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Purpose of Review: This narrative review explores the efficacy and applicability of anti-EGFR therapy as the first-line treatment for patients with RAS wild-type (WT) left-sided metastatic colorectal cancer (mCRC). It critically examines current guidelines, along with recent evidence in the literature, to assess whether it should be universally applied. Recent Findings: Recent evidences highlight the variability of the response to anti-EGFR therapies due to molecular diversity and several clinical factors, such as RAS mutational status and primary tumor location. Summary: Anti-EGFR plus chemotherapy is the standard first-line treatment for most patients with MSS, RAS-WT, left-sided mCRC. Whether this combination is the best treatment for these patients remains an open question. This review delves into the role of EGFR inhibition in mCRC, focusing on clinical factors and the knowledge of biology, molecular targets, and biomarkers. It underscores the crucial role of a personalized approach, empowering healthcare providers and equipping them with the confidence to make informed decisions. [ABSTRACT FROM AUTHOR]

Mismatch repair (MMR) immunohistochemical (IHC) evaluation has entered pathology routine practice as the first-line screening method to identify patients with MMR deficient (MMRd)/microsatellite instability (MSI) colorectal cancer (CRC), and its misdiagnosis may significantly impact the personalization of CRC patient care. To determine the prevalence of MMR protein intratumor heterogeneity in real-world practice, we collected a series of 8282 CRCs tested for MMR proteins in the setting of Lynch syndrome universal screening. Four heterogenous cases were also investigated for tumor infiltrating lymphocytes count, MSI status, and consensus molecular subtypes by Nanostring nCounter® Platform. Overall, 1056 (12.8%) CRCs showed a MMR altered status, with 46 cases showing a heterogeneous MMR profile (0.56% of the total, and 4.36% of all MMRd cases). To conclude, the authors make some critical remarks regarding the approach to MMR heterogeneity in clinical practice and routine diagnostics. [ABSTRACT FROM AUTHOR]

Purpose: The clinical outcome and the efficacy of chemotherapy in pancreatic cancer patients with BRCA1/2 Variants of Unknown Significance (VUS) is unknown. We explored the effects of chemotherapy with or without Platinum in non metastatic and metastatic pancreatic cancer patients with BRCA1/2 VUS. Methods: A retrospective analysis of non-metastatic or metastatic pancreatic cancer patients with gBRCA1/2 VUS treated in 13 Italian centers between November 2015 and December 2020 was performed. All patients were assessed for toxicity and RECIST 1.1 response. Metastatic patients were evaluated for survival outcome. Results: 30 pancreatic cancer patients with gBRCA1/2 VUS were considered: 20 were M+ and 10 were non-M+. Pl-CT was recommended to 16 patients: 10 M+ (6 FOLFIRINOX and 4 PAXG) and 6 non-M+ (3 FOLFIRINOX and 3 PAXG); 11 patients received Nabpaclitaxel-Gemcitabine (AG; 8 M+) and 3 patients (2 M+) were treated with Gemcitabine (G). The RECIST 1.1 response rate was 27% for AG and 44% for Pl-CT (22% for (m) FOLFIRINOX and 71% PAXG). 1 year Progression-Free Survival was 37.5% for patients treated with AG and 33% in the Pl-CT subgroup. Median Overall Survival (OS) was 23.5 months for patients treated with AG and 14 months for the Pl-CT subgroup. 1 Year and 2 Year OS were numerically better for AG (1 Year OS: 75% vs 60% and 2 Year OS: 50% and 20% in AG and Pl-CT subgroups, respectively) as well. Conclusions: Pl-CT does not seem to be associated with a better outcome compared to AG chemotherapy in PDAC patients with BRCA 1/2 VUS. [ABSTRACT FROM AUTHOR]

Opinion statement: Circulating tumor DNA (ctDNA) has already shown clinically relevant results in early-stage colon cancer patient management. Its prognostic value is by far much stronger than that of the available clinico-pathological biomarkers, therefore, has the potential to personalize the treatment after radical surgery through intensifying or de-intensifying the adjuvant therapy. Further developments and improvements should be pursued by (a) optimizing ctDNA assays and (b) validating its clinical utility in the different stages of this disease. Two main avenues of ctDNA testing are being pursued: tumor-informed vs tumor-agnostic assays. Two main clinical trial designs are under study: ctDNA-based strategy and ctDNA-by-treatment interaction. The former needs large sample sizes to address the main questions of the studies; thus, the target delta benefit may be the main challenge in these trial designs. The latter may be challenged by unavoidable contamination bias. To date, several clinical trials are ongoing worldwide. We believe that this large number of trials may provide an excellent common database for the demonstration of surrogacy of ctDNA for the classical 3-year disease-free survival endpoint. This would mark a huge methodological improvement to speed up new drug testing and development in the adjuvant treatment of this disease. [ABSTRACT FROM AUTHOR]

A correction notice was issued for an article on the prevalence and type of MMR expression heterogeneity in colorectal adenocarcinoma, with therapeutic implications and reporting considerations. The short title "MMR IHC heterogeneity in colorectal cancer" was mistakenly included in the final publication and has been removed. The original article has been corrected, and Springer Nature maintains neutrality regarding jurisdictional claims and institutional affiliations. The authors involved in the correction are Federica Grillo, Valentina Angerilli, Paola Parente, Alessandro Vanoli, Claudio Luchini, Stefania Sciallero, Alberto Puccini, Francesca Bergamo, Sara Lonardi, Nicola Valeri, Luca Mastracci, and Matteo Fassan. [Extracted from the article]

Lymph nodes (LNs) and distant metastases can arise from independent subclones of the primary tumor. Herein, we characterized the molecular landscape and the differences between LNs, distant metastases and primary colorectal cancers (CRCs). Samples were analyzed using next generation sequencing (NGS, MiSeq on 47 genes, NextSeq on 592 genes) and immunohistochemistry. Tumor mutational burden (TMB) was calculated based on somatic nonsynonymous missense mutations, and microsatellite instability (MSI) was evaluated by NGS of known MSI loci. In total, 11,871 samples were examined, comprising primaries (N = 5862), distant (N = 5605) and LNs metastases (N = 404). The most frequently mutated genes in LNs were TP53 (72%), APC (61%), KRAS (39%), ARID1A (20%), PIK3CA (12%). LNs showed a higher mean TMB (13 mut/MB) vs distant metastases (9 mut/MB, p < 0.0001). TMB-high (≥17mut/MB) and MSI-H (8.8% and 6.9% vs 3.7%, p < 0.001 and p = 0.017, respectively) classifications were more frequent in primaries and LNs vs distant metastases (9.5% and 8.8% vs 4.2%, p < 0.001 and p = 0.001, respectively). TMB-high is significantly more common in LNs vs distant metastases and primaries (P < 0.0001), regardless MSI-H status. Overall, LNs showed significantly different rates of mutations in APC, KRAS, PI3KCA, KDM6A, and BRIP1 (p < 0.01) vs primaries, while presenting a distinct molecular profile compared to distant metastases. Our cohort of 30 paired samples confirmed the molecular heterogeneity between primaries, LNs, and distant metastases. Our data support the hypothesis that lymphatic and distant metastases harbor different mutational landscape. Our findings are hypothesis generating and need to be examined in prospective studies. [ABSTRACT FROM AUTHOR]

KRAS status serves as a predictive biomarker of response to treatment in metastatic colorectal cancer (mCRC). We hypothesize that complex interactions between multiple pathways contribute to prognostic differences between KRAS wild-type and KRAS mutant patients with mCRC, and aim to identify polymorphisms predictive of clinical outcomes in this subpopulation. Most pathway association studies are limited in assessing gene–gene interactions and are restricted to an individual pathway. In this study, we use a random survival forests (RSF) method for identifying predictive markers of overall survival (OS) and progression-free survival (PFS) in mCRC patients treated with FOLFIRI/bevacizumab. A total of 486 mCRC patients treated with FOLFIRI/bevacizumab from two randomized phase III trials, TRIBE and FIRE-3, were included in the current study. Two RSF approaches were used, namely variable importance and minimal depth. We discovered that Wnt/β-catenin and tumor associated macrophage pathway SNPs are strong predictors of OS and PFS in mCRC patients treated with FOLFIRI/bevacizumab independent of KRAS status, whereas a SNP in the sex-differentiation pathway gene, DMRT1, is strongly predictive of OS and PFS in KRAS mutant mCRC patients. Our results highlight RSF as a useful method for identifying predictive SNPs in multiple pathways. [ABSTRACT FROM AUTHOR]

Summary: Soft tissue sarcomas are rare diseases that encompass a very heterogeneous group of tumors with diverse pathology and clinically overlapping characteristics. Although some treatment options may be used across different subtypes, each is characterized by specific features and may benefit more from specific approaches. In such a rare and peculiar group of diseases, it is rather important to define the best strategy to prolong survival and improve the quality of life of the patients. Although anthracycline-based chemotherapy remains a milestone in the first-line setting, in recent years novel targeted and immune therapies have been developed and more tailored strategies are possible. For these reasons, every case should be discussed in a multidisciplinary board that includes all specialists involved in the treatment of these patients, since the combination of systemic and local treatments can often be proposed. In this short review, we present the state of the art and offer future perspectives for the management of soft tissue sarcomas. [ABSTRACT FROM AUTHOR]

The role of aberrant hepatocyte growth factor receptor (c-MET, also known as tyrosine-protein kinase MET)/hepatocyte growth factor (HGF) signaling in cancer progression and invasion has been extensively studied. c-MET inhibitors have shown promising pre-clinical and early phase clinical trial anti-tumor activity in several tumor types, although results of most phase III trials with these agents have been negative. To date, two small molecule c-MET inhibitors, cabozantinib and crizotinib, have been approved by regulatory authorities for the treatment of selected cancer types, but several novel c-MET inhibitors (either monoclonal antibodies or small molecule c-MET tyrosine kinase inhibitors) and treatment combinations are currently under study in different settings. Here we provide an overview of the mechanism of action and rationale of c-MET inhibition in cancer, the efficacy of approved agents, and novel promising c-MET-inhibitors and novel targeted combination strategies under development in different cancer types, with a focus on the safety profile and tolerability of these compounds. [ABSTRACT FROM AUTHOR]

Purpose of Review: While the incidence and mortality of colorectal cancer have been declining in the USA in the last decades, there is a considerable increase in the incidence of this malignancy in the young adult patients. Several environmental and genetic factors have been studied and known to be associated with colorectal cancer. However, the exact causes of this increase are not clear. Therefore, in this review, we aimed to provide insights in terms of novel findings and avenues of research that may lead to a better way to treat this population of patients.Recent Findings: Obesity and its associated behaviors, such as unhealthy dietary patterns and sedentary lifestyles, as well as gut microbiota may play a crucial role in colorectal cancer (CRC) risk for young adults. Recently, the American Cancer Society recommends that adults aged 45 years and older with an average risk of CRC undergo regular screening with either a high-sensitivity stool-based test or a structural examination, depending on patient preference and test availability. It is important to note that data on outcomes associated with systemic cytotoxic and biologic therapy specifically in young patients with CRC are lacking.Summary: In this review, we provide an overview on the most recent evidence regarding incidence, screening, molecular features, and management of young patients with colorectal cancer. [ABSTRACT FROM AUTHOR]

Purpose of Review: During the past few years, several important clinical and molecular differences have been observed simply based on anatomic tumor location of colorectal cancer. With this review, we aimed to give an updated overview of the recent findings on tumor location as a surrogate of embryological, molecular, and clinical differences that have a direct impact on our daily clinical practice.Recent Findings: Increasing evidence has demonstrated a role for the microbiota in shaping inflammatory environments and promoting CRC growth and spread, and now we know that bacterial phylotypes vary depending on the primary tumor location. Compelling evidence has shown that tumor sidedness has both a strong prognostic and predictive value. In fact, right-sided colon cancers display a markedly worse prognosis compared to left-sided tumors; moreover, it seems that right-sided RAS wild-type metastatic colorectal cancer benefits from bevacizumab-based therapy while left-sided tumors have better outcomes with cetuximab-based treatment in the first-line setting. Since the underlying reasons of these differences are yet unknown, further investigations are warranted in this expanding and relevant field.Summary: In this review, we summarize the actual knowledge on the clinical, microbiome, and molecular differences observed between right- and left-sided colon cancers. We also present an overview of the existing data on the prognostic and predictive impact of tumor sidedness on metastatic colorectal cancer patient outcome. [ABSTRACT FROM AUTHOR]

The introduction of oxaliplatin as adjuvant treatment for stage III colon cancer in 2004 has been the last practice changing progress in adjuvant treatment for patients with early colon cancer. Since then, many prognostic and predictive biomarkers have been studied, but only DNA mismatch repair status has been validated as having an important prognostic value. Accordingly, TNM and clinical-pathological patterns, such as pT4 lesions and lymph node sampling <12 nodes, are the main factors that guide physicians' choice regarding adjuvant treatment. More recently, many biomarkers showed promising results: POLE, ErbB2, CDX2, SMAD4, BRAF and KRAS. In addition to these, immune-contexture, molecular classification, and gene signatures could become new ways to better classify colon cancer patients with more discriminatory power than TNM. The aim of this review is to report the state-of-the-art of prognostic and predictive factors in the adjuvant setting and which of these could modify clinical practice and maybe replace TNM classification. [ABSTRACT FROM AUTHOR]

Opinion Statement: Small bower cancer is a rare disease, despite its incidence is increasing in the last decade. Both benign and malignant tumors can arise from the small intestine. The main histological cancer types are adenocarcinomas, neuroendocrine tumors, sarcomas, gastrointestinal stromal tumors (GISTs), and lymphomas. Due to the rarity of these malignances, all the currently available data are based on small studies or retrospective series, although recent breakthroughs are redirecting our approach to these patients. Immunotherapy for small bowel adenocarcinomas, several multikinase inhibitors in resistant GIST patients, as well as everolimus and 177Lu-DOTATATE in neuroendocrine tumors are only few of the novel therapeutic options that have changed, or may change in the future, the therapeutic landscape of these rare cancers. Larger and more powerful studies on the molecular profile of these tumors may lead to a better design of clinical trials, which eventually would provide our patients with more efficacious treatments to improve both overall survival and quality of life. [ABSTRACT FROM AUTHOR]