Towards precision oncology for HER2 blockade in gastroesophageal adenocarcinoma

Gastroesophageal adenocarcinoma (GEA) represents a very heterogeneous disease and patients in advanced stages have a very poor prognosis. Although several molecular classifications have been proposed, precision medicine for HER2-amplified GEA patients still represents a challenge. Despite improvement in clinical outcomes obtained by adding trastuzumab to first-line platinum-based chemotherapy, no other anti-HER2 agents used first-line or beyond progression have demonstrated any benefit. Several factors contribute to this failure. Among them, variable HER2 amplification assessment, tumour heterogeneity, molecular mechanisms of resistance and microenvironmental factors could limit the effecti…

Precision Medicine to Treat Advanced Gastroesophageal Adenocarcinoma: A Work in Progress

Gastroesophageal adenocarcinoma (GEA) represents a heterogeneous disease and, when diagnosed as locally advanced or metastatic, it is characterized by poor prognosis. During the last few years, several molecular classifications have been proposed to try to personalize treatment for those patients diagnosed with advanced disease. Nevertheless, despite the great effort, precision medicine is still far from being a reality. The improvement in the molecular analysis due to the application of high throughput technologies based on DNA and RNA sequencing has opened a novel scenario leading to the personalization of treatment. The possibility to target epidermal growth factor receptor (HER)2, Claud…

Circulating tumor DNA to detect minimal residual disease, response to adjuvant therapy, and identify patients at high risk of recurrence in patients with stage I-III CRC.

4009 Background: The clinical utility of tracking circulating tumor DNA (ctDNA) as a non-invasive biomarker for detecting minimal residual disease (MRD) and stratifying patients based on their risk of developing relapse has been well established in colorectal cancer (CRC). This study evaluates the detection and longitudinal monitoring of ctDNA in CRC patients pre- and post-operatively, during and after adjuvant chemotherapy (ACT). Methods: The prospective, multicenter cohort study recruited patients (n = 193) diagnosed with resected stage I-III CRC. Plasma samples (n = 1052) were collected at various timepoints with a median follow up of 21.6 months (4.6-38.5 months). Individual tumors and…

PO-182 The upregulation of EPDR1 is related to tumour invasiveness in a cohort of localised colorectal cancer patients

Introduction Colorectal cancer (CRC) represents a relevant public health problem. Despite new therapeutic advances, prognosis of patients diagnosed with advanced disease is still poor. The identification of new markers involved in the mechanisms of invasiveness represents a priority in order to better understand cancer development and generate new therapeutic targets. We describe here the possible role of EPDR1, a gene not yet well characterised, which encodes a protein related to ependymins, a family of piscine transmembrane proteins involved in cell adhesion. To evaluate the role of EPDR1, a translational investigation was planned to explore the consequences of the upregulation of EPDR1 i…

Circulating Tumor DNA in Stage III Colorectal Cancer, beyond Minimal Residual Disease Detection, toward Assessment of Adjuvant Therapy Efficacy and Clinical Behavior of Recurrences

Abstract Purpose: Sensitive methods for risk stratification, monitoring therapeutic efficacy, and early relapse detection may have a major impact on treatment decisions and patient management for stage III colorectal cancer patients. Beyond assessing the predictive power of postoperative ctDNA detection, we explored the added benefits of serial analysis: assessing adjuvant chemotherapy (ACT) efficacy, early relapse detection, and ctDNA growth rates. Experimental Design: We recruited 168 patients with stage III colorectal cancer treated with curative intent at Danish and Spanish hospitals between 2014 and 2019. To quantify ctDNA in plasma samples (n = 1,204), 16 patient-specific somatic sing…

NRF2 activation via PI3K/AKT/mTOR/RPS6 causes resistance to anti-HER2 agents among HER2 amplified gastric cancer

Assessing molecular subtypes of gastric cancer: microsatellite unstable and Epstein-Barr virus subtypes. Methods for detection and clinical and pathological implications.

Background The molecular classification of gastric cancer recognises two subtypes prone to immune checkpoint blockade: the microsatellite unstable and the Epstein-Barr virus (EBV)-related tumours. We aim to assess the concordance between immunohistochemistry and PCR for microsatellite status evaluation, and explore the value of microsatellite instability (MSI) and EBV as predictive survival factors. Material and methods We collected 246 consecutively diagnosed gastric cancer cases in all stages and evaluated the microsatellite status using immunohistochemistry for mismatched repair (MMR) proteins and PCR. EBV expression was studied through in situ hybridisation. Results Forty-five (18%) cas…

Circulating Tumor DNA Detection by Digital-Droplet PCR in Pancreatic Ductal Adenocarcinoma: A Systematic Review

Simple Summary Pancreatic cancer is a digestive tumor that is most difficult to treat and carries one of the worst prognoses. The anatomical location of the pancreas makes it very difficult to obtain enough tumor material to establish a molecular diagnosis, so knowing the biology of this tumor and implementing new targeted-therapies is still a pending issue. The use of liquid biopsy, a blood sample test to detect circulating-tumor DNA fragments (ctDNA), is key to overcoming this difficulty and improving the evolution of this tumor. Liquid biopsies are equally representative of the tissue from which they come and allow relevant molecular and diagnostic information to be obtained in a faster …

Serial circulating tumor DNA analysis to assess recurrence risk, benefit of adjuvant therapy, growth rate and early relapse detection in stage III colorectal cancer patients

3540 Background: Challenges in the postoperative management of stage III colorectal cancer include: 1) selection of high-risk patients for adjuvant chemotherapy (ACT), 2) lack of markers to assess ACT efficacy, 3) assessment of recurrence risk after ACT, and 4) lack of markers to guide treatment decisions for high-risk patients e.g. additional therapy or intensified surveillance. Circulating tumor DNA (ctDNA) is a promising marker with potential to mitigate the challenges. Here we used serial ctDNA measurements to assess the correlation between recurrence and ctDNA detection: postoperative, during and after ACT, and during surveillance; and to assess growth rates of metachronous metastases…

Detection of postoperative plasma circulating tumour DNA and lack of CDX2 expression as markers of recurrence in patients with localised colon cancer

BACKGROUND: Colon cancer (CC) is a heterogeneous disease. Novel prognostic factors beyond pathological staging are required to accurately identify patients at higher risk of relapse. Integrating these new biological factors, such as plasma circulating tumour DNA (ctDNA), CDX2 staining, inflammation-associated cytokines and transcriptomic consensus molecular subtypes (CMS) classification, into a multimodal approach may improve our accuracy in determining risk of recurrence.; METHODS: One hundred and fifty patients consecutively diagnosed with localised CC were prospectively enrolled in our study. ctDNA was tracked to detect minimal residual disease by droplet digital PCR. CDX2 expression was…

Low miR200c expression in tumor budding of invasive front predicts worse survival in patients with localized colon cancer and is related to PD-L1 overexpression

At the histological level, tumor budding in colon cancer is the result of cells undergoing at least partial epithelial-to-mesenchymal transition. The microRNA 200 family is an important epigenetic driver of this process, mainly by downregulating zinc-finger E-box binding homeobox (ZEB) and transforming growth factor beta (TGF-β) expression. We retrospectively explored the expression of the miR200 family, and ZEB1 and ZEB2, and their relationship with immune resistance mediated through PD-L1 overexpression. For this purpose, we analyzed a series of 125 colon cancer cases and took samples from two different tumor sites: the area of tumor budding at the invasive front and from the tumor center…

Development of a living organoid biobank derived from colorectal cancer patients: Towards personalized medicine

Abstract Background Organoids are 3D in vitroprimary culture of great interest for translational research representing an efficient and reproducible cancer model. The aim of this project is to generate a biobank of colorectal cancer (CRC) patients derived organoids (PDOs) that could be used to analyze molecular characteristics and to test different treatments as well as to study the underlying molecular causes of cancer and treatment resistance. Methods Primary or metastatic CRC tissues have been obtained from patients who underwent surgery. Tissue has been washed and incubated with antibiotics. After mechanical and enzymatic digestion, free cells have been seeded in Matrigel with proper me…

Borderline resectable pancreatic cancer. Challenges and controversies.

Abstract Pancreatic cancer is a dismal disease with an increasing incidence. Despite the majority of patients are not candidates for curative surgery, a subgroup of patients classified as borderline resectable pancreatic cancer can be selected in whom a sequential strategy of neoadjuvant therapy followed by surgery can provide better outcomes. Multidisciplinary approach and surgical pancreatic expertise are essential for successfully treating these patients. However, the lack of consensual definitions and therapies make the results of studies very difficult to interpret and hard to be implemented in some settings. In this article, we review the challenges of borderline resectable pancreatic…

Prognostic implications of surgical specimen quality on the oncological outcomes of open and laparoscopic surgery in mid and low rectal cancer

Abstract Purpose Determine differences in pathologic outcomes between laparoscopic (LAP) and open surgery (OPEN) for mid and low rectal cancer and its influence in long-term oncological outcomes. Methods Retrospective case matched study at a tertiary institution. Adults with rectal cancer below 12 cm from the anal verge operated between January 2005 and September 2018 were included. Primary outcomes were quality of specimen, overall survival (OS), disease-free survival (DFS), and local recurrence (LR). Results The study included 311 patients, LAP = 108 (34.7%), OPEN = 203 (65,3%). A successful resection was accomplished in 81% of the LAP group and in 84.5% of the OPEN (p = 0.505). No differ…

Why Do We Have to Use Chemotherapy?

The use of chemotherapy (CT) in localized rectal cancer (LARC) has two aims: first, to improve the local effect of radiotherapy by giving concomitant chemoradiation and second, to decrease systemic relapses by early treatment for occult micrometastatic disease or to shrink bulky local tumours. Neoadjuvant treatment is reserved for locally advanced disease, as defined by pelvic magnetic resonance imaging, a very useful and accurate tool to identify high-risk features for local or systemic relapse [1]. We are going to address why we have to use CT in LARC.

Neoadjuvant treatment for locally advanced unresectable and borderline resectable pancreatic cancer: oncological outcomes at a single academic centre.

INTRODUCTION: Pancreatic cancer (PC), even in the absence of metastatic disease, has a dismal prognosis. One-third of them are borderline resectable (BRPC) or locally advanced unresectable PC (LAUPC) at diagnosis. There are limited prospective data supporting the best approach on these tumours. Neoadjuvant chemotherapy (ChT) is being increasingly used in this setting. METHODS: This is a retrospective series of consecutive patients staged as BRPC or LAUPC after discussion in the multidisciplinary board (MDB) at an academic centre. All received neoadjuvant ChT, followed by chemoradiation (ChRT) in some cases, and those achieving enough downstaging had a curative-intent surgery. Descriptive da…

Targeted next-generation sequencing of circulating-tumor DNA for tracking minimal residual disease in localized colon cancer.

A high percentage of patients diagnosed with localized colon cancer (CC) will relapse after curative treatment. Although pathological staging currently guides our treatment decisions, there are no biomarkers determining minimal residual disease (MRD) and patients are at risk of being undertreated or even overtreated with chemotherapy in this setting. Circulating-tumor DNA (ctDNA) can to be a useful tool to better detect risk of relapse.One hundred and fifty patients diagnosed with localized CC were prospectively enrolled in our study. Tumor tissue from those patients was sequenced by a custom-targeted next-generation sequencing (NGS) panel to characterize somatic mutations. A minimum varian…

Trifluridine/tipiracil in earlier lines of chemotherapy for advanced colorectal cancer

“Are There New Chemotherapy Drugs Behind the Corner?”

Up to now, the backbone of both adjuvant and palliative chemotherapy for colorectal cancer is still represented by 5-fluorouracil (5FU). However, we have currently several approved drugs with significant clinical activity in metastatic colon cancer. Apart from cytotoxics such as oxaliplatin, irinotecan, and fluoropyrimidines, we have antiangiogenics (bevacizumab, aflibercept, and ramucirumab), anti-epidermal growth factor receptor (EGFR), and tyrosine kinase inhibitors such as regorafenib. Despite remarkable prolongation of median survival, exceeding 24 months, most patients will be progressing over different lines of therapy, and there is a need and a role for new compounds to be added to …

How we treat metastatic colorectal cancer.

Colorectal cancer is the second leading cause of cancer-related death worldwide. About 20% of patients suffer from metastatic disease at diagnosis, while about one-third of patients treated with curative intent relapsed. In these patients, an accurate staging allows to plan a treatment strategy within a multidisciplinary team in order to achieve predefined goals. Patient's clinical features, tumour characteristics and molecular profile (RAS/BRAF and microsatellite instability (MSI) status) should be considered during the treatment choice. Combination of chemotherapy (fluoropyrimidines, oxaliplatin and irinotecan) plus biological agents (antiepidermal growth factor receptor or antiangiogenic…

NRF2 through RPS6 Activation Is Related to Anti-HER2 Drug Resistance in HER2-Amplified Gastric Cancer

Abstract Purpose: Despite the clinical advantage of the combination of trastuzumab and platinum-based chemotherapy in HER2-amplified tumors, resistance will eventually develop. The identification of molecular mechanisms related to primary and acquired resistance is needed. Experimental Design: We generated lapatinib- and trastuzumab-resistant clones deriving from two different HER2-amplified gastric cancer cell lines. Molecular changes such as protein expression and gene-expression profile were evaluated to detect alterations that could be related to resistance. Functional studies in vitro were corroborated in vivo. The translational relevance of our findings was verified in a patient cohor…

Circulating tumor DNA analysis for assessment of recurrence risk, benefit of adjuvant therapy, and early relapse detection after treatment in colorectal cancer patients.

11 Background: Timely detection of recurrence, as well as identification of patients at high risk of recurrence after surgery and after completion of adjuvant therapy, are major challenges in the treatment of colorectal cancer (CRC). Postsurgical circulating tumor DNA (ctDNA) analysis is a promising tool for the identification of patients with minimal residual disease (MRD) and a high risk of recurrence. The objective of this prospective, multicenter study was to determine whether serial postsurgical ctDNA analysis could identify the patients at high risk of recurrence, provide an assessment of adjuvant therapy efficacy and detect relapse earlier than standard-of-care radiological imaging.…

EPDR1 up-regulation in human colorectal cancer is related to staging and favours cell proliferation and invasiveness

The finding of novel molecular markers for prediction or prognosis of invasiveness in colorectal cancer (CRC) constitutes an appealing challenge. Here we show the up-regulation of EPDR1 in a prospective cohort of 101 CRC patients, in a cDNA array of 43 patients and in in silico analyses. EPDR1 encodes a protein related to ependymins, a family of glycoproteins involved in intercellular contacts. A thorough statistical model allowed us to conclude that the gene is significantly up-regulated in tumour tissues when compared with normal mucosa. These results agree with those obtained by the analysis of three publicly available databases. EPDR1 up-regulation correlates with the TNM staging parame…

Personalized Medicine: Recent Progress in Cancer Therapy

Translational research has revolutionized how we develop new treatments for cancer patients. The change from an organ-centric concept guiding treatment choice towards deep molecular analysis, driving a personalized approach, is one of the most important advances of modern oncology. Several tools such as next generation sequencing and RNA sequencing have greatly improved the capacity to detect predictive and prognostic molecular alterations. Detection of gene mutations, amplifications, and fusions has therefore altered the history of several diseases in both a localized and metastatic setting. This shift in perspective, in which attention is focused on the specific molecular alterations of t…

New guidelines for optimal patient care with localized colon cancer: recommending what is proven, but also watching what research is bringing

Neoadjuvant Chemotherapy in Locally Advanced Rectal Cancer

Simple Summary The outcome for patients with rectal cancer has significantly improved over the last thirty years. Previously, local relapses in the pelvis occurred in more than one third of all patients with apparently localized tumors. Total mesorectal excision was the first step to improve local control by reducing local relapses to less than 5%. Preoperative radiation, either short-course or long-course with concurrent administration of chemotherapy, was a second important step for reducing local relapses to a minimum, even in locally advanced tumors where a clean surgical resection was not possible or would not be curative. Magnetic resonance imaging is a very useful tool for locoregion…

The role of tumor-associated macrophages in gastric cancer development and their potential as a therapeutic target.

Gastric cancer (GC) represents the fifth cause of cancer-related death worldwide. Molecular biology has become a central area of research in GC and there are currently at least three major classifications available to elucidate the mechanisms that drive GC oncogenesis. Further, tumor microenvironment seems to play a crucial role, and tumor-associated macrophages (TAMs) are emerging as key players in GC development. TAMs are cells derived from circulating chemokine- receptor-type 2 (CCR2) inflammatory monocytes in blood and can be divided into two main types, M1 and M2 TAMs. M2 TAMs play an important role in tumor progression, promoting a pro-angiogenic and immunosuppressive signal in the tu…

1480P M2 macrophages could promote an immunosuppressive phenotype in a prospective cohort of advanced gastric cancer patients

Gene expression changes responsible for lapatinib acquired resistance in HER2 positive gastric cancer cell lines: a microarray analysis

Improving tumour budding evaluation in colon cancer by extending the assessment area in colectomy specimens.

AIMS It is recommended that tumour budding in colon cancer be counted on haematoxylin and eosin-stained sections in a hotspot area of 0.785 mm2 with a ×20 microscope objective. However, tumour buds may be difficult to visualise on haematoxylin and eosin-stained sections, and counting in such a limited area may result in overestimation in cases with focal budding. The aim of this study was to assess the contributions of various factors to improving tumour budding risk stratification: increasing the number of fields counted, using cytokeratin immunostaining, and recording proliferation, the apoptotic index and the emperipoletic index in tumour buds. METHODS AND RESULTS We created an explorato…