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Robust Intratumor Partitioning to Identify High-Risk Subregions in Lung Cancer: A Pilot Study.

ABSTRACT: To develop an intratumor partitioning framework for identifying high-risk subregions from (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) and computed tomography (CT) imaging and to test whether tumor burden associated with the high-risk subregions is prognostic of outcomes in lung cancer.In this institutional review board-approved retrospective study, we analyzed the pretreatment FDG-PET and CT scans of 44 lung cancer patients treated with radiation therapy. A novel, intratumor partitioning method was developed, based on a 2-stage clustering process: first at the patient level, each tumor was over-segmented into many superpixels by k-means clustering of integrated PET and CT images; next, tumor subregions were identified by merging previously defined superpixels via population-level hierarchical clustering. The volume associated with each of the subregions was evaluated using Kaplan-Meier analysis regarding its prognostic capability in predicting overall survival (OS) and out-of-field progression (OFP).Three spatially distinct subregions were identified within each tumor that were highly robust to uncertainty in PET/CT co-registration. Among these, the volume of the most metabolically active and metabolically heterogeneous solid component of the tumor was predictive of OS and OFP on the entire cohort, with a concordance index or CI of 0.66-0.67. When restricting the analysis to patients with stage III disease (n=32), the same subregion achieved an even higher CI of 0.75 (hazard ratio 3.93, log-rank P=.002) for predicting OS, and a CI of 0.76 (hazard ratio 4.84, log-rank P=.002) for predicting OFP. In comparison, conventional imaging markers, including tumor volume, maximum standardized uptake value, and metabolic tumor volume using threshold of 50% standardized uptake value maximum, were not predictive of OS or OFP, with CI mostly below 0.60 (log-rank P>.05).We propose a robust intratumor partitioning method to identify clinically relevant, high-risk subregions in lung cancer. We envision that this approach will be applicable to identifying useful imaging biomarkers in many cancer types.

SUBMITTER: Wu J

PROVIDER: S-EPMC4969127 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Robust Intratumor Partitioning to Identify High-Risk Subregions in Lung Cancer: A Pilot Study.

Wu Jia J Gensheimer Michael F MF Dong Xinzhe X Rubin Daniel L DL Napel Sandy S Diehn Maximilian M Loo Billy W BW Li Ruijiang R

International journal of radiation oncology, biology, physics 20160324 5

<h4>Purpose</h4>To develop an intratumor partitioning framework for identifying high-risk subregions from (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) and computed tomography (CT) imaging and to test whether tumor burden associated with the high-risk subregions is prognostic of outcomes in lung cancer.<h4>Methods and materials</h4>In this institutional review board-approved retrospective study, we analyzed the pretreatment FDG-PET and CT scans of 44 lung cancer patients treate ...[more]

PMID: 27212196

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Project description:Purpose The substratification of high-risk neuroblastoma is challenging, and new predictive imaging biomarkers are warranted for better patient selection. The aim of the study was to evaluate the prognostic role of PET-based intratumor heterogeneity and its potential ability to improve risk stratification in neuroblastoma. Methods Pretreatment 18F-FDG PET/CT scans from 112 consecutive children with newly diagnosed neuroblastoma were retrospectively analyzed. The primary tumor was segmented in the PET images. SUVs, volumetric parameters including metabolic tumor volume (MTV) and total lesion glycolysis (TLG), and texture features were extracted. After the exclusion of imaging features with poor and moderate reproducibility, the relationships between the imaging indices and clinicopathological factors, as well as event-free survival (EFS), were assessed. Results The median follow-up duration was 33 months. Multivariate analysis showed that PET-based intratumor heterogeneity outperformed clinicopathological features, including age, stage, and MYCN, and remained the most robust independent predictor for EFS [training set, hazard ratio (HR): 6.4, 95% CI: 3.1–13.2, p < 0.001; test set, HR: 5.0, 95% CI: 1.8–13.6, p = 0.002]. Within the clinical high-risk group, patients with a high metabolic heterogeneity showed significantly poorer outcomes (HR: 3.3, 95% CI: 1.6–6.8, p = 0.002 in the training set; HR: 4.4, 95% CI: 1.5–12.9, p = 0.008 in the test set) compared to those with relatively homogeneous tumors. Furthermore, intratumor heterogeneity outran the volumetric indices (MTVs and TLGs) and yielded the best performance of distinguishing high-risk patients with different outcomes with a 3-year EFS of 6% vs. 47% (p = 0.001) in the training set and 9% vs. 51% (p = 0.004) in the test set. Conclusion PET-based intratumor heterogeneity was a strong independent prognostic factor in neuroblastoma. In the clinical high-risk group, intratumor heterogeneity further stratified patients with distinct outcomes.

Project description:The notion of personalized medicine demands proper prognostic biomarkers to guide the optimal therapy for an invasive breast cancer patient. However, various risk prediction models based on conventional clinicopathological factors and emergent molecular assays have been frequently limited by either a low strength of prognosis or restricted applicability to specific types of patients. Therefore, there is a critical need to develop a strong and general prognosticator. Methods: We observed five large-scale tumor-associated collagen signatures (TACS4-8) obtained by multiphoton microscopy at the invasion front of the breast primary tumor, which contrasted with the three tumor-associated collagen signatures (TACS1-3) discovered by Keely and coworkers at a smaller scale. Highly concordant TACS1-8 classifications were obtained by three independent observers. Using the ridge regression analysis, we obtained a TACS-score for each patient based on the combined TACS1-8 and established a risk prediction model based on the TACS-score. In a blind fashion, consistent retrospective prognosis was obtained from 995 breast cancer patients in both a training cohort (n= 431) and an internal validation cohort (n = 300) collected from one clinical center, and in an external validation cohort (n = 264) collected from a different clinical center. Results: TACS1-8 model alone competed favorably with all reported models in predicting disease-free survival (AUC: 0.838, [0.800-0.872]; 0.827, [0.779-0.868]; 0.807, [0.754-0.853] in the three cohorts) and stratifying low- and high-risk patients (HR 7.032, [4.869-10.158]; 6.846, [4.370-10.726], 4.423, [2.917-6.708]). The combination of these factors with the TACS-score into a nomogram model further improved the prognosis (AUC: 0.865, [0.829-0.896]; 0.861, [0.816-0.898]; 0.854, [0.805-0.894]; HR 7.882, [5.487-11.323]; 9.176, [5.683-14.816], and 5.548, [3.705-8.307]). The nomogram identified 72 of 357 (~20%) patients with unsuccessful 5-year disease-free survival that might have been undertreated postoperatively. Conclusions: The risk prediction model based on TACS1-8 considerably outperforms the contextual clinical model and may thus convince pathologists to pursue a TACS-based breast cancer prognosis. Our methodology identifies a significant portion of patients susceptible to undertreatment (high-risk patients), in contrast to the multigene assays that often strive to mitigate overtreatment. The compatibility of our methodology with standard histology using traditional (non-tissue-microarray) formalin-fixed paraffin-embedded (FFPE) tissue sections could simplify subsequent clinical translation.

Dataset Information

Robust Intratumor Partitioning to Identify High-Risk Subregions in Lung Cancer: A Pilot Study.

Publications

Robust Intratumor Partitioning to Identify High-Risk Subregions in Lung Cancer: A Pilot Study.

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