PO-1193 The impact of driver mutations on the pathologic response to Chemoradiation (CRT) in LANSCLC

2021 ◽  
Vol 161 ◽  
pp. S989-S990
Author(s):  
S. Appel ◽  
J. Bar ◽  
Y.R. Lawrence
Keyword(s):  
Pathologic Response ◽  
Driver Mutations ◽  
The Impact

scholarly journals Clonal approaches to understanding the impact of mutations on hematologic disease development

Blood ◽  
2019 ◽  
Vol 133 (13) ◽  
pp. 1436-1445 ◽  
Author(s):  
Jyoti Nangalia ◽  
Emily Mitchell ◽  
Anthony R. Green
Keyword(s):  
Somatic Mutations ◽  
Clonal Selection ◽  
Single Cells ◽  
Driver Mutations ◽  
Great Promise ◽  
Tumor Evolution ◽  
Disease Development ◽  
Hematopoietic Tissue ◽  
The Impact

Abstract Interrogation of hematopoietic tissue at the clonal level has a rich history spanning over 50 years, and has provided critical insights into both normal and malignant hematopoiesis. Characterization of chromosomes identified some of the first genetic links to cancer with the discovery of chromosomal translocations in association with many hematological neoplasms. The unique accessibility of hematopoietic tissue and the ability to clonally expand hematopoietic progenitors in vitro has provided fundamental insights into the cellular hierarchy of normal hematopoiesis, as well as the functional impact of driver mutations in disease. Transplantation assays in murine models have enabled cellular assessment of the functional consequences of somatic mutations in vivo. Most recently, next-generation sequencing–based assays have shown great promise in allowing multi-“omic” characterization of single cells. Here, we review how clonal approaches have advanced our understanding of disease development, focusing on the acquisition of somatic mutations, clonal selection, driver mutation cooperation, and tumor evolution.

The predictive value of MAP2K1/2 mutations for efficiency of immunotherapy in melanoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21587-e21587
Author(s):  
Ting Ye ◽  
Jieying Zhang ◽  
Xinyi Liu ◽  
Mengmei Yang ◽  
Yuhan Zhou ◽  
...  
Keyword(s):  
Overall Survival ◽  
Predictive Value ◽  
Cox Regression ◽  
Treatment Options ◽  
Objective Response ◽  
Progression Free Survival ◽  
Driver Mutations ◽  
Cox Regression Analysis ◽  
Melanoma Patients ◽  
The Impact

e21587 Background: Immunotherapies targeting immune checkpoint receptors have become the cornerstone of systemic treatment options for malignant melanoma. The response to these immunotherapies may correlate with driver mutations. MAP2K1/2 genes are mutated in approximately 10% of melanomas, however, the impact of MAP2K1/2 gene alterations on the efficiency of immunotherapy has not been clarified. Methods: Six metastatic melanoma clinical cohorts treated with ICIs were included to investigate the association between clinical efficacy of immunotherapy and MAP2K1/2 mutations. Survival analyses were conducted in cohorts receiving two kinds of ICB agents, namely anti-CTLA-4 or anti-PD-1. RNA expression profiling from these cohorts and from the TCGA melanoma cohort were used to explore the potential mechanism related to immune activation. Results: In an independent anti-CTLA-4-treated cohort (n = 110), we found that MAP2K1/2 mutations are predictive of high objective response rate (17.6% vs 1.3%, p = 0.0185) and long progression-free survival [median OS, 49.2 months vs 8.3 months; hazard ratio (HR) = 0.37; 95% CI, 0.15–0.91; p = 0.0307] and overall survival (median PFS, 19.4 months vs 2.8 months; HR = 0.2; 95% CI, 0.05–0.83; p = 0.0262). This predictive value was further validated in a pooled anti-CTLA-4-treated cohort (n = 235) in terms of overall survival (median OS, 49.3 months vs 22.0 months; HR = 0.44; 95% CI, 0.22–0.91; p = 0.0255). However, no correlation between MAP2K1/2 mutations and overall survival was observed in the anti-PD-1-treated cohort (n = 285). Subgroup Cox regression analysis indicated that MAP2K-mutated patients receive less benefit from the anti-PD-1 monotherapy than from the anti-CTLA-4 treatment (median OS, 27.0 months vs 49.3 months; HR = 3.26; 95% CI, 1.18–9.02; p = 0.0225), which was contrary to the result obtained for the total population. Furthermore, transcriptome profiling analysis revealed that MAP2K-mutated tumors are enriched in CD8+ T cells, B cells, and neutrophil cells and also express high levels of CD33 and IL10, which might be the underlying mechanism for melanoma patients with MAP2K1/2-mutated benefit more from anti-CTLA-4 treatment. Conclusions: We identified mutations in MAP2K1/2 genes as the independent predictive factors for anti-CTLA-4 therapy in melanoma patients and found that anti-CTLA-4 treatment in patient harbouring MAP2K1/2 mutations might be more effective than the anti-PD-1 therapy.

scholarly journals Clonal Hematopoiesis and Mutations of Myeloproliferative Neoplasms

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2100
Author(s):  
Lasse Kjær
Keyword(s):  
Myeloproliferative Neoplasms ◽  
Philadelphia Chromosome ◽  
Clinical Intervention ◽  
Driver Mutation ◽  
Response Monitoring ◽  
Driver Mutations ◽  
Clonal Hematopoiesis ◽  
Disease Biology ◽  
Background Population ◽  
The Impact

Myeloproliferative neoplasms (MPNs) are associated with the fewest number of mutations among known cancers. The mutations propelling these malignancies are phenotypic drivers providing an important implement for diagnosis, treatment response monitoring, and gaining insight into the disease biology. The phenotypic drivers of Philadelphia chromosome negative MPN include mutations in JAK2, CALR, and MPL. The most prevalent driver mutation JAK2V617F can cause disease entities such as essential thrombocythemia (ET) and polycythemia vera (PV). The divergent development is considered to be influenced by the acquisition order of the phenotypic driver mutation relative to other MPN-related mutations such as TET2 and DNMT3A. Advances in molecular biology revealed emergence of clonal hematopoiesis (CH) to be inevitable with aging and associated with risk factors beyond the development of blood cancers. In addition to its well-established role in thrombosis, the JAK2V617F mutation is particularly connected to the risk of developing cardiovascular disease (CVD), a pertinent issue, as deep molecular screening has revealed the prevalence of the mutation to be much higher in the background population than previously anticipated. Recent findings suggest a profound under-diagnosis of MPNs, and considering the impact of CVD on society, this calls for early detection of phenotypic driver mutations and clinical intervention.

Optimal timing of surgical resection after radiation therapy in locally advanced rectal adenocarcinoma: An analysis of the National Cancer Database (NCDB).

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 510-510 ◽  
Author(s):  
Ciara R Huntington ◽  
Danielle Boselli ◽  
Joshua S. Hill ◽  
Jonathan C. Salo
Keyword(s):  
Radiation Therapy ◽  
Surgical Resection ◽  
Cox Model ◽  
Locally Advanced ◽  
Rectal Adenocarcinoma ◽  
Pathologic Response ◽  
Complete Pathologic Response ◽  
Risk Of Mortality ◽  
Increased Risk ◽  
The Impact

510 Background: In treatment of rectal adenocarcinoma, an increased time delay (TD) of 6-12 weeks from the end of radiation therapy to surgery may increase the rate of complete pathologic response (pCR), but the optimal TD with respect to survival has not been established. This study evaluates the impact of TD on overall mortality. Methods: The NCDB was queried for patients with adenocarcinoma of the rectum and no evidence of metastasis at diagnosis, who underwent preoperative chemoradiation followed by radical surgical resection. Standard statistical methods were employed for descriptive statistics and Cox model development. Results: The study included 6805 patients, predominantly Caucasian (87.2%) and males (63.9%) who generally were treated with low anterior resection (57.3%), colonanal reanastomosis (8.4%), or abdominoperineal resection (28.4%), and had median survival of 66.6 months. The effects of age, surgical margins (-/+), comorbidity index, time to discharge after surgery, TMN pathologic staging, surgical volume, and patient income significantly impacted mortality after radiation and surgery (p<0.05 for all values). There was a significant relationship between TD and pCR (p=.0002). At TD less than 30 days, 4.0% of patients achieved pCR, while 9.3% of patients have achieved pCR by 75 days. In TD of greater than 75 days, the rate of pCR decreased. Overall, 6.8% of patients (n=461) achieved pCR. Using a refined cox model, a TD of more than 60 days was associated with 20% greater risk of mortality (95% CI 1.068 – 1.367). This effect became more pronounced with increasing TD; a TD of greater than 75 days was associated with 28% (95% CI 1.06-1.55) increased risk of mortality, while patients with TD less than 60 days saw a survival benefit. Conclusions: Though an interval up to 75 days between radiation and surgery may achieve higher rates of complete pathologic response, delay of more than 60 days from radiation to surgical resection and subsequent systemic chemotherapy decreases overall survival in patients with rectal cancer.

Response to neoadjuvant chemotherapy and impact on survival for resected gastric cancer.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 122-122
Author(s):  
Erin Greenleaf ◽  
Christopher S Hollenbeak ◽  
Joyce Wong
Keyword(s):  
Gastric Cancer ◽  
Adjuvant Chemotherapy ◽  
Neoadjuvant Chemotherapy ◽  
Disease Progression ◽  
Median Time ◽  
Pathologic Response ◽  
Early Stage Disease ◽  
Stage Disease ◽  
The Impact ◽  
Response To Neoadjuvant Chemotherapy

122 Background: This study assesses the survival impact of perioperative chemotherapy, with further analysis of pathologic response to neoadjuvant chemotherapy (NAC), in patients undergoing gastrectomy for gastric cancer (GC) in a large US sample. Methods: Using the 2003-2012 ACS National Cancer Database, 16,128 patients underwent gastrectomy for cancer. Treatment groups were categorized as: NAC, adjuvant chemotherapy, and surgery only. Patients receiving NAC were further categorized as: down-staged, no response, and disease progression. Univariate and multivariate analyses were performed to estimate the impact of treatment on overall survival. Results: Of patients undergoing gastrectomy, 36.6% received NAC, 19.5% received adjuvant chemotherapy, and 43.9% underwent surgery only. Median time of survival was longer in patients with more advanced disease who underwent either NAC or adjuvant chemotherapy versus surgery alone (see Table). In multivariate analysis, patients who received NAC had 20% lower hazard of death than surgery only patients (HR = 0.80, p < 0.0001). Within the NAC cohort (N = 5,909), 47.7% were down-staged, 36.5% had no response, and 15.7% demonstrated disease progression. Having a pathologic response to NAC was associated with having private insurance (OR = 1.22, p < 0.0001), higher socioeconomic status (OR = 1.21, p = 0.003), treatment in the central US (p < 0.0001, both), and undergoing proximal gastrectomy (OR = 1.59, p < 0.0001). Among patients who received NAC, median time of survival was longer if NAC down-staged patients to stages 0 or 1, with no survival difference in advanced stage disease. Conclusions: Neoadjuvant chemotherapy elicits a survival benefit in patients with advanced GC. Pathologic response is achieved in nearly half of patients undergoing NAC and is associated with improved survival, although only when down-staging to early stage disease. [Table: see text] [Table: see text]

Dissecting outcomes of patients (pts) with

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 5043-5043
Author(s):  
Praful Ravi ◽  
Gregory Russell Pond ◽  
Leonidas Nikolaos Diamantopoulos ◽  
Rohit K. Jain ◽  
William Paul Skelton ◽  
...  
Keyword(s):  
Urinary Tract ◽  
Cox Regression ◽  
Pathologic Complete Response ◽  
Multivariable Analysis ◽  
Pathologic Response ◽  
Cox Regression Analysis ◽  
Risk Of Recurrence ◽  
Split Dose ◽  
Female Sex ◽  
The Impact

5043 Background: Pathologic complete response (pCR) after NAC for MIBC is strongly correlated with long-term overall survival. However, there are sparse data on the risk of recurrence based on depth of pathologic response (pT0, pTa, pTis, pT1), and the differential impact of clinicopathologic factors and NAC regimen on recurrence. Methods: Baseline data on all pts with cT2-4N0-1 MIBC receiving NAC and who achieved < ypT2N0 disease at radical cystectomy (RC) from 9 international centers were obtained. The key outcome was time to recurrence (TTR) – defined as the time to any recurrence in the urinary tract or regional/distant metastasis, with death (in the absence of recurrence) considered a competing risk. Cox regression analysis was used to analyze the impact of clinical factors on recurrence. Results: A total of 506 pts were available. Median age was 66 years (range 33-86) and 78% (n = 396) were male; median follow-up after RC was 2.6 years. The majority of patients had pure urothelial histology (n = 371, 73%), and baseline stage was cT2N0 (n = 368, 73%), cT3-4N0 (n = 95, 19%) and TanyN1 (n = 43, 9%). NAC regimens were gemcitabine-cisplatin (GC, n = 296, 59%), dose-dense methotrexate-vinblastine-doxorubicin-cisplatin (ddMVAC, n = 141, 28%), split-dose GC (n = 29, 6%), MVAC (n = 29, 6%) and non-cisplatin based regimens (n = 11, 2%). At RC, 304 patients (60%) had ypT0N0 disease, 32 (6%) had ypTaN0, 107 (21%) had ypTisN0 and 63 (13%) had ypT1N0. Overall, 43 patients (8%) recurred with a median TTR of 56 weeks (range 7-251); 5-year freedom from recurrence was 87% (95% CI 83-91). The majority (n = 38) recurred outside the urinary tract. On multivariable analysis, ypTa (HR = 3.36 [1.24-9.11]) and ypT1 (HR = 2.88 [1.33-6.22], p = 0.013) disease at RC were predictors of shorter TTR, while female sex was associated with longer TTR (HR = 0.52 [0.27-0.98], p = 0.043). The type of NAC was not predictive of TTR (GC vs. other, HR = 1.49 [0.75-2.97], p = 0.26). Conclusions: To our knowledge, this is the largest study to quantify the risk of recurrence in pts achieving pathologic response after NAC and RC for MIBC. 8% of patients undergoing NAC and achieving < ypT2N0 at RC recurred. Residual ypTa and ypT1 disease conferred a significantly higher risk of recurrence, while ypTis did not; female sex was associated with a lower risk of recurrence. Importantly, the type of cisplatin-based NAC regimen used was not an independent predictor of recurrence.

scholarly journals P1.02-068 The Impact of TP53 Overexpression on EMT and the Prognosis in Lung Adenocarcinoma Harboring Driver Mutations

2017 ◽  
Vol 12 (1) ◽  
pp. S529-S530
Author(s):  
Shigeto Nishikawa ◽  
Toshi Menju ◽  
Terumasa Soawa ◽  
Koji Takahashi ◽  
Ryo Miyata ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Driver Mutations ◽  
The Impact

scholarly journals The Impact of FLT3 Mutations on the Development of Acute Myeloid Leukemias

2013 ◽  
Vol 2013 ◽  
pp. 1-14 ◽  
Author(s):  
Ugo Testa ◽  
Elvira Pelosi
Keyword(s):  
Therapeutic Targets ◽  
Driver Mutations ◽  
Causative Role ◽  
Genetic Studies ◽  
Internal Tandem Duplication ◽  
Genetic Abnormalities ◽  
Myeloid Leukemias ◽  
The Impact ◽  
Selection Of ◽  
Acute Myeloid

The development of the genetic studies on acute myeloid leukemias (AMLs) has led to the identification of some recurrent genetic abnormalities. Their discovery was of fundamental importance not only for a better understanding of the molecular pathogenesis of AMLs, but also for the identification of new therapeutic targets. In this context, it is essential to identify AML-associated “driver” mutations, which have a causative role in leukemogenesis. Evidences accumulated during the last years indicate that activating internal tandem duplication mutations in FLT3 (FLT3-ITD), detected in about 20% of AMLs, represents driver mutations and valid therapeutic targets in AMLs. Furthermore, the screening of FLT3-ITD mutations has also considerably helped to improve the identification of more accurate prognostic criteria and of the therapeutic selection of patients.

scholarly journals The Impact of Digital Histopathology Batch Effect on Deep Learning Model Accuracy and Bias

2020 ◽  
Author(s):  
Frederick M. Howard ◽  
James Dolezal ◽  
Sara Kochanny ◽  
Jefree Schulte ◽  
Heather Chen ◽  
...  
Keyword(s):  
Deep Learning ◽  
Expression Patterns ◽  
Model Performance ◽  
Batch Effect ◽  
The Cancer Genome Atlas ◽  
Driver Mutations ◽  
Cancer Subtypes ◽  
Breast Cancer Cohort ◽  
Quadratic Programming Method ◽  
The Impact

AbstractThe Cancer Genome Atlas (TCGA) is one of the largest biorepositories of digital histology. Deep learning (DL) models have been trained on TCGA to predict numerous features directly from histology, including survival, gene expression patterns, and driver mutations. However, we demonstrate that these features vary substantially across tissue submitting sites in TCGA for over 3,000 patients with six cancer subtypes. Additionally, we show that histologic image differences between submitting sites can easily be identified with DL. This site detection remains possible despite commonly used color normalization and augmentation methods, and we quantify the digital image characteristics constituting this histologic batch effect. As an example, we show that patient ethnicity within the TCGA breast cancer cohort can be inferred from histology due to site-level batch effect, which must be accounted for to ensure equitable application of DL. Batch effect also leads to overoptimistic estimates of model performance, and we propose a quadratic programming method to guide validation that abrogates this bias.

scholarly journals Stochasticity in the Genotype-Phenotype Map: Implications for the Robustness and Persistence of Bet-Hedging

2016 ◽  
Author(s):  
Daniel Nichol ◽  
Mark Robertson-Tessi ◽  
Peter Jeavons ◽  
Alexander RA Anderson
Keyword(s):  
Treatment Resistance ◽  
Molecular Switch ◽  
Phenotypic Heterogeneity ◽  
Driver Mutations ◽  
Phenotypic Change ◽  
Bet Hedging ◽  
Genetic Characteristics ◽  
Hedging Strategies ◽  
Genes And Environment ◽  
The Impact

For the last few decades modern biology has focused on quantifying, understanding and mapping the genetic characteristics of cells. This genotype-driven perspective has led to significant advances in our understanding and treatment of diseases such as cancer e.g. the discovery of driver mutations and the development of molecularly-targeted therapeutics. However, this perspective has largely ignored the functional outcome of genetic changes: the cellular phenotype. In part, this is simply because phenotypes are neither easy to define or measure as they critically depend on both genotype and context. Heterogeneity at the gene scale has been known for sometime, and there has been significant effort invested in trying to find patterns within it, but much less is understood about how this heterogeneity manifests itself in phenotypic change, i.e. the genotype-phenotype map (GP-map). This mapping is not one-to-one but many-to-many and is fundamentally the junction at which both genes and environment meet to produce phenotypes. Many genotypes produce similar phenotypes, and multiple phenotypes can emerge from a single genotype. To further complicate matters, genetically identical cells in uniform environments still exhibit phenotypic heterogeneity. Therefore a central open question in biology today is how can we connect the abundance of genomic data with cell phenotypic behaviour, this is especially pertinent to the issue of treatment resistance as many therapies act on cellular phenotypes. Our focus here is to tackle the GP-map question through the use of the simplest functional mapping we can define that also captures phenotypic heterogeneity: a molecular switch. Molecular switches are ubiquitous in biology, observed in many organisms and naturally map molecular components to decisions (i.e. phenotypes). Often stochastic in nature, such switches can be the difference between life or death in environments that fluctuate unpredictably, since they will ensure that at least some offspring are adapted to future environments. For convenience we use Chemical Reaction Networks (CRNs) to define the map of gene products to phenotypes, allowing us to investigate the impact of distinct mappings (CRNs) and perturbations to them. We observe that key biological properties naturally emerge, including both robustness and persistence. Robustness may explain why such bet hedging strategies are common in biology, and not readily destroyed through mutation. Whereas persistence may explain the apparent paradox of bet-hedging - why does phenotypic hedging exist in environments beneficial to only one of the phenotypes, when selection necessarily acts against it? The structure of the molecular switch, itself subject to selection, can slow the loss of hedging to ensure a survival mechanism even against environmental catastrophes which are very rare. Critically, these properties when taken together have profound and significant implications for the emergence of treatment resistance, since the timescale of extinction depends heavily on the underlying GP-map.

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