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The occurrence of gastric cancer has been associated with an increased risk of lobular breast tumors in a subset of patients harboring selected germline mutations. Among all, the germline alteration of the gene coding for E-Cadherin (CDH1) was associated with an increased risk of gastric cancer diffuse-histotype and lobular breast cancer. However, the risk assessment of breast neoplasms and the role of multiple prophylactic procedures in these patients has never been systematically addressed. In addition, the performance of the common screening procedures for lobular breast cancer like mammography is suboptimal. Therefore, recalling the need for a better articulation of the patient-centered strategies of surveillance for individuals with germline CDH1 and other similar alterations, to offer comprehensive approaches for prevention, early diagnosis, and treatment. Accordingly, this chapter aims to discuss the value and the role of integrated oncological care in the era of oncology sub-specializations. Additionally, it sheds light on how the harmonization across the health providers can enhance patient care in this setting., (© 2023. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Background: The combination of trifluridine-tipiracil and bevacizumab was compared with trifluridine-tipiracil monotherapy in a randomized, open-label, phase II trial, resulting in a statistically significant and clinically relevant improvement in progression-free survival (PFS), with tolerable toxicity in patients with refractory metastatic colorectal cancer (mCRC); however, evidence supporting the role of this combination in a real-world setting is limited., Objective: The aim of our work was to provide further evidence on the activity and safety of this combination in a real-world series of Western mCRC patients refractory or intolerant to previous therapies., Patient and Methods: We conducted a retrospective, observational study of patients with mCRC refractory or intolerant to standard therapies. Patients were treated with trifluridine-tipiracil and bevacizumab. Previous therapy with fluoropyrimidines, irinotecan, oxaliplatin, bevacizumab, aflibercept, regorafenib, and cetuximab or panitumumab (only RAS wild-type) was allowed, as was previous participation in clinical trials. Clinicopathological characteristics, overall response rate (ORR), disease control rate (DCR), overall survival (OS), PFS, and safety data were retrospectively collected and analyzed., Results: We recorded 31 patients treated between 1 December 2017 and 30 June 2022. Median age was 69 years (range 38-82 years), 39% were male, 100% had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1, tumor location was left-sided in 77% of cases, 54% had synchronous presentation, 35% were RAS mutant, 3% were BRAF mutant, and 71% underwent primary tumor resection; 64% of patients had liver metastases, 55% had lung metastases, and 23% had peritoneal carcinomatosis. The median number of previous treatment lines was 2 (range 0-5), and 84% of patients received at least one previous anti-angiogenic agent. The ORR and DCR were 3% and 71%, respectively. With a median follow-up of 8 months (range 2-39), median PFS was 6 months (95% confidence interval [CI] 3.1-8.9 months) and median OS was 14 months (95% CI 10.1-17.8 months). Adverse events of any grade were reported in 58% of patients. The most common grade 3-4 toxicities were neutropenia (19%) and anemia (6%); 35% of patients required either dose delays or dose reductions due to toxicity. Granulocyte colony-stimulating factor (G-CSF) prophylaxis was administered either on first or subsequent cycles of treatment in 35% of patients. No treatment-related deaths occurred. Sixty percent of the patients who discontinued treatment eventually received one or more lines of subsequent therapy., Conclusions: Our series provides further evidence on the activity and safety of the combination of trifluridine-tipiracil and bevacizumab in a real-world series of Western refractory mCRC patients., (© 2022. The Author(s).)

Traditionally, lymph node metastases (LNM) evaluation is essential to the staging of colon cancer patients according to the TNM (tumor-node-metastasis) system. However, in recent years evidence has accumulated regarding the role of emerging pathological features, which could significantly impact the prognosis of colorectal cancer patients. Lymph Node Ratio (LNR) and Log Odds of Positive Lymph Nodes (LODDS) have been shown to predict patients' prognosis more accurately than traditional nodal staging and it has been suggested that their implementation in existing classification could help stratify further patients with overlapping TNM stage. Tumor deposits (TD) are currently factored within the N1c category of the TNM classification in the absence of lymph node metastases. However, studies have shown that presence of TDs can affect patients' survival regardless of LNM. Moreover, evidence suggest that presence of TDs should not be evaluated as dichotomic but rather as a quantitative variable. Extranodal extension (ENE) has been shown to correlate with presence of other adverse prognostic features and to impact survival of colorectal cancer patients. In this review we will describe current staging systems and prognostic/predictive factors in colorectal cancer and elaborate on available evidence supporting the implementation of LNR/LODDS, TDs and ENE evaluation in existing classification to improve prognosis estimation and patient selection for adjuvant treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Arrichiello, Pirozzi, Facchini, Facchini, Paragliola, Nacca, Nicastro, Canciello, Orlando, Caterino, Ciardiello, Della Corte, Fasano, Napolitano, Troiani, Ciardiello, Martini and Martinelli.)

Colorectal cancer (CRC) is one of the most frequent tumours and one of the major causes of morbidity and mortality globally. Its incidence has increased in recent years and could be linked to unhealthy dietary habits combined with environmental and hereditary factors, which can lead to genetic and epigenetic changes and induce tumour development. The model of CRC progression has always been based on a genomic, parametric, static and complex approach involving oncogenes and tumour suppressor genes. Recent advances in omics sciences have sought a paradigm shift to a multiparametric, immunological-stromal, and dynamic approach for a better understanding of carcinogenesis and tumour heterogeneity. In the present paper, we review the most important preclinical and clinical data and present recent discoveries in the field of transcriptomics, proteomics, metagenomics and radiomics in CRC disease.

Biliary tract cancer (BTC) is an aggressive tumor characterized by a poor prognosis. In the latest years, targetable genetic alterations have been discovered in BTC patients, leading to the approval of new targeted therapies. Liquid biopsy, which is a non-invasive method for detecting tumor biomarkers from fluid samples, is a useful tool for diagnosis and molecular characterization, but also for prognosis assessment and monitoring of treatment response. In this review, recent works on liquid biopsy in BTC patients were analyzed, focusing on some relevant aspects for clinical use and trying to depict the future role of this technique. Moreover, differences between plasma and bile samples were pointed out, in light of the peculiar biology of BTC and the possibility of using bile as an alternative source of cell-free DNA (cfDNA) for genomic analysis. In the era of precision oncology, the increasing adoption of liquid biopsy in BTC patients will certainly improve the management of this disease., Competing Interests: The authors declare that they have no conflicts of interest., (© The Author(s) 2022.)

Cutaneous melanoma is a lethal disease, even when diagnosed in advanced stages. Although recent progress in biology and treatment has dramatically improved survival rates, new therapeutic approaches are still needed. Deregulation of epigenetics, which mainly controls DNA methylation status and chromatin remodeling, is implied not only in cancer initiation and progression, but also in resistance to antitumor drugs. Epigenetics in melanoma has been studied recently in both melanoma preclinical models and patient samples, highlighting its potential role in different phases of melanomagenesis, as well as in resistance to approved drugs such as immune checkpoint inhibitors and MAPK inhibitors. This review summarizes what is currently known about epigenetics in melanoma and dwells on the recognized and potential new targets for testing epigenetic drugs, alone or together with other agents, in advanced melanoma patients.

Immunotherapy has recently become a major treatment modality for several types of solid tumours, achieving remarkable and long-lasting remissions. In metastatic colorectal cancer patients (mCRC), immune checkpoint inhibitors (ICIs) were found to be effective as treatment for deficient mismatch repair (dMMR)/ microsatellite instability high (MSI-H) tumours and received regulatory approval for this indication. However, mCRC is a complex disease and dMMR/MSI-H tumours represent a minority of the cases; therefore, new strategies are needed to extend the benefits of immunotherapy to a larger population of patients. This review explores the immunological differences between dMMR/MSI-H and proficient mismatch repair (pMMR)/ microsatellite instability low (MSI-L) tumours, focuses on new proposed biomarkers to predict response to immunotherapy and illustrates results reported from the main clinical trials with immunotherapeutic agents in CRC, addressing the most promising approaches being currently developed., (Copyright © 2021. Published by Elsevier Ltd.)

Squamous cell carcinoma of the anus (SCCA) is a rising health issue, strongly related to other relevant medical conditions such as (HIV) and human papillomavirus (HPV) infection. Correct assessment of patients with SCCA requires a multidisciplinary evaluation and adequate follow-up. Accurate local and systemic staging, as well as risk evaluation, are essential to optimal treatment planning. Early stage tumours can be definitively treated with a combination of chemotherapy and radiotherapy, while salvage surgery is usually reserved for patients who develop local recurrence. Distant recurrence and de novo metastatic disease are associated with poorer prognosis and require palliative systemic chemotherapy, with different single agent and combination options available. Finally, recent discoveries on the carcinogenesis of SCCA have allowed the development of innovative treatment options, the most promising being immune checkpoint inhibitors. The limited systemic treatments for SCCA and low incidence of the disease, together with insufficient data from clinical research could explain the poor outcomes of these patients, which should therefore be managed in high volume centres and enrolled in clinical trials whenever possible. This article summarises the main strategies for treating patients with SCCA., Competing Interests: Competing interests: EM: advisory board for Amgen, Bayer, Merck, Roche, Sanofi, Servier and expert opinion for European Society of Medical Oncology., (© Author (s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ on behalf of the European Society for Medical Oncology.)

Tumor heterogeneity represents a possible cause of error in detecting predictive genetic alterations on tumor tissue and can be overcome by testing alterations in circulating tumor DNA (ctDNA) using liquid biopsy. We assessed 72 consecutive patients with a diagnosis of metastatic colorectal cancer (mCRC) using Idylla™ Biocartis, a fully automated platform that evaluates the most frequent mutations of KRAS, NRAS and BRAF genes. We correlated the results of liquid biopsy and standard tissue-based next generation sequencing (NGS) analyses to patient clinical features. The overall agreement was 81.94%. Concordance was 85.71% and 96.15% in treatment-naïve patients and in the patient subgroup with liver metastases, respectively. In liver metastases positive, treatment-naïve patients, sensitivity, specificity and positive predictive value (PPV) were 92.31%, 100% and 100%, respectively. Circulating mutational fraction (CMF) was significantly higher in patients with liver metastases and high carcinoembryonic antigen (CEA) levels. In a subgroup of patients pre-treated with anti-Epidermal Growth Factor Receptor (EGFR) agents, emerging KRAS mutations were evidenced in 33% of cases. Testing RAS/BRAF mutations on plasma using the Idylla™ Biocartis platform is feasible and reliable in mCRC patients in clinical practice., Competing Interests: P.P.V.: consultancy for Biocartis. E.M.: advisory board for Amgen, Bayer, Merck, Roche, Sanofi, Servier and expert opinion for ESMO (European Society of Medical Oncology). T.T.: advisory board for Amgen, Bayer, Merck, Novartis, Roche, Sanofi. F.M.: advisory board for Lilly, MSD. F.D.V.: advisory board for Amgen, Lilly, Roche, Celgene. F.C.: advisory board for Merck, Roche, Amgen, Bayer, Servier, Symphogen,Pfizer and research funding from Roche, Merck, Amgen, Bayer, Ipsen. V.D.F., E.F.G., D.C., C.C., C.B., L.P., M.T., G.A., V.C., A.D.L., V.F., V.M.I., F.M., G.M., S.N., R.F., A.L., M.C. declare no competing conflict of interest regarding the following manuscript. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.