples. Importantly, 80.6% of 1,344 tested prostate carcinomas and 87.8% of 1,144 tested lung adenocarcinomas yielded results informing treatment selection. ConclusionMost real-world tumor tissue samples from patients with advanced cancer desiring CGP are limited, requiring optimized CGP approaches to produce meaningful results. An optimized PCR-CGP test, coupled with an inclusive exception testing policy, delivered reportable results for >94% of samples, potentially expanding the proportion of CGP-testable patients, and thus the impact of biomarker-guided targeted and immunotherapies.

60: COVID-19 Mortality in Cancer Patients: A Report from a Tertiary Cancer Centre in India
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Posted 15 Sep 2020

COVID-19 Mortality in Cancer Patients: A Report from a Tertiary Cancer Centre in India
771 downloads medRxiv oncology

Anurag Mehta, Smreti Vasudevan, Anuj Parkash, Anurag Sharma, Tanu Vashist, Vidya Krishna

Background: Cancer patients, especially those receiving cytotoxic therapy are assumed to have a higher probability of death from COVID-19. We have conducted this study to identify the Case Fatality Rate (CFR) in cancer patients with COVID-19 and have explored the relationship of various clinical factors to mortality in our patient cohort. Methods: All active cancer cases presented to the hospital from 8th June to 24 August 2020, and developed symptoms/ radiological features suspicious of COVID-19 were tested by Real-time polymerase chain reaction assay and/or cartridge-based nucleic acid amplification test from a combination of naso-oropharyngeal swab for SARS-CoV-2. Clinical data, treatment details, and outcomes were assessed from the medical records. Results: Of the total 3101 cancer patients admitted to the hospital, 1088 patients were tested and 186 patients were positive for SARS-CoV-2. The CFR in the cohort was 27/186 (14.5%). Univariate analysis showed that the risk of death was significantly associated with the presence of comorbidities [OR: 2.68; (95%CI: 1.13-6.32); P=0.02], multiple comorbidities [OR: 3.01; (95%CI: 1.02-9.07); P=0.046 for multiple vs. single], and the severity of COVID-19 presentation [OR: 27.48; (95%CI: 5.34-141.49); P=0.0001 for severe vs. not severe]. Among all comorbidities, diabetes [OR: 3.3; (95%CI: 1.35-8.09); P=0.008] and cardiovascular diseases [OR: 3.77; (95%CI: 1.02-13.91); P=0.045] were significant risk factors for death. The receipt of anticancer treatments including chemotherapy, surgery, radiotherapy, targeted therapy, and immunotherapy within a month before the onset of COVID-19 symptoms had no significant effect on the mortality of cancer patients. Conclusion: To the best of our knowledge, this is the first study from India reporting the CFR, clinical associations, and risk factors for mortality in SARS-CoV-2 infected cancer patients. Our study shows that the frequency of COVID-19 in cancer patients is high, and the CFR is 7.6 times more than the national average. Anticancer therapies did not increase the risk of death. Pre-existing comorbidities specially diabetes, multiple comorbidities, and severity of COVID-19 presenting symptoms are significantly linked with COVID-19 related death in the cohort.

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