Advanced metastatic cancer poses utmost clinical challenges and may present molecular and cellular features distinct from an early-stage cancer. Herein, we present single-cell transcriptome profiling ...of metastatic lung adenocarcinoma, the most prevalent histological lung cancer type diagnosed at stage IV in over 40% of all cases. From 208,506 cells populating the normal tissues or early to metastatic stage cancer in 44 patients, we identify a cancer cell subtype deviating from the normal differentiation trajectory and dominating the metastatic stage. In all stages, the stromal and immune cell dynamics reveal ontological and functional changes that create a pro-tumoral and immunosuppressive microenvironment. Normal resident myeloid cell populations are gradually replaced with monocyte-derived macrophages and dendritic cells, along with T-cell exhaustion. This extensive single-cell analysis enhances our understanding of molecular and cellular dynamics in metastatic lung cancer and reveals potential diagnostic and therapeutic targets in cancer-microenvironment interactions.
Objectives
To examine the correlation of diffusion-weighted and dynamic contrast-enhanced magnetic resonance imaging (MRI) parameters with Ki-67 labeling index (LI) in soft tissue sarcoma (STS).
...Methods
The institutional review board approved this retrospective study, and the requirement for informed consent was waived. Thirty-six patients with STS who underwent 3.0-T MRI, including diffusion-weighted and dynamic contrast-enhanced MRI, between July 2011 and February 2018, were included in this study. The mean and minimum apparent diffusion coefficients (ADCs) (ADC
mean
and ADC
min
, respectively), volume transfer constant, reflux rate, and volume fraction of the extravascular extracellular matrix of each lesion were independently analyzed by two readers. Their relationship with the Ki-67 LI was examined using Spearman’s correlation analyses. Differences between low- and high-proliferation groups based on Ki-67 LI were evaluated statistically. Optimal cut-off points were determined using the area under the curve analysis for significant parameters. Interobserver agreement was assessed with the intraclass correlation coefficient.
Results
ADC
mean
(
ρ
= − 0.333,
p
= 0.047) was significantly and inversely correlated with Ki-67 LI. The high-proliferation group showed a significantly lower ADC
mean
than did the low-proliferation group (median, 1.08 vs. 1.20;
p
= 0.048). When a cut-off ADC
mean
value of 1.16 × 10
−3
mm
2
/s was used, the sensitivity, specificity, and area under the curve for differentiating low- and high-proliferation groups were 75.0%, 60.0%, and 0.712, respectively. Interobserver agreements between the two readers were almost perfect for all parameters.
Conclusions
ADC
mean
was correlated with Ki-67 LI and could help differentiate between STS with low and high proliferation potential.
Key Points
• ADC
mean
was significantly and inversely correlated with Ki-67 labeling index in soft tissue sarcoma.
• In the high-proliferation group, ADC
mean
values were significantly lower than those of the low-proliferation group.
To elucidate the effects of neoadjuvant chemotherapy (NAC), we conduct whole transcriptome profiling coupled with histopathology analyses of a longitudinal breast cancer cohort of 146 patients ...including 110 pairs of serial tumor biopsies collected before treatment, after the first cycle of treatment and at the time of surgery. Here, we show that cytotoxic chemotherapies induce dynamic changes in the tumor immune microenvironment that vary by subtype and pathologic response. Just one cycle of treatment induces an immune stimulatory microenvironment harboring more tumor infiltrating lymphocytes (TILs) and up-regulation of inflammatory signatures predictive of response to anti-PD1 therapies while residual tumors are immune suppressed at end-of-treatment compared to the baseline. Increases in TILs and CD8+ T cell proportions in response to NAC are independently associated with pathologic complete response. Further, on-treatment immune response is more predictive of treatment outcome than immune features in paired baseline samples although these are strongly correlated.
Well‐differentiated liposarcoma (WDLPS) and dedifferentiated liposarcoma (DDLPS) are the most common types of liposarcoma. Although WDLPS and DDLPS patients receive intensive treatment including ...radical surgery and systemic therapy, their overall 5‐year survival rates are 90% and 30%, respectively, indicating that DDLPS is clinically more aggressive. We examined whether adipogenic stimulation induces adipogenesis in human WDLPS/DDLPS cells by using dexamethasone, indomethacin, insulin, and 3‐isobutyl‐1‐methylxanthine (IBMX), all putative medications or drugs. Functional in vitro experiments showed that treatment with these four compounds induced adipogenic potency by transcriptional and translational upregulation of genes related to the maintenance of stemness and adipogenic differentiation. Using in vivo xenograft models, we found that the induction of stemness and adipogenesis inhibited the tumorigenic potency of DDLPS. This study suggests a potential application of drug repositioning in which adipogenesis‐inducing compounds could be used to treat DDLPS patients in a clinical setting.
Induction of adipogenesis using four compounds used as medication or possible drug inhibited the tumor potency of DDLPS. Our finding suggests the potential application of drug repositioning in which adipogenic‐inducing compounds can be used to treat DDLPS patients in clinical therapy.
Breast cancer (BC) in the Asia Pacific regions is enriched in younger patients and rapidly rising in incidence yet its molecular bases remain poorly characterized. Here we analyze the whole exomes ...and transcriptomes of 187 primary tumors from a Korean BC cohort (SMC) enriched in pre-menopausal patients and perform systematic comparison with a primarily Caucasian and post-menopausal BC cohort (TCGA). SMC harbors higher proportions of HER2+ and Luminal B subtypes, lower proportion of Luminal A with decreased ESR1 expression compared to TCGA. We also observe increased mutation prevalence affecting BRCA1, BRCA2, and TP53 in SMC with an enrichment of a mutation signature linked to homologous recombination repair deficiency in TNBC. Finally, virtual microdissection and multivariate analyses reveal that Korean BC status is independently associated with increased TIL and decreased TGF-β signaling expression signatures, suggesting that younger Asian BCs harbor more immune-active microenvironment than western BCs.
CD24 is associated with unfavourable prognoses in various cancers, but the prevalence of CD24 expression and its influence on clinical outcome in subtypes of breast cancers remain unclear. CD24 ...expression was analyzed by immunohistochemistry in 747 breast cancer tissues, and DNA methylation and histone modification status in the promoter region of CD24 were assessed using bisulfite sequencing and chromatin immunoprecipitation assay. 213 (28.5%) samples exhibited high CD24 expression in the membrane and/or cytoplasm of breast cancer cells, and CD24 overexpression was significantly correlated with the presence of lymph node metastasis and more advanced pathological stage. Patients with CD24-high tumours had significantly shorter patient survival than those with CD24-low tumours. Importantly, multivariate analysis that included tumour size, lymph node metastasis and chemotherapy demonstrated that high CD24 expression is independently associated with poorer survival in luminal A and triple-negative breast cancer (TNBC) subtypes. Furthermore, CD24 gene expression was associated with histone acetylation independent of DNA methylation, suggesting its epigenetic regulation in breast cancer. Our results suggest that CD24 overexpression is an independent unfavourable prognostic factor in breast cancer, especially for luminal A and TNBC subtypes, and CD24 may be a promising therapeutic target for specific subtypes of breast cancer.
Biomarkers on the basis of tumor-infiltrating lymphocytes (TIL) are potentially valuable in predicting the effectiveness of immune checkpoint inhibitors (ICI). However, clinical application remains ...challenging because of methodologic limitations and laborious process involved in spatial analysis of TIL distribution in whole-slide images (WSI).
We have developed an artificial intelligence (AI)-powered WSI analyzer of TIL in the tumor microenvironment that can define three immune phenotypes (IPs): inflamed, immune-excluded, and immune-desert. These IPs were correlated with tumor response to ICI and survival in two independent cohorts of patients with advanced non-small-cell lung cancer (NSCLC).
Inflamed IP correlated with enrichment in local immune cytolytic activity, higher response rate, and prolonged progression-free survival compared with patients with immune-excluded or immune-desert phenotypes. At the WSI level, there was significant positive correlation between tumor proportion score (TPS) as determined by the AI model and control TPS analyzed by pathologists (
< .001). Overall, 44.0% of tumors were inflamed, 37.1% were immune-excluded, and 18.9% were immune-desert. Incidence of inflamed IP in patients with programmed death ligand-1 TPS at < 1%, 1%-49%, and ≥ 50% was 31.7%, 42.5%, and 56.8%, respectively. Median progression-free survival and overall survival were, respectively, 4.1 months and 24.8 months with inflamed IP, 2.2 months and 14.0 months with immune-excluded IP, and 2.4 months and 10.6 months with immune-desert IP.
The AI-powered spatial analysis of TIL correlated with tumor response and progression-free survival of ICI in advanced NSCLC. This is potentially a supplementary biomarker to TPS as determined by a pathologist.
Background
Because of the growing number of actionable biomarkers in non–small cell lung cancer (NSCLC), sufficient tissue availability for testing is becoming a greater challenge. Liquid biopsy ...offers a potential solution by complementing standard tissue‐based methods. In this study, the authors analyzed the concordance of actionable genomic alterations sequenced from circulating tumor DNA (ctDNA; Guardant360) and tissue (Oncomine Focus Assay).
Methods
From September 2015 to May 2018, 421 paired plasma and tissue samples from patients with advanced NSCLC who had previously undergone tissue testing by standard methods were collected. Both types of samples were available for 287 patients (262 in cohort 1 treatment‐naive and 25 in cohort 2 treatment failure), and only 1 sample type was available for 134 patients (50 in cohort 3 plasma only and 84 in cohort 4 tissue only).
Results
In cohort 1, 198 samples (77.6%) showed concordance between tissue and plasma next‐generation sequencing (NGS). Among the discordant cases, plasma testing detected additional genomic alterations in 11 patients (4.2%). In 50 patients without tissue‐based NGS results (cohort 3), the ctDNA‐based test detected genomic alterations in 20 samples (40.0%). The median allele frequency (AF) of mutations identified with ctDNA‐based NGS (0.74%) was lower than that identified with the tissue‐based NGS test (13.90%). Clinical responses to matched targeted therapy occurred, regardless of the ctDNA AF. Upfront ctDNA‐based testing identified 60.4% of patients with genomic alterations. In addition, ctDNA‐based testing uncovered 12.0% more actionable alterations when it was performed after tissue‐based NGS testing.
Conclusions
The results indicate that a ctDNA‐based test identifies additional patients with actionable genomic alterations and could, therefore, be used to complement traditional tissue‐based testing for NSCLC.
Lay Summary
Circulating tumor DNA (ctDNA)–based next‐generation sequencing (NGS) testing is becoming essential as the number of actionable genomic biomarker increases for the treatment selection of non–small cell lung cancer.
This study demonstrates the additive value of ctDNA‐based testing in addition to tissue‐based NGS and standard of care–based biomarker testing for detecting additional patients with actionable genomic alterations.
Clinical responses have also been observed in patients with a low allele frequency detected by ctDNA‐based NGS testing.
The results of this study support the benefit of circulating tumor DNA–based next‐generation sequencing (NGS) when it is used along with the tissue‐based standard of care and NGS to prevent undergenotyping in patients with non–small cell lung cancer at the time of the initial diagnosis and during later disease progression.
Purpose
To evaluate the role of positron emission tomography/computed tomography (PET/CT) in predicting pathologic complete response (pCR) and identify relevant prognostic factors from ...clinico-imaging-pathologic features of locally advanced esophageal squamous cell carcinoma (eSCC) patients undergoing trimodality therapy.
Methods
We evaluated 275 patients with eSCCs of T3-T4aN0M0 and T1-T4aN1-N3M0 who received trimodality therapy. We correlated volume-based PET/CT parameters before and after concurrent chemoradiation therapy with pCR after surgery, clinico-imaging-pathologic features, and patient survival.
Results
pCR occurred in 75 (27.3%) of 275 patients, of whom 61 (80.9%) showed 5-year survival. Pre-total lesion glycolysis (pre-TLG, OR = 0.318, 95% CI 0.169 to 0.600), post-metabolic tumor volume (post-MTV, OR = 0.572, 95% CI 0.327 to 0.999), and % decrease of average standardized uptake value (% SUVavg decrease, OR = 2.976, 95% CI = 1.608 to 5.507) were significant predictors for pCR. Among them, best predictor for pCR was pre-TLG with best cutoff value of 205.67 and with AUC value of 0.591.
Performance status (HR = 5.171, 95% CI 1.737 to 15.397), pathologic tumor size (HR = 1.645, 95% CI 1.351 to 2.002), pathologic N status (N1, HR = 1.572, 95% CI 1.010 to 2.446; N2, HR = 3.088, 95% CI 1.845 to 5.166), and post-metabolic tumor volume (HR = 1.506, 95% CI 1.033 to 2.195) were significant predictors of overall survival.
Conclusion
Pre-TLG, post-MTV, and % SUVavg decrease are predictive of pCR. Additionally, several clinico-imaging-pathologic factors are significant survival predictors in locally advanced eSCC patients undergoing trimodality therapy.
Breast cancer cell lines have been used widely to investigate breast cancer pathobiology and new therapies. Breast cancer is a molecularly heterogeneous disease, and it is important to understand how ...well and which cell lines best model that diversity. In particular, microarray studies have identified molecular subtypes-luminal A, luminal B, ERBB2-associated, basal-like and normal-like-with characteristic gene-expression patterns and underlying DNA copy number alterations (CNAs). Here, we studied a collection of breast cancer cell lines to catalog molecular profiles and to assess their relation to breast cancer subtypes.
Whole-genome DNA microarrays were used to profile gene expression and CNAs in a collection of 52 widely-used breast cancer cell lines, and comparisons were made to existing profiles of primary breast tumors. Hierarchical clustering was used to identify gene-expression subtypes, and Gene Set Enrichment Analysis (GSEA) to discover biological features of those subtypes. Genomic and transcriptional profiles were integrated to discover within high-amplitude CNAs candidate cancer genes with coordinately altered gene copy number and expression.
Transcriptional profiling of breast cancer cell lines identified one luminal and two basal-like (A and B) subtypes. Luminal lines displayed an estrogen receptor (ER) signature and resembled luminal-A/B tumors, basal-A lines were associated with ETS-pathway and BRCA1 signatures and resembled basal-like tumors, and basal-B lines displayed mesenchymal and stem/progenitor-cell characteristics. Compared to tumors, cell lines exhibited similar patterns of CNA, but an overall higher complexity of CNA (genetically simple luminal-A tumors were not represented), and only partial conservation of subtype-specific CNAs. We identified 80 high-level DNA amplifications and 13 multi-copy deletions, and the resident genes with concomitantly altered gene-expression, highlighting known and novel candidate breast cancer genes.
Overall, breast cancer cell lines were genetically more complex than tumors, but retained expression patterns with relevance to the luminal-basal subtype distinction. The compendium of molecular profiles defines cell lines suitable for investigations of subtype-specific pathobiology, cancer stem cell biology, biomarkers and therapies, and provides a resource for discovery of new breast cancer genes.
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