In the literature: July 2022.

Targeting HER2-AXL Heterodimerization To Overcome Resistance To HER2 Blockade In Breast Cance

An Open-Label Phase II Study Evaluating the Safety and Efficacy of Ramucirumab Combined With mFOLFOX-6 as First-Line Therapy for Metastatic Colorectal Cancer

Background.Vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR-2) are believed to mediate angiogenesis in colorectal cancer (CRC). Ramucirumab (RAM; IMC-1121B) is a human IgG1 monoclonal antibody that inhibits VEGF ligand binding to VEGFR-2, inhibiting VEGFR-2 activation and signaling.Methods.Patients with metastatic CRC, Eastern Cooperative Oncology Group performance status 0–1, and adequate organ function who had not received chemotherapy for metastatic disease received RAM and the modified FOLFOX-6 regimen every 2 weeks. Endpoints included progression-free survival (PFS), objective response rate, overall survival, and safety. The sample size was based on a potentially improved median PFS from 8 months to 11 months.Results.Forty-eight patients received therapy. Median PFS was 11.5 months (95% confidence interval [CI]: 8.6–13.1 months). The objective response rate was 58.3% (95% CI: 43.21–72.39). The disease control rate (complete or partial response plus stable disease) was 93.8% (95% CI: 82.8–98.7). Median overall survival was 20.4 months (95% CI: 18.5–25.1 months). The most frequent grade 3–4 adverse events included neutropenia (grade 3: 33.3%; grade 4: 8.3%), hypertension (grade 3: 16.7%), and neuropathy (grade 3: 12.5%). Two patients died during the study due to myocardial infarction and cardiopulmonary arrest.Conclusion.RAM may enhance the efficacy of modified FOLFOX-6 chemotherapy with an acceptable safety profile in metastatic CRC

The LEGACy study: a European and Latin American consortium to identify risk factors and molecular phenotypes in gastric cancer to improve prevention strategies and personalized clinical decision making globally

Background: Gastric Cancer (GC) is the fourth most deadly cancer worldwide. Enhanced understanding of its key epidemiological and molecular drivers is urgently needed to lower the incidence and improve outcomes. Furthermore, tumor biology in European (EU) and Latin American (LATAM) countries is understudied. The LEGACy study is a Horizon 2020 funded multi-institutional research approach to 1) detail the epidemiological features including risk factors of GC in current time and 2) develop cost-effective methods to identify and integrate biological biomarkers needed to guide diagnostic and therapeutic approaches with the aim of filling the knowledge gap on GC in these areas. Methods: This observational study has three parts that are conducted in parallel during 2019-2023 across recruiting centers from four EU and four LATAM countries: Part 1) A case-control study (800 cases and 800 controls) using questionnaires on candidate risk factors for GC, which will be correlated with clinical, demographic and epidemiological parameters. Part 2) A case-control tissue sampling study (400 cases and 400 controls) using proteome, genome, microbiome and immune analyses to characterize advanced (stage III and IV) GC. Patients in this part of the study will be followed over time to observe clinical outcomes. The first half of samples will be used as training cohort to identify the most relevant risk factors and biomarkers, which will be selected to propose cost-effective diagnostic and predictive methods that will be validated with the second half of samples. Part 3) An educational study, as part of our prevention strategy (subjects recruited from the general public) to test and disseminate knowledge on GC risk factors and symptoms by a questionnaire and informative video. Patients could be recruited for more than one of the three LEGACy studies

Prognostic implications of circumferential location of distal rectal cancer

Aim: This study evaluated the prognostic importance of circumferential tumour position of mid and low rectal cancers. Method: All uT2, uT3 and uT4 tumours of the middle and lower rectum that underwent total mesorectal excision (TME) with curative intent between 1996 and 2006 were included. The predominant circumferential tumour position (anterior, posterior or circumferential) was defined on preoperative endorectal ultrasound examination (ERUS). The relationships between tumour position and other characteristics and recurrence were explored. Results: Two hundred and five patients with distal rectal cancer were operated on for a uT2-T4 tumour. Median follow up was 49 months. The location of the tumour was predominantly anterior, posterior or circumferential in 128, 49 and 27 patients, respectively. Anterior tumours were more likely to receive neoadjuvant therapy (P = 0.016) and perioperative blood transfusion (P = 0.012). No significant differences were observed between circumferential position and pT or pN stage, circumferential resection margin involvement or mesorectal excision quality. Sixty-three (30.7%) patients developed recurrence, which was local only in 16 (7.8%). Although tumours involving 360° of the rectal wall had a higher risk of local recurrence (P = 0.048), those with a predominant anterior or posterior position were not related to a higher risk of local or overall recurrence. Conclusion: Anterior rectal tumours do not differ in pathological characteristics from posterior tumours, and their prognosis is no worse when circumferential resection is complete

Real time quantification in plasma of human telomerase reverse transcriptase (hTERT) mRNA in patients with colorectal cancer

Background: Increased telomerase activity can be found in almost 90% of colorectal tumours. We aim to describe the preliminary results for quantification in plasma of hTERT mRNA in colorectal cancer patients. Materials and methods: Fifty patients undergoing surgery for colorectal cancer and a control group of 50 healthy volunteers were prospectively studied. Pre-operative venous blood samples were taken from all cancer patients and volunteers. Plasma hTERT expression was determined from peripheral blood based on real-time quantitative RT-PCR (qRT-PCR) method normalized to the amount of RNA input using 18S rRNA gene expression. Plasma pre-operative CEA levels were also determined. Results: Median values for normalized hTERT (hTERT(N)) gene expression were higher in colorectal cancer patients (11.62, range 0.23-47.67) than healthy volunteers (0.29, range 0.00-4.63) (P 0.05). No significant correlation was found between hTERT(N) expression and CEA values (Spearman's rank test = 0.136, P = 0.348). Conclusions: These results show that detection of mRNA based on the qRT-PCR of the telomerase hTERT(N) gene in plasma clearly differentiates between healthy and colorectal cancer patients and that hTERT(N) can be detected and quantified in plasma. This opens up a new field as a noninvasive blood test for colorectal cancer diagnosis

Macroscopic assessment of mesorectal excision in rectal cancer: a useful tool for improving quality control in a multidisciplinary team

Background: High quality of surgical technique and the use of descriptive measures to assess and report surgical proficiency have been shown to influence locoregional tumor control in patients with rectal cancer. In this study, the authors have aimed to audit the implementation of a macroscopic assessment of mesorectal excision (MAME) and to investigate factors that influenced surgical quality and disease recurrence. Methods: All curative resections for rectal cancer were prospectively evaluated for MAME between 1998 and 2007. Mesorectal specimens were graded into 3 types: complete, nearly complete, and incomplete categories. Univariate and multivariate analyses identified independent risk factors for noncomplete mesorectum categories as well as local and overall tumor recurrence. Results: Of 359 specimens, 294 (81.9%) underwent evaluation; 82.3% were 'complete.' Abdominoperineal resection (APR) was the sole covariate associated with inadequate mesorectal excision (odds ratio [OR]=2.7; P=.003). Independent predictors of local recurrence were circumferential resection margin (CRM) involvement (OR=3.6; P=.027) and noncomplete mesorectum (OR=4.4; P=.008). CRM+ (OR=3.1; P=.004), poorly differentiated tumors (OR=14.2; P=.010), nodal involvement (OR=2.9; P=.010), and APR (OR=2.9; P=.006) were independent risk factors for overall recurrence. In lower third tumors, noncomplete mesorectum occurred more frequently in APR compared with sphincter-saving procedures (31.1% vs 18.8%; P=.088). Conclusions: This study demonstrates the value of auditing MAME. Good proficiency of mesorectal excision is associated with lower tumor recurrences after curative surgery, and is a morphological tool found to be useful in clinical practice

Sequencing paired tumor DNA and white blood cells improves circulating tumor DNA tracking and detects pathogenic germline variants in localized colon cancer

In the setting of localized colon cancer (CC), circulating tumor DNA (ctDNA) monitoring in plasma has shown potential for detecting minimal residual disease (MRD) and predicting a higher risk of recurrence. With the tumor-only sequencing approach, however, germline variants may be misidentified as somatic variations, precluding the possibility of tracking in up to 11% of patients due to a lack of known somatic mutations. In this study, we assess the potential value of adding white blood cells (WBCs) to tumor tissue sequencing to enhance the accuracy of sequencing results. Patients and Methods: A total of 148 patients diagnosed with localized CC were prospectively recruited at the Hospital Clínico Universitario in Valencia (Spain). Employing a custom 29-gene panel, sequencing was conducted on tumor tissue, plasma and corresponding WBCs. Droplet digital PCR and amplicon-based NGS were performed on plasma samples post-surgery to track MRD. Oncogenic somatic variants were identified by annotating with COSMIC, OncoKB and an internal repository of pathogenic mutations database. A variant prioritization analysis, mainly characterized by the match of oncogenic mutations with the evidence levels defined in OncoKB, was carried out to select specific targeted therapies. Results: Utilizing paired tumor and WBCs sequencing, we identified somatic mutations in all patients (100%) within our cohort, compared to 89% using only tumor tissue. Consequently, the top 10 most frequently mutated genes for plasma monitoring were altered. The sequencing of WBCs identified 9% of patients with pathogenic mutations in the germline, with APC and TP53 being the most frequently mutated genes. Additionally, mutations in genes related to clonal hematopoiesis of indeterminate potential were detected in 27% of the cohort, with TP53, KRAS, and KMT2C being the most frequently altered genes. There were no observed differences in the sensitivity of monitoring MRD using ddPCR or amplicon-based NGS (p ¼ 1). Ultimately, 41% of the patients harbored potentially targetable alterations at diagnosis. Conclusion: The germline testing method not only enhanced sequencing results and raised the proportion of patients eligible for plasma monitoring, but also uncovered the existence of pathogenic germline variations, thereby aiding in the identification of patients at a higher risk of hereditary cancer syndromes