molecular subgroup
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Cancers ◽  
2022 ◽  
Vol 14 (2) ◽  
pp. 414
Author(s):  
Anita Mahajan ◽  
Helen Shih ◽  
Marta Penas-Prado ◽  
Keith Ligon ◽  
Kenneth Aldape ◽  
...  

Unlike medulloblastoma (MB) in children, robust prospective trials have not taken place for older patients due to the low incidence of MB in adults and adolescent and young adults (AYA). Current MB treatment paradigms for older patients have been extrapolated from the pediatric experience even though questions exist about the applicability of these approaches. Clinical and molecular classification of MB now provides better prognostication and is being incorporated in pediatric therapeutic trials. It has been established that genomic alterations leading to activation of the sonic hedgehog (SHH) pathway occur in approximately 60% of MB in patients over the age of 16 years. Within this cohort, protein patched homolog (PTCH) and smoothened (SMO) mutations are commonly found. Among patients whose tumors harbor the SHH molecular signature, it is estimated that over 80% of patients could respond to SHH pathway inhibitors. Given the advances in the understanding of molecular subgroups and the lack of robust clinical data for adult/AYA MB, the Alliance for Clinical Trial in Oncology group developed the AMBUSH trial: Comprehensive Management of AYA and Adult Patients with Medulloblastoma or Pineal Embryonal Tumors with a Randomized Placebo Controlled Phase II Focusing on Sonic Hedgehog Pathway Inhibition in SHH Subgroup Patients (Adult & Adolescent MedulloBlastoma Using Sonic Hedgehog Trial). This trial will enroll patients 18 years of age or older with MB (any molecular subgroup and risk stratification) or pineal embryonal tumor. Patients will be assigned to one of three cohorts: (1) average risk non-SHH-MB, (2) average risk SHH-MB, and (3) high risk MB or pineal embryonal tumors. All patients will receive protocol-directed comprehensive treatment with radiation therapy and chemotherapy. Patients with SHH-MB in cohort 1 will be randomized to a smoothened inhibitor or placebo as maintenance therapy for one year.


2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi133-vi134
Author(s):  
Julia Cluceru ◽  
Joanna Phillips ◽  
Annette Molinaro ◽  
Yannet Interian ◽  
Tracy Luks ◽  
...  

Abstract In contrast to the WHO 2016 guidelines that use genetic alterations to further stratify patients within a designated grade, new recommendations suggest that IDH mutation status, followed by 1p19q-codeletion, should be used before grade when differentiating gliomas. Although most gliomas will be resected and their tissue evaluated with genetic profiling, non-invasive characterization of genetic subgroup can benefit patients where surgery is not otherwise advised or a fast turn-around is required for clinical trial eligibility. Prior studies have demonstrated the utility of using anatomical images and deep learning to distinguish either IDH-mutant from IDH-wildtype tumors or 1p19q-codeleted from non-codeleted lesions separately, but not combined or using the most recent recommendations for stratification. The goal of this study was to evaluate the effects of training strategy and incorporation of Apparent Diffusion Coefficient (ADC) maps from diffusion-weighted imaging on predicting new genetic subgroups with deep learning. Using 414 patients with newly-diagnosed glioma (split 285/50/49 training/validation/test) and optimized training hyperparameters, we found that a 3-class approach with T1-post-contrast, T2-FLAIR, and ADC maps as inputs achieved the best performance for molecular subgroup classification, with overall accuracies of 86.0%[CI:0.839,1.0], 80.0%[CI:0.720,1.0], and 85.7%[CI:0.771,1.0] on training, validation, and test sets, respectively, and final test class accuracies of 95.2%(IDH-wildtype), 88.9%(IDH-mutated,1p19qintact), and 60%(IDHmutated,1p19q-codeleted). Creating an RGB-color image from 3 MRI images and applying transfer learning with a residual network architecture pretrained on ImageNet resulted in an 8% averaged increase in overall accuracy. Although classifying both IDH and 1p19q mutations together was overall advantageous compared with a tiered structure that first classified IDH mutational status, the 2-tiered approach better generalized to an independent multi-site dataset when only anatomical images were used. Including biologically relevant ADC images improved model generalization to our test set regardless of modeling approach, highlighting the utility of incorporating diffusion-weighted imaging in future multi-site analyses of molecular subgroup.


2021 ◽  
pp. 1758-1767
Author(s):  
Iris van 't Erve ◽  
Nina J. Wesdorp ◽  
Jamie E. Medina ◽  
Leonardo Ferreira ◽  
Alessandro Leal ◽  
...  

PURPOSE Somatic KRAS mutations occur in approximately half of the patients with metastatic colorectal cancer (mCRC). Biologic tumor characteristics differ on the basis of the KRAS mutation variant. KRAS mutations are known to influence patient prognosis and are used as predictive biomarker for treatment decisions. This study examined clinical features of patients with mCRC with a somatic mutation in KRAS G12, G13, Q61, K117, or A146. METHODS A total of 419 patients with colorectal cancer with initially unresectable liver-limited metastases, who participated in a multicenter prospective trial, were evaluated for tumor tissue KRAS mutation status. For the subgroup of patients who carried a KRAS mutation and were treated with bevacizumab and doublet or triplet chemotherapy (N = 156), pretreatment circulating tumor DNA levels were analyzed, and total tumor volume (TTV) was quantified on the pretreatment computed tomography images. RESULTS Most patients carried a KRAS G12 mutation (N = 112), followed by mutations in G13 (N = 15), A146 (N = 12), Q61 (N = 9), and K117 (N = 5). High plasma circulating tumor DNA levels were observed for patients carrying a KRAS A146 mutation versus those with a KRAS G12 mutation, with median mutant allele frequencies of 48% versus 19%, respectively. Radiologic TTV revealed this difference to be associated with a higher tumor load in patients harboring a KRAS A146 mutation (median TTV 672 cm3 [A146] v 74 cm3 [G12], P = .036). Moreover, KRAS A146 mutation carriers showed inferior overall survival compared with patients with mutations in KRAS G12 (median 10.7 v 26.4 months; hazard ratio = 2.5; P = .003). CONCLUSION Patients with mCRC with a KRAS A146 mutation represent a distinct molecular subgroup of patients with higher tumor burden and worse clinical outcomes, who might benefit from more intensive treatments. These results highlight the importance of testing colorectal cancer for all KRAS mutations in routine clinical care.


2021 ◽  
Vol 12 ◽  
Author(s):  
Trinh Nguyen ◽  
John W Pepper ◽  
Cu Nguyen ◽  
Yu Fan ◽  
Ying Hu ◽  
...  

Background: Acute myeloid leukemia (AML) is a clinically heterogeneous group of cancers. While some patients respond well to chemotherapy, we describe here a subgroup with distinct molecular features that has very poor prognosis under chemotherapy. The classification of AML relies substantially on cytogenetics, but most cytogenetic abnormalities do not offer targets for development of targeted therapeutics. Therefore, it is important to create a detailed molecular characterization of the subgroup most in need of new targeted therapeutics.Methods: We used a multi-omics approach to identify a molecular subgroup with the worst response to chemotherapy, and to identify promising drug targets specifically for this AML subgroup.Results: Multi-omics clustering analysis resulted in three primary clusters among 166 AML adult cancer cases in TCGA data. One of these clusters, which we label as the high-risk molecular subgroup (HRMS), consisted of cases that responded very poorly to standard chemotherapy, with only about 10% survival to 2 years. The gene TP53 was mutated in most cases in this subgroup but not in all of them. The top six genes over-expressed in the HRMS subgroup included E2F4, CD34, CD109, MN1, MMLT3, and CD200. Multi-omics pathway analysis using RNA and CNA expression data identified in the HRMS subgroup over-activated pathways related to immune function, cell proliferation, and DNA damage.Conclusion: A distinct subgroup of AML patients are not successfully treated with chemotherapy, and urgently need targeted therapeutics based on the molecular features of this subgroup. Potential drug targets include over-expressed genes E2F4, and MN1, as well as mutations in TP53, and several over-activated molecular pathways.


2021 ◽  
Author(s):  
Akhouayri Laila ◽  
Meriem Regragui ◽  
samira benayad ◽  
Nisrine Bennani Guebessi ◽  
Farida Marnissi ◽  
...  

BACKGROUND Breast carcinoma is one of the most common histological types of Breast Cancer, exploring a new approach that allows to do a quantitative description in order to characterize its heterogeneity and refine its classification is one of the main interests for pathologists. OBJECTIVE The purpose of our study is to explore further statistically significant subdivisions beyond breast cancer molecular classification that is routinely established in pathology departments. METHODS We conducted a 5-year retrospective study on 1266 invasive breast carcinomas of moroccan pa-tients, collected at the Pathology Department of Ibn-Rochd University Hospital in Casablanca, and followed at King MohammedVI National Centre for the Treatment of Cancers. We elaborated an Estimation-Maximization clustering, based on the main Breast cancer prognosis biomarkers: Ki-67, HER2, oestrogen and progesterone receptors, evaluated by Immunohistochemistry. RESULTS Each molecular subgroup could be partitioned into two further subdivisions: Cluster1, with average Ki-67 of 16.26%(±11.9) across all molecular subgroups and higher frequency within luminal sub-groups, and Cluster2, with average Ki-67 of 68.8%(±18) across all molecular subgroups; and higher frequency in HER2 as well as in triple negative subgroups. Overall Survival of the two clusters was significantly different, with 5-year rates of 52 and 37 months for Cluster1 and Cluster2, respectively (p=0.000001). Moreover, patient survival within the same molecular subgroup varied remarkably depending on cluster membership. Three independent datasets (Algerian, TCGA-BRCA and METABRIC) were also analysed to assess the reproducibility of this new “2-clusters partition” through several clustering methods and validation measures. Two different al-gorithms to evaluate the prognostic importance, VSURF and MinimalDepth, confirmed that this new subdivision is able to predict patient survival better than several histoprognostic features. CONCLUSIONS Our results highlight a new refinement of the breast cancer molecular classification and provide a simple and improved way to classify tumors that could be applied in low to medium income countries. This is the first study of its kind addressed in an African context.


2021 ◽  
Vol 104 (10) ◽  
pp. 1648-1657

Objective: To determine the correlation between clinical characteristics and molecular subgroups of medulloblastoma (MB) in Thai pediatric patients at the Queen Sirikit National Institute of Child Health (QSNICH), Thailand. Materials and Methods: MB specimens operated between 2004 and 2018 were classified by Nanostring into four molecular subgroups, including Wingless signaling pathway (WNT), Sonic Hedgehog signaling pathway (SHH), Group 3, and Group 4. For the present cases, the clinical records were retrospectively analyzed. Results: Twenty-two MB cases with complete clinical records were analyzed. Group 4 was the most common molecular subgroup (31.82%), followed by WNT (27.27%), SHH (22.73%), and Group 3 (18.18%). The histologic subtypes included 18, three, and one cases of classic MB, MB with extensive nodularity (MBEN), and large cell MB, respectively. All SHH MBs were found in infants. All MBENs belonged to SHH subgroup, and the large cell MB was Group 3. All six WNT MB cases did not experience tumor recurrence. Five-year cause specific survival rates were 100% in WNT, 60% in SHH, 57.1% in Group 4, and 0% in Group 3. Five-year recurrence-free survival rates were 100% in WNT, 42.9% in Group 4, and 0% in SHH and Group 3. Conclusion: MB is a heterogeneous disease. Classification of MB, especially at the molecular subtype, is helpful for the management and prognostication. Keywords: Medulloblastoma; Molecular subgroup


2021 ◽  
Author(s):  
Maura Massimino ◽  
Francesco Barretta ◽  
Piergiorgio Modena ◽  
Pascal Johann ◽  
Paolo Ferroli ◽  
...  

Abstract Background More than 40% of patients with intracranial ependymoma need a salvage treatment within 5 years after diagnosis, and no standard treatment is available as yet. We report the outcome after first relapse of 64 patients treated within the 2 nd AIEOP protocol. Methods We considered relapse sites and treatments ,i.e. various combinations of complete/incomplete surgery, if followed by standard or hypo-fractionated radiation(RT) ± chemotherapy(CT). Molecular analyses were available for 38/64 samples obtained at first diagnosis. Of the 64 cases, 55 were suitable for subsequent analyses. Results The median follow-up was 147 months after diagnosis, 84 after first relapse, 5-year EFS/OS were 26.2%/30.8% (median EFS/OS 13/32 months) after relapse. For patients with a local relapse(LR), the 5-year cumulative incidence of second LRs was 51.6%, with a 5-year event-specific probability of being LR-free of 40.0%. Tumor site/grade, need for shunting, age above/below 3 years, molecular subgroup at diagnosis, had no influence on outcomes. Due to variation in the RT dose/fractionation used and the subgroup sizes it was not possible to assess the impact of the different RT modalities. Multivariable analyses identified completion of surgery, absence of symptoms at relapse, and female sex as prognostically favorable. Tumors with a 1q gain carried a higher cumulative incidence of dissemination after first relapse. Conclusions Survival after recurrence was significantly influenced by symptoms and completeness of surgery. Only a homogeneous protocol with well posed, randomized questions could clarify the numerous issues, orient salvage treatment and ameliorate prognosis for this group of patients.


2021 ◽  
Vol 22 (18) ◽  
pp. 10105
Author(s):  
Thomas Cluzeau ◽  
Michael Loschi ◽  
Pierre Fenaux ◽  
Rami Komrokji ◽  
David A. Sallman

Targeting TP53 mutated myelodysplastic syndromes and acute myeloid leukemia remains a significant unmet need. Recently, new drugs have attempted to improve the outcomes of this poor molecular subgroup. The aim of this article is to review all the current knowledge using active agents including hypomethylating agents with venetoclax, eprenetapopt or magrolimab. We include comprehensive analysis of clinical trials to date evaluating these drugs in TP53 myeloid neoplasms as well as discuss future novel combinations for consideration. Additionally, further understanding of the unique clinicopathologic components of TP53 mutant myeloid neoplasms versus wild-type is critical to guide future study. Importantly, the clinical trajectory of patients is uniquely tied with the clonal burden of TP53, which enables serial TP53 variant allele frequency analysis to be a critical early biomarker in investigational studies. Together, significant optimism is now possible for improving outcomes in this patient population.


2021 ◽  
Author(s):  
Trinh Nguyen ◽  
John W Pepper ◽  
Cu Nguyen ◽  
Yu Fan ◽  
Ying Hu ◽  
...  

Abstract Background: Acute myeloid leukemia (AML) is a clinically heterogeneous group of diseases with poor outcomes that are partly due to its complex and poorly understood heterogeneity. Methods: Here, we use a multi-omics approach to identify a molecular subgroup with the worst response to chemotherapy, and to identify promising drug targets specifically for this AML subgroup. Results: Multi-omics clustering analysis using RNA and CNA expression data resulted in the three primary clusters of 166 AML adult TCGA cancer cases. One of these clusters, which we label as the high-risk molecular subgroup (HRMS), consisted of cases that responded very poorly to standard chemotherapy, with only about 10% survival to two years. The gene TP53 was mutated in most cases in the HRMS, but not in other cases. The top 6 genes over-expressed in the HRMS included E2F4, CD34, CD109, MN1, MMLT3, and CD200. Multi-omics pathway analysis using RNA and CNA expression data identified in the HRMS subgroup over-expressed pathways related to immune function, cell proliferation, and DNA damage. Conclusion: Some AML patients are not successfully treated with the current standard of care chemotherapy, and urgently need targeted therapeutics. Potential drug targets include over-expressed genes E2F4, and MN1, as well as mutations in TP53, and several molecular pathways.


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