Evolving applications of liquid biopsies in gastrointestinal cancers.

Liquid biopsy is a test that allows for the diagnosis and analysis of cancer by sampling cancer cells or byproducts present in biological fluids such as blood or urine. It has the potential to create a new paradigm in oncologic care, being a less invasive approach than conventional tissue biopsy. Liquid biopsy has multifaceted applications for longitudinal disease monitoring in terms of surveillance, treatment response, and identification of emerging resistance mechanisms. Multiple assays currently exist or are in development for detecting circulating tumor cells, DNA, RNA, exosomes, proteins, fragmentomic markers, and metabolomes. Here, we review the applications of liquid biopsy in gastrointestinal cancers, emphasizing its use in both perioperative and advanced settings. We also examine its role in screening, diagnostics, and other cancer-related scenarios.

Lessons Learned in Managing Patients with Colorectal Cancer During the COVID-19 Pandemic.

OPINION STATEMENT: The COVID-19 pandemic forced us to rapidly and dramatically shift our medical priorities and decision making. With little literature or experience to rely on, the initial priority was to minimize patient exposure to the hospital and to others. It remains unclear whether cancer patients are at higher risk of infection or serious complications, or if it is our traditional therapies that place them to be at higher risk. By far, the greatest negative impact was on screening. Routine colonoscopies were considered elective, and as a result, delays in diagnosis will be felt for years to come. The most positive changes were the incorporation of tele-visits, increased use of oral therapies, alterations in treatment schedules of both chemotherapy and radiation, and an increased emphasis on neoadjuvant therapy. These too will be felt for years to come. The colorectal cancer medical community has responded collaboratively and effectively to maintain treatment and to optimize outcomes for our patients during the COVID-19 pandemic.

The Relevance of Hereditary Cancer Risks to Precision Oncology: What Should Providers Consider When Conducting Tumor Genomic Profiling?

Through tumor genomic profiling (TGP), existing and novel treatments can be selected to better target the specific dysregulated molecular pathways that drive growth and spread of a patient's tumor. Although the primary purpose of TGP is to detect targetable somatic mutations for treatment, TGP may also uncover germline mutations with important implications for patients and family members. Oncology care providers should be aware of the hereditary cancer risks associated with genes commonly tested by TGP. Further, patients should be informed about the possible discovery of hereditary cancer risk information and the relevance of this information to their health and that of family members, and should have their preferences toward further evaluation of hereditary risk information that could be revealed by TGP documented in the medical record and followed.

Perioperative therapy landscape for locally advanced, resectable esophageal cancer: an updated literature review.

Background and Objective: The poor oncologic outcomes associated with esophageal cancer (EC) are primarily due to its presentation at an advanced stage and patient comorbidities. While multimodal therapy improves overall outcomes, there is a lack of uniform practice in terms of perioperative management, partly because this is a rapidly evolving field in a heterogeneous patient population. With numerous recent studies incorporating precision medicine with radiographic, pathologic, and genomic biomarkers and with emerging trials using targeted therapies, it is necessary for providers who care for these patients to be familiar with the current and evolving treatment standards to optimize patient outcomes. The objective of this paper is to perform an updated review of the main historical and recently emerging studies that impact the perioperative management of patients with locally advanced, upfront-resectable EC. Methods: We mined and reviewed PubMed and American Society of Clinical Oncology databases for pivotal works shaping the current perioperative treatment landscape in locally advanced EC. Key Content and Findings: EC are a vastly heterogeneous disease, and treatment options vary based on tumor anatomic location, histology, and patient comorbidities. Perioperative chemotherapy (CTX), chemoradiation (CRT), and, recently, immunotherapy have improved survival in patients with locally advanced disease. However, optimizing sequencing, de-escalating therapy, and incorporating novel targeted therapies in the perioperative setting are promising strategies that are under ongoing investigation to improve patient outcomes further. Conclusions: There is an ongoing need to identify predictive biomarkers and novel treatment strategies to personalize perioperative approaches and optimize outcomes of patients with EC.

Prognostic utility of preoperative and postoperative KRAS-mutated circulating tumor DNA (ctDNA) in resected pancreatic ductal adenocarcinoma: A systematic review and meta-analysis.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a challenging disease, with surgery being the only possible cure. However, despite surgery, the majority of patients experience recurrence. Recent evidence suggests that perioperative KRAS-mutated circulating tumor DNA (ctDNA) may have prognostic value. Therefore, we conducted a systematic review and meta-analysis to explore the prognostic significance of preoperative and postoperative KRAS-mutated ctDNA testing in resected PDAC. METHODS: We searched PubMed/MEDLINE, Embase, and Cochrane Central Register of Controlled Trials databases for studies that reported the effect of preoperative and postoperative KRAS-mutated ctDNA on overall survival (OS) and/or relapse-free survival (RFS) in resected PDAC. We used a random-effects model to determine the pooled OS and RFS hazard ratios (HR) and their corresponding 95 % confidence intervals (CI). RESULTS: We identified 15 studies (868 patients) eligible for analysis. In the preoperative setting, positive ctDNA correlated with worse RFS in 8 studies (HR, 2.067; 95 % CI, 1.346-3.174, P < 0.001) and worse OS in 10 studies (HR, 2.170; 95 % CI, 1.451-3.245, P < 0.001) compared to negative ctDNA. In the postoperative setting, positive ctDNA correlated with worse RFS across 9 studies (HR, 3.32; 95 % CI, 2.19-5.03, P < 0.001) and worse OS in 6 studies (HR, 6.62; 95 % CI, 2.18-20.16, P < 0.001) compared to negative ctDNA. CONCLUSION: Our meta-analysis supports the utility of preoperative and postoperative KRAS-mutated ctDNA testing as a prognostic marker for resected PDAC. Further controlled studies are warranted to confirm these results and to investigate the potential therapeutic implications of positive KRAS-mutated ctDNA.

Propagated Circulating Tumor Cells Uncover the Potential Role of NFκB, EMT, and TGFß Signaling Pathways and COP1 in Metastasis.

Circulating tumor cells (CTCs), a population of cancer cells that represent the seeds of metastatic nodules, are a promising model system for studying metastasis. However, the expansion of patient-derived CTCs ex vivo is challenging and dependent on the collection of high numbers of CTCs, which are ultra-rare. Here we report the development of a combined CTC and cultured CTC-derived xenograft (CDX) platform for expanding and studying patient-derived CTCs from metastatic colon, lung, and pancreatic cancers. The propagated CTCs yielded a highly aggressive population of cells that could be used to routinely and robustly establish primary tumors and metastatic lesions in CDXs. Differential gene analysis of the resultant CTC models emphasized a role for NF-κB, EMT, and TGFß signaling as pan-cancer signaling pathways involved in metastasis. Furthermore, metastatic CTCs were identified through a prospective five-gene signature (BCAR1, COL1A1, IGSF3, RRAD, and TFPI2). Whole-exome sequencing of CDX models and metastases further identified mutations in constitutive photomorphogenesis protein 1 (COP1) as a potential driver of metastasis. These findings illustrate the utility of the combined patient-derived CTC model and provide a glimpse of the promise of CTCs in identifying drivers of cancer metastasis.

Immunotherapy for Colorectal Cancer.

Colorectal cancer is a common malignancy that is frequently able to evade immune defenses. Although this may contribute to promoting and propagating cancer growth, recent advances suggest that for some tumors, particularly those with high levels of microsatellite instability and hypermutability from DNA mismatch repair defects, immunotherapy is effective to control tumor progression. Unfortunately, the overwhelming majority of patients have poor antitumoral immune cell penetration and fewer molecular defects within the cancer to successfully mount an anticancer defense. Studies, primarily in early phases of investigation, are underway to evaluate new combinations of immune checkpoint inhibitors, other targeted therapies, cellular therapies, and vaccines.

The Role of Immunotherapy in Pancreatic Cancer.

Pancreatic adenocarcinoma remains one of the most lethal cancers globally, with a significant need for improved therapeutic options. While the recent breakthroughs of immunotherapy through checkpoint inhibitors have dramatically changed treatment paradigms in other malignancies based on considerable survival benefits, this is not so for pancreatic cancer. Chemotherapies with modest benefits are still the cornerstone of advanced pancreatic cancer treatment. Pancreatic cancers are inherently immune-cold tumors and have been largely refractory to immunotherapies in clinical trials. Understanding and overcoming the current failures of immunotherapy through elucidating resistance mechanisms and developing novel therapeutic approaches are essential to harnessing the potential durable benefits of immune-modulating therapy in pancreatic cancer patients.

The current state of molecular profiling in gastrointestinal malignancies.

This is a review of the current state of molecular profiling in gastrointestinal (GI) cancers and what to expect from this evolving field in the future. Individualized medicine is moving from broad panel testing of numerous genes or gene products in tumor biopsy samples, identifying biomarkers of prognosis and treatment response, to relatively noninvasive liquid biopsy assays, building on what we have learned in our tumor analysis and growing into its own evolving predictive and prognostic subspecialty. Hence, the field of GI precision oncology is exploding, and this review endeavors to summarize where we are now in preparation for the journey ahead.

Genomic Alterations and Their Implications on Survival in Nonmetastatic Colorectal Cancer: Status Quo and Future Perspectives.

The selection of treatment according to genomic alterations is a standard approach in metastatic colorectal cancer but is only starting to have an impact in the earlier stages of the disease. The status if genes like KRAS, BRAF, and MMR has substantial survival implications, and concerted research efforts have revolutionized treatment towards precision oncology. In contrast, a genomic-based approach has not changed the adjuvant setting after curative tumor-resection in the daily routine so far. This review focuses on the current knowledge regarding prognostic and predictive genomic biomarkers in patients with locally advanced nonmetastasized colorectal cancer. Furthermore, we provide an outlook on future challenges for a personalized adjuvant treatment approach in patients with colorectal cancer.

Allogeneic hematopoietic stem cell transplantation in advanced stage mycosis fungoides and Sézary syndrome: a concise review.

Mycosis fungoides and Sézary syndrome encompass over 70% of all cases of cutaneous T-cell lymphoma (CTCL). While early stage disease has excellent long-term survival rates, advanced stage disease (IIB-IV) carries a poor prognosis with a median 5-year overall survival rate of approximately 50%. Early stage and advanced stage disease have different treatment algorithms with systemic therapy being indicated upfront in the later. The role of allogeneic hematopoietic stem cell transplant (HSCT) has gained considerable interest in recent years as a treatment option for CTCL given the increasingly promising long-term outcomes in an otherwise incurable disease. Herein, we provide a brief update on the current advances in HSCT followed by a concise review of the role of HSCT for CTCL. We conclude with our recommendations to approaching HSCT as a curative treatment option for CTCL.