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1.
Ann Thorac Surg ; 2024 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-39424119

RESUMO

BACKGROUND: The contemporary management and resectability of locally advanced lung cancer are undergoing significant changes as new data emerge regarding immunotherapy and targeted treatments. The objective of this document is to review the literature and present consensus among a group of multidisciplinary experts to guide the determination of resectability and management of locally advanced non-small cell lung cancer (NSCLC) in the context of contemporary evidence. METHODS: The Society of Thoracic Surgeon Workforce on Thoracic Surgery assembled a multidisciplinary expert panel comprised of thoracic surgeons and medical and radiation oncologists with established expertise in the management of lung cancer. A focused literature review was performed, and expert consensus statements were developed using a modified Delphi process to address three major themes: (1) Assessing Resectability and Multidisciplinary Management of Locally Advanced Lung Cancer, (2) Neoadjuvant (including peri-operative) therapy, and (3) Adjuvant therapy. RESULTS: A consensus was reached on 19 recommendations. These consensus statements reflect updated insights on resectability and multidisciplinary management of locally advanced lung cancer based on the latest literature and current clinical experience, mainly focusing on the appropriateness of surgical therapy and emerging data regarding neoadjuvant and adjuvant therapies. CONCLUSIONS: Despite the complex decision-making process in managing locally advanced lung cancer, this expert panel agreed on several key recommendations. This document provides guidance for thoracic surgeons and other medical professionals in the optimal management of locally advanced lung cancer based on the most updated evidence and literature.

2.
J Clin Med ; 13(15)2024 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-39124563

RESUMO

Treatment guidelines for non-small cell lung cancer (NSCLC) vary by several factors including pathological stage, patient candidacy, and goal of treatment. With many therapeutics and even more combinations available in the NSCLC clinician's toolkit, a multitude of questions remain unanswered vis-a-vis treatment optimization. While some studies have begun exploring the interplay among the many pillars of NSCLC treatment-surgical resection, radiotherapy, chemotherapy, and immunotherapy-the vast number of combinations and permutations of different therapy modalities in addition to the modulation of each constituent therapy leaves much to be desired in a field that is otherwise rapidly evolving. Given NSCLC's high incidence and lethality, the experimentation of synergistic benefits that combinatorial treatment may confer presents a ripe target for advancement and increased understanding without the cost and burden of novel drug development. This review introduces, synthesizes, and compares prominent NSCLC therapies, placing emphasis on the interplay among types of therapies and the synergistic benefits some combinatorial therapies have demonstrated over the past several years.

3.
Adv Radiat Oncol ; 9(9): 101545, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39184143

RESUMO

Purpose: Head and neck lymphedema (HNL) following radiation therapy for head and neck cancer (HNC) causes patient morbidity. Predicting individual patients' risk of HNL after treatment is challenging. We aimed to identify the demographic, disease-related, and treatment-related factors associated with external and internal HNL following treatment of HNC with definitive or adjuvant radiation therapy. Methods and Materials: Relevant clinical, pathologic, and dosimetric data for 76 consecutive patients who received definitive or adjuvant radiation ± chemotherapy were retrospectively collected from a single institution. Multivariable models predictive of external and internal lymphedema using clinicopathologic variables alone and in combination with dosimetric variables were constructed and optimized using competing risk regression. Results: After median follow-up of 550 days, the incidence of external and internal HNL at 360 days was 70% and 34%, respectively. When evaluating clinical and treatment-related factors alone, number of lymph nodes removed and advanced adenopathy status were predictive of external lymphedema. With incorporation of dosimetric variables, the optimized model included the percentage volume of the contralateral lymph node level VII receiving 30Gy V30 ≥50%, number of lymph nodes removed, and advanced adenopathy status. For internal lymphedema, our clinicopathologic model identified both adjuvant radiation, as opposed to definitive radiation, and advanced adenopathy status. With inclusion of a dosimetric variable, the optimized model included larynx V45 ≥50% and advanced adenopathy. Conclusions: HNL following HNC treatment is common. For both external and internal lymphedema, nodal disease burden at diagnosis predicts increased risk. For external lymphedema, increasing extent of lymph node dissection prior to adjuvant therapy increases risk. The contralateral level VII lymph node region is also predictive of external lymphedema when radiation dose to V30 is ≥50%, meriting investigation. For internal lymphedema, we confirm that increasing radiation dose to the larynx is the most significant dosimetric predictor of mucosal edema when larynx V45 is ≥50%.

4.
JAMA Netw Open ; 7(4): e244630, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38564215

RESUMO

Importance: Artificial intelligence (AI) large language models (LLMs) demonstrate potential in simulating human-like dialogue. Their efficacy in accurate patient-clinician communication within radiation oncology has yet to be explored. Objective: To determine an LLM's quality of responses to radiation oncology patient care questions using both domain-specific expertise and domain-agnostic metrics. Design, Setting, and Participants: This cross-sectional study retrieved questions and answers from websites (accessed February 1 to March 20, 2023) affiliated with the National Cancer Institute and the Radiological Society of North America. These questions were used as queries for an AI LLM, ChatGPT version 3.5 (accessed February 20 to April 20, 2023), to prompt LLM-generated responses. Three radiation oncologists and 3 radiation physicists ranked the LLM-generated responses for relative factual correctness, relative completeness, and relative conciseness compared with online expert answers. Statistical analysis was performed from July to October 2023. Main Outcomes and Measures: The LLM's responses were ranked by experts using domain-specific metrics such as relative correctness, conciseness, completeness, and potential harm compared with online expert answers on a 5-point Likert scale. Domain-agnostic metrics encompassing cosine similarity scores, readability scores, word count, lexicon, and syllable counts were computed as independent quality checks for LLM-generated responses. Results: Of the 115 radiation oncology questions retrieved from 4 professional society websites, the LLM performed the same or better in 108 responses (94%) for relative correctness, 89 responses (77%) for completeness, and 105 responses (91%) for conciseness compared with expert answers. Only 2 LLM responses were ranked as having potential harm. The mean (SD) readability consensus score for expert answers was 10.63 (3.17) vs 13.64 (2.22) for LLM answers (P < .001), indicating 10th grade and college reading levels, respectively. The mean (SD) number of syllables was 327.35 (277.15) for expert vs 376.21 (107.89) for LLM answers (P = .07), the mean (SD) word count was 226.33 (191.92) for expert vs 246.26 (69.36) for LLM answers (P = .27), and the mean (SD) lexicon score was 200.15 (171.28) for expert vs 219.10 (61.59) for LLM answers (P = .24). Conclusions and Relevance: In this cross-sectional study, the LLM generated accurate, comprehensive, and concise responses with minimal risk of harm, using language similar to human experts but at a higher reading level. These findings suggest the LLM's potential, with some retraining, as a valuable resource for patient queries in radiation oncology and other medical fields.


Assuntos
Radioterapia (Especialidade) , Humanos , Inteligência Artificial , Estudos Transversais , Idioma , Assistência ao Paciente
5.
Clin Transl Radiat Oncol ; 46: 100747, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38450218

RESUMO

Background and purpose: The ability to determine the risk and predictors of lymphedema is vital in improving the quality of life for head and neck (HN) cancer patients. However, selecting robust features is challenging due to the multicollinearity and high dimensionality of radiotherapy (RT) data. This study aims to overcome these challenges using an ensemble feature selection technique with machine learning (ML). Materials and methods: Thirty organs-at-risk, including bilateral cervical lymph node levels, were contoured, and dose-volume data were extracted from 76 HN treatment plans. Clinicopathologic data was collected. Ensemble feature selection was used to reduce the number of features. Using the reduced features as input to ML and competing risk models, internal and external lymphedema prediction capability was evaluated with the ML models, and time to lymphedema event and risk stratification were estimated using the risk models. Results: Two ML models, XGBoost and random forest, exhibited robust prediction performance. They achieved average F1-scores and AUCs of 84 ± 3.3 % and 79 ± 11.9 % (external lymphedema), and 64 ± 12 % and 78 ± 7.9 % (internal lymphedema). Predictive ML and risk models identified common predictors, including bulky node involvement, high dose to various lymph node levels, and lymph nodes removed during surgery. At 180 days, removing 0-25, 26-50, and > 50 lymph nodes increased external lymphedema risk to 72.1 %, 95.6 %, and 57.7 % respectively (p = 0.01). Conclusion: Our approach, involving the reduction of HN RT data dimensionality, resulted in effective ML models for HN lymphedema prediction. Predictive dosimetric features emerged from both predictive and competing risk models. Consistency with clinicopathologic features from other studies supports our methodology.

6.
Radiother Oncol ; 182: 109571, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36822361

RESUMO

BACKGROUND AND PURPOSE: Radiation dose prescriptions are foundational for optimizing treatment efficacy and limiting treatment-related toxicity. We sought to assess the lack of standardization of SBRT dose prescriptions across institutions. MATERIALS & METHODS: Dosimetric data from 1298 patients from 9 academic institutions treated with IMRT and VMAT were collected. Dose parameters D100, D98, D95, D50, and D2 were used to assess dosimetric variability. RESULTS: Disease sites included lung (48.3 %) followed by liver (29.7 %), prostate (7.5 %), spine (6.8 %), brain (4.1 %), and pancreas (2.5 %). The PTV volume in lung varied widely with bimodality into two main groups (22.0-28.7 cm3) and (48.0-67.1 cm3). A hot spot ranging from 120-150 % was noted in nearly half of the patients, with significant variation across institutions. A D50 ≥ 110 % was found in nearly half of the institutions. There was significant dosimetric variation across institutions. CONCLUSIONS: The SBRT prescriptions in the literature or in treatment guidelines currently lack nuance and hence there is significant variation in dose prescriptions across academic institutions. These findings add greater importance to the identification of dose parameters associated with improved clinical outcome comparisons as we move towards more hypofractionated treatments. There is a need for standardized reporting to help institutions in adapting treatment protocols based on the outcome of clinical trials. Dosimetric parameters are subsequently needed for uniformity and thereby standardizing planning guidelines to maximize efficacy, mitigate toxicity, and reduce treatment disparities are urgently needed.


Assuntos
Radiocirurgia , Radioterapia de Intensidade Modulada , Masculino , Humanos , Radiocirurgia/métodos , Planejamento da Radioterapia Assistida por Computador/métodos , Radioterapia de Intensidade Modulada/métodos , Dosagem Radioterapêutica , Prescrições
7.
JCO Clin Cancer Inform ; 7: e2200100, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36652661

RESUMO

PURPOSE: We developed a deep neural network that queries the lung computed tomography-derived feature space to identify radiation sensitivity parameters that can predict treatment failures and hence guide the individualization of radiotherapy dose. In this article, we examine the transportability of this model across health systems. METHODS: This multicenter cohort-based registry included 1,120 patients with cancer in the lung treated with stereotactic body radiotherapy. Pretherapy lung computed tomography images from the internal study cohort (n = 849) were input into a multitask deep neural network to generate an image fingerprint score that predicts time to local failure. Deep learning (DL) scores were input into a regression model to derive iGray, an individualized radiation dose estimate that projects a treatment failure probability of < 5% at 24 months. We validated our findings in an external, holdout cohort (n = 271). RESULTS: There were substantive differences in the baseline patient characteristics of the two study populations, permitting an assessment of model transportability. In the external cohort, radiation treatments in patients with high DL scores failed at a significantly higher rate with 3-year cumulative incidences of local failure of 28.5% (95% CI, 19.8 to 37.8) versus 10.2% (95% CI, 5.9 to 16.2; hazard ratio, 3.3 [95% CI, 1.74 to 6.49]; P < .001). A model that included DL score alone predicted treatment failures with a concordance index of 0.68 (95% CI, 0.59 to 0.77), which had a similar performance to a nested model derived from within the internal cohort (0.70 [0.64 to 0.75]). External cohort patients with iGray values that exceeded the delivered doses had proportionately higher rates of local failure (P < .001). CONCLUSION: Our results support the development and implementation of new DL-guided treatment guidance tools in the image-replete and highly standardized discipline of radiation oncology.


Assuntos
Redes Neurais de Computação , Tomografia Computadorizada por Raios X , Humanos , Dosagem Radioterapêutica , Tomografia Computadorizada por Raios X/métodos , Falha de Tratamento , Modelos de Riscos Proporcionais
8.
Sci Adv ; 8(50): eabp8674, 2022 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-36516249

RESUMO

Studies to date have not resolved how diverse transcriptional programs contribute to the intratumoral heterogeneity of small cell lung carcinoma (SCLC), an aggressive tumor associated with a dismal prognosis. Here, we identify distinct and commutable transcriptional states that confer discrete functional attributes in individual SCLC tumors. We combine an integrative approach comprising the transcriptomes of 52,975 single cells, high-resolution measurement of cell state dynamics at the single-cell level, and functional and correlative studies using treatment naïve xenografts with associated clinical outcomes. We show that individual SCLC tumors contain distinctive proportions of stable cellular states that are governed by bidirectional cell state transitions. Using drugs that target the epigenome, we reconfigure tumor state composition in part by altering individual state transition rates. Our results reveal new insights into how single-cell transition behaviors promote cell state equilibrium in SCLC and suggest that facile plasticity underlies its resistance to therapy and lethality.


Assuntos
Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Humanos , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Pequenas Células do Pulmão/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Prognóstico
9.
Clin Cancer Res ; 28(24): 5343-5358, 2022 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-36222846

RESUMO

PURPOSE: Large-scale sequencing efforts have established that cancer-associated genetic alterations are highly diverse, posing a challenge to the identification of variants that regulate complex phenotypes like radiation sensitivity. The impact of the vast majority of rare or common genetic variants on the sensitivity of cancers to radiotherapy remains largely unknown. EXPERIMENTAL DESIGN: We developed a scalable gene editing and irradiation platform to assess the role of categories of variants in cells. Variants were prioritized on the basis of genotype-phenotype associations from a previously completed large-scale cancer cell line radiation profiling study. Altogether, 488 alleles (396 unique single-nucleotide variants) from 92 genes were generated and profiled in an immortalized lung cell line, BEAS-2B. We validated our results in other cell lines (TRT-HU1 and NCI-H520), in vivo via the use of both cell line and patient-derived murine xenografts, and in clinical cohorts. RESULTS: We show that resistance to radiation is characterized by substantial inter- and intra-gene allelic variation. Some genes (e.g., KEAP1) demonstrated significant intragenic allelic variation in the magnitude of conferred resistance and other genes (e.g., CTNNB1) displayed both resistance and sensitivity in a protein domain-dependent manner. We combined results from our platform with gene expression and metabolite features and identified the upregulation of amino acid transporters that facilitate oxidative reductive capacity and cell-cycle deregulation as key regulators of radiation sensitivity. CONCLUSIONS: Our results reveal new insights into the genetic determinants of tumor sensitivity to radiotherapy and nominate a multitude of cancer mutations that are predicted to impact treatment efficacy.


Assuntos
Fator 2 Relacionado a NF-E2 , Neoplasias , Humanos , Camundongos , Animais , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Fator 2 Relacionado a NF-E2/genética , Radiação Ionizante , Mutação , Tolerância a Radiação/genética , Neoplasias/genética , Neoplasias/radioterapia
11.
Med Phys ; 49(11): 7347-7356, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-35962958

RESUMO

INTRODUCTION: Deep learning (DL) models that use medical images to predict clinical outcomes are poised for clinical translation. For tumors that reside in organs that move, however, the impact of motion (i.e., degenerated object appearance or blur) on DL model accuracy remains unclear. We examine the impact of tumor motion on an image-based DL framework that predicts local failure risk after lung stereotactic body radiotherapy (SBRT). METHODS: We input pre-therapy free breathing (FB) computed tomography (CT) images from 849 patients treated with lung SBRT into a multitask deep neural network to generate an image fingerprint signature (or DL score) that predicts time-to-event local failure outcomes. The network includes a convolutional neural network encoder for extracting imaging features and building a task-specific fingerprint, a decoder for estimating handcrafted radiomic features, and a task-specific network for generating image signature for radiotherapy outcome prediction. The impact of tumor motion on the DL scores was then examined for a holdout set of 468 images from 39 patients comprising: (1) FB CT, (2) four-dimensional (4D) CT, and (3) maximum-intensity projection (MIP) images. Tumor motion was estimated using a 3D vector of the maximum distance traveled, and its association with DL score variance was assessed by linear regression. FINDINGS: The variance and amplitude in 4D CT image-derived DL scores were associated with tumor motion (R2  = 0.48 and 0.46, respectively). Specifically, DL score variance was deterministic and represented by sinusoidal undulations in phase with the respiratory cycle. DL scores, but not tumor volumes, peaked near end-exhalation. The mean of the scores derived from 4D CT images and the score obtained from FB CT images were highly associated (Pearson r = 0.99). MIP-derived DL scores were significantly higher than 4D- or FB-derived risk scores (p < 0.0001). INTERPRETATION: An image-based DL risk score derived from a series of 4D CT images varies in a deterministic, sinusoidal trajectory in a phase with the respiratory cycle. These results indicate that DL models of tumors in motion can be robust to fluctuations in object appearance due to movement and can guide standardization processes in the clinical translation of DL models for patients with lung cancer.


Assuntos
Aprendizado Profundo , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/radioterapia
12.
Neurosurgery ; 90(5): 506-514, 2022 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-35229827

RESUMO

BACKGROUND: Local management for vestibular schwannoma (VS) is associated with excellent local control with focus on preserving long-term serviceable hearing. Fractionated proton radiation therapy (FPRT) may be associated with greater hearing preservation because of unique dosimetric properties of proton radiotherapy. OBJECTIVE: To investigate hearing preservation rates of FPRT in adults with VS and secondarily assess local control and treatment-related toxicity. METHODS: A prospective, single-arm, phase 2 clinical trial was conducted of patients with VS from 2010 to 2019. All patients had serviceable hearing at baseline and received FPRT to a total dose of 50.4 to 54 Gy relative biological effectiveness (RBE) over 28 to 30 fractions. Serviceable hearing preservation was defined as a Gardner-Robertson score of 1 to 2, measured by a pure tone average (PTA) of ≤50 dB and a word recognition score (WRS) of ≥50%. RESULTS: Twenty patients had a median follow-up of 4.0 years (range 1.0-5.0 years). Local control at 4 years was 100%. Serviceable hearing preservation at 1 year was 53% (95% CI 29%-76%), and primary end point was not yet reached. Median PTA and median WRS both worsened 1 year after FPRT (P < .0001). WRS plateaued after 6 months, whereas PTA continued to worsen up to 1 year after FPRT. Median cochlea D90 was lower in patients with serviceable hearing at 1 year (40.6 Gy [RBE] vs 46.9 Gy [RBE]), trending toward Wilcoxon rank-sum test statistical significance (P = .0863). Treatment was well-tolerated, with one grade 1 cranial nerve V dysfunction and no grade 2+ cranial nerve dysfunction. CONCLUSION: FPRT for VS did not meet the goal of serviceable hearing preservation. Higher cochlea doses trended to worsening hearing preservation, suggesting that dose to cochlea correlates with hearing preservation independent of treatment modality.


Assuntos
Perda Auditiva , Neuroma Acústico , Radiocirurgia , Adulto , Seguimentos , Audição , Perda Auditiva/etiologia , Perda Auditiva/prevenção & controle , Humanos , Neuroma Acústico/cirurgia , Estudos Prospectivos , Prótons , Radiocirurgia/efeitos adversos , Estudos Retrospectivos , Resultado do Tratamento
13.
Cancers (Basel) ; 13(13)2021 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-34202748

RESUMO

Epidermal growth factor receptor-targeting tyrosine kinase inhibitors (EGFR TKIs) are the standard of care for patients with EGFR-mutated metastatic lung cancer. While EGFR TKIs have initially high response rates, inherent and acquired resistance constitute a major challenge to the longitudinal treatment. Ongoing work is aimed at understanding the molecular basis of these resistance mechanisms, with exciting new studies evaluating novel agents and combination therapies to improve control of tumors with all forms of EGFR mutation. In this review, we first provide a discussion of EGFR-mutated lung cancer and the efficacy of available EGFR TKIs in the clinical setting against both common and rare EGFR mutations. Second, we discuss common resistance mechanisms that lead to therapy failure during treatment with EGFR TKIs. Third, we review novel approaches aimed at improving outcomes and overcoming resistance to EGFR TKIs. Finally, we highlight recent breakthroughs in the use of EGFR TKIs in non-metastatic EGFR-mutated lung cancer.

15.
J Natl Cancer Inst ; 113(10): 1285-1298, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-33792717

RESUMO

Cellular senescence is an essential tumor suppressive mechanism that prevents the propagation of oncogenically activated, genetically unstable, and/or damaged cells. Induction of tumor cell senescence is also one of the underlying mechanisms by which cancer therapies exert antitumor activity. However, an increasing body of evidence from preclinical studies demonstrates that radiation and chemotherapy cause accumulation of senescent cells (SnCs) both in tumor and normal tissue. SnCs in tumors can, paradoxically, promote tumor relapse, metastasis, and resistance to therapy, in part, through expression of the senescence-associated secretory phenotype. In addition, SnCs in normal tissue can contribute to certain radiation- and chemotherapy-induced side effects. Because of its multiple roles, cellular senescence could serve as an important target in the fight against cancer. This commentary provides a summary of the discussion at the National Cancer Institute Workshop on Radiation, Senescence, and Cancer (August 10-11, 2020, National Cancer Institute, Bethesda, MD) regarding the current status of senescence research, heterogeneity of therapy-induced senescence, current status of senotherapeutics and molecular biomarkers, a concept of "one-two punch" cancer therapy (consisting of therapeutics to induce tumor cell senescence followed by selective clearance of SnCs), and its integration with personalized adaptive tumor therapy. It also identifies key knowledge gaps and outlines future directions in this emerging field to improve treatment outcomes for cancer patients.


Assuntos
Senescência Celular , Neoplasias , Biomarcadores , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Fenótipo Secretor Associado à Senescência
16.
Res Pract Thromb Haemost ; 4(1): 117-123, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31989093

RESUMO

BACKGROUND: The propensity to develop venous thromboembolism (VTE) on the basis of individual tumor biological features remains unknown. OBJECTIVES: We conducted a whole transcriptome RNA sequencing strategy, focusing on a single cancer type (lung cancer), to identify biomarkers of cancer-associated VTE. METHODS: Twelve propensity-matched patients, 6 each with or without VTE, were identified from a prospective institutional review board-approved registry at the Cleveland Clinic with available tissue from surgical excision of a primary lung mass between 2010 and 2015. Patients were propensity matched based on age, sex, race, history of prior cancer, date of cancer diagnosis, stage, histology, number of lines of chemotherapy, and length of follow-up. RNA sequencing was performed on tumor tissue, and gene set enrichment analysis (GSEA) was performed on differentially expressed genes. RESULTS: We identified 1037 genes with differential expression. In patients with VTE, 869 genes were overexpressed and 168 were underexpressed compared to patients without VTE. Of these, 276 overexpressed and 35 underexpressed were significantly different (Q < 0.05). GSEA revealed upregulation of genes in complement, inflammation, and KRAS signaling pathways in tumors from patients with VTE. CONCLUSIONS: These differentially expressed genes and associated pathways provide biologic insights into cancer-associated VTE and may provide insignts to develop new risk stratification schemes, prevention, or treatment strategies.

17.
Nat Commun ; 10(1): 5143, 2019 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-31723142

RESUMO

Molecular determinants governing the evolution of tumor subclones toward phylogenetic branches or fixation remain unknown. Using sequencing data, we model the propagation and selection of clones expressing distinct categories of BRAF mutations to estimate their evolutionary trajectories. We show that strongly activating BRAF mutations demonstrate hard sweep dynamics, whereas mutations with less pronounced activation of the BRAF signaling pathway confer soft sweeps or are subclonal. We use clonal reconstructions to estimate the strength of "driver" selection in individual tumors. Using tumors cells and human-derived murine xenografts, we show that tumor sweep dynamics can significantly affect responses to targeted inhibitors of BRAF/MEK or DNA damaging agents. Our study uncovers patterns of distinct BRAF clonal evolutionary dynamics and nominates therapeutic strategies based on the identity of the BRAF mutation and its clonal composition.


Assuntos
Evolução Clonal/genética , Neoplasias/genética , Proteínas Proto-Oncogênicas B-raf/genética , Adenocarcinoma de Pulmão/patologia , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Células Clonais , Dano ao DNA , Dosagem de Genes , Loci Gênicos , Humanos , Camundongos , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Mutação/genética , Fenótipo , Inibidores de Proteínas Quinases/farmacologia
18.
Cancer Res ; 79(24): 6227-6237, 2019 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-31558563

RESUMO

Radiotherapy is integral to the care of a majority of patients with cancer. Despite differences in tumor responses to radiation (radioresponse), dose prescriptions are not currently tailored to individual patients. Recent large-scale cancer cell line databases hold the promise of unravelling the complex molecular arrangements underlying cellular response to radiation, which is critical for novel predictive biomarker discovery. Here, we present RadioGx, a computational platform for integrative analyses of radioresponse using radiogenomic databases. We fit the dose-response data within RadioGx to the linear-quadratic model. The imputed survival across a range of dose levels (AUC) was a robust radioresponse indicator that correlated with biological processes known to underpin the cellular response to radiation. Using AUC as a metric for further investigations, we found that radiation sensitivity was significantly associated with disruptive mutations in genes related to nonhomologous end joining. Next, by simulating the effects of different oxygen levels, we identified putative genes that may influence radioresponse specifically under hypoxic conditions. Furthermore, using transcriptomic data, we found evidence for tissue-specific determinants of radioresponse, suggesting that tumor type could influence the validity of putative predictive biomarkers of radioresponse. Finally, integrating radioresponse with drug response data, we found that drug classes impacting the cytoskeleton, DNA replication, and mitosis display similar therapeutic effects to ionizing radiation on cancer cell lines. In summary, RadioGx provides a unique computational toolbox for hypothesis generation to advance preclinical research for radiation oncology and precision medicine. SIGNIFICANCE: The RadioGx computational platform enables integrative analyses of cellular response to radiation with drug responses and genome-wide molecular data. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/79/24/6227/F1.large.jpg.See related commentary by Spratt and Speers, p. 6076.


Assuntos
Biomarcadores Tumorais/genética , Biologia Computacional/métodos , Modelos Biológicos , Neoplasias/radioterapia , Tolerância a Radiação/genética , Linhagem Celular Tumoral , Reparo do DNA/efeitos da radiação , Bases de Dados Genéticas/estatística & dados numéricos , Conjuntos de Dados como Assunto , Relação Dose-Resposta à Radiação , Perfilação da Expressão Gênica , Humanos , Mutação , Neoplasias/genética , Neoplasias/mortalidade , Medicina de Precisão/métodos , Resultado do Tratamento
19.
Cancer Res ; 79(21): 5640-5651, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31387923

RESUMO

Targeted α-particle-emitting radionuclides have great potential for the treatment of a broad range of cancers at different stages of progression. A platform that accurately measures cancer cellular sensitivity to α-particle irradiation could guide and accelerate clinical translation. Here, we performed high-content profiling of cellular survival following exposure to α-particles emitted from radium-223 (223Ra) using 28 genetically diverse human tumor cell lines. Significant variation in cellular sensitivity across tumor cells was observed. 223Ra was significantly more potent than sparsely ionizing irradiation, with a median relative biological effectiveness of 10.4 (IQR: 8.4-14.3). Cells that are the most resistant to γ radiation, such as Nrf2 gain-of-function mutant cells, were sensitive to α-particles. Combining these profiling results with genetic features, we identified several somatic copy-number alterations, gene mutations, and the basal expression of gene sets that correlated with radiation survival. Activating mutations in PIK3CA, a frequent event in cancer, decreased sensitivity to 223Ra. The identification of cellular and genetic determinants of sensitivity to 223Ra may guide the clinical incorporation of targeted α-particle emitters in the treatment of several cancer types. SIGNIFICANCE: These findings address limitations in the preclinical guidance and prediction of radionuclide tumor sensitivity by identifying intrinsic cellular and genetic determinants of cancer cell survival following exposure to α-particle irradiation.See related commentary by Sgouros, p. 5479.


Assuntos
Partículas alfa , Compostos Radiofarmacêuticos , Sobrevivência Celular , Raios gama , Humanos , Radioisótopos
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