Targeting KRAS in Pancreatic Ductal Adenocarcinoma: The Long Road to Cure.

Pancreatic ductal adenocarcinoma (PDAC) remains an important cause of cancer-related mortality, and it is expected to play an even bigger part in cancer burden in the years to come. Despite concerted efforts from scientists and physicians, patients have experienced little improvement in survival over the past decades, possibly because of the non-specific nature of the tested treatment modalities. Recently, the discovery of potentially targetable molecular alterations has paved the way for the personalized treatment of PDAC. Indeed, the central piece in the molecular framework of PDAC is starting to be unveiled. KRAS mutations are seen in 90% of PDACs, and multiple studies have demonstrated their pivotal role in pancreatic carcinogenesis. Recent investigations have shed light on the differences in prognosis as well as therapeutic implications of the different KRAS mutations and disentangled the relationship between KRAS and effectors of downstream and parallel signaling pathways. Additionally, the recognition of other mechanisms involving KRAS-mediated pathogenesis, such as KRAS dosing and allelic imbalance, has contributed to broadening the current knowledge regarding this molecular alteration. Finally, KRAS G12C inhibitors have been recently tested in patients with pancreatic cancer with relative success, and inhibitors of KRAS harboring other mutations are under clinical development. These drugs currently represent a true hope for a meaningful leap forward in this dreadful disease.

Minimal Residual Disease in Colorectal Cancer: Are We Finding the Needle in a Haystack?

Despite significant advances in the surgical and systemic therapy of colorectal cancer (CRC) in recent decades, recurrence rates remain high. Apart from microsatellite instability status, the decision to offer adjuvant chemotherapy to patients with CRC is solely based on clinicopathologic factors, which offer an inaccurate risk stratification of patients who derive benefit from adjuvant therapy. Owing to the recent improvements of molecular techniques, it has been possible to detect small allelic fractions of circulating tumor DNA (ctDNA), and therefore, to identify patients with minimal residual disease (MRD) after curative-intent therapies. The incorporation of ctDNA identifying MRD in clinical practice may dramatically change the standard of care of CRC, refining the selection of patients who are candidates for escalation and de-escalation of adjuvant chemotherapy, and even for organ-preservation strategies in rectal cancer. In the present review, we describe the current standard of care and the DNA sequencing methodologies and assays, present the data from completed clinical studies and list ongoing potential landmark clinical trials whose results are eagerly awaited, as well as the impact and perspectives for the near future. The discussed data bring optimism for the future of oncologic care through the hope of refined utilization of adjuvant therapies with higher efficacy and safety for patients with both localized and advanced CRC.

Risk of Cancer in Inflammatory Bowel Disease and Pitfalls in Oncologic Therapy.

BACKGROUND: Inflammatory bowel disease (IBD), represented by ulcerative colitis and Crohn's disease, is an idiopathic condition caused by a dysregulated immune response to host intestinal microflora, leading to chronic relapsing intestinal inflammation. Individuals with IBD are more prone to die from several diseases, including cancer. METHODS: An extensive search was conducted of PubMed using the following medical subject heading-"inflammatory bowel disease" OR "Crohn's disease" OR "ulcerative colitis" AND "cancer." RESULTS: In this review article, we discuss the oncogenic mechanisms and genomics of colitis-associated colorectal cancer. Beyond this, we describe the multiple other malignancies that IBD patients are at risk for, discuss caveats in the screening and diagnosis of those cancers, and shed light on pitfalls on the management and treatment of cancer in IBD patients. CONCLUSION: Patients, caregivers, and health professionals who deal with IBD must be educated on how to identify warning signs so that cancers can be diagnosed and treated as early as possible.

Biologics in rectal cancer.

INTRODUCTION: Despite the use of multimodality therapy, locally advanced rectal cancer (LARC) still presents high rates of disease recurrence. Fluoropyrimidine-based chemotherapy concurrently with radiation therapy (RT) remains the cornerstone of neoadjuvant therapy of LARC, and novel therapies are urgently needed in order to improve the clinical outcomes. AREAS COVERED: We aim to summarize data from completed and ongoing clinical trials addressing the role of biological therapies, including monoclonal antibodies, immune checkpoint inhibitors (ICIs), antibody-drug conjugates, bispecific antibodies, and gene therapies in the systemic therapy of rectal cancer. EXPERT OPINION: Deeper understanding of the molecular biology of colorectal cancer (CRC) has allowed meaningful advances in the systemic therapy of metastatic disease in the past few years. The larger applicability of biological therapy in CRC, including genome-guided targeted therapy, antiangiogenics, and immunotherapy, gives us optimism for the personalized management of rectal cancer. Microsatellite instability (MSI) tumors have demonstrated high sensitivity to ICIs, and preliminary findings in the neoadjuvant setting of rectal cancer are promising. To date, antiangiogenic and anti-EGFR therapies in LARC have not demonstrated the same benefit seen in metastatic disease. The outstanding results accomplished by biomarker-guided therapy in metastatic CRC will guide future developments of biological therapy in LARC.

Biomarkers in Anal Cancer: Current Status in Diagnosis, Disease Progression and Therapeutic Strategies.

Squamous cell carcinoma of the anal canal (SCCA) is a rare neoplasm, but with rising incidence rates in the past few decades; it is etiologically linked with the human papillomavirus (HPV) infection and is especially prevalent in immunocompromised patients, mainly those infected with HIV. Fluoropyrimidine-based chemoradiotherapy remains the cornerstone of the treatment of non-metastatic disease, but the locally advanced disease still presents high rates of disease recurrence and systemic therapy of SCCA is an unmet clinical need. Despite sharing common molecular aspects with other HPV-related malignancies, such as cervical and head and neck cancers, SCCA presents specific epigenomic, genomic, and transcriptomic abnormalities, which suggest that genome-guided personalized therapies should be specifically designed for this disease. Actionable mutations are rare in SCCA and immune checkpoint inhibition has not yet been proven useful in an unselected population of patients. Therefore, advances in systemic therapy of SCCA will only be possible with the identification of predictive biomarkers and the subsequent development of targeted therapies or immunotherapeutic approaches that consider the unique tumor microenvironment and the intra- and inter-tumoral heterogeneity. In the present review, we address the molecular characterization of SCCA and discuss potential diagnostic, predictive and prognostic biomarkers of this complex and challenging disease.

Anal Cancer: Emerging Standards in a Rare Disease.

The social stigma surrounding an anal cancer diagnosis has traditionally prevented open discussions about this disease. However, as recent treatment options and an increasing rate of diagnoses are made worldwide, awareness is growing. In the United States alone, 9,090 individuals were expected to be diagnosed with anal cancer in 2021. The US annual incidence of squamous cell carcinoma of the anus continues to increase by 2.7% yearly, whereas the mortality rate increases by 3.1%. The main risk factor for anal cancer is a human papillomavirus infection; those with chronic immunosuppression are also at risk. Patients with HIV are 19 times more likely to develop anal cancer compared with the general population. In this review, we have provided an overview of the carcinoma of the anal canal, the role of screening, advancements in radiation therapy, and current trials investigating acute and chronic treatment-related toxicities. This article is a comprehensive approach to presenting the existing data in an effort to encourage continuous international interest in anal cancer.

The Role of Immunotherapy in the Treatment of Anal Cancer and Future Strategies.

OPINION STATEMENT: Despite being markedly sensitive to chemoradiotherapy, patients with locally advanced (T3-4 and/or node-positive) squamous cell carcinoma of the anal canal (SCCA) still present high rates of disease recurrence, which is characterized by meaningful morbidity and mortality. Abdominoperineal resection as salvage surgery may be considered for patients with local recurrence, but with an important negative impact in the quality of life. Systemic therapy of advanced SCCA is an unmet clinical need. Palliative chemotherapy for the management of unresectable or metastatic disease yields approximately 60% of objective response rate; however, it still portends a grim prognosis. Based on the recently published InterAACT trial, carboplatin plus paclitaxel has become the standard of care of advanced disease; modified DCF (docetaxel, cisplatin, and 5-fluorouracil) may also be considered for fit patients amenable to intensive therapy. There are no FDA-approved therapies for the treatment of chemorefractory patients. Nevertheless, both nivolumab and pembrolizumab may be considered for these patients with promising results, regardless of PD-L1 expression or other predictive biomarkers. It is estimated that approximately 1 out of 5 patients with SCCA will derive large benefit from PD-1 inhibitors, which may produce considerable durations of response. Ongoing clinical trials exploring the combination of chemotherapy plus immune checkpoint inhibitors in the first-line therapy, combination of anti-PD-1/PD-L1 plus anti-CTLA-4, and emerging immunotherapeutic approaches, such as adoptive T cell therapies, are eagerly awaited and may bring practice-changing results in the next few years for the treatment of this challenging disease.

A comprehensive framework for early-onset colorectal cancer research.

Sporadic colorectal cancer has traditionally been viewed as a malignancy of older individuals. However, as the global prevalence of the disease diagnosed in younger individuals (<50 years) is expected to increase within the next decade, greater recognition is now being given to early-onset colorectal cancer. The cause of the predicted rise in prevalence is largely unknown and probably multifactorial. In this Series paper, we discuss the potential underlying causes of early-onset colorectal cancer, the role of energy balance, biological and genomic mechanisms (including microbiome aspects), and the treatment of early-onset colorectal cancer. We have specifically considered the psychosocial challenges of being diagnosed with colorectal cancer at younger age and the potential financial toxicity that might ensue. This Series paper brings a comprehensive review based on the existing data in the hopes of optimising the overall outcomes for patients with early-onset colorectal cancer.

Efficacy and Safety Associated With Immune Checkpoint Inhibitors in Unresectable Hepatocellular Carcinoma: A Meta-analysis.

Importance: Immune checkpoint inhibitors (ICIs) have yielded conflicting results in hepatocellular carcinoma (HCC). The overall effect of ICIs compared with standard therapies in unresectable HCC requires more research. Objective: To estimate the efficacy and safety associated with ICIs compared with standard therapies in patients with unresectable HCC. Data Sources: PubMed, Cochrane Library, Web of Science, Latin American and Caribbean Health Sciences Literature, and American Society of Clinical Oncology and European Society of Medical Oncology meeting proceedings were systematically searched. Reference lists from studies selected by electronic searching were manually searched to identify additional relevant studies. The search included literature published or presented from February 2010 to February 2020. Study Selection: From December 2019 to February 2020, independent reviewers evaluated each database, scanning the title, abstract, and keywords of every record retrieved. Full articles were further assessed if the information given suggested that the study was a randomized clinical trial (RCT) comparing ICIs vs standard therapies in the treatment of unresectable HCC. Data Extraction and Synthesis: The full text of the resulting studies and extracted data were reviewed independently according to PRISMA guidelines. Summary hazard ratios (HRs) of overall survival (OS) and progression-free survival (PFS) were calculated by a random-effects model. The likelihood of ICIs being associated with overall response rate (ORR) and treatment-related adverse events (TRAEs) was expressed by odds ratios (ORs) using a random-effects model. Main Outcomes and Measures: The main outcomes were OS, PFS, ORR, and TRAEs. Results: Of 1836 studies yielded by the search, 3 were retained, totaling 1657 patients (985 treated with ICIs vs 672 receiving standard treatment). Two studies evaluated ICIs as monotherapy, and 1 study investigated the combination of ICIs with bevacizumab. Compared with standard therapies (sorafenib in first-line therapy or placebo in second-line therapy), ICIs were associated with significantly improved OS (HR, 0.75; 95% CI, 0.62-0.92; P = .006), PFS (HR, 0.74; 95% CI, 0.56-0.97; P = .03), and ORR (OR, 2.82; 95% CI 2.02-3.93; P < .001). The probability of grade 3 or 4 TRAEs was lower with ICIs than with sorafenib (OR, 0.44; 95% CI, 0.20-0.96; P = .04). Conclusions and Relevance: This meta-analysis found superior efficacy and safety associated with ICIs compared with standard therapies and highlights the survival benefit associated with the combination of antiangiogenic therapy with ICIs in first-line systemic therapy of unresectable HCC.

Effect of Adding Bevacizumab to Chemotherapy on Pathologic Response to Preoperative Systemic Therapy for Resectable Colorectal Liver Metastases: A Systematic Review and Meta-analysis.

BACKGROUND: Liver-limited metastatic colorectal cancer is a potentially curable disease. Pathologic response (pR) to preoperative chemotherapy (CT) for colorectal liver metastases (CLM) is a surrogate endpoint for overall survival (OS). We conducted the first meta-analysis of observational studies to estimate the overall effect of bevacizumab on pR in preoperative systemic therapy for CLM. METHODS: We systematically searched PubMed, Cochrane Library, CINAHL, Web of Science, Embase, and LILACS for studies published between January 2004 and August 2019 that compared the pR of CT plus bevacizumab to CT alone as preoperative therapy for CLM. The primary endpoint was pathologic complete response (pCR). Secondary endpoints were pathologic major (pMaR) and minor (pMiR) response. Overall effects were expressed by odds ratios (ORs) and 95% confidence intervals (CIs) using a random-effects model. RESULTS: Of the 1,452 studies yielded by the search, 9 were eligible, totaling 1,202 patients (516 CT plus bevacizumab and 686 CT alone). The addition of bevacizumab to CT increased the pCR rate without reaching statistical significance (OR: 1.24, 95% CI 0.81 to 1.92, P = .32). However, pMaR was significantly higher (OR: 2.45, 95% CI 1.85 to 3.25, P < .001), and pMiR was significantly lower (OR: 0.41, 95% CI 0.31 to 0.54, P < .001), in the bevacizumab group. The analyses showed a low level of heterogeneity (I2 = 0% to 6%). Publication bias was not found. CONCLUSIONS: This meta-analysis demonstrates that bevacizumab plus preoperative CT is associated with higher rates of pR in CLM. Antiangiogenics might improve the OS of CLM patients and should be evaluated in randomized clinical trials. MICROABSTRACT: The benefit of perioperative chemotherapy for colorectal liver metastases (CLM) is uncertain, but pathologic response (pR) to preoperative chemotherapy is a strong prognostic factor. Our meta-analysis of observational studies compared the pR of bevacizumab plus chemotherapy to chemotherapy alone as preoperative systemic therapy in the management of CLM. The addition of bevacizumab was associated with significantly higher rates of pR.

Emerging and Experimental Agents for Anal Cancer: What is New?

Squamous cell carcinoma of the anal canal (SCCA) is an HPV-related malignancy with rising incidence in the past few decades in the US, characterized by high rates of complete response to chemoradiotherapy with curative intent. However, in a long-term follow-up, a meaningful subgroup of patients with locally advanced disease presents disease recurrence, which demands treatments with high morbidity and important impact in the quality of life. In metastatic or unresectable disease, palliative chemotherapy is the standard of care, but it is still associated with a dismal prognosis. Novel agents are urgently needed in the systemic therapy of SCCA. From a translational standpoint, there are many hurdles to overcome, since PI3KCA mutation is the most frequent genetic abnormality and actionable mutations are rarely found in SCCA, as well as it is characterized by low tumor mutational burden and low rates of high-frequency microsatellite instability. But the latest studies of immunotherapeutic approaches have produced promising findings and this therapeutic strategy is the major path being followed in the ongoing clinical trials. The latest advances in the systemic therapy of SCCA have provided the framework for the conception of new clinical trials. Therefore, carboplatin plus paclitaxel have become the backbone for novel agents. Immune checkpoint inhibitors (ICIs), mainly anti-PD-1 monoclonal antibodies, such as retifanlimab, nivolumab, and atezolizumab have been studied in Phase III trials with chemotherapy in first-line therapy. Likewise, ICIs have been evaluated in locally advanced and refractory disease. Novel technologies, such as bispecific antibodies, and immunotherapeutic approaches, such as vaccines and adoptive T-cell therapies, have also been tested in ongoing clinical trials. Immunotherapy may bring practice-changing advances in the systemic therapy of SCCA in the next few years and it might play a larger role in the therapeutic management of this challenging disease.

Development and Validation of a Novel Nomogram for Individualized Prediction of Survival in Cancer of Unknown Primary.

PURPOSE: Prognostic uncertainty is a major challenge for cancer of unknown primary (CUP). Current models limit a meaningful patient-provider dialogue. We aimed to establish a nomogram for predicting overall survival (OS) in CUP based on robust clinicopathologic prognostic factors. EXPERIMENTAL DESIGN: We evaluated 521 patients with CUP at MD Anderson Cancer Center (MDACC; Houston, TX; 2012-2016). Baseline variables were analyzed using Cox regression and nomogram developed using significant predictors. Predictive accuracy and discriminatory performance were assessed by calibration curves, concordance probability estimate (CPE ± SE), and concordance statistic (C-index). The model was subjected to bootstrapping and multi-institutional external validations using two independent CUP cohorts: V1 [MDACC (2017), N = 103] and V2 (BC Cancer, Vancouver, Canada and Sarah Cannon Cancer Center/Tennessee Oncology, Nashville, TN; N = 302). RESULTS: Baseline characteristics of entire cohort (N = 926) included: median age (63 years), women (51%), Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1 (64%), adenocarcinomas (52%), ≥3 sites of metastases (30%), and median follow-up duration and OS of 40.1 and 14.7 months, respectively. Five independent prognostic factors were identified: gender, ECOG PS, histology, number of metastatic sites, and neutrophil-lymphocyte ratio. The resulting model predicted OS with CPE of 0.69 [SE: ± 0.01; C-index: 0.71 (95% confidence interval: 0.68-0.74)] outperforming Culine/Seve prognostic models (CPE: 0.59 ± 0.01). CPE for external validation cohorts V1 and V2 were 0.67 (± 0.02) and 0.70 (± 0.01), respectively. Calibration curves for 1-year OS showed strong agreement between nomogram prediction and actual observations in all cohorts. CONCLUSIONS: Our user-friendly CUP nomogram integrating commonly available baseline factors provides robust personalized prognostication which can aid clinical decision making and selection/stratification for clinical trials.

Brazilian Group of Gastrointestinal Tumours' consensus guidelines for the management of oesophageal cancer.

Oesophageal cancer is among the ten most common types of cancer worldwide. More than 80% of the cases and deaths related to the disease occur in developing countries. Local socio-economic, epidemiologic and healthcare particularities led us to create a Brazilian guideline for the management of oesophageal and oesophagogastric junction (OGJ) carcinomas. The Brazilian Group of Gastrointestinal Tumours invited 50 physicians with different backgrounds, including radiology, pathology, endoscopy, nuclear medicine, genetics, oncological surgery, radiotherapy and clinical oncology, to collaborate. This document was prepared based on an extensive review of topics related to heredity, diagnosis, staging, pathology, endoscopy, surgery, radiation, systemic therapy (including checkpoint inhibitors) and follow-up, which was followed by presentation, discussion and voting by the panel members. It provides updated evidence-based recommendations to guide clinical management of oesophageal and OGJ carcinomas in several scenarios and clinical settings.

Determinants of COVID-19 Mortality in Patients With Cancer From a Community Oncology Practice in Brazil.

PURPOSE: The COVID-19 pandemic remains a public health emergency of global concern. Determinants of mortality in the general population are now clear, but specific data on patients with cancer remain limited, particularly in Latin America. MATERIALS AND METHODS: A longitudinal multicenter cohort study of patients with cancer and confirmed COVID-19 from Oncoclínicas community oncology practice in Brazil was conducted. The primary end point was all-cause mortality after isolation of the SARS-CoV-2 by Real-Time Polymerase Chain Reaction (RT-PCR) in patients initially diagnosed in an outpatient environment. We performed univariate and multivariable logistic regression analysis and recursive partitioning modeling to define the baseline clinical determinants of death in the overall population. RESULTS: From March 29 to July 4, 2020, 198 patients with COVID-19 were prospectively registered in the database, of which 167 (84%) had solid tumors and 31 (16%) had hematologic malignancies. Most patients were on active systemic therapy or radiotherapy (77%), largely for advanced or metastatic disease (64%). The overall mortality rate was 16.7% (95% CI, 11.9 to 22.7). In univariate models, factors associated with death after COVID-19 diagnosis were age ≥ 60 years, current or former smoking, coexisting comorbidities, respiratory tract cancer, and management in a noncurative setting (P < .05). In multivariable logistic regression and recursive partitioning modeling, only age, smoking history, and noncurative disease setting remained significant determinants of mortality, ranging from 1% in cancer survivors under surveillance or (neo)adjuvant therapy to 60% in elderly smokers with advanced or metastatic disease. CONCLUSION: Mortality after COVID-19 in patients with cancer is influenced by prognostic factors that also affect outcomes of the general population. Fragile patients and smokers are entitled to active preventive measures to reduce the risk of SARS-CoV-2 infection and close monitoring in the case of exposure or COVID-19-related symptoms.

The prognostic impact of RAS on overall survival following liver resection in early versus late-onset colorectal cancer patients.

BACKGROUND: The impact of molecular aberrations on survival after resection of colorectal liver metastases (CLM) in patients with early-age-onset (EOCRC) versus late-age-onset colorectal cancer (LOCRC) is unknown. METHODS: Patients who underwent liver resection for CLM with known RAS, BRAF and MSI status were retrospectively studied. The prognostic impact of RAS mutations by age was analysed with age as a categorical variable and a continuous variable. RESULTS: The study included 573 patients, 192 with EOCRC and 381 with LOCRC. The younger the age of onset of CRC, the greater the negative impact on overall survival of RAS mutations in the LOCRC, EOCRC, and ≤40 years (hazard ratio (HR), 1.64 (95% confidence interval (CI), 1.23-2.20), 2.03 (95% CI, 1.30-3.17), and 2.97 (95% CI, 1.44-6.14), respectively. Age-specific mortality risk and linear regression analysis also demonstrated that RAS mutations had a greater impact on survival in EOCRC than in LOCRC (slope: -4.07, 95% CI -8.10 to 0.04, P = 0.047, R2 = 0.08). CONCLUSION: Among patients undergoing CLM resection, RAS mutations have a greater negative influence on survival in patients with EOCRC, more so in patients ≤40 years, than in patients with LOCRC and should be considered as a prognostic factor in multidisciplinary treatment planning.

Brazilian Group of Gastrointestinal Tumours' consensus guidelines for the management of gastric cancer.

Gastric cancer is among the ten most common types of cancer worldwide. Most cases and deaths related to the disease occur in developing countries. Local socio-economic, epidemiologic and healthcare particularities led us to create a Brazilian guideline for the management of gastric carcinomas. The Brazilian Group of Gastrointestinal Tumors (GTG) invited 50 physicians with different backgrounds, including radiology, pathology, endoscopy, nuclear medicine, genetics, oncological surgery, radiotherapy and clinical oncology, to collaborate. This document was prepared based on an extensive review of topics related to heredity, diagnosis, staging, pathology, endoscopy, surgery, radiation, systemic therapy and follow-up, which was followed by presentation, discussion, and voting by the panel members. It provides updated evidence-based recommendations to guide clinical management of gastric carcinomas in several scenarios and clinical settings.

Outcomes with anti-EGFR monoclonal antibodies in metastatic and recurrent anal squamous cell carcinoma.

OBJECTIVES: Metastatic squamous cell carcinoma anal cancer (SCCA) is rare. Prospective data recommends front-line platinum doublet combinations and second-line anti-programmed death-1 therapy. Standard therapy beyond these treatments are currently unknown. We evaluated anti-EGFR monoclonal antibody (mAb) outcomes in metastatic SCCA. METHODS: Metastatic SCCA patients given anti-EGFR mAb from Oct 2011-May 2018 were included. Primary endpoints included best response, progression-free survival, and overall survival. RESULTS: 56 patients were evaluated with a median of one prior therapy. Most patients (~90%) received anti-EGFR mAbs with chemotherapy. Response rate (any response) was 41%. Median PFS was 4.3 months with a median OS of 16 M. Seven patients with disease control proceeded onto maintenance therapy (anti-EGFR mAb ± a fluoropyrimidine) with a median PFS of 13.8 M. Next generation sequencing of 16 pts (28%) showed 4 pts had a PIK3CA mutation with 3 of these 4 patients demonstrating progression on initial restaging. CONCLUSION: Our analysis suggests anti-EGFR mAb therapy with chemotherapy provides clinical benefit in previously treated metastatic SCCA. Our maintenance therapy and the role of PIK3CA MT outcomes were thought-provoking. EXPERT OPINION: Metastatic SCCA patients have limited options; therefore, anti-EGFR mAbs may provide benefit in the treatment armamentarium and should be further explored.

Integrated clinico-molecular profiling of appendiceal adenocarcinoma reveals a unique grade-driven entity distinct from colorectal cancer.

BACKGROUND: Appendiceal adenocarcinoma (AA) is an orphan disease with unique clinical attributes but often treated as colorectal cancer (CRC). Understanding key molecular differences between AA and CRC is critical. METHODS: We performed retrospective analyses of AA patients (N = 266) with tumour and/or blood next-generation sequencing (NGS) (2013-2018) with in-depth clinicopathological annotation. Overall survival (OS) was examined. For comparison, CRC cohorts annotated for sidedness, consensus molecular subtypes (CMS) and mutations (N = 3283) were used. RESULTS: Blood-NGS identified less RAS/GNAS mutations compared to tissue-NGS (4.2% vs. 60.9%, P < 0.0001) and showed poor concordance with tissue for well-/moderately differentiated tumours. RAS (56.2%), GNAS (28.1%) and TP53 (26.9%) were most frequent mutations. Well/moderately differentiated tumours harboured more RAS (69.2%/64.0% vs. 40.5%) and GNAS (48.7%/32.0% vs. 10.1%) while moderate/poorly differentiated tumours had more TP53 (26.0%/27.8% vs. 7.7%) mutations. Appendiceal adenocarcinoma (compared to CRC) harboured significantly fewer APC (9.1% vs. 55.4%) and TP53 (26.9% vs. 67.5%) and more GNAS mutations (28.1% vs. 2.0%) (P < 0.0001). Appendiceal adenocarcinoma mutation profile did not resemble either right-sided CRC or any of the four CMS in CRC. High grade, but no mutation, was independently predictive of survival. CONCLUSION: Integrated clinico-molecular profiling of AA identified key molecular drivers distinct from CRC. Appendiceal adenocarcinoma has a predominantly grade-driven biology that trumps mutations.

FOLFOXIRI Versus Doublet Regimens in Right-Sided Metastatic Colorectal Cancer: Focus on Subsequent Therapies and Impact on Overall Survival.

INTRODUCTION: It has been determined that right-sided metastatic colorectal cancer (mCRC) has a worse prognosis for overall survival (OS). Currently, there is no consensus on the best systemic regimen for treatment-naive right-sided tumors. We compared the impact of subsequent therapies on OS of patients treated with FOLFOXIRI (leucovorin, 5-fluorouracil, oxaliplatin, irinotecan) versus doublet regimens. PATIENTS AND METHODS: Data of patients with treatment-naive right-sided mCRC who received FOLFOXIRI or doublet regimens between January 2001 to December 2018 were retrospectively analyzed. OS was compared between the two groups, and prognostic factors were assessed by multivariate analysis. RESULTS: A total of 196 patients were selected; 33 patients received FOLFOXIRI and 163 patients doublet therapy. Median follow-up was 82.3 months. The FOLFOXIRI cohort received fewer subsequent lines of therapies (61% vs. 78%, P = .043). The greater the number of subsequent lines of therapy, the lower the risk of death (hazard ratio [95% confidence interval] 0.67 [0.46-0.99], 0.62 [0.45-0.86], and 0.56 [0.39-0.81] for > 1, > 2, and > 3 lines, respectively). By multivariate analysis, metastasectomy and bevacizumab with subsequent lines of therapy were the variables with greatest positive impact on OS (respectively, hazard ratio [95% confidence interval] 0.54 [0.38-0.78] and 0.61 [0.44-0.84]). CONCLUSION: Patients with treatment-naive right-sided mCRC who received front-line FOLFOXIRI had a lower number of subsequent therapies than patients who received doublet regimens. Our findings highlight the relevance of the continuum of care in mCRC, regardless of the first-line regimen, and the importance of careful selection of patients for the FOLFOXIRI regimen.

Bevacizumab Does Not Influence the Efficacy of Partial Splenic Embolization in the Management of Chemotherapy-Induced Hypersplenism.

BACKGROUND: Antiangiogenics attenuate chemotherapy-related hepatotoxicity and portal hypertension. The potential impact of bevacizumab on the efficacy and safety of partial splenic embolization (PSE) in the management of chemotherapy-induced hypersplenism (CIH) has never been investigated. PATIENTS AND METHODS: We conducted a retrospective study with gastrointestinal cancer patients who have undergone PSE for the treatment of thrombocytopenia resulting from hypersplenism. Pre- and post-PSE platelet count (PC), the percentage of patients who resumed systemic therapy, and complication rates were compared between patients exposed and not exposed to bevacizumab. RESULTS: A total of 110 patients were eligible. Colorectal cancer was the predominant neoplasm (60%), and 5-fluorouracil, oxaliplatin, and bevacizumab were the most commonly provided drugs (70%, 65%, and 65% of patients, respectively). After PSE, 80% of patients recovered PC ≥ 100 × 109/L (100K). Systemic therapy was resumed in 81% of patients. Seventy-one patients exposed to bevacizumab had a median PC before PSE of 77.5K and after PSE of 167.0K, with a mean difference of 108K (P < .0001). Thirty-nine patients not exposed to bevacizumab had a median PC of pre-PSE of 73.0K and post-PSE of 187.0K, with a mean difference of 117.7K (P < .0001). Both groups had similar values of percentages of patients with PC post-PSE ≥ 100K (83% vs. 74%; P = .463), resumption of systemic therapy (85% vs. 74%; P = .213), and complication rates. A linear association between splenic infarction rate and increment in PC was found (P < .0001). CONCLUSION: PSE is a safe and effective procedure in the management of CIH, regardless of the provision of bevacizumab. Splenic infarction rate should be optimized to enhance patient outcomes.