Update of the recommendations for the determination of biomarkers in colorectal carcinoma: National Consensus of the Spanish Society of Medical Oncology and the Spanish Society of Pathology.

In this update of the consensus of the Spanish Society of Medical Oncology (Sociedad Española de Oncología Médica-SEOM) and the Spanish Society of Pathology (Sociedad Española de Anatomía Patológica-SEAP), advances in the analysis of biomarkers in advanced colorectal cancer (CRC) as well as susceptibility markers of hereditary CRC and molecular biomarkers of localized CRC are reviewed. Recently published information on the essential determination of KRAS, NRAS and BRAF mutations and the convenience of determining the amplification of human epidermal growth factor receptor 2 (HER2), the expression of proteins in the DNA repair pathway and the study of NTRK fusions are also evaluated. From the pathological point of view, the importance of analysing the tumour budding and poorly differentiated clusters, and its prognostic value in CRC is reviewed, as well as the impact of molecular lymph node analysis on lymph node staging in CRC. The incorporation of pan-genomic technologies, such as next-generation sequencing (NGS) and liquid biopsy in the clinical management of patients with CRC is also outlined. All these aspects are developed in this guide, which, like the previous one, will remain open to any necessary revision in the future.

TRIM72 Immunohistochemical Expression Can Predict Relapse in Colorectal Carcinoma.

Large bowel adenocarcinoma is one of the most frequent human neoplasms and despite recent insights into the pathophysiology and molecular basis of this disease, mortality remains high in advanced and metastatic cases. Most guidelines recommend adjuvant chemotherapy for tumours involving lymph nodes, but not for patients with localized stage I or II disease. However, it is well known that approximately 20% of stage II colorectal carcinoma patients eventually recur, mainly with distant or peritoneal involvement and show bad prognosis. It would be important to predict which patients are at increased risk of recurrence to guide potential adjuvant therapy use in this controversial setting. In this sense, only microsatellite stability has been proposed as a predictive tool in some guidelines. The tripartite motif family protein 72 (TRIM72) is a ubiquitin ligase, involved in the cell membrane repair machinery and known to be associated to insulin resistance. Its potential role in colon cancer has recently been proposed. The aim of this study is to determine the potential predictive value of TRIM72 immunohistochemical expression in stage II colon carcinoma. We have retrospectively reviewed a series of 95 patients with stage II colon microsatellite stable carcinomas operated with a curative intent at a single large tertiary hospital in Madrid (Spain) between 2006 and 2012. None of the patients received adjuvant chemotherapy. We reviewed the histopathological slides and constructed a tissue microarray (TMA) of three representative areas to perform immunohistochemical staining for TRIM72. In our series 30 patients (31.7%) recurred after a median follow-up of 17.5 months. Lack of immunohistochemical expression of TRIM72 in the tumor was significantly and independently associated to recurrence. A recent report by Chen et al. has shown that TRIM72 can be measured in plasma for colon carcinoma detection as an alternative to CEA or CA19.9, with lower levels in patients with carcinoma. Our report is the first one to show that lower immunohistochemical expression of TRIM72 predicts recurrence in colon stage II carcinoma. We feel this predictive influence can be related to its crucial role as a central regulator in many signaling pathways (PI3K-AKT, ERK). As an ubiquitin ligase, the lack of TRIM72 could increase the levels of several potential oncogenic molecules and therefore lead to a more aggressive phenotype. It remains to be shown whether chemotherapy could change the clinical behaviour of this bad prognosis group. We propose TRIM72 immunohistochemical analysis as a potential tool to predict recurrence risk in stage II colon carcinoma patients. Our results should be confirmed in larger series, but could open the way to management strategies refinement in this early stage group of patients.

Author Correction: Combination of KIR2DS4 and FcγRIIa polymorphisms predicts the response to cetuximab in KRAS mutant metastatic colorectal cancer.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Combination of KIR2DS4 and FcγRIIa polymorphisms predicts the response to cetuximab in KRAS mutant metastatic colorectal cancer.

Cetuximab is a standard-of-care treatment for RAS wild-type metastatic colorectal cancer (mCRC) but not for those harbor a KRAS mutation since MAPK pathway is constitutively activated. Nevertheless, cetuximab also exerts its effect by its immunomodulatory activity despite the presence of RAS mutation. The aim of this study was to determine the impact of polymorphism FcγRIIIa V158F and killer immunoglobulin-like receptor (KIR) genes on the outcome of mCRC patients with KRAS mutations treated with cetuximab. This multicenter Phase II clinical trial included 70 mCRC patients with KRAS mutated. We found KIR2DS4 gene was significantly associated with OS (HR 2.27; 95% CI, 1.08-4.77; P = 0.03). In non-functional receptor homozygotes the median OS was 2.6 months longer than in carriers of one copy of full receptor. Multivariate analysis confirmed KIR2DS4 as a favorable prognostic marker for OS (HR 6.71) in mCRC patients with KRAS mutation treated with cetuximab. These data support the potential therapeutic of cetuximab in KRAS mutated mCRC carrying non-functional receptor KIR2DS4 since these patients significantly prolong their OS even after heavily treatment. KIR2DS4 typing could be used as predictive marker for identifying RAS mutated patients that could benefit from combination approaches of anti-EGFR monoclonal antibodies and other immunotherapies to overcome the resistance mediated by mutation in RAS.

Prognostic value of Ki-67 according to age in patients with triple-negative breast cancer.

PURPOSE: The prognostic value of Ki-67 in triple-negative breast cancer (TNBC) is yet unclear because the cut-off points employed differ widely and its predictive effect may vary according to age. The purpose of this study was to analyze the role of Ki-67 among patients with TNBC, and determine the optimal Ki-67 cut-off point to demonstrate its prognostic relevance associated with patient age and treatment strategy. METHODS/PATIENTS: 201 consecutive patients treated for primary TNBC from 1999 to 2014 were analyzed. Clinicopathological characteristics and outcomes were compared between patients treated with neoadjuvant or adjuvant chemotherapy. We used time-dependent receiver operating characteristic (ROC) curve and time-dependent area under the ROC curve (AUC) to evaluate the discriminative ability of Ki-67 at 3 and 5 years of follow-up. A Ki-67 cut-off point that maximized sensibility and specificity was established. Interaction effect between age and Ki-67 on disease-free survival (DFS) and overall survival (OS) was evaluated by stratified analysis. RESULTS: According to the coordinates of the ROC curves, the best cut-off point for Ki-67 was 60% (high/low). In the whole group, there was not a statistically significant association between Ki-67 and OS and DFS, using a cut-off point of 60%. In multivariate analysis (COX proportional hazards regression), for DFS high Ki-67 (> 60%) was a poor prognostic factor in patients > 40 years old and a better prognostic factor among the patients < 40 years old. CONCLUSION: Prognostic value of Ki-67 in TNBC, using a cut-off point of 60%, may vary depending on age.

Laparoscopic paraaortic surgical staging in locally advanced cervical cancer: a single-center experience.

BACKGROUND: One aim of this study was to assess the efficacy and safety of laparoscopic paraaortic lymphadenectomy for paraaortic lymph node staging in locally advanced cervical carcinoma. The second aim was to identify prognostic factors in the evolution of this disease and to evaluate how the results of the surgery modify the oncological treatment of patients. MATERIALS AND METHODS: We analyzed 59 patients diagnosed with locally advanced cervical cancer International Federation of Gynecology and Obstetrics stage IB2-IVA who underwent laparoscopic paraaortic lymphadenectomy at our hospital between 2009 and 2015. Depending on the results of the paraaortic lymphadenectomy, treatment consisted of pelvic- or extended-field chemoradiotherapy. RESULTS: The mean age at diagnosis was 52.3 years. The median operative time was 180 min. The mean hospital stay was 1.7 days. The mean number of paraaortic lymph nodes excised was 16.4. Eight patients (13.5%) had positive paraaortic lymph nodes. Thirteen patients (22%) underwent surgery via the transperitoneal route, and 46 (78%) underwent surgery via the retroperitoneal route. The sensitivity and specificity of computerized axial tomography (CT) scanning for detecting paraaortic lymph node involvement was 75 and 86%, respectively. The statistically significant prognostic factors that affected survival were surgical paraaortic lymph node involvement, radiological pelvic lymph node involvement, and radiological tumor size as assessed with nuclear magnetic resonance. The rate of serious complications was 1.7%. CONCLUSIONS: Pretherapeutic laparoscopic paraaortic lymphadenectomy for locally advanced cervical carcinoma allows the adaption of radiotherapy fields to avoid false-positive and false-negative imaging results.

The potential predictive value of DEK expression for neoadjuvant chemoradiotherapy response in locally advanced rectal cancer.

BACKGROUND: Limited data are available regarding the ability of biomarkers to predict complete pathological response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer. Complete response translates to better patient survival. DEK is a transcription factor involved not only in development and progression of different types of cancer, but is also associated with treatment response. This study aims to analyze the role of DEK in complete pathological response following chemoradiotherapy for locally advanced rectal cancer. METHODS: Pre-treated tumour samples from 74 locally advanced rectal-cancer patients who received chemoradiation therapy prior to total mesorectal excision were recruited for construction of a tissue microarray. DEK immunoreactivity from all samples was quantified by immunohistochemistry. Then, association between positive stained tumour cells and pathologic response to neoadjuvant treatment was measured to determine optimal predictive power. RESULTS: DEK expression was limited to tumour cells located in the rectum. Interestingly, high percentage of tumour cells with DEK positiveness was statistically associated with complete pathological response to neoadjuvant treatment based on radiotherapy and fluoropyrimidine-based chemotherapy and a marked trend toward significance between DEK positiveness and absence of treatment toxicity. Further analysis revealed an association between DEK and the pro-apoptotic factor P38 in the pre-treated rectal cancer biopsies. CONCLUSIONS: These data suggest DEK as a potential biomarker of complete pathological response to treatment in locally advanced rectal cancer.

Oncologist's knowledge and implementation of guidelines for breakthrough cancer pain in Spain: CONOCE study.

PURPOSE: Breakthrough cancer pain (BTcP) has been shown to be a prevalent and poor prognostic factor for oncologic patients, which remain under diagnosed and undertreated. In 2012, the Spanish Society of Medical Oncology (SEOM) published a clinical practice guideline (CPG) for the treatment of cancer pain which specifically addressed the management of BTcP. METHODS: Fundación ECO designed a qualitative study using an Internet-based survey to investigate the attitudes toward, compliance with, and use of SEOM Guideline. RESULTS: A total of 83 oncologists with a mean experience of 13 years responded. Overall, 82% were aware of different guidelines to manage BTcP. Notably, attitudes toward guidelines were highly positive and there was nearly unanimous agreement that CPG provided the best scientific evidence available (99%), on the minimum information to be gathered for the medical history (100%), on the need for a specific treatment for BTcP (100%), and fentanyl as the first-choice drug (99%). Interestingly, there were discrepancies between what oncologists agreed with and what they do in clinical practice. In fact, 87.6% declare full compliance with SEOM guideline, although adherence to registration of BTcP data in medical records ranged from 30.1 to 91.6% (mean 64.5%); therapeutic management compliance was higher ranging from 75.9 to 91.6%. Main barriers identified were time pressure together with vague statements and limited dissemination of the guidelines. CONCLUSION: Despite oncologist's clinical practice is increasingly guided by GPC, it suffers from limited compliance, at least in part due to suboptimal statements. Improved dissemination and education are needed to enhance guideline implementation.

Incorporating BEAMing technology as a liquid biopsy into clinical practice for the management of colorectal cancer patients: an expert taskforce review.

The importance of mutation identification for advanced colorectal cancer treatment with anti-epidermal growth factor receptor agents is well established. However, due to delays in turnaround time, low-quality tissue samples, and/or lack of standardization of testing methods a significant proportion of patients are being treated without the information that Kirsten rat sarcoma and neuroblastoma rat sarcoma (RAS) testing can provide. The detection of mutated circulating tumor DNA by BEAMing technology addresses this gap in care and allows these patients to receive international guideline-recommended expanded RAS testing with rapid turnaround times. Furthermore, the overall concordance between OncoBEAM RAS colorectal cancer testing and standard of care tissue testing is very high (93.3%). This article presents an overview of the clinical utility and potential applications of this minimally invasive method, such as early detection of emergent resistance to anti-epidermal growth factor receptor therapy. If appropriately implemented, BEAMing technology holds considerable promise to enhance the quality of patient care and improve clinical outcomes.

Predictors of psychological distress in advanced cancer patients under palliative treatments.

This work aims to investigate the factors associated with psychological distress in advanced cancer patients under palliative treatment. We comprehensively assessed the demographic, psychosocial and health factors of 158 advanced cancer patients. Patients with high and low distress, according to the Hospital Anxiety and Depression Scale, were compared. A regression analysis was built to identify the best predictors of distress. Patients with high psychological distress (81%) were more likely to have lung cancer, suicidal ideation, hopelessness, low quality of life and poor body image than those without. In the multivariate model, only poor emotional functioning (OR = .89; 95% CI = .83-.95; p ≤ .001), hopelessness (OR = .86; 95% CI = .78-.94; p ≤ .001) and body image distortions (OR = .77; 95% CI = .68-.85; p = .005) were retained. High levels of hopelessness, impaired emotional functioning and body image distortions are the main factors associated with psychological distress in patients with advanced cancer. Potential interventions to modify these factors in palliative units are discussed.

Is regorafenib providing clinically meaningful benefits to pretreated patients with metastatic colorectal cancer?

Treatment with regorafenib has demonstrated statistically significant improvements in terms of overall survival, progression-free survival and disease control when compared with placebo in pretreated patients with metastatic colorectal cancer in two placebo-controlled, randomized, phase III trials (CORRECT and CONCUR). Similar results were observed in two open-label, single-arm studies (REBECCA and CONSIGN) performed in the real-world setting. But several authors have suggested that the benefit provided by regorafenib may not be clinically meaningful for these patients. Moreover, it has been suggested that not all subgroups of patients might benefit from regorafenib. The intention of this review is to provide an overview of the existing evidence for regorafenib in terms of efficacy, tolerability and quality of life in different subpopulations according to clinical and biological characteristics. Additionally, the magnitude of the clinical benefit provided by regorafenib to these patients has been explored and whether there are poorer outcomes in certain subpopulations.

PLK-1 Expression is Associated with Histopathological Response to Neoadjuvant Therapy of Hepatic Metastasis of Colorectal Carcinoma.

Polo-like kinase 1 (PLK1) is a serine/threonine-protein kinase expressed during mitosis and overexpressed in multiple human cancers, including leukemia and also many solid tumors. PLK1 knockdown has been shown to block proliferation of leukemic cell lines and the clonogenic potential of tumor cells grown from patients with cancer. PLK1 inhibition is a promising strategy for the treatment of some tumors. We aim to analyze expression of PLK1 in metastatic colorectal carcinoma. Retrospective analysis of colorectal carcinomas with hepatic metastasis during follow-up receiving neoadjuvant chemotherapy (NAC), based on oxaliplatin. Immunohistochemistry for PLK-1 in paraffin-embedded tissue from the primary and also from the metastasis. 50 patients. 32% showed good histopathological response. 43% of the primaries were positive for PLK1, as opposed to 23.5% of the metastasis. Expression of PLK1 was significantly reduced in metastasis compared with the primaries (p = 0.05), what could be due to therapy or to a phenotypic change of the metastatic nodule. Analysis of the prognostic influence of PLK1 expression showed significant association between PLK1 expression in metastasis and lower overall survival (p = 0.000). We have also found a significant association between PLK1 expression and histopathological response (p = 0.02). All the tumors with high expression of PLK1 showed minor response (11/11). This study shows the association between survival and poor histopathological response to therapy and high expression of PLK1 in metastasis. Our results could open a new therapeutic approach through the inhibition of PLK1.

Suicide ideation among oncologic patients in a Spanish ward.

Oncologic patients are exposed to a higher risk of suicidal behaviors than the general population. In this study, we aim to examine the severity of suicidal ideation in a sample of oncologic patients considering different psychological and clinical features. We interviewed 202 inpatients receiving curative or palliative treatment in a medical oncology ward of a Spanish hospital during the period 2012-2014. A complete assessment of psychosocial factors, cancer diagnoses (lung, colon rectum, and genitourinary system), and suicidal behaviors were made during admission, including validated questionnaires about depression, anxiety, personality, quality of life, body image, life threatening events, hopelessness, and suicidal ideation. The characteristics of inpatients with high and low suicidal ideation were retrospectively compared. A logistic regression model was constructed to examine the relationship between the significant factors retained after the univariate analyses. One of every four patients (n = 51; 25.24%) presented high scores of suicidal ideation. Logistic regression analyses retained depression (OR = 3.55; 95% CI = 1.25-11.68; p = .016), hopelessness (OR = 8.78; 95% CI = 3.44-25.88; p ≤ .001), personality (OR = .44; 95% CI = .2-.96; p = .038), and advanced age (OR = 2.60; 95% CI = 1.18-5.98; p = .016) as the main risk factors for high suicidal ideation. Suicidal ideation was frequent among oncologic patients. These patients should receive closer monitoring, especially, when old, retired, or severely depressed.

Clinical guideline SEOM: hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) represents the second leading cause of cancer-related death worldwide. Surveillance with abdominal ultrasound every 6 months should be offered to patients with a high risk of developing HCC: Child-Pugh A-B cirrhotic patients, all cirrhotic patients on the waiting list for liver transplantation, high-risk HBV chronic hepatitis patients (higher viral load, viral genotype or Asian or African ancestry) and patients with chronic hepatitis C and bridging fibrosis. Accurate diagnosis, staging and functional hepatic reserve are crucial for the optimal therapeutic approach. Characteristic findings on dynamic CT/MR of arterial hyperenhancement with "washout" in the portal venous or delayed phase are highly specific and sensitive for a diagnosis of HCC in patients with previous cirrhosis, but a confirmed histopathologic diagnosis should be done in patients without previous evidence of chronic hepatic disease. BCLC classification is the most common staging system used in Western countries. Surgical procedures, local therapies and systemic treatments should be discussed and planned for each patient by a multidisciplinary team according to the stage, performance status, liver function and comorbidities. Surgical interventions remain as the only curative procedures but both local and systemic approaches may increase survival and should be offered to patients without contraindications.

Identification of Poor-outcome Biliopancreatic Carcinoma Patients With Two-marker Signature Based on ATF6α and p-p38 "STARD Compliant".

Biliopancreatic cancer is one of the most aggressive solid neoplasms, and incidence is rising worldwide. It is known that ATF6α is one of the transmembrane proteins that acts crucially in endoplasmic reticulum stress response, and knockdown induces apoptosis of pancreatic cells. Apart from this, p-p38 has been previously correlated with better outcome in pancreatic cancer. Interestingly, ATF6α knockdown pancreatic cells showed increased p-p38. The aim of this study was to evaluate the expression of these 2 proteins, p-p38 and ATF6α, and their correlation with the outcome of biliopancreatic adenocarcinoma patients. Samples from patients with biliopancreatic adenocarcinoma that underwent pancreaticoduodenectomy from 2007 to 2013 were used to construct a tissue microarray to evaluate p-p38 and ATF6α proteins by immunohistochemistry. We observed that both markers showed a tendency to impact in the time to recurrence; then a combination of these 2 proteins was analyzed. Combination of ATF6α(high) and p-p38(low) was strongly associated with a higher risk of recurrence (hazard ratio 2.918, P = 0.013). This 2-protein model remained significant after multivariate adjustment.We proposed a 2-protein signature based on ATF6α(high) and p-p38(low) as a potential biomarker of risk of recurrence in resected biliopancreatic adenocarcinoma patients.

Updated guidelines for biomarker testing in colorectal carcinoma: a national consensus of the Spanish Society of Pathology and the Spanish Society of Medical Oncology.

Publication of this consensus statement is a joint initiative of the Spanish Society of Pathology (SEAP) and the Spanish Society of Medical Oncology (SEOM), intended to revise and update the diagnostic and treatment recommendations published 2 years ago on biomarker use and the management of patients with colorectal carcinoma (CRC), thereby providing an opportunity to improve healthcare efficiency and resource use in these patients. This expert group recommends testing for KRAS and NRAS status in all patients with metastatic CRC being considered for anti-epidermal growth factor receptor (anti-EGFR) therapy, as this type of treatment should only be used in patients not harbouring mutations in these genes. In contrast, testing for BRAF, EGFR, PI3K and PTEN mutation status is not necessary for therapeutic decision making, so does not need to be done routinely.