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Colorectal cancer (CRC) is a complex and genetically heterogeneous disease presenting a specific metastatic pattern, with the liver being the most common site of metastasis. Around 20%-25% of patients with CRC will develop exclusively hepatic metastatic disease throughout their disease history. With its specific characteristics and therapeutic options, liver-limited disease (LLD) should be considered as a specific entity. The identification of these patients is particularly relevant in view of the growing interest in liver transplantation in selected patients with advanced CRC. Identifying why some patients will develop only LLD remains a challenge, mainly because of a lack of a systemic understanding of this complex and interlinked phenomenon given that cancer has traditionally been investigated according to distinct physiological compartments. Recently, multidisciplinary efforts and new diagnostic tools have made it possible to study some of these complex issues in greater depth and may help identify targets and specific treatment strategies to benefit these patients. In this review we analyze the underlying biology and available tools to help clinicians better understand this increasingly common and specific disease., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Combination of a BRAF inhibitor (BRAFi) and an anti-epidermal growth factor receptor (EGFR), with or without a MEK inhibitor (MEKi), improves survival in BRAF-V600E-mutant metastatic colorectal cancer (mCRC) over standard chemotherapy. However, responses are heterogeneous and there are no available biomarkers to assess patient prognosis or guide doublet- or triplet-based regimens. In order to better characterize the clinical heterogeneity observed, we assessed the prognostic and predictive role of the plasmatic BRAF allele fraction (AF) for these combinations., Patients and Methods: A prospective discovery cohort including 47 BRAF-V600E-mutant patients treated with BRAFi-anti-EGFR ± MEKi in clinical trials and real-world practice was evaluated. Results were validated in an independent multicenter cohort (n= 29). Plasmatic BRAF-V600E AF cut-off at baseline was defined in the discovery cohort with droplet digital PCR (ddPCR). All patients had tissue-confirmed BRAF-V600E mutations., Results: Patients with high AF have major frequency of liver metastases and more metastatic sites. In the discovery cohort, median progression-free survival (PFS) and overall survival (OS) were 4.4 and 10.1 months, respectively. Patients with high BRAF AF (≥2%, n = 23) showed worse PFS [hazard ratio (HR) 2.97, 95% confidence interval (CI) 1.55-5.69; P = 0.001] and worse OS (HR 3.28, 95% CI 1.58-6.81; P = 0.001) than low-BRAF AF patients (<2%, n = 24). In the multivariable analysis, BRAF AF levels maintained independent significance. In the validation cohort, high BRAF AF was associated with worse PFS (HR 3.83, 95% CI 1.60-9.17; P = 0.002) and a trend toward worse OS was observed (HR 1.86, 95% CI 0.80-4.34; P = 0.15). An exploratory analysis of predictive value showed that high-BRAF AF patients (n = 35) benefited more from triplet therapy than low-BRAF AF patients (n = 41; PFS and OS interaction tests, P < 0.01)., Conclusions: Plasmatic BRAF AF determined by ddPCR is a reliable surrogate of tumor burden and aggressiveness in BRAF-V600E-mutant mCRC treated with a BRAFi plus an anti-EGFR with or without a MEKi and identifies patients who may benefit from treatment intensification. Our results warrant further validation of plasmatic BRAF AF to refine clinical stratification and guide treatment strategies., Competing Interests: Disclosure JR declares personal speaker honoraria from Sanofi and AMGEN, and accommodation expenses from Pierre-Fabre, Servier, Amgen, and Merck. GV declares personal speaker honoraria from Sanofi and AMGEN, and accommodation expenses from Pierre-Fabre, Servier, Amgen, and Merck. GM declares personal speaker honoraria from Servier. IB declares to have received honoraria from Sanofi; and to have received travel and accommodations expenses from Amgen, Sanofi, Merck, and Servier. NS declares to have received honoraria from Amgen. FS declares personal financial interests, honoraria for advisory role, travel grants, research grants (past 5 years): Hoffman La-Roche, Sanofi Aventis, Amgen, Merck Serono, Servier, Bristol-Myers Squibb. Institutional financial interests, honoraria due to investigator contribution in clinical trials from: Hoffman La-Roche, Sanofi Aventis, Amgen, Merck Serono, MSD, Boehringer Ingelheim, AbbVie, Array Pharmaceuticals, Pierre-Fabre, Novartis, Bristol-Myers Squibb, GlaxoSmithKline, Medimmune. RT holds a Miguel Servet-I research contract by Institute of Health Carlos III (ISCIII) of the Ministry of Economy [grant number CP17/00199] and Competitiveness from the Spanish government and is supported by an Olga Torres Foundation emerging researcher grant, by the Swiss Bridge Award, and received a research grant from Novartis, Astrazeneca, Beigene. EM has served as adviser and speaker for AstraZeneca, Amgen, Bayer, Merck-Serono, Roche, Sanofi, Servier, Pierre Fabre. FP reports personal fees from Amgen, Merck-Serono, Pierre-Fabre, Servier, Bayer, MSD, and Lilly; grants and personal fees from AstraZeneca and BMS; and grants from Incyte. CC declares honoraria: Roche, Amgen, Bayer, Servier, MSD, Merck, Pierre Fabre, Organon; consulting or advisory role: Roche, Bayer, Amgen, MSD, Pierre Fabre, Nordic Pharma; speakers’ bureau: Servier, Merck, Pierre Fabre; research funding: Merck, Bayer, Roche, Servier. RD reports receiving honoraria for speaker activities from Roche, Ipsen, Amgen, Sanofi, Servier Laboratories, Merck and Sharp & Dohme; an advisory role at Roche and Boehringer Ingelheim; and research grants from Merck and Pierre Fabre. JT reports personal financial interest in the form of scientific consultancy role for Array Biopharma, AstraZeneca, Bayer, Boehringer Ingelheim, Chugai, Daiichi Sankyo, F. Hoffmann-La Roche Ltd, Genentech Inc, HalioDX SAS, Hutchison MediPharma International, Ikena Oncology, Inspirna Inc, IQVIA, Lilly, Menarini, Merck Serono, Merus, MSD, Mirati, Neophore, Novartis, Ona Therapeutics, Orion Biotechnology, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Scandion Oncology, Scorpion Therapeutics, Seattle Genetics, Servier, Sotio Biotech, Taiho, Tessa Therapeutics, and TheraMyc. Stocks: Oniria Therapeutics and also educational collaboration with Imedex/HMP, Medscape Education, MJH Life Sciences, PeerView Institute for Medical Education and Physicians Education Resource (PER). AV declares to be stockholder of Reveal Genomics, consultants of Reveal Genomics, reports personal fees from Bayer, personal fees from Bristol Meyers Squibb, personal fees from Guardant Health, personal fees from Merck, personal fees from Novartis, personal fees from Roche, personal fees from Incyte, and has a patent O2015145388A3 licensed. EE has received personal speaker honoraria from Organon and Novartis; and personal advisory board honoraria from Amgen, Bayer, Hoffman-La Roche, Merck Serono, Sanofi, Pierre Fabre, MSD, and Servier. Her institution has received research funding from Amgen Inc, Array Biopharma Inc, AstraZeneca Pharmaceuticals LP, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Debiopharm International SA, F. Hoffmann-La Roche Ltd, Genentech Inc, HalioDX SAS, Hutchison MediPharma International, Janssen-Cilag SA, MedImmune, Menarini, Merck Health KGAA, Merck Sharp & Dohme, Merus NV, Mirati, Novartis Farmacéutica SA, Pfizer, Pharma Mar, Sanofi Aventis Recherche & Développement, Servier, Taiho Pharma USA Inc. She held/holds non-remunerated roles as Coordinator of the SEOM +MIR Section of Residents and Young Assistants of the Sociedad Española de Oncología Médica (SEOM), speaker of the ESMO Academy of the European Society for Medical Oncology (ESMO), and volunteer member of the ASCO Annual Meeting Scientific Program Committee: Developmental Therapeutics – Immunotherapy of the American Society of Clinical Oncology (ASCO). All other authors have declared no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Historically women were frequently excluded from clinical trials and drug usage to protect unborn babies from potential harm. As a consequence, the impact of sex and gender on both tumour biology and clinical outcomes has been largely underestimated. Although interrelated and often used interchangeably, sex and gender are not equivalent concepts. Sex is a biological attribute that defines species according to their chromosomal makeup and reproductive organ, while gender refers to a chosen sexual identity. Sex dimorphisms are rarely taken into account, in either preclinical or clinical research, with inadequate analysis of differences in outcomes according to sex or gender still widespread, reflecting a gap in our knowledge for a large proportion of the target population. Underestimation of sex-based differences in study design and analyses has invariably led to 'one-drug' treatment regimens for both males and females. For patients with colorectal cancer (CRC), sex also has an impact on the disease incidence, clinicopathological features, therapeutic outcomes, and tolerability to anticancer treatments. Although the global incidence of CRC is higher in male subjects, the proportion of patients presenting right-sided tumours and BRAF mutations is higher among females. Concerning sex-related differences in treatment efficacy and toxicity, drug dosage does not take into account sex-specific differences in pharmacokinetics. Toxicity associated with fluoropyrimidines, targeted therapies, and immunotherapies has been reported to be more extensive for females with CRC than for males, although evidence about differences in efficacy is more controversial. This article aims to provide an overview of the research achieved so far into sex and gender differences in cancer and summarize the growing body of literature illustrating the sex and gender perspective in CRC and their impact in relation to tumour biology and treatment efficacy and toxicity. We propose endorsing research on how biological sex and gender influence CRC as an added value for precision oncology., Competing Interests: Disclosure IB has received accommodation and travel expenses from Amgen, Merck, Sanofi, and Servier. JR has received personal speaker honoraria from Sanofi and Amgen, and accommodation expenses from Pierre-Fabre, Servier, Amgen, and Merck. NS has received accommodation and travel expenses from Amgen and Merck. FS reports personal financial interests, honoraria for advisory role, travel grants, research grants (past 5 years): Hoffman La-Roche, Sanofi Aventis, Amgen, Merck Serono, Servier, Bristol-Myers Squibb. MRC has received personal speaker honoraria from ROVI and accommodation expenses from BMS, Amgen, and Merck. JT reports personal financial interest in the form of scientific consultancy role for Array Biopharma, AstraZeneca, Bayer, Boehringer Ingelheim, Chugai, Daiichi Sankyo, F. Hoffmann-La Roche Ltd, Genentech Inc, HalioDX SAS, Hutchison MediPharma International, Ikena Oncology, Inspirna Inc, IQVIA, Lilly, Menarini, Merck Serono, Merus, MSD, Mirati, Neophore, Novartis, Ona Therapeutics, Orion Biotechnology, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Scandion Oncology, Scorpion Therapeutics, Seattle Genetics, Servier, Sotio Biotech, Taiho, Tessa Therapeutics, TheraMyc, and Tolremo Therapeutics. Stocks: Oniria Therapeutics and also educational collaboration with Imedex/HMP, Medscape Education, MJH Life Sciences, PeerView Institute for Medical Education, and Physicians Education Resource (PER). EÉ has received personal speaker honoraria from Organon and Novartis; and personal advisory board honoraria from Amgen, Bayer, Hoffman-La Roche, Merck Serono, Sanofi, Pierre Fabre, MSD, and Servier. Her institution has received research funding from Amgen Inc, Array Biopharma Inc, AstraZeneca Pharmaceuticals LP, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Debiopharm International SA, F. Hoffmann-La Roche Ltd, Genentech Inc, HalioDX SAS, Hutchison MediPharma International, Janssen-Cilag SA, MedImmune, Menarini, Merck Health KGAA, Merck Sharp & Dohme, Merus NV, Mirati, Novartis Farmacéutica SA, Pfizer, Pharma Mar, Sanofi Aventis Recherche & Développement, Servier, Taiho Pharma USA Inc. She held/holds non-remunerated roles as Coordinator of the SEOM +MIR Section of Residents and Young Assistants of the Sociedad Española de Oncología Médica (SEOM), Speaker of the ESMO Academy of the European Society for Medical Oncology (ESMO), and Volunteer member of the ASCO Annual Meeting Scientific Program Committee: Developmental Therapeutics – Immunotherapy of the American Society of Clinical Oncology (ASCO). AG has declared no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)