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…

Current questions for the treatment of advanced gastric cancer.

Abstract Background Gastric cancer remains a major health problem worldwide. Treatment of advanced gastric cancer is controversial and there is no standard regimen for first- or second-line chemotherapy (CT). This review aims to give an overview of the hot topics concerning treatment, prognostic factors and new strategies in advanced gastric cancer. Material and methods Seven questions of special clinical interest have been formulated previously to the literature review. With the aim of answering each of these questions, a specific search of the relevant trials and meta-analyses published or communicated from 1990 to date was performed. Results Patients treated with CT have a survival benef…

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…

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…

EGF-Induced Acetylation of Heterogeneous Nuclear Ribonucleoproteins Is Dependent on KRAS Mutational Status in Colorectal Cancer Cells.

KRAS mutational status is considered a negative predictive marker of the response to anti-EGFR therapies in colorectal cancer (CRC) patients. However, conflicting data exist regarding the variable response to EGFR-targeted therapy. The effects of oncogenic KRAS on downstream targets were studied in cell lines with different KRAS mutations. Cells harboring a single KRASG13D allele showed the most tumorigenic profile, with constitutive activation of the downstream pathway, rendering them EGF-unresponsive. Conversely, KRASA146T cells showed a full EGF-response in terms of signal transduction pathways, cell proliferation, migration or adhesion. Moreover, the global acetylome of CRC cells was al…

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

In the literature: April 2020

Deficient DNA mismatch repair (dMMR) may be caused by germline or somatic mutations in mismatch repair genes ( MLH1 , MSH2 , MSH3 , MSH6 and PMS2 ) or through epigenetic silencing of MLH1 .1 dMMR induces a hypermutator phenotype, also known as microsatellite instability (MSI). Next-generation sequencing identifies MSI in 12 cancer types. The highest prevalence is seen in endometrial cancer (31.4%), followed by colorectal cancer (19.7%) and gastric cancer (GC, 19.1%). MSI was related to better prognosis for colorectal cancer and GC . Moreover, the dMMR/MSI hypermutator phenotype is thought to produce large numbers of immunogenic neoantigens that can be recognised by immune cells, leading to …

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…

Preoperative chemoradiation may not always be needed for patients with T3 and T2N+ rectal cancer

BACKGROUND: Preoperative chemoradiation is becoming the standard treatment for patients with locally advanced rectal cancer. However, since the introduction of total mesorectal excision (TME), local recurrence rates have been reduced significantly, and some patients can be spared from potentially toxic over treatment. The current study was designed to assess the factors that predict recurrence in an institutional series of patients with rectal cancer who had clinical T2 lymph node-positive (cT2N+) tumors or cT3N0/N+ tumors and underwent radical surgery without receiving preoperative chemoradiation. METHODS: Between November 1997 and November 2008, the authors' multidisciplinary group preope…

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 …

490P Metastatic colorectal cancer derived organoids recapitulate genomic profile and treatment response of the original tumor

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…

In the literature: February 2020.

The phosphatidylinositol-3-kinase (PI3K)/Akt and the mammalian target of rapamycin (mTOR) signaling pathways is one of the most frequently deregulated pathways in human cancers. This pathway controls multiple cellular processes, including metabolism, motility, proliferation, growth and survival. It can be aberrantly activated through multiple mechanisms, including diverse genomic alterations involving oncogenes and tumour suppressor genes.1 These alterations offer opportunities for therapeutic targeting of the pathway. PI3Kα protein complex is composed of regulatory (p85α) and catalytic (p110α) subunits. Pik3ca codes for p110α, which is the most frequently mutated oncogene across different …

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…

Abstract 3363: Pharmacodynamic (PD) assessment of drug activity in tumor tissue from patients (pts) enrolled in a Phase I study of MEHD7945A (MEHD), a first-in-class HER3/EGFR dual action antibody, in pts with locally advanced or metastatic epithelial tumors.

Abstract Background Members of the human epidermal growth factor receptor (HER) family of oncogenes are often co-expressed and heterodimerized, suggesting that simultaneous blockade of multiple HER family receptors may be more effective than targeting single receptors. MEHD is a dual-action human IgG1 antibody that can bivalently bind to HER3 and EGFR and block ligand binding to either. FDG-PET imaging is a recognized method of assessing PD modulation with EGFR inhibitors in the clinic. HER3 and EGFR signaling via the MAPK and PI3K pathways can be monitored in tissue by examining phosphorylation of downstream markers. Methods A Phase 1, multicenter, open-label study was conducted to evaluat…

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…

In the literature: June 2020.

Immunotherapy based on checkpoint blockade has revolutionised cancer treatment during last years. Whereas this approach fails in a relevant group of patients, the knowledge on tumour microenvironment (TME) opened the possibility to the use of additional therapeutic strategies to potentiate antitumour immunity, including depletion of protumourigenic or immune suppressive and activation of specific immune populations using agonistic antibodies. Nevertheless, due to the complexity of the TME, many of these strategies have been indiscriminately advanced to the clinic without clear mechanistic hypotheses. Nowadays, single-cell RNA sequencing (scRNA-seq)-based transcriptome analyses identify T ce…

Phase I Pharmacokinetic/Pharmacodynamic Study of MLN8237, an Investigational, Oral, Selective Aurora A Kinase Inhibitor, in Patients with Advanced Solid Tumors

Abstract Purpose: Aurora A kinase (AAK) is a key regulator of mitosis and a target for anticancer drug development. This phase I study investigated the safety, pharmacokinetics, and pharmacodynamics of MLN8237 (alisertib), an investigational, oral, selective AAK inhibitor, in 59 adults with advanced solid tumors. Experimental Design: Patients received MLN8237 once daily or twice daily for 7, 14, or 21 consecutive days, followed by 14 days recovery, in 21-, 28-, or 35-day cycles. Dose-limiting toxicities (DLT) and the maximum-tolerated dose (MTD) for the 7- and 21-day schedules were determined. Pharmacokinetic parameters were derived from plasma concentration–time profiles. AAK inhibition in…

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…

Safety and Pharmacokinetics/Pharmacodynamics of the First-in-Class Dual Action HER3/EGFR Antibody MEHD7945A in Locally Advanced or Metastatic Epithelial Tumors.

Abstract Purpose: The novel dual-action humanized IgG1 antibody MEHD7945A targeting HER3 and EGFR inhibits ligand-dependent HER dimer signaling. This phase I study evaluated the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of MEHD7945A. Experimental Design: Patients with locally advanced or metastatic epithelial tumors received escalating doses of MEHD7945A (1–30 mg/kg) every 2 weeks (q2w) until disease progression or intolerable toxicity. An expansion cohort was enrolled at the recommended phase II dose (14 mg/kg, q2w). Plasma samples, tumor biopsies, FDG-PET were obtained for assessment of pharmacokinetics, and pharmacodynamic modulation downstream of EGFR and HER3. …

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…

PI3K/AKT Activation and Response in Phase IB: AKT Inhibitor GDC-0068 with Docetaxel (D) Or MFOLFOX6 (F) in Refractory Solid Tumors

R. Meng1, L. R. Molife2, L. de Mattos-Arruda3, A. Hollebecque4, S. J. Isakoff5, D. Roda6, Y. Yan1, A. Cervantes6, J. C. Soria4, J. Mateo2, G. Argiles3, J. C. Bendell7 Genentech, South San Francisco, CA, USA, Institute of Cancer Research/ Royal Marsden Hospital, Sutton, United Kingdom, Vall d’Hebron University Hospital, Barcelona, Spain, Institut Gustave Roussy, Villejuif, France, Massachusetts General Hospital, Boston, MA, USA, Institute of Health Research INCLIVA, University of Valenica, Valencia, Spain, Sarah Cannon Research Institute, Nashville, TN, USA

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

Abstract CT-08: A Phase 1 study of MEHD7945A (MEHD), a first-in-class EGFR/HER3 dual action antibody, in patients (pts) with locally advanced or metastatic epithelial tumors

Abstract Background Dysregulated human epidermal growth factor receptor tyrosine kinase (HER RTK) signaling is an important driver of tumor growth, metastasis, and survival. Extensive HER RTK co-expression and heterodimerization suggest that simultaneous blockade of multiple RTKs may be more effective than targeting individual RTKs, and may help prevent or delay development of resistance mechanisms. MEHD is a novel dual-action human IgG1 antibody. Each antigen-binding fragment blocks ligand binding to both EGFR and HER3, which is meant to inhibit the activity of the major ligand-dependent HER dimers in cancer. MEHD also elicits antibody-dependent cell-mediated cytotoxicity, and has single-a…

Safety and efficacy of anti-PD-1 inhibitor ABBV-181 in lung and head and neck carcinoma

Abstract Background ABBV-181 is a humanized anti-PD1 monoclonal antibody; dose finding and early safety, PK and pharmacodynamic data have been reported (ESMO18). This report summarizes data from the head and neck squamous cell carcinoma (HNSCC) and non-small cell lung cancer (NSCLC) expansion cohorts in the Ph1 FIH study (NCT03000257). Methods Patients (pts) with previously treated, advanced HNSCC and NSCLC received ABBV-181 IV, 250 mg Q2W or 500 mg Q4W to progression. Response was assessed by RECIST v1.1 and iRECIST. Results As of April 2019, 81 pts were dosed. Table . 1288P n (%) HNSCC n = 41 NSCLC n = 40 Median days on treatment, range 72, 1–407 71, 1–421 Dose: 250 mg/500 mg 31/10 19/21 …

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…

Short-term outcomes of colorectal cancer surgery in older patients : a novel nomogram predicting postoperative morbi-mortality

Abstract Purpose To analyze short-term outcomes of curative-intent cancer surgery in all adult patients diagnosed with colorectal cancer undergoing surgery from January 2010 to December 2019 and determine risk factors for postoperative complications and mortality. Methods Retrospective study conducted at a single tertiary university institution. Patients were stratified by age into two groups: < 75 years and ≥ 75 years. Primary outcome was the influence of age on 30-day complications and mortality. Independent risk factors for postoperative adverse events or mortality were analyzed, and two novel nomograms were constructed. Results Of the 1486 patients included, 580 were older (≥ 75 year…

Combination of the mTOR inhibitor ridaforolimus and the anti-IGF1R monoclonal antibody dalotuzumab: preclinical characterization and phase I clinical trial.

Abstract Purpose: Mammalian target of rapamycin (mTOR) inhibition activates compensatory insulin–like growth factor receptor (IGFR) signaling. We evaluated the ridaforolimus (mTOR inhibitor) and dalotuzumab (anti-IGF1R antibody) combination. Experimental Design: In vitro and in vivo models, and a phase I study in which patients with advanced cancer received ridaforolimus (10–40 mg/day every day × 5/week) and dalotuzumab (10 mg/kg/week or 7.5 mg/kg/every other week) were explored. Results: Preclinical studies demonstrated enhanced pathway inhibition with ridaforolimus and dalotuzumab. With 87 patients treated in the phase I study, main dose-limiting toxicities (DLT) of the combination were p…

Evaluation and clinical analyses of downstream targets of the Akt inhibitor GDC-0068.

Abstract Purpose: The oncogenic PI3K/Akt/mTOR pathway is an attractive therapeutic target in cancer. However, it is unknown whether the pathway blockade required for tumor growth inhibition is clinically achievable. Therefore, we conducted pharmacodynamic studies with GDC-0068, an ATP competitive, selective Akt1/2/3 inhibitor, in preclinical models and in patients treated with this compound. Experimental Design: We used a reverse phase protein array (RPPA) platform to identify a biomarker set indicative of Akt inhibition in cell lines and human-tumor xenografts, and correlated the degree of pathway inhibition with antitumor activity. Akt pathway activity was measured using this biomarker se…

Phase I Pharmacokinetic and Pharmacodynamic Dose-Escalation Study of RG7160 (GA201), the First Glycoengineered Monoclonal Antibody Against the Epidermal Growth Factor Receptor, in Patients With Advanced Solid Tumors

Purpose We conducted a phase I dose-escalation study to characterize the safety, efficacy, pharmacokinetic (PK), and pharmacodynamic properties of RG7160 (GA201), a humanized and glycoengineered immunoglobulin G1 anti–epidermal growth factor receptor (EGFR) monoclonal antibody with enhanced antibody-dependent cell-mediated cytotoxicity. Patients and Methods Seventy-five patients with advanced EGFR-positive solid tumors received RG7160 (50 to 1,400 mg) administered every week, every 2 weeks, or every 3 weeks. Dose escalation followed a three-plus-three trial design. Results No maximum-tolerated dose was reached for any dosing schedule. Common adverse events (AEs) included rash (80% of patien…

Understanding the clinical behavior of relapsed colon cancers with microsatellite instability relative to BRAF mutations

Background Microsatellite instable/deficient mismatch repair (MSI/dMMR) metastatic colorectal cancers have been reported to have a poor prognosis. Frequent co-occurrence of MSI/dMMR and BRAFV600E complicates the association. Patients and methods Patients with resected stage III colon cancer (CC) from seven adjuvant studies with available data for disease recurrence and MMR and BRAFV600E status were analyzed. The primary end point was survival after recurrence (SAR). Associations of markers with SAR were analyzed using Cox proportional hazards models adjusted for age, gender, performance status, T stage, N stage, primary tumor location, grade, KRAS status, and timing of recurrence. Results A…

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

Shortening adjuvant chemotherapy in stage III colon cancer: are we ready for a change?

Oxaliplatin-based adjuvant chemotherapy for 6 months is considered the standard of care after a curative resection in patients with stage III colon cancer. The addition of oxaliplatin provides a benefit on overall survival confirmed in three randomised phase 3 trials1–3 with an long-term absolute increase ranging from 2.7% to 6%. Since oxaliplatin was incorporated into the adjuvant setting more than a decade ago, the standard in adjuvant therapy has remained unchanged because of the lack of novel agents with relevant activity in this scenario. Unfortunately, this combination can have also acute and long-term side effects that can interfere with daily life activities in potentially cured pat…

The treatment of advanced gastric cancer: current strategies and future perspectives.

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 chemotherapy in localized and locally advanced rectal cancer: A systematic revision

Curative treatment of rectal cancer depends on an optimal surgical resection, with the addition of neoadjuvant radiotherapy (RT) with or without concomitant chemotherapy (ChT) in more advanced tumors. The role of adjuvant ChT is controversial and a more intensified neoadjuvant approach with the addition of ChT before or after RT, or even as single modality, is currently being explored in trials. A systematic review selecting randomised phase II and III trials on the role of ChT in localized rectal cancer was performed. Data show that neoadjuvant ChRT improves locoregional control in resected rectal cancer. Short-course RT (SCRT) could give similar outcomes to ChRT. The addition of oxaliplat…

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…

A First-in-Human Phase I Study of the ATP-Competitive AKT Inhibitor Ipatasertib Demonstrates Robust and Safe Targeting of AKT in Patients with Solid Tumors.

Abstract Activation of AKT signaling by PTEN loss or PIK3CA mutations occurs frequently in human cancers, but targeting AKT has been difficult due to the mechanism-based toxicities of inhibitors that target the inactive conformation of AKT. Ipatasertib (GDC-0068) is a novel selective ATP-competitive small-molecule inhibitor of AKT that preferentially targets active phosphorylated AKT (pAKT) and is potent in cell lines with evidence of AKT activation. In this phase I study, ipatasertib was well tolerated; most adverse events were gastrointestinal and grade 1–2 in severity. The exposures of ipatasertib ≥200 mg daily in patients correlated with preclinical TGI90, and pharmacodynamic studies co…

Open-label, multicentre expansion cohort to evaluate imgatuzumab in pre-treated patients with KRAS-mutant advanced colorectal carcinoma.

Abstract Aim Imgatuzumab (GA201) is a novel anti-epidermal growth factor receptor (anti-EGFR) antibody glycoengineered for enhanced antibody-dependent cell-mediated cytotoxicity (ADCC). We investigated the efficacy of imgatuzumab in patients with EGFR-positive, KRAS -mutant advanced colorectal cancer. Methods Patients received single-agent imgatuzumab (1400 mg on day 1 and 8 followed by q2W) as third line therapy in an open-label, multicentre, non-randomised, expansion study. The primary end-point was tumour response. Pre- and on-treatment biopsies and blood samples were investigated for biomarkers related to imgatuzumab’s believed mechanism of action (MoA). Results 25 patients were treated…

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…

Integrating Downstaging in the Risk Assessment of Patients With Locally Advanced Rectal Cancer Treated With Neoadjuvant Chemoradiotherapy: Validation of Valentini's Nomograms and the Neoadjuvant Rectal Score

Abstract Background Adjuvant chemotherapy is controversial in patients with locally advanced rectal cancer after preoperative chemoradiation. Valentini et al developed 3 nomograms (VN) to predict outcomes in these patients. The neoadjuvant rectal score (NAR) was developed after VN to predict survival. We aimed to validate these tools in a retrospective cohort at an academic institution. Patients and Methods VN and the NAR were applied to 158 consecutive patients with locally advanced rectal cancer treated with chemoradiation followed by surgery. According to the score, they were divided into low, intermediate, or high risk of relapse or death. For statistical analysis, we performed Kaplan-M…

In the literature: October 2018

Several trials with the check-point inhibitors pembrolizumab or nivolumab demonstrated some antitumour efficacy in chemorefractory advanced gastric cancer with a response rate ranging from 10% to 26%. However, no clear predictive biomarkers were found to facilitate a proper selection of patients. A series of 61 patients with advanced gastric cancer received second-line or third-line treatment with pembrolizumab in a prospective phase 2 trial.1 In a cooperative effort carried out by Korean and American investigators, a molecular characterisation of all tumours was performed including whole-exome sequencing and RNA sequencing of tissue biopsies, as well as circulating tumour DNA (ctDNA) from …

488P Patient-derived organoids as a tool for modelling localized colorectal cancer

Clinical application of mutational analysis in breast cancer patients: The relevance of PIK3CA analysis for precision medicine

Abstract Background The identification of biomarkers to drive treatment is one of the most important objectives of precision medicine. During last years, the role of PIK3CA mutations have been related to clinical benefit deriving from treatment with PI3K, and mTOR inhibitors. In breast cancer (BC), PIK3CA mutations are widely present and the use, in clinical trials, of selective inhibitors improved clinical outcomes. The aim of this study is to assess the value of a monocentric genomic screening program to select patients for trials with experimental targeted agents. Methods We examined PIK3CA mutation in a cohort of 312 metastatic BC patients diagnosed at Hospital Clinico Valencia-INCLIVA …