Frontiers in Oncology

There is an entrenched belief among pathologists, biologists and clinicians alike that metastatic tumours are histologically similar to the primary. Although this belief has never been scientifically tested, it forms the conceptual foundation upon which metastasis research has been based for decades. In order to scientifically test this dogma, we conducted a blinded experiment in which three highly experienced professor grade cancer pathologists were asked to predict the site of origin of 298 metastatic tumours arising at nine different sites. The accuracy of prediction of all three examiners was just under 50%. However, there was very little inter-observer agreement, and Kappa statistic generated the value of 0.27 which is much below the figure of 0.4 required to detect even a moderate level of concordance. In only 56 / 298 (18.8%) cases did the examiners agree with each others diagnosis. Thus the possibility cannot be excluded that the correct diagnoses made by the examiners had happened by play of chance. Our finding suggests that histological relationship between primary and metastatic tumours requires further investigation.

Withdrawal statementThe authors have withdrawn their manuscript owing to because authors want to do further study about period2-mediated downregulation of ERK/MAPK phosphorylation in nasopharyngeal carcinoma. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.

Prostate cancer (PCa) continues to trend among top 3 cancers that kill men over 20 years in the United Kingdom and worldwide despite extensive research and resources directed towards its treatment and prevention. In the application of a hallmark of survival mechanisms by the cancer, our study used mRNA seq data to identify genes that are increasingly mutated with progressing PCa from a cohort of 491 PCa patients. We found that ENOX1, CCDC122 and LACC1 deep deletion was positively associated with increasing age of diagnosis. Pathway analysis of enriched genes, following their deep deletion identified estrogen biosynthesis, KSRP signalling, omega 3 and 6 fatty acid biosynthesis and, Rap1 signalling as the top 5 enriched pathways. Previous individual and combined role of these genes in PCa progression was not fully established but thanks to this study, these pathways could be druggable targets in PCa patients with these gene deep deletions.

BackgroundThis meta-analysis seeks to investigate the association between HPV and p16 status with overall survival in laryngeal and hypopharyngeal carcinoma. MethodsMedline, Scopus, EMBASE, and the Cochrane Library were used to identify studies for inclusion. Abstracts that discussed HPV/p16 status and prognosis in laryngeal or hypopharyngeal carcinoma were included. Next, full-text articles were screened and included based upon a checklist established a priori. Pooled hazard ratios for overall survival were generated using a random effects model. RevMan 5.3, Meta Essentials, and OpenMeta[Analyst] were used for statistical analysis. ResultsThirteen studies published between 2014 and 2019 with sample sizes ranging from 31 to 9,656 were selected for inclusion in this meta-analysis. The pooled data demonstrated that p16 status was not significantly associated with OS in either laryngeal or hypopharyngeal carcinoma with HRs of 1.03 (95% CI: 0.73-1.45; p = 0.88) and 1.02 (95% CI: 0.55-1.86; p = 0.96), respectively. The pooled data showed that HPV status was predictive of OS in laryngeal cancer with 0.63 (95% CI: 0.41-0.97; p = 0.03). ConclusionsOur results suggest that p16-positivity does not provide a survival benefit in LC and HPC. This is in contrast to studies in the oropharynx, where p16 status is a standard proxy for HPV infection and HPV infection is associated with improved prognosis.

BackgroundPharmacogenomics has emerged as a crucial tool in precision medicine, offering the potential to personalise cancer treatments by predicting and managing therapy-induced toxicities. This systematic review examined the genetic basis of toxicities associated with radiotherapy, chemotherapy, and immunotherapy in solid tumours. MethodsA comprehensive literature search was conducted across PubMed, Google Scholar, and PharmKB databases, covering the period from December 2019 to July 2024. This review focused on genetic variants linked to different treatment-related toxicities, including chemotherapy, radiotherapy, and immunotherapy, across various solid tumour types. ResultsThe review primarily assessed immune-related adverse events and dermatologic, haematologic, neurological, and organ-specific toxicities (e.g. ototoxicity, hepatotoxicity, nephrotoxicity, and cardiotoxicity). This review highlights single-nucleotide variants (SNVs) as essential genetic markers for identifying treatment-related toxicities. However, data on many SNVs remains limited, highlighting the need for further research and clinical validation. These findings suggest that the understanding of genetic factors that contribute to toxicity may support treatment decisions, optimise patient outcomes, and promote advances in the field of precision oncology. ConclussionThe identification of specific genetic variants could prevent the use of expensive and ineffective treatments and guide the selection of patients most likely to benefit from a specific therapy. Here, we provide valuable insights into the current state of knowledge regarding the genetic basis of toxicity in solid tumour treatments and emphasise the importance of integrating pharmacogenomics into personalised cancer care. To enhance patient outcomes and reduce the economic burden of cancer treatment, further research must validate these genetic markers and integrate the findings into clinical practice, thereby avoiding ineffective treatments for patients.

Invasion of high-grade glioma (HGG) cells through the brain and spinal cord is a leading cause of cancer death in children. Despite advances in treatment, survivors often suffer from lifelong adverse effects of the current toxic therapies used for management. This study investigated the influence of nutritional ketosis on the therapeutic action of mebendazole (MBZ) and devimistat (CPI-613) against the highly invasive VM-M3 and non-invasive CT-2A glioblastoma cells grown orthotopically in juvenile syngeneic mice. Additionally, both drugs were tested in the human pediatric GBM cell line SF-188. DON (6-Diazo-5-oxo-L-norleucine) was used as a positive drug control for glutamine targeting. Cerebral implantation of the VM-M3 cells, which are mesenchymal origin, invaded throughout the brain and the spinal column similar to that seen in children with HGG. Neither the CT-2A nor the VM-NM1 glioblastoma stem cell tumors showed distal invasion in syngeneic juvenile mouse brains. The maximum therapeutic benefit of MBZ and CPI-613 on tumor invasion, growth, and mouse survival occurred only when the drugs were administered together with a ketogenic diet (KD). MBZ treatment inhibited both the glutaminolysis and the glycolysis pathways in VM-M3 cells grown either in vivo or in vitro. Both MBZ and CPI-613 significantly reduced the in vitro growth and viability of the SF-188 cells. Moreover, drug administration together with the KD allowed for lower dosing thus minimizing toxicity while improving overall survival of the mice. This preclinical study in two different HGGs, grown in syngeneic juvenile mice, highlights the potential importance of diet/drug therapeutic strategies for managing childhood brain cancer.

The rare HOXB13 G84E variant is one of few established high-risk prostate cancer variants, yet the underlying molecular mechanisms by which it drives tumour development remain poorly understood. Prostate tumours from six G84E variant carriers and 18 non-carriers (wildtype) were examined using the Human AmpliSeq Transcriptome Gene Expression Panel and mass spectrometry. We identified a 799-gene expression profile and a 75-protein expression profile in G84E positive tumours when compared to wildtype tumours. Cluster analysis revealed that the top cluster consisted of 23 proteins which mapped to several lipogenesis pathways. Integration of the transcriptome and proteome data revealed overlapping differential expression of three genes (NCLN, NFIB and VASN), two of which have an established link to lipid metabolic pathways. Examination of publicly available transcriptome data from 493 TCGA primary PrCa tumours revealed 52 tumours with a similar pattern of differential expression of these three genes. We provide the first evidence from patient samples that the G84E variant is associated with upregulation of genes in the steroid metabolic, lipid biosynthesis and fatty acid metabolic pathways. We are also the first, to our knowledge, to use a proteogenomic approach to identify key molecular changes in prostate tumours from any high-risk rare variant carriers.

In recent years, research on the competing endogenous RNAs (ceRNAs) in cancer is in full swing. These investigations are discovering the importance of critical RNAs in cancer progression. Enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) is one of these RNAs that has been identified as a potential therapeutic target in many types of cancer. Up to now, many studies have been conducted to elucidate ceRNA role of EZH2 in cancer. Due to EZH2s dual role as an oncogene and tumor suppressor in cancer, a more thorough exploration of its ceRNA functions may enhance clinical approaches to cancer treatment. In the current scoping review, we searched online databases including PubMed, Web of Science, Scopus, Embase, Cochrane Library, and Google Scholar to identify experimentally-validated ceRNA axes including EZH2 in human cancers. We identified 62 unique axes consisting of 30 microRNAs (miRNAs), 31 long non-coding RNAs (lncRNAs), 9 messenger RNAs (mRNAs), and 14 circular RNAs (circRNAs). Notably, SPRY4-IT1 - miR-101-3p - EZH2 and XIST - miR-101-3p - EZH2 were recurrent axes observed in multiple cancer types. Among the most frequent miRNAs were miR-101-3p, miR-144-3p, and miR-124-3p, and ceRNAs including SPRY4-IT1, XIST, SNHG6, HOXA11-AS, MALAT1, and TUG1 emerged as frequent competitors of EZH2 for miRNA binding. This scoping review highlights the prevalence and diversity of EZH2-containing ceRNA axes in cancer, suggesting their potential as therapeutic targets. Future research should delve deeper into these axes to elucidate their functional significance and assess their clinical applicability.

BackgroundAllograft models enable characterisation of genomic drivers and treatment responses by modelling immune and micro-environmental changes more accurately than xenografts. Despite this, few models are available to the prostate cancer (PCa) community. This study presents a novel allograft model of high-risk, localised PCa. In characterising this model we have focused on its response to radiotherapy (RT). MethodsThe DVL3 cell line was derived from a transgenic trp53-/-/Pten-/- mouse model and characterised both in vitro and in vivo. The DVL3 cells were allografted and response to RT was investigated and compared to the TRAMP-C1 model. Extensive tumour profiling in the DVL3 model was performed using flow cytometry, immunohistochemistry and RNA-seq. ResultsIn vitro the DVL3 cells expressed basal and luminal markers. DVL3 cells formed tumours with distinct glandular morphology which expressed androgen receptor, similar to human localised PC. DVL3 tumour growth was delayed following administration of fractionated RT, with infiltration of myeloid derived suppressor cells (MDSC). ConclusionsThe DVL3 allograft model represents substantial progress in PCa modelling, displaying; luminal differentiation, strong AR expression, and an immunosuppressive microenvironment, similar to observations in high-risk PCa patients. This model is ideally suited for development and validation of novel therapeutics, in particular immune-modulatory agents in combination with RT.

PurposeInflammatory markers, such as Lymphocyte-to-Monocyte Ratio (LMR), Neutrophil-to-Lymphocyte Ratio (NLR), and Platelet-to-Lymphocyte Ratio (PLR), have been shown to hold significant prognostic value in the context of head and neck cancer (HNC). Recently, delta inflammatory markers, the difference between pre and post- treatment inflammatory marker ratios, have been suggested as potentially significant values in predicting cancer prognosis. Our objective was to evaluate the prognostic utility of delta LMR, NLR, and PLR in head and neck squamous cell carcinoma (HNSCC). MethodsRetrospective cohort study in a tertiary academic hospital setting. Patients diagnosed with HNSCC in the oral cavity, larynx, and oropharynx treated with curative intent treatment were included. The variables collected were age, sex, BMI, alcohol/tobacco exposure, performance scores, ACE-27, tumor characteristics, adjuvant treatment, ECOG score, and lab values. Overall Survival (OS) and Event-Free Survival (EFS) were chosen as endpoints. OS was defined as time from date of treatment to date of last follow-up or death from any cause, and EFS was defined as the start of treatment to any progression, recurrence, or death from any cause. Univariate and multivariate analyses were performed on the primary endpoints. ResultsA total of 89 patients were included from 2010 to 2017. In multivariate analysis, EFS was found to be significantly associated with an N stage of 3 (p=0.0005) and delta LMR > -1.48 (p=0.0241). No significant relationships were uncovered with OS in multivariate analysis. ConclusionA higher delta LMR value (>-1.48) was associated with poorer EFS, but was not associated with OS.

BackgroundWarthins tumor (WT) is the second most common parotid gland neoplasm with rising incidence. As some WT patients are not suitable for surgery, non-surgical treatment options are needed. This is the first study to evaluate the feasibility of ultrasound-guided bleomycin sclerotherapy (UGBS) for WT. Patients and methodsWT patients with concordant clinical, imaging, and cytology data were included. UGBS was proposed for patients who desired non-surgical intervention and fulfilled the inclusion criteria. Tumor volume and tumor-related symptoms were registered before UGBS and six months after. ResultsNine patients underwent UGBS between September 2021 and September 2022. In seven of the nine patients (78%), the tumor volume had diminished on average by 34% at six-month follow-up. Also, tumor-related pain, and cosmetic and functional discomfort decreased during the follow-up. One patient was later referred to partial parotidectomy. ConclusionUGBS could be an alternative non-surgical treatment for WT, especially for patients with risk factors for surgery.

Background/objectivePain is the most common acute toxicity following radiation therapy (RT) for head and neck cancer (HNC). The multifactorial origin of radiotherapy-induced pain makes it highly challenging to manage in HNC patients. Multiple studies have been conducted to identify different germline genetic variants associated with cancer pain, however few of them focused on RT-induced acute pain. In this systematic review, we summarize potential mechanisms of acute pain after radiotherapy in HNC focusing on oral cavity/oropharyngeal cancer and identify genetic variants associated with radiotherapy-induced acute pain and other relevant acute toxicities. MethodsA comprehensive search of Ovid Medline, EMBASE and Web of Science databases using concepts and terms including "Variants", "Polymorphisms", "Radiotherapy", "Acute pain", "Acute toxicity" published up to February 28, 2022 was performed by two reviewers. Review articles and citations were reviewed manually. The reported SNPs associated with RT-induced acute pain and toxicities were reported, and the molecular function of the associated genes and pathways were described based on genetic annotation using The Human Gene Database; GeneCards. ResultsA total of 386 articles were identified electronically and an additional 8 articles were included after manual search. 39 articles were finally included. 51 variants were associated with 40 genes, of which 30 % had function in DNA damage response and repair, 25% in inflammatory and immune response, 17.5 % in cell death or cell cycle, and were associated with RT-inflammatory pain and acute mucositis or dermatitis. 4 variants in 4 genes were associated with neuropathy and neuropathic pain. 13 variants in 10 genes and were associated with RT-induced mixed types of post-RT-pain. ConclusionDifferent types of pain develop after RT, including inflammatory pain (acute mucositis and acute skin reaction); neuropathic pain; nociceptive pain; and mixed oral pain. Genetic variants involved in DNA damage response and repair, cell death, inflammation and neuropathic pathways may affect pain presentation post-RT. These variants could be used for acute pain prediction and personalized pain management in HNC patients receiving RT.

Prostate cancer is the most commonly diagnosed cancer in men worldwide. Early diagnosis of the disease provides better treatment options for these patients. Magnetic resonance imaging (MRI) provides an overall assessment of prostate disease. Quantitative metrics (radiomics) from the MRI provide a better evaluation of the tumor and have been shown to improve disease detection. Recent studies have demonstrated that plasma extracellular vesicle microRNAs (miRNAs) are functionally linked to cancer progression, metastasis, and aggressiveness. In our study, we analyzed a matched cohort with baseline blood plasma and MRI to access tumor morphology using imaging-based radiomics and cellular characteristics using miRNAs-based transcriptomics. Our findings indicate that the univariate feature-based model with the highest Youdens index achieved average areas under the receiver operating characteristic curve (AUC) of 0.76, 0.82, and 0.84 for miRNA, MR-T2W, and MR-ADC features, respectively, in identifying clinically aggressive (Gleason grade) disease. The multivariable feature-based model demonstrated an average AUC of 0.88 and 0.95 using combinations of miRNA markers with imaging features in MR-ADC and MR-T2W, respectively. Our study demonstrates combining miRNA markers with MRI-based radiomics improves predictability of clinically aggressive prostate cancer.

BackgroundAdolescents and young adults with cancer (AYA) represent a distinct patient group with unique challenges. Most studies reporting outcomes use registry data, leaving local care aspects underreported. AimTo understand demographic and clinical characteristics of AYA patients focusing on variations by cancer type, sex, and age, as well as fertility preservation, palliative care, clinical trial participation, and survival outcomes. MethodsA retrospective single-centre study examined electronic medical records of AYA patients (age 15-39 years) treated for their initial diagnosis of cancer at University Hospital Bern (Inselspital) in the period 2015 -2021. Descriptive statistics summarized patient characteristics, and Kaplan-Meier survival curves and logistic regression were used for survival prediction. ResultsThe AYA cancer cohort consisted of 395 patients (67% male) with a median age of 27. Testicular cancer and Hodgkin lymphoma were the commonest diagnoses (24% and 25% respectively), followed by non-Hodgkin lymphoma (11%), leukaemia (11%), and central nervous system tumours (11%). The median time from diagnosis to first treatment was 13 days. Clinical trial participation was 29% and 58% attended fertility consultations with higher rates among males (61%) than females (50%). Five-year survival for the entire cohort was 84%; lower in older patients and those with metastatic disease. ConclusionThis study provides the first Swiss dataset on AYA cancer patients at a tertiary centre. While survival rates were high, disparities existed by diagnosis and metastatic status. Further research is needed to enhance survival in specific cancers and improve palliative and fertility care.

Hepatobiliary cancers (HBCs) are the most aggressive and sixth most diagnosed cancers globally. Biomarkers for timely diagnosis and targeted therapy in HBCs are still limited. Considering the gap, our objective is to identify unique and overlapping molecular signatures associated with HBCs. We analyzed publicly available transcriptomic datasets on Gallbladder cancer (GBC), Hepatocellular carcinoma (HCC), and Intrahepatic cholangiocarcinoma (ICC) to identify potential biomarkers using integrative systems approaches. An effective Common and Unique Molecular Signature Identification (CUMSI) approach has been developed, which contains analysis of differential gene expression (DEG), gene co-expression networks (GCN), and protein-protein interactions (PPIs) networks. Functional analysis of the DEGs unique for GBC, HCC, and ICC indicated that GBC is associated with cellular processes, HCC is associated with immune signaling pathways, and ICC is associated with lipid metabolic pathways. Our findings shows that the hub genes and pathways identified for each individual cancer type of the HBS are related with the primary function of each organ and each cancer exhibit unique expression patterns despite being part of the same organ system.

BackgroundPancreatic ductal adenocarcinoma (PDAC) is formidable in its advanced, metastatic stage. Aggressive spread of malignant cells from the pancreas to distant organs like the liver and lungs is often detected late, complicating treatment by markedly limiting therapeutic options and worsening prognosis by drastically diminishing survival. Understanding the molecular intricacies driving metastasis is crucial for developing targeted therapies for this deadly disease with otherwise narrow recourse. MethodWe obtained single-cell transcriptomes (GSE154778) from the website of the United States National Institutes of Health. The single-cell RNA profiles of 10 PDAC primary tumors and six metastatic lesions, dissociated from one another, were obtained using the 10x Genomics Chromium platform. Our analysis focused on identifying genes, pathways, and gene ontology terms with distinct expression patterns between metastatic and primary single cells. ResultsThrough single-cell RNA-sequencing (RNA-seq), we discerned significant alterations in gene expression profiles between primary tumors and metastatic lesions in PDAC, particularly emphasizing the dysregulation of ribosomal protein (RP) gene family as potential drivers of aggressive cancer behavior. Moreover, the enrichment of pathways related to metabolism, hypoxia response, and microbial influences underscores the intricate interplay between cellular adaptations and the tumor microenvironment in facilitating metastasis. Conversely, the downregulation of signaling pathways and extracellular matrix remodeling suggests a loss of regulatory control and enhanced invasive potential in metastatic cells. ConclusionsIn our comparison of primary and metastatic PDAC using single-cell RNA-seq, we have identified numerous differentially expressed genes, pathways, and gene ontology terms. The most significant finding may be that the ribosomal protein (RP) gene family is shared by 48 of the top 50 overexpressed pathways (comprising 5,848 genes), meaning that altering any member of this family as a potential driver could affect 48 pathways simultaneously. This revelation that metastatic cells may be regressed to a non-metastatic state by downregulating the RP gene family presents a promising pathway since this family is druggable.

Human papillomavirus-associated oropharyngeal squamous cell carcinomas (HPV+OPSCC) release circulating tumor HPV DNA (ctHPVDNA) into the blood which we, and others, have shown is an accurate real-time biomarker of disease status. In a prior prospective observational trial of 34 patients with AJCC 8 stage I-II HPV+OPSCC treated with surgery, we reported that ctHPVDNA was rapidly cleared within hours of surgery in patients who underwent complete cancer extirpation, yet remained elevated in those with macroscopic residual disease. The primary outcomes of this study were to assess 2-year OS and RFS between patients with and without molecular residual disease (MRD) following completion of treatment in this prospective cohort. MRD was defined as persistent elevation of ctHPVDNA at two consecutive time points, without clinical evidence of disease. The secondary outcomes were 2-year OS and RFS between patients with and without detectable MRD after surgery. We observed that patients with MRD after treatment completion were more likely to recur compared to patients without MRD, while there was no difference in recurrence rates between patients with MRD and without MRD on postoperative day 1. OS did not significantly differ between patients with MRD after surgery or treatment completion compared to patients without MRD; however, time to death was significantly different between the groups in both settings, suggesting that with a larger sample size OS would differ significantly between the groups or that the impact of MRD detection on survival is time dependent.

Up to now, the prognostic significance of latent membrane protein 1 (LMP1) in nasopharyngeal carcinoma (NPC) tissues still remains controversial. This study aims to investigate aberrant localization of LMP1 and its relationship with epithelial-mesenchymal transition (EMT) in NPC samples by immunohistochemistry and immunofluorescence. Both cytoplasmic and nuclear LMP1 expressions were observed in NPC tissues. In some tissues, nuclear LMP1 was frequently observed at tumor invasive front and tumor buddings. Nuclear LMP1 expression was significantly associated with lymph node metastasis (P=0.031), local recurrence (P=0.002), lymphatic invasion (P= 0.004) and tumor budding (P=0.001). Furthermore, nuclear LMP1 showed significant correlations with EMT markers including E-cadherin (P=0.037), Vimentin (P < 0.001), N-cadherin (P=0.003), Snail (P=0.003) and Twist (P=0.002), but not significantly linked with Fibronectin (P=0.103) and Slug (P=0.503). According to cytoplasmic LMP1, it correlated strongly with lymphatic invasion (P=0.044), vascular invasion (P=0.003) and EMT proteins including E-cadherin (P=0.014), Vimentin (P=0.006), N-cadherin (P=0.003), Snail (P=0.008) and Slug (P=0.007), whereas not significantly associated with Fibronectin (P=0.221) and Twist (P=0.106). However, multivariate analysis showed that nuclear LMP1 (P=0.844) and cytoplasmic LMP1 (P=0.291) were not independent predictors for NPC. In conclusion, we demonstrate firstly that abnormal localization of LMP1 correlates with EMT properties and aggressiveness in NPC, respectively.

Due to heterogeneity in presentation and outcome, patients with metastatic disease cannot be considered a single group. The timing, location and combinations of recurrences determine the feasibility of treatment of the individual patient in an era in which the options for local and systemic treatment have expanded. Studies investigating this complexity are hampered by the lack of both large cohorts and adequate methods. In a well-defined cohort of rectal cancer patients from a randomized clinical trial, with long standardized follow-up, we applied spatial projection models derived from population ecology to overcome the complexity problem. We describe the recurrence patterns in detail and performed stochastic simulation experiments resulting in 1.5 million evaluable patients. The risk of subsequent recurrences was dependent on the presentation of the first recurrent event and decreased with increasing recurrence-free interval. The risk of local recurrence for the median patient (65.8 years, pT3 adenocarcinoma) was threefold increased after the development of rare metastases. The risk of development of rare metastases was increased after the development of other extrahepatic metastases. Our cross-disciplinary approach delivers insights allowing for the development of personalized strategies for (local) treatment of recurrent disease, as well as for surveillance strategies that may potentially impact large patient cohorts. In this proofof-principle study we demonstrate the feasibility of spatial projection models for cancer research.

BackgroundThe standard initial treatment for locally advanced rectal cancer (LARC) is neoadjuvant chemoradiotherapy (nCRT). In order to select patients who would benefit the most from nCRT, there is a strong need for predictive biomarkers. The aim of this study was to evaluate the role of clinical, pathological, radiological, inflammation-related genetic, and hematological parameters in the prediction of response after nCRT. MethodsIn silico analysis of published transcriptomics datasets was conducted to identify the best candidate genes, whose expression will be measured using quantitative Real Time PCR (qRT-PCR) in pretreatment formaline-fixed paraffin-embedded (FFPE) samples. In this study, 75 patients with LARC, between June 2020 and January 2022, were prospectively included. Patients were assessed for tumor response in the 8th week after nCRT completion with pelvic MRI scan and rigid proctoscopy. For patients with a clinical complete response (cCR) and initially distant located tumor no immediate surgery was suggested ("watch and wait" approach). The response after surgery was assessed using histopathological tumor regression grading (TRG) categories from postoperative specimens by Mandard. Responders (R) were defined as patients with cCR without operative treatment, and those with TRG 1 and TRG 2 postoperative categories. Non-responders (NR) were patients classified as TRG 3-5. ResultsResponders group comprised 35 patients (46.6%) and NR group included 53.4% of patients. Analysis of published transcriptomics data identified genes that could predict response to treatment and their significance was assessed in our cohort by qRT-PCR. When comparison was made in the subgroup of patients who were operated (TRG1 vs. TRG4), the expression of IDO1 was significantly deregulated (p<0.05). Among hematological parameters between R and NR a significant difference in the response was detected for neutrophil-to-monocyte ratio (NMR), initial basophil, eosinophil and monocyte counts (p<0.01). According to MRI findings, non-responders were more often presented with extramural vascular invasion (p<0.05). ConclusionBased on logistic regression model, factors associated with favorable response to nCRT were found to be tumor morphology as well as hematological parameters which can be easily and routinely derived from initial laboratory results (NMR, eosinophil, basophil and monocyte counts) in a minimally invasive manner. Using various metrics, an aggregated score of the initial eosinophil, basophil, and monocyte counts demonstrated the best predictive performance.