[Treatment of localized rectal cancer in 2024]. / Prise en charge du cancer du rectum localisé en 2024.

The management of localized rectal cancer has evolved significantly over the last two years. On one hand, intensification of treatments (radio-chemotherapy, chemotherapy, then surgery) for the most advanced tumors has shown an improvement in clinical results compared to less intense regiments. On the other hand, the possibility, as for prostate cancers, of opting for active surveillance without surgery in patients presenting a complete clinical response after a treatment phase, is now accepted. More recently, the Swiss recommendations for the surveillance of rectal cancer have been modified and now differ from those of colon cancers, by incorporating pelvic MRI and rectoscopy in addition, as well as special guidelines for tumors under active surveillance.

La prise en charge du cancer du rectum localisé a beaucoup évolué ces deux dernières années. D'un côté, l'intensification des traitements (radio-chimiothérapie, chimiothérapie, puis chirurgie) pour les tumeurs les plus avancées a montré une amélioration des résultats cliniques par rapport aux traitements moins intenses. De l'autre côté, la possibilité, comme pour les cancers de la prostate, d'opter pour une surveillance active sans chirurgie chez les patients présentant une réponse clinique complète après une phase de traitement est aujourd'hui acceptée. Plus récemment, les recommandations suisses pour la surveillance du cancer du rectum ont été modifiées et se différencient maintenant de celles des cancers du côlon, en incorporant IRM pelvienne et rectoscopie en sus, de même qu'un suivi spécial pour les tumeurs en surveillance active.

Study protocol of a phase II study to evaluate safety and efficacy of neo-adjuvant pembrolizumab and radiotherapy in localized rectal cancer.

BACKGROUND: Reshaping the tumor microenvironment by novel immunotherapies represents a key strategy to improve cancer treatment. Nevertheless, responsiveness to these treatments is often correlated with the extent of T cell infiltration at the tumor site. Remarkably, microsatellite stable rectal cancer is characterized by poor T cell infiltration and, therefore, does not respond to immune checkpoint blockade. To date, the only available curative option for these patients relies on extensive surgery. With the aim to broaden the application of promising immunotherapies, it is necessary to develop alternative approaches to promote T cell infiltration into the tumor microenvironment of these tumors. In this regard, recent evidence shows that radiotherapy has profound immunostimulatory effects, hinting at the possibility of combining it with immunotherapy. The combination of long-course chemoradiotherapy and immune checkpoint inhibition was recently shown to be safe and yielded promising results in rectal cancer, however short-course radiotherapy and immune checkpoint inhibition have never been tested in these tumors. METHODS: Our clinical trial investigates the clinical and biological impact of combining pembrolizumab with short-course radiotherapy in the neo-adjuvant treatment of localized rectal cancer. This phase II non-randomized study will recruit 25 patients who will receive short-course preoperative radiotherapy (5 Gy × 5 days) and four injections of pembrolizumab starting on the same day and on weeks 4, 7 and 10. Radical surgery will be performed three weeks after the last pembrolizumab injection. Our clinical trial includes an extensive translational research program involving the transcriptomic and proteomic analysis of tumor and blood samples throughout the course of the treatment. DISCUSSION: Our study is the first clinical trial to combine short-course radiotherapy and immune checkpoint inhibition in rectal cancer, which could potentially result in a major breakthrough in the treatment of this cancer. Additionally, the translational research program will offer insights into immunological changes within the tumor and blood and their correlation with patient outcome. Taken together, our work will help optimizing future treatment combinations and, possibly, better selecting patients. TRIAL REGISTRATION: This study was registered with www. CLINICALTRIAL: gov : NCT04109755 . Registration date: June, 2020.

A brief history of organoids.

In vitro cell cultures are crucial research tools for modeling human development and diseases. Although the conventional monolayer cell cultures have been widely used in the past, the lack of tissue architecture and complexity of such model fails to inform the true biological processes in vivo. Recent advances in the organoid technology have revolutionized the in vitro culture tools for biomedical research by creating powerful three-dimensional (3D) models to recapitulate the cellular heterogeneity, structure, and functions of the primary tissues. Such organoid technology enables researchers to recreate human organs and diseases in a dish and thus holds great promises for many translational applications such as regenerative medicine, drug discovery, and precision medicine. In this review, we provide an overview of the organoid history and development. We discuss the strengths and limitations of organoids as well as their potential applications in the laboratory and the clinic.

IL-8 and CXCR1 expression is associated with cancer stem cell-like properties of clear cell renal cancer.

Recent studies suggest that clear cell renal cell carcinoma (ccRCC) possesses a rare population of cancer stem cells (CSCs) that might contribute to tumor heterogeneity, metastasis and therapeutic resistance. Nevertheless, their relevance for renal cancer is still unclear. In this study, we successfully isolated CSCs from established human ccRCC cell lines. CSCs displayed high expression of the chemokine IL-8 and its receptor CXCR1. While recombinant IL-8 significantly increased CSC number and properties in vitro, CXCR1 inhibition using an anti-CXCR1 antibody or repertaxin significantly reduced these features. After injection into immune-deficient mice, CSCs formed primary tumors that metastasized to the lung and liver. All xenografted tumors in mice expressed high levels of IL-8 and CXCR1. Furthermore, IL-8/CXCR1 expression significantly correlated with decreased overall survival in ccRCC patients. These results suggest that the IL-8/CXCR1 phenotype is associated with CSC-like properties in renal cancer. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Detecting circulating tumor DNA in renal cancer: An open challenge.

BACKGROUND: Detection of circulating tumor DNA (ctDNA) in blood of cancer patients is regarded as an important step towards personalized medicine and treatment monitoring. In the present study, we investigated the clinical applicability of ctDNA as liquid biopsy in renal cancer. METHODS: ctDNA in serum and plasma samples derived from ccRCC and colon cancer patients as well as ctDNA isolated from RCC xenografts with known VHL mutation status was investigated using next generation sequencing (NGS). Additionally, a Taqman mutation specific assay was used for specific VHL mutation detection in blood. RESULTS: In our study, we successfully identified KRAS mutation in colon cancer patients. We also confirmed the presence of specific VHL mutations in ctDNA derived from RCC xenografts indicating the capability of renal tumors to release DNA into the blood circulation. However, we could not detect any VHL mutation in plasma or serum samples derived from nine ccRCC patients. To increase the sensitivity, a VHL mutation specific Taqman assay was tested. With this approach, the pVHL mutation p.Val130Leu in exon 2 in one patient was successfully detected. CONCLUSION: These data suggest a reduced tumor DNA shedding and an increased clearance of the tumor DNA from the circulation in renal cancer patients independently of tumor size, metastases, and necrosis. This implies that highly sensitive detection methods for mutation calling and prior knowledge of the mutation are required for liquid biopsies in ccRCC.

Promises and Challenges of Predictive Blood Biomarkers for Locally Advanced Rectal Cancer Treated with Neoadjuvant Chemoradiotherapy.

The treatment of locally advanced rectal cancer (LARC) requires a multimodal approach combining neoadjuvant radiotherapy or chemoradiotherapy (CRT) and surgery. Predicting tumor response to CRT can guide clinical decision making and improve patient care while avoiding unnecessary toxicity and morbidity. Circulating biomarkers offer both the advantage to be easily accessed and followed over time. In recent years, biomarkers such as proteins, blood cells, or nucleic acids have been investigated for their predictive value in oncology. We conducted a comprehensive literature review with the aim to summarize the status of circulating biomarkers predicting response to CRT in LARC. Forty-nine publications, of which forty-seven full-text articles, one review and one systematic review, were retrieved. These studies evaluated circulating markers (CEA and CA 19-9), inflammatory biomarkers (CRP, albumin, and lymphocytes), hematologic markers (hemoglobin and thrombocytes), lipids and circulating nucleic acids (cell-free DNA [cfDNA], circulating tumor DNA [ctDNA], and microRNA [miRNA]). Post-CRT CEA levels had the most consistent association with tumor response, while cfDNA integrity index, MGMT promoter methylation, ERCC-1, miRNAs, and miRNA-related SNPs were identified as potential predictive markers. Although circulating biomarkers hold great promise, inconsistent results, low statistical power, and low specificity and sensibility prevent them from reliably predicting tumor response following CRT. Validation and standardization of methods and technologies are further required to confirm results.

The first comprehensive genomic characterization of rectal squamous cell carcinoma.

BACKGROUND: Rectal cancers represent 35% of colorectal cancers; 90% are adenocarcinomas, while squamous cell carcinoma accounts for 0.3% of them. Given its rarity, little is known concerning its pathogenesis, molecular profile and therapeutic management. The current treatment trend is to treat rectal squamous cell carcinoma by analogy to anal squamous cell carcinoma with definitive chemo-radiotherapy, setting aside surgery in case of local recurrence. METHODS: We performed an in-depth genomic analysis (next-generation sequencing, copy number variation, and human papilloma virus characterization) on 10 rectal squamous cell carcinoma samples and compared them in silico to those of anal squamous cell carcinoma and rectal adenocarcinoma. RESULTS: Rectal squamous cell carcinoma shows 100% HPV positivity. It has a mutational (PIK3CA, PTEN, TP53, ATM, BCL6, SOX2) and copy number variation profile (3p, 10p, 10q, 16q deletion and 1q, 3q, 5p, 8q, 20p gain) similar to anal squamous cell carcinoma. PI3K/Akt/mTOR is the most commonly affected signaling pathway similarly to anal squamous cell carcinoma. Most commonly gained or lost genes seen in rectal adenocarcinoma (FLT3, CDX2, GNAS, BCL2, SMAD4, MALT1) are not found in rectal squamous cell carcinoma. CONCLUSION: This study presents the first comprehensive genomic characterization of rectal squamous cell carcinoma. We confirm the existence of this rare histology and its molecular similarity with anal squamous cell carcinoma. This molecular proximity confirms the adequacy of therapeutic management based on histology and not localization, suggesting that rectal squamous cell carcinoma should be treated like anal squamous cell carcinoma and not as a rectal adenocarcinoma.

Emerging Trends for Radio-Immunotherapy in Rectal Cancer.

Rectal cancer is a heterogeneous disease at the genetic and molecular levels, both aspects having major repercussions on the tumor immune contexture. Whilst microsatellite status and tumor mutational load have been associated with response to immunotherapy, presence of tumor-infiltrating lymphocytes is one of the most powerful prognostic and predictive biomarkers. Yet, the majority of rectal cancers are characterized by microsatellite stability, low tumor mutational burden and poor T cell infiltration. Consequently, these tumors do not respond to immunotherapy and treatment largely relies on radiotherapy alone or in combination with chemotherapy followed by radical surgery. Importantly, pre-clinical and clinical studies suggest that radiotherapy can induce a complete reprograming of the tumor microenvironment, potentially sensitizing it for immune checkpoint inhibition. Nonetheless, growing evidence suggest that this synergistic effect strongly depends on radiotherapy dosing, fractionation and timing. Despite ongoing work, information about the radiotherapy regimen required to yield optimal clinical outcome when combined to checkpoint blockade remains largely unavailable. In this review, we describe the molecular and immune heterogeneity of rectal cancer and outline its prognostic value. In addition, we discuss the effect of radiotherapy on the tumor microenvironment, focusing on the mechanisms and benefits of its combination with immune checkpoint inhibitors.

Debating Pros and Cons of Total Neoadjuvant Therapy in Rectal Cancer.

Recently, two large, randomised phase III clinical trials of total neoadjuvant therapy (TNT) in locally advanced rectal cancer were published (RAPIDO and PRODIGE 23). These two trials compared short-course radiotherapy (SCRT) followed by chemotherapy with standard chemoradiotherapy (CRT) and chemotherapy followed by CRT with standard CRT, respectively. They showed improvement in some of the outcomes such as distant recurrence and pathological complete response (pCR). No improvement, however, was observed in local disease control or the de-escalation of surgical procedures. Although it seems lawful to integrate TNT within the treatment algorithm of localised stage II and III rectal cancer, many questions remain unanswered, including which are the optimal criteria to identify patients who are most likely to benefit from this intensive treatment. Instead of providing a sterile summary of trial results, we put these in perspective in a pros and cons manner. Moreover, we discuss some biological aspects of rectal cancer, which may provide some insights into the current decision-making process, and represent the basis for the future development of alternative, more effective treatment strategies.

Tracing Clonal Dynamics Reveals that Two- and Three-dimensional Patient-derived Cell Models Capture Tumor Heterogeneity of Clear Cell Renal Cell Carcinoma.

BACKGROUND: Extensive DNA sequencing has led to an unprecedented view of the diversity of individual genomes and their evolution among patients with clear cell renal cell carcinoma (ccRCC). OBJECTIVE: To understand subclonal architecture and dynamics of patient-derived two-dimensional (2D) and three-dimensional (3D) ccRCC models in vitro, in order to determine whether they mirror ccRCC inter- and intratumor heterogeneity. DESIGN, SETTING, AND PARTICIPANTS: We have established a comprehensive platform of living renal cancer cell models from ccRCC surgical specimens. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We confirmed the concordance of 2D and 3D patient-derived cell (PDC) models with the original tumor tissue in terms of histology, biomarker expression, cancer driver mutations, and copy number alterations. We addressed inter- and intrapatient heterogeneity by analyzing clonal dynamics during serial passaging. RESULTS AND LIMITATIONS: In-depth genetic characterization verified the presence of heterogeneous cell populations, and revealed a high degree of similarity between subclonal compositions of monolayer and organoid cell cultures and the corresponding parental ccRCCs. Clonal dynamics were evident during serial passaging of cells in vitro, suggesting that PDC cultures can offer insights into evolutionary potential and treatment susceptibility of ccRCC subclones in vivo. Proof-of-concept drug profiling using selected ccRCC-targeted therapy agents highlighted patient-specific vulnerabilities in PDC models that could not be anticipated by interrogating commercially available cell lines. CONCLUSIONS: We demonstrate that PDC models mirror inter- and intratumor heterogeneity of ccRCC in vitro. Based on our findings, we envision that the use of these models will advance our understanding of the trajectories that cause genetic diversity and their consequences for treatment on an individual level. PATIENT SUMMARY: In this study, we developed two- and three-dimensional patient-derived models from clear cell renal cell carcinoma (ccRCC) as "mini-tumors in a dish." We show that these cell models retain important features of the human ccRCCs such as the profound tumor heterogeneity, thus highlighting their importance for cancer research and precision medicine.

Expression and Mutation Patterns of PBRM1, BAP1 and SETD2 Mirror Specific Evolutionary Subtypes in Clear Cell Renal Cell Carcinoma.

Bi-allelic inactivation of the VHL gene on chromosome 3p is the characteristic feature in most clear cell renal cell carcinomas (ccRCC). Frequent gene alterations were also identified in SETD2, BAP1 and PBRM1, all of which are situated on chromosome 3p and encode histone/chromatin regulators. The relationship between gene mutation, loss of protein expression and the correlations with clinicopathological parameters is important for the understanding of renal cancer progression. We analyzed PBRM1 and BAP1 protein expression as well as the tri-methylation state of H3K36 as a surrogate marker for SETD2 activity in more than 700 RCC samples. In ccRCC loss of nuclear PBRM1 (68%), BAP1 (40%) and H3K36me3 (47%) expression was significantly correlated with each other, advanced tumor stage, poor tumor differentiation (P < .0001 each), and necrosis (P < .005) Targeted next generation sequencing of 83 ccRCC samples demonstrated a significant association of genetic mutations in PBRM1, BAP1, and SETD2 with absence of PBRM1, BAP1, and HEK36me3 protein expression (P < .05, each). By assigning the protein expression patterns to evolutionary subtypes, we revealed similar clinical phenotypes as suggested by TRACERx Renal. Given their important contribution to tumor suppression, we conclude that combined functional inactivation of PBRM1, BAP1, SETD2 and pVHL is critical for ccRCC progression.

Biomarker discovery for renal cancer stem cells.

Characterised by high intra- and inter-tumor heterogeneity, metastatic renal cell carcinoma (RCC) is resistant to chemo- and radiotherapy. Therefore, the development of new prognostic and diagnostic markers for RCC patients is needed. Cancer stem cells (CSCs) are a small population of neoplastic cells within a tumor which present characteristics reminiscent of normal stem cells. CSCs are characterised by unlimited cell division, maintenance of the stem cell pool (self-renewal), and capability to give rise to all cell types within a tumor; and contribute to metastasis in vivo (tumourigenicity), treatment resistance and recurrence. So far, many studies have tried to establish unique biomarkers to identify CSC populations in RCC. At the same time, different approaches have been developed with the aim to isolate CSCs. Consequently, several markers were found to be specifically expressed in CSCs and cancer stem-like cells derived from RCC such as CD105, ALDH1, OCT4, CD133, and CXCR4. However, the contribution of genetic and epigenetic mechanisms, and tumor microenvironment, to cellular plasticity have made the discovery of unique biomarkers a very difficult task. In fact, contrasting results regarding the applicability of such markers to the isolation of renal CSCs have been reported in the literature. Therefore, a better understanding of the mechanism underlying CSC may help dissecting tumor heterogeneity and drug treatment efficiency.