Development of a machine learning-based radiomics signature for estimating breast cancer TME phenotypes and predicting anti-PD-1/PD-L1 immunotherapy response.

Since breast cancer patients respond diversely to immunotherapy, there is an urgent need to explore novel biomarkers to precisely predict clinical responses and enhance therapeutic efficacy. The purpose of our present research was to construct and independently validate a biomarker of tumor microenvironment (TME) phenotypes via a machine learning-based radiomics way. The interrelationship between the biomarker, TME phenotypes and recipients' clinical response was also revealed. In this retrospective multi-cohort investigation, five separate cohorts of breast cancer patients were recruited to measure breast cancer TME phenotypes via a radiomics signature, which was constructed and validated by integrating RNA-seq data with DCE-MRI images for predicting immunotherapy response. Initially, we constructed TME phenotypes using RNA-seq of 1089 breast cancer patients in the TCGA database. Then, parallel DCE-MRI images and RNA-seq of 94 breast cancer patients obtained from TCIA were applied to develop a radiomics-based TME phenotypes signature using random forest in machine learning. The repeatability of the radiomics signature was then validated in an internal validation set. Two additional independent external validation sets were analyzed to reassess this signature. The Immune phenotype cohort (n = 158) was divided based on CD8 cell infiltration into immune-inflamed and immune-desert phenotypes; these data were utilized to examine the relationship between the immune phenotypes and this signature. Finally, we utilized an Immunotherapy-treated cohort with 77 cases who received anti-PD-1/PD-L1 treatment to evaluate the predictive efficiency of this signature in terms of clinical outcomes. The TME phenotypes of breast cancer were separated into two heterogeneous clusters: Cluster A, an "immune-inflamed" cluster, containing substantial innate and adaptive immune cell infiltration, and Cluster B, an "immune-desert" cluster, with modest TME cell infiltration. We constructed a radiomics signature for the TME phenotypes ([AUC] = 0.855; 95% CI 0.777-0.932; p < 0.05) and verified it in an internal validation set (0.844; 0.606-1; p < 0.05). In the known immune phenotypes cohort, the signature can identify either immune-inflamed or immune-desert tumor (0.814; 0.717-0.911; p < 0.05). In the Immunotherapy-treated cohort, patients with objective response had higher baseline radiomics scores than those with stable or progressing disease (p < 0.05); moreover, the radiomics signature achieved an AUC of 0.784 (0.643-0.926; p < 0.05) for predicting immunotherapy response. Our imaging biomarker, a practicable radiomics signature, is beneficial for predicting the TME phenotypes and clinical response in anti-PD-1/PD-L1-treated breast cancer patients. It is particularly effective in identifying the "immune-desert" phenotype and may aid in its transformation into an "immune-inflamed" phenotype.

Han X ，Guo Y ，Ye H ，Chen Z ，Hu Q ，Wei X ，Liu Z ，Liang C ... -  《-》

A radiomics approach to assess tumour-infiltrating CD8 cells and response to anti-PD-1 or anti-PD-L1 immunotherapy: an imaging biomarker, retrospective multicohort study.

Because responses of patients with cancer to immunotherapy can vary in success, innovative predictors of response to treatment are urgently needed to improve treatment outcomes. We aimed to develop and independently validate a radiomics-based biomarker of tumour-infiltrating CD8 cells in patients included in phase 1 trials of anti-programmed cell death protein (PD)-1 or anti-programmed cell death ligand 1 (PD-L1) monotherapy. We also aimed to evaluate the association between the biomarker, and tumour immune phenotype and clinical outcomes of these patients. In this retrospective multicohort study, we used four independent cohorts of patients with advanced solid tumours to develop and validate a radiomic signature predictive of immunotherapy response by combining contrast-enhanced CT images and RNA-seq genomic data from tumour biopsies to assess CD8 cell tumour infiltration. To develop the radiomic signature of CD8 cells, we used the CT images and RNA sequencing data of 135 patients with advanced solid malignant tumours who had been enrolled into the MOSCATO trial between May 1, 2012, and March 31, 2016, in France (training set). The genomic data, which are based on the CD8B gene, were used to estimate the abundance of CD8 cells in the samples and data were then aligned with the images to generate the radiomic signatures. The concordance of the radiomic signature (primary endpoint) was validated in a Cancer Genome Atlas [TGCA] database dataset including 119 patients who had available baseline preoperative imaging data and corresponding transcriptomic data on June 30, 2017. From 84 input variables used for the machine-learning method (78 radiomic features, five location variables, and one technical variable), a radiomics-based predictor of the CD8 cell expression signature was built by use of machine learning (elastic-net regularised regression method). Two other independent cohorts of patients with advanced solid tumours were used to evaluate this predictor. The immune phenotype internal cohort (n=100), were randomly selected from the Gustave Roussy Cancer Campus database of patient medical records based on previously described, extreme tumour-immune phenotypes: immune-inflamed (with dense CD8 cell infiltration) or immune-desert (with low CD8 cell infiltration), irrespective of treatment delivered; these data were used to analyse the correlation of the immune phenotype with this biomarker. Finally, the immunotherapy-treated dataset (n=137) of patients recruited from Dec 1, 2011, to Jan 31, 2014, at the Gustave Roussy Cancer Campus, who had been treated with anti-PD-1 and anti-PD-L1 monotherapy in phase 1 trials, was used to assess the predictive value of this biomarker in terms of clinical outcome. We developed a radiomic signature for CD8 cells that included eight variables, which was validated with the gene expression signature of CD8 cells in the TCGA dataset (area under the curve [AUC]=0·67; 95% CI 0·57-0·77; p=0·0019). In the cohort with assumed immune phenotypes, the signature was also able to discriminate inflamed tumours from immune-desert tumours (0·76; 0·66-0·86; p<0·0001). In patients treated with anti-PD-1 and PD-L1, a high baseline radiomic score (relative to the median) was associated with a higher proportion of patients who achieved an objective response at 3 months (vs those with progressive disease or stable disease; p=0·049) and a higher proportion of patients who had an objective response (vs those with progressive disease or stable disease; p=0·025) or stable disease (vs those with progressive disease; p=0·013) at 6 months. A high baseline radiomic score was also associated with improved overall survival in univariate (median overall survival 24·3 months in the high radiomic score group, 95% CI 18·63-42·1; vs 11·5 months in the low radiomic score group, 7·98-15·6; hazard ratio 0·58, 95% CI 0·39-0·87; p=0·0081) and multivariate analyses (0·52, 0·35-0·79; p=0·0022). The radiomic signature of CD8 cells was validated in three independent cohorts. This imaging predictor provided a promising way to predict the immune phenotype of tumours and to infer clinical outcomes for patients with cancer who had been treated with anti-PD-1 and PD-L1. Our imaging biomarker could be useful in estimating CD8 cell count and predicting clinical outcomes of patients treated with immunotherapy, when validated by further prospective randomised trials. Fondation pour la Recherche Médicale, and SIRIC-SOCRATE 2.0, French Society of Radiation Oncology.

Sun R ，Limkin EJ ，Vakalopoulou M ，Dercle L ，Champiat S ，Han SR ，Verlingue L ，Brandao D ，Lancia A ，Ammari S ，Hollebecque A ，Scoazec JY ，Marabelle A ，Massard C ，Soria JC ，Robert C ，Paragios N ，Deutsch E ，Ferté C ... -  《-》

Magnetic resonance imaging radiomics predicts preoperative axillary lymph node metastasis to support surgical decisions and is associated with tumor microenvironment in invasive breast cancer: A machine learning, multicenter study.

in current clinical practice, the standard evaluation for axillary lymph node (ALN) status in breast cancer has a low efficiency and is based on an invasive procedure that causes operative-associated complications in many patients. Therefore, we aimed to use machine learning techniques to develop an efficient preoperative magnetic resonance imaging (MRI) radiomics evaluation approach of ALN status and explore the association between radiomics and the tumor microenvironment in patients with early-stage invasive breast cancer. in this retrospective multicenter study, three independent cohorts of patients with breast cancer (n = 1,088) were used to develop and validate signatures predictive of ALN status. After applying the machine learning random forest algorithm to select the key preoperative MRI radiomic features, we used ALN and tumor radiomic features to develop the ALN-tumor radiomic signature for ALN status prediction by the support vector machine algorithm in 803 patients with breast cancer from Sun Yat-sen Memorial Hospital and Sun Yat-sen University Cancer Center (training cohort). By combining ALN and tumor radiomic features with corresponding clinicopathologic information, the multiomic signature was constructed in the training cohort. Next, the external validation cohort (n = 179) of patients from Shunde Hospital of Southern Medical University and Tungwah Hospital of Sun Yat-Sen University, and the prospective-retrospective validation cohort (n = 106) of patients treated with neoadjuvant chemotherapy in prospective phase 3 trials [NCT01503905], were included to evaluate the predictive value of the two signatures, and their predictive performance was assessed by the area under operating characteristic curve (AUC). This study was registered with ClinicalTrials.gov, number NCT04003558. the ALN-tumor radiomic signature for ALN status prediction comprising ALN and tumor radiomic features showed a high prediction quality with AUC of 0·88 in the training cohort, 0·87 in the external validation cohort, and 0·87 in the prospective-retrospective validation cohort. The multiomic signature incorporating tumor and lymph node MRI radiomics, clinical and pathologic characteristics, and molecular subtypes achieved better performance for ALN status prediction with AUCs of 0·90, 0·91, and 0·93 in the training cohort, the external validation cohort, and the prospective-retrospective validation cohort, respectively. Among patients who underwent neoadjuvant chemotherapy in the prospective-retrospective validation cohort, there were significant differences in the key radiomic features before and after neoadjuvant chemotherapy, especially in the gray-level dependence matrix features. Furthermore, there was an association between MRI radiomics and tumor microenvironment features including immune cells, long non-coding RNAs, and types of methylated sites. Interpretation this study presented a multiomic signature that could be preoperatively and conveniently used for identifying patients with ALN metastasis in early-stage invasive breast cancer. The multiomic signature exhibited powerful predictive ability and showed the prospect of extended application to tailor surgical management. Besides, significant changes in key radiomic features after neoadjuvant chemotherapy may be explained by changes in the tumor microenvironment, and the association between MRI radiomic features and tumor microenvironment features may reveal the potential biological underpinning of MRI radiomics. No funding.

Yu Y ，He Z ，Ouyang J ，Tan Y ，Chen Y ，Gu Y ，Mao L ，Ren W ，Wang J ，Lin L ，Wu Z ，Liu J ，Ou Q ，Hu Q ，Li A ，Chen K ，Li C ，Lu N ，Li X ，Su F ，Liu Q ，Xie C ，Yao H ... -  《EBioMedicine》

Exploration of a noninvasive radiomics classifier for breast cancer tumor microenvironment categorization and prognostic outcome prediction.

Breast cancer progression and treatment response are significantly influenced by the tumor microenvironment (TME). Traditional methods for assessing TME are invasive, posing a challenge for patient care. This study introduces a non-invasive approach to TME classification by integrating radiomics and machine learning, aiming to predict the TME status using imaging data, thereby aiding in prognostic outcome prediction. Utilizing multi-omics data from The Cancer Genome Atlas (TCGA) and The Cancer Imaging Archive (TCIA), this study employed CIBERSORT and MCP-counter algorithms analyze immune infiltration in breast cancer. A radiomics classifier was developed using a random forest algorithm, leveraging quantitative features extracted from intratumoral and peritumoral regions of Dynamic Contrast-Enhanced Magnetic Resonance Imaging (DCE-MRI) scans. The classifer's ability to predict diverse TME states were and their prognostic implications were evaluated using Kaplan-Meier survival curves. Three distinct TME states were identified using RNA-Seq data, each displaying unique prognostic and biological characteristics. Notably, patients with increased immune cell infiltration showed significantly improved prognoses (P < 0.05). The classifier, comprising 24 radiomic features, demonstrated high predictive accuracy (AUC of training set = 0.960, 95 % CI: 0.922, 0.997; AUC of testing set = 0.853, 95 % CI: 0.687, 1.000) in differentiating these TME states. Predictions from the classifier also correlated significantly with overall patient survival (P < 0.05). This study offers a detailed analysis of the complex TME states in breast cancer and presents a reliable, noninvasive radiomics classifier for TME assessment. The classifer's accurate prediction of TME status and its correlation with prognosis highlight its potential as a tool in personalized breast cancer treatment, paving the way for more individualized and less invasive therapeutic strategies.

Han X ，Gong Z ，Guo Y ，Tang W ，Wei X ... -  《-》

A Machine Learning Model Based on PET/CT Radiomics and Clinical Characteristics Predicts Tumor Immune Profiles in Non-Small Cell Lung Cancer: A Retrospective Multicohort Study.

The tumor immune microenvironment (TIME) phenotypes have been reported to mainly impact the efficacy of immunotherapy. Given the increasing use of immunotherapy in cancers, knowing an individual's TIME phenotypes could be helpful in screening patients who are more likely to respond to immunotherapy. Our study intended to establish, validate, and apply a machine learning model to predict TIME profiles in non-small cell lung cancer (NSCLC) by using 18F-FDG PET/CT radiomics and clinical characteristics. The RNA-seq data of 1145 NSCLC patients from The Cancer Genome Atlas (TCGA) cohort were analyzed. Then, 221 NSCLC patients from Daping Hospital (DPH) cohort received18F-FDG PET/CT scans before treatment and CD8 expression of the tumor samples were tested. The Artificial Intelligence Kit software was used to extract radiomic features of PET/CT images and develop a radiomics signature. The models were established by radiomics, clinical features, and radiomics-clinical combination, respectively, the performance of which was calculated by receiver operating curves (ROCs) and compared by DeLong test. Moreover, based on radiomics score (Rad-score) and clinical features, a nomogram was established. Finally, we applied the combined model to evaluate TIME phenotypes of NSCLC patients in The Cancer Imaging Archive (TCIA) cohort (n = 39). TCGA data showed CD8 expression could represent the TIME profiles in NSCLC. In DPH cohort, PET/CT radiomics model outperformed CT model (AUC: 0.907 vs. 0.861, P = 0.0314) to predict CD8 expression. Further, PET/CT radiomics-clinical combined model (AUC = 0.932) outperformed PET/CT radiomics model (AUC = 0.907, P = 0.0326) or clinical model (AUC = 0.868, P = 0.0036) to predict CD8 expression. In the TCIA cohort, the predicted CD8-high group had significantly higher immune scores and more activated immune pathways than the predicted CD8-low group (P = 0.0421). Our study indicates that 18F-FDG PET/CT radiomics-clinical combined model could be a clinically practical method to non-invasively detect the tumor immune status in NSCLCs.

Tong H ，Sun J ，Fang J ，Zhang M ，Liu H ，Xia R ，Zhou W ，Liu K ，Chen X ... -  《Frontiers in Immunology》