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This paper presents the latest development of HyGenSys, a new sustainable process and technology for the conversion of natural gas to hydrogen and power. The concept combines a specific steam reforming reactor-exchanger with a gas turbine. The heat necessary for the steam reforming reaction comes from hot pressurized flue gases produced in a gas turbine instead of a conventional furnace. Thanks to this high level of heat integration, the overall efficiency is improved and the natural gas consumption is reduced which represents an advantage with regard to economics and CO2 emission reduction. In addition to the efficient HyGenSys process scheme itself, the technology of the reactorexchanger also offers a high level of heat integration for even more energy saving. Two main alternatives are examined in order to meet two different requirements. The first one, named HyGenSys-0, focuses on the hydrogen production for the refining and petrochemical application. The second one named HyGenSys-1, concerns the centralized power production with pre-combustion CO2capture. In that case, the produced hydrogen is fully used to fuel a power gas turbine. HyGenSys-1 has been developed and optimised in CACHET, a European Community funded project. The CACHET electrical power objective was 400 MW at the minimum. HyGenSys-0 and HyGenSys-1 are described in detail with challenges and advantages compared to existing technologies. For both alternatives, the heart of the technology is the reactor-exchanger. The reactor-exchanger design relies on an innovative arrangement of bayonet tubes that allows, at large scale, multiple heat exchanges between hot pressurized flue gas, natural gas feed and hydrogen rich stream produced. Cet article présente les développements récents d’HyGenSys, nouvel éco-procédé de conversion du gaz naturel en hydrogène et électricité. Le concept combine un réacteur-échangeur spécifique de reformage à la vapeur avec une turbine à gaz. En fait, la chaleur nécessaire pour la réaction de reformage à la vapeur provient des fumées pressurisées produites dans une turbine à gaz au lieu d’un four conventionnel. Grâce à cette intégration thermique poussée, l’efficacité globale est améliorée et la consommation de gaz naturel réduite, ce qui représente un avantage d’un point de vue économique et environnemental notamment vis-à-vis de la réduction des émissions de CO2. Deux déclinaisons du procédé sont détaillées, elles répondent chacune à des besoins différents. La première, appelée HyGenSys-0, correspond à la production d’hydrogène pour le raffinage et la pétrochimique. La deuxième, appelée HyGenSys-1, permet la production d’énergie centralisée avec la capture de CO2 en précombustion. Dans ce cas, l’hydrogène produit est entièrement utilisé pour alimenter une turbine de production d’électricité. HyGenSys-1 a été développé et optimisé au cours du projet CACHET, financé par la Communauté européenne, avec comme objectif de fournir une puissance de 400 MW minimum. Les versions HyGenSys-0 et HyGenSys-1 du procédé sont décrites en détail avec les défis et avantages comparés aux technologies existantes. Dans les deux cas, le coeur de la technologie est le réacteuréchangeur dont le développement est également présenté en détail. La conception de réacteur-échangeur est basée sur un arrangement innovant de tubes à baïonnette autorisant une conception à grande échelle, de l’échange thermique multiple entre la fumée pressurisée chaude, l’alimentation de gaz naturel et l’effluent riche en hydrogène.

Objective: To evaluate the efficacy of neoadjuvant chemotherapy combination with liposomal irinotecan, 5-fluorouracil, leucovorin, and oxaliplatin in patients with locally advanced rectal cancer., Methods: This was a phase 2, nonrandomized, multicenter study in adults with stage II or III rectal cancer and an Eastern Cooperative Oncology Group performance status of 0 to 1. Total neoadjuvant therapy (TNT) consisted of neoadjuvant chemotherapy combination with liposomal irinotecan (60 mg/m2), oxaliplatin (60 mg/m2), leucovorin (400 mg/m2), and fluorouracil (2400 mg/m²), followed by chemoradiotherapy [ie, capecitabine (825 mg/m2) and radiotherapy according to the standard of care]. The primary efficacy endpoint was the proportion of patients who achieved clinical complete response (cCR), defined as the normalization of pelvic magnetic resonance imaging, rectoscopy, computed tomography scan, and tumor markers., Results: The median follow-up was 32.3 months. Of the 30 patients who underwent TNT and were evaluated, 6 (20.0%; 95% CI: 5.2%-34.8%) patients achieved a cCR. There were no deaths. The median disease-free survival (DFS) for patients with cCR was not reached after a follow-up of 32 months; the 1-year DFS rate was 90.0% (95% CI: 71.0%-100%), and the 2-year and 3-year DFS rates were 80.0% (95% CI: 55.0%-100%). No grade ≥4 adverse events (AEs) were observed. Grade 3 AEs occurred in 18 patients (60%), most frequent was diarrhea (n = 9, 30%). Eleven (36.7%) patients experienced serious AEs, with diarrhea being the most frequent (n = 6, 20.0%)., Conclusion: TNT with 5-fluorouracil, leucovorin, and oxaliplatin and chemoradiation is a safe and effective therapeutic alternative for the management of locally advanced rectal cancer., Competing Interests: C.M. has received funding from Servier. M.C.R.M. has received a speaker honorarium from Servier, Roche, MSD, Merck; research grants to institution from BMS, MSD; and travel grants from Servier, Merck, Amgen, MSD. L.U. has received speaker honorarium from MSD, Merck, Fresenius; and travel grants from MSD, Merck, BMS, Roche. P.G.A. has received speaker honorarium from Amgen, Merck, MSD, BMS Sanofi, Servier, Pere Fabre; research grants to institution from Amgen; advisory honorarium from Amgen, Merck, MSD, Sanofi, Pere Fabre; and travel grants from Amgen, Merck, MSD, Sanofi, Pere Fabre. P.P. has received speaker honorarium from Merck; and travel grants from Merck and Roche. E.S.G. has received research grants from Novartis and GSK. The remaining authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: Clinical extranodal extension (cENE) is a cN modifier in TNM-8 for laryngo-hypopharygeal carcinoma (LHC). We hypothesize that image-detected ENE (iENE) can provide additional prognostic value over cENE in LHC., Methods: Baseline CTs/MRIs of cN+ LHC patients treated with definitive (chemo-)radiotherapy between 2010-2019 were re-reviewed by a neuroradiologist using internationally accepted criteria for iENE-positive/negative (iENE+/iENE-). Overall survival (OS) was compared by iENE status. Multivariable analysis (MVA) was performed to confirm the prognostic value of iENE, adjusted for known potential confounders., Results: A total of 232 LHC patients were identified, including 154 iENE-/cENE-, 60 iENE+/cENE-, and 18 iENE+/cENE+. A higher proportion of iENE+ (vs iENE-) patients had lymph node (LN) size > 3 cm [53 (67 %) vs 4 (3 %)], >=5 LNs [51 (65 %) vs 33 (21 %)], and retropharyngeal LN [12 (15 %) vs 6 (4 %)] (all p < 0.01). Median follow-up was 4.8 years. iENE+/cENE- and iENE+/cENE+patients had similarly low 5-year OS [28 % (18-44) and 29 % (13-63)] vs iENE-/cENE- [53 % (45-62)] (p < 0.001). On MVA, mortality risk was higher with iENE+vs iENE- [hazard ratio (HR) 2.22 (95 % CI 1.47-3.36)]. The prognostic value of iENE remained with MVA in larynx (n = 124) (HR 2.51 [1.35-4.68], p = 0.004] or hypopharynx (n = 108) (HR 1.87 [1.02-3.43], p = 0.04) patients, separately., Conclusions: Our study confirms the independent prognostic importance of iENE for LHC following definitive (chemo-)radiotherapy beyond TNM-8 cN status that already contains the cENE parameter. Further research is needed to explore whether iENE could replace cENE for future cN classification., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: The use of immunotherapy in mismatch repair proficient colorectal cancer (pMMR-CRC) or pancreatic adenocarcinoma (PDAC) is associated with limited efficacy. DAPPER (NCT03851614) is a phase 2, basket study randomizing patients with pMMR CRC or PDAC to durvalumab with olaparib (durvalumab + olaparib) or durvalumab with cediranib (durvalumab + cediranib)., Methods: PDAC or pMMR-CRC patients were randomized to either durvalumab+olaparib (arm A), or durvalumab + cediranib (arm B). Co-primary endpoints included pharmacodynamic immune changes in the tumor microenvironment (TME) and safety. Objective response rate, progression-free survival (PFS) and overall survival (OS) were determined. Paired tumor samples were analyzed by multiplexed immunohistochemistry and RNA-sequencing., Results: A total of 31 metastatic pMMR-CRC patients were randomized to arm A (n = 16) or B (n = 15). In 28 evaluable patients, 3 patients had stable disease (SD) (2 patients treated with durvalumab + olaparib and 1 patient treated with durvalumab + cediranib) while 25 had progressive disease (PD). Among patients with PDAC (n = 19), 9 patients were randomized to arm A and 10 patients were randomized to arm B. In 18 evaluable patients, 1 patient had a partial response (unconfirmed) with durvalumab + cediranib, 1 patient had SD with durvalumab + olaparib while 16 had PD. Safety profile was manageable and no grade 4-5 treatment-related adverse events were observed in either arm A or B. No significant changes were observed for CD3+/CD8+ immune infiltration in on-treatment biopsies as compared to baseline for pMMR-CRC and PDAC independent of treatment arms. Increased tumor-infiltrating lymphocytes at baseline, low baseline CD68+ cells and different immune gene expression signatures at baseline were associated with outcomes., Conclusions: In patients with pMMR-CRC or PDAC, durvalumab + olaparib and durvalumab + cediranib showed limited antitumor activity. Different immune components of the TME were associated with treatment outcomes., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Early kinetics of circulating tumor DNA (ctDNA) in plasma predict response to pembrolizumab but typically requires sequencing of matched tumor tissue or fixed gene panels. We analyzed genome-wide methylation and fragment-length profiles using cell-free methylated DNA immunoprecipitation and sequencing (cfMeDIP-seq) in 204 plasma samples from 87 patients before and during treatment with pembrolizumab from a pan-cancer phase II investigator-initiated trial (INSPIRE). We trained a pan-cancer methylation signature using independent methylation array data from The Cancer Genome Atlas to quantify cancer-specific methylation (CSM) and fragment-length score (FLS) for each sample. CSM and FLS are strongly correlated with tumor-informed ctDNA levels. Early kinetics of CSM predict overall survival and progression-free survival, independently of tumor type, PD-L1, and tumor mutation burden. Early kinetics of FLS are associated with overall survival independently of CSM. Our tumor-naïve mutation-agnostic ctDNA approach integrating methylomics and fragmentomics could predict outcomes in patients treated with pembrolizumab., Significance: Analysis of methylation and fragment length in plasma using cfMeDIP-seq provides a tumor-naive approach to measure ctDNA with results comparable with a tumor-informed bespoke ctDNA. Early kinetics within the first weeks of treatment in methylation and fragment quantity can predict outcomes with pembrolizumab in patients with various advanced solid tumors. This article is featured in Selected Articles from This Issue, p. 897., (©2024 The Authors; Published by the American Association for Cancer Research.)

Up to 30% of patients with locally advanced head and neck squamous cell carcinoma (LA-HNSCC) relapse. Molecular residual disease (MRD) detection using multiple assays after definitive therapy has not been reported. In this study, we included patients with LA-HNSCC (stage III Human Papilloma virus (HPV)-positive, III-IVB HPV-negative) treated with curative intent. Plasma was collected pre-treatment, at 4-6 weeks (FU1) and 8-12 weeks (FU2) post-treatment. Circulating tumor DNA (ctDNA) was analyzed using a tumor-informed (RaDaR®) and a tumor-naïve (CAPP-seq) assay. HPV DNA was measured using HPV-sequencing (HPV-seq) and digital PCR (dPCR). A total of 86 plasma samples from 32 patients were analyzed; all patients with at least 1 follow-up sample. Most patients were stage III HPV-positive (50%) and received chemoradiation (78%). No patients had radiological residual disease at FU2. With a median follow-up of 25 months, there were 7 clinical relapses. ctDNA at baseline was detected in 15/17 (88%) by RaDaR and was not associated with recurrence free survival (RFS). Two patients relapsed within a year after definitive therapy and showed MRD at FU2 using RaDaR; detection of ctDNA during follow-up was associated with shorter RFS (p < 0.001). ctDNA detection by CAPP-seq pre-treatment and during follow-up was not associated with RFS (p = 0.09). HPV DNA using HPV-seq or dPCR during follow-up was associated with shorter RFS (p < 0.001). Sensitivity and specificity for MRD at FU2 using RaDaR was 40% and 100% versus 20 and 90.5% using CAPP-seq. Sensitivity and specificity for MRD during follow-up using HPV-seq was 100% and 91.7% versus 50% and 100% using dPCR. In conclusion, HPV DNA and ctDNA can be detected in LA-HNSCC before definitive therapy. The RaDaR assay but not CAPP-seq may detect MRD in patients who relapse within 1 year. HPV-seq may be more sensitive than dPCR for MRD detection., (© 2024. The Author(s).)

Peritoneal metastases (PM) are common in metastatic colorectal cancer (mCRC). We aimed to characterize patients with mCRC and PM from a clinical and molecular perspective using the American Association of Cancer Research Genomics Evidence Neoplasia Information Exchange (GENIE) Biopharma Collaborative (BPC) registry. Patients' tumor samples underwent targeted next-generation sequencing. Clinical characteristics and treatment outcomes were collected retrospectively. Overall survival (OS) from advanced disease and progression-free survival (PFS) from start of cancer-directed drug regimen were estimated and adjusted for the left truncation bias. A total of 1,281 patients were analyzed, 244 (19%) had PM at time of advanced disease. PM were associated with female sex [OR: 1.67; 95% confidence interval (CI): 1.11-2.54; P = 0.014] and higher histologic grade (OR: 1.72; 95% CI: 1.08-2.71; P = 0.022), while rectal primary tumors were less frequent in patients with PM (OR: 0.51; 95% CI: 0.29-0.88; P < 0.001). APC occurred less frequently in patients with PM (N = 151, 64% vs. N = 788, 79%) while MED12 alterations occurred more frequently in patients with PM (N = 20, 10% vs. N = 32, 4%); differences in MED12 were not significant when restricting to oncogenic and likely oncogenic variants according to OncoKB. Patients with PM had worse OS (HR: 1.45; 95% CI: 1.16-1.81) after adjustment for independently significant clinical and genomic predictors. PFS from initiation of first-line treatment did not differ by presence of PM. In conclusion, PM were more frequent in females and right-sided primary tumors. Differences in frequencies of MED12 and APC alterations were identified between patients with and without PM. PM were associated with shorter OS but not with PFS from first-line treatment., Significance: Utilizing the GENIE BPC registry, this study found that PM in patients with colorectal cancer occur more frequently in females and right-sided primary tumors and are associated with worse OS. In addition, we found a lower frequency of APC alterations and a higher frequency in MED12 alterations in patients with PM., (© 2024 The Authors; Published by the American Association for Cancer Research.)

Purpose: To evaluate early circulating tumor DNA (ctDNA) kinetics using a tumor-naïve assay and correlate it with clinical outcomes in early phase immunotherapy (IO) trials., Methods: Plasma samples were analyzed using a 425-gene next-generation sequencing panel at baseline and before cycle 2 (3-4 weeks) in patients with advanced solid tumors treated with investigational IO agents. Variant allele frequency (VAF) for mutations in each gene, mean VAF (mVAF) from all mutations, and change in mVAF between both time points were calculated. Hyperprogression (HyperPD) was measured using Matos and Caramella criteria., Results: A total of 162 plasma samples were collected from 81 patients with 27 different tumor types. Patients were treated in 37 different IO phase I/II trials, 72% of which involved a PD-1/PD-L1 inhibitor. ctDNA was detected in 122 plasma samples (75.3%). A decrease in mVAF from baseline to precycle 2 was observed in 24 patients (37.5%) and was associated with longer progression-free survival (hazard ratio [HR], 0.43; 95% CI, 0.24 to 0.77; P < .01) and overall survival (HR, 0.54; 95% CI, 0.3 to 0.96; P = .03) compared with an increase. These differences were more marked if there was a >50% decrease in mVAF for both progression-free survival (HR, 0.29; 95% CI, 0.13 to 0.62; P < .001) and overall survival (HR, 0.23; 95% CI, 0.09 to 0.6; P = .001). No differences in mVAF changes were observed between the HyperPD and progressive disease patients., Conclusion: A decrease in ctDNA within 4 weeks of treatment was associated with treatment outcomes in patients in early phase IO trials. Tumor-naïve ctDNA assays may be useful for identifying early treatment benefits in phase I/II IO trials.

Background: Recent studies have demonstrated that T cells can induce vasodilation in a choline-acetyltransferase dependent manner, leading to an increase in T cell migration to infected tissues in response to viral infection, but its role in cancer is unclear. Choline acetyltransferase catalyzes the production of acetylcholine from choline and acetyl-CoA, however, acetylcholine is challenging to quantify due to its extremely short half-life while choline is stable. This study aims to correlate serum choline levels in patients with advanced solid tumors receiving pembrolizumab with treatment outcomes., Methods: Blood samples were collected at baseline and at week 7 (pre-cycle 3) in patients treated with pembrolizumab in the INvestigator-initiated Phase 2 Study of Pembrolizumab Immunological Response Evaluation phase II trial (NCT02644369). Samples were analyzed for choline and circulating tumor DNA (ctDNA). Multivariable Cox models were used to assess the association between choline and overall survival (OS) and progression-free survival (PFS) when including ΔctDNA C3 (the change in ctDNA from baseline to cycle 3), cohort, PD-L1 expression and tumor mutation burden (TMB). An independent validation cohort from the LIBERATE study (NCT03702309) included patients on early phase trials treated with a PD-1 inhibitor., Results: A total of 106 pts were included in the analysis. With a median follow-up of 12.6 months, median PFS and OS were 1.9 and 13.7 months, respectively. An increase in serum choline level at week 7 compared with baseline (Δcholine C3 ) in 81 pts was significantly associated with a better PFS (aHR 0.48, 95% CI 0.28 to 0.83, p=0.009), and a trend toward a better OS (aHR 0.64, 95% CI 0.37 to 1.12, p=0.119). A combination of ΔctDNA C3 and Δcholine C3 was prognostic for both OS and PFS. Multivariable analyses show Δcholine C3 was a prognostic factor for PFS independent of ΔctDNA C3 , cohort, PD-L1 and TMB. In the independent validation cohort (n=51), an increase in serum choline at cycle 2 was associated with a trend to improved PFS., Conclusions: This is the first exploratory report of serum choline levels in pan-cancer patients receiving pembrolizumab. The association between improved PFS and Δcholine C3 suggests a possible role for the cholinergic system in the regulation of antitumor immunity. Further pre-clinical and clinical studies are required to validate this finding., Trial Registration Number: NCT03702309., Competing Interests: Competing interests: ESG, W-JZ, ZAL, SCY, SL, SK, HB, SG, WX have no disclosures. GAW received travel grants from Bristol Myers Squibb and Abbvie, and honoraria from Pfizer. BW has received honoraria from AstraZeneca and Tessa Therapeutics. PLB: consulting/advisory (uncompensated) with Bristol-Myers Squibb, Seattle Genetics, Gilead, Merck, Pfizer, Amgen, Lilly; and institution receives clinical trials support from Novartis, Bristol-Myers Squibb, Pfizer, GlaxoSmithKline, Roche/Genentech, AstraZeneca, Merck, Amgen, Zymeworks, Seattle Genetics, Nektar Therapeutics, Lilly, and Bicara Therapeutics. MOB Ad boards: Merck, BMS, Novartis, Adaptimmune, GSK, Sanofi, LaRoche Possey, Sun Pharma, Instil Bio, IOVANCE, Pfizer. Grant funding: Merck, Takara Bio, Novartis. Safety Review Committee: Adaptimmune, GSK. Honoraria for talks: BMS, Novartis, Merck, Sanofi, Pfizer. SL is principal investigator and co-investigators of different industry-sponsor or investigated initiated trials. I received honoraria from AZ, GSK, Roche, Merck, Eisai and Shattuck labs. DC: Consulting/Advisory Boards: AstraZeneca, Dynamo Therapeutics, Eisai, Exact Sciences, Gilead, GlaxoSmithKline, Merck, Novartis, Pfizer and Roche. Research funding to institution: GlaxoSmithKline, Inivata, Merck, Pfizer, and Roche. Patent (US62/675,228) for methods of treating cancers characterized by a high expression level of spindle and kinetochore associated complex subunit 3 (ska3) gene. ARH reports institutional support for clinical trials conduct from Novartis, Bristol-Myers Squibb, Pfizer, Boehringer-Ingelheim, GlaxoSmithKline, Roche/Genentech, Karyopharm, AstraZeneca/Medimmune, Merck, Astellas and Bayer; and compensated consulting/advisory boards for AstraZeneca, Merck and GlaxoSmithKline. AAR has received research funding from Roche, Genentech, Eli Lilly, Merck, Boehringer Ingelheim, Novartis, AbbVie, Deciphera, Karyopharm, Astra Zeneca, Medimmune, Blueprint, Bristol Myers Squibb, GSK, Entremed/Casi Pharmaceuticals, Adaptimmune and BetaCat. He also has also served the advisory board for Eli Lilly, Merck, Adaptimmune, Boehringer Ingelheim. AS has served as an advisory board consultant for Merck (compensated), Bristol-Myers Squibb (compensated), Novartis (compensated), Oncorus (compensated), Janssen (compensated). She has also received research funding from Novartis, Bristol-Myers Squibb, Symphogen AstraZeneca/Medimmune, Merck, Bayer, Surface Oncology, Northern Biologics, Janssen Oncology/Johnson & Johnson, Roche, Regeneron, Alkermes, Array Biopharma, GSK. TWM Cofounder Treadwell Therapeutics. Stock ownership Agios Therapeutics Stock, Agios, Treadwell LS: consulting/advisory arrangements with Merck, Pfizer, Celgene, AstraZeneca, Morphosys, Roche, Oncorus, Symphogen, Seattle Genetics, GlaxoSmithKline, Voronoi, Arvinas, Tessa, Navire, Relay, Rubius, Janpix, Daiichi Sanyko; stock ownership of Agios (spouse); leadership position in Treadwell Therapeutics (spouse); and institution receives clinical trials support from Novartis, Bristol-Myers Squibb, Pfizer, Boerhinger-Ingelheim, GlaxoSmithKline, Roche/Genentech, Karyopharm, AstraZeneca, Merck, Celgene, Astellas, Bayer, Abbvie, Amgen, Symphogen, Intensity Therapeutics, Mirati Therapeutics, Shattucks, Avid. EC: honoria from Bayer and Taiho; institution receives clinical trials support from Novartis, Bristol-Myers Squibb, Roche, AstraZeneca, Merck, 1Globe, Mirati Therapetuics, Zymeworks and Amgen., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Circulating tumor DNA (ctDNA) has emerged as a biomarker with wide-ranging applications in cancer management. While its role in guiding precision medicine in certain tumors via noninvasive detection of susceptibility and resistance alterations is now well established, recent evidence has pointed to more generalizable use in treatment monitoring. Quantitative changes in ctDNA levels over time (i.e., ctDNA kinetics) have shown potential as an early indicator of therapeutic efficacy and could enable treatment adaptation. However, ctDNA kinetics are complex and heterogeneous, affected by tumor biology, host physiology, and treatment factors. This review outlines the current preclinical and clinical knowledge of ctDNA kinetics in cancer and how early on-treatment changes in ctDNA levels could be applied in clinical research to collect evidence to support implementation in daily practice.

Eligibility criteria restrict patient enrollment in clinical trials. A Nature paper applied a machine-learning algorithm in a real-world database to show that relaxing some criteria may not jeopardize efficacy and safety. This may enable more patients to have earlier access to new therapies and make results more generalizable to clinical practice., Competing Interests: Declaration of interests Enrique Sanz-Garcia declares no competing interests. Benjamin Haibe-Kains has consulting arrangements with Code Ocean Inc. Lillian L. Siu has consulting/advisory arrangements with Merck, Pfizer, Celgene, AstraZeneca, Morphosys, Roche, Oncorus, Symphogen, Seattle Genetics, GlaxoSmithKline, Voronoi, Arvinas, Tessa, Navire, Relay, Rubius, Janpix, and Daiichi Sanyko; stock ownership of Agios (spouse); and a leadership position in Treadwell Therapeutics (spouse); and her institution receives clinical trials support from Novartis, Bristol-Myers Squibb, Pfizer, Boerhinger-Ingelheim, GlaxoSmithKline, Roche/Genentech, Karyopharm, AstraZeneca, Merck, Celgene, Astellas, Bayer, Abbvie, Amgen, Symphogen, Intensity Therapeutics, Mirati Therapeutics, Shattucks, and Avid., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Sequencing of tumors is now routine and guides personalized cancer therapy. Mutant allele fractions (MAFs, or the 'mutation dose') of a driver gene may reveal the genomic structure of tumors and influence response to targeted therapies. We performed a comprehensive analysis of MAFs of driver alterations in unpaired primary and metastatic colorectal cancer (CRC) at our institution from 2010 to 2015 and studied their potential clinical relevance. Of 763 CRC samples, 622 had detailed annotation on overall survival in the metastatic setting (OSmet) and 89 received targeted agents matched to KRAS (MEK inhibitors), BRAF (BRAF inhibitors), or PIK3CA mutations (PI3K pathway inhibitors). MAFs of each variant were normalized for tumor purity in the sample (adjMAFs). We found lower adjMAFs for BRAF V 600E and PIK3CA than for KRAS, NRAS, and BRAF non-V600 variants. TP53 and BRAF V 600E adjMAFs were higher in metastases as compared to primary tumors, and high KRAS adjMAFs were found in CRC metastases of patients with KRAS wild-type primary tumors previously exposed to EGFR antibodies. Patients with RAS- or BRAF V 600E -mutated tumors, irrespective of adjMAFs, had worse OSmet. There was no significant association between adjMAFs and time to progression on targeted therapies matched to KRAS, BRAF, or PIK3CA mutations, potentially related to the limited antitumor activity of the employed drugs (overall response rate of 4.5%). In conclusion, the lower BRAF V 600E and PIK3CA adjMAFs in subsets of primary CRC tumors indicate subclonality of these driver genes. Differences in adjMAFs between metastases and primary tumors suggest that approved therapies may result in selection of BRAF V 600E - and KRAS-resistant clones and an increase in genomic heterogeneity with acquired TP53 alterations. Despite significant differences in prognosis according to mutations in driver oncogenes, adjMAFs levels did not impact on survival and did not help predict benefit with matched targeted agents in the metastatic setting., (© 2017 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.)

Introduction: Colorectal cancer (CRC) is one of the leading causes of cancer deaths worldwide. Despite the introduction of several new drugs targeting the vascular endothelial growth factor or epidermal growth factor receptor (EGFR) signaling pathways, survival and disease control in metastatic CRC remains poor., Areas Covered: Chemotherapy based on fluoropyrimidines and irinotecan or oxaliplatin has been the cornerstone of CRC standard of care for several decades. Optimal regimens are selected according to toxicity profiles and patient characteristics. The addition of targeted drugs inhibiting angiogenesis, notably bevacizumab, aflibercept and ramucirumab, has improved chemotherapy outcomes in metastatic CRC. Anti-EGFR agents, cetuximab and panitumumab, in combination with chemotherapy have also improved survival in patients with wild-type RAS tumors. In the refractory setting, there are emerging drugs such as regorafenib or TAS-102 that also have demonstrated impact on outcomes., Expert Opinion: Drugs targeting signaling pathways involved in tumorigenesis improve patient outcomes over chemotherapy alone. Determining the most suitable combination and sequence should be carefully selected, with studies yet to provide a definitive solution to this unknown. Molecular mechanisms of colorectal cancer are at the forefront of research. Knowledge in this domain will help overcome resistance to therapies and introduce new drugs in the personalized CRC therapeutic scenario.

Introduction: Colorectal cancer (CRC) is currently one of the most lethal and prevalent tumors worldwide. Prognosis in the metastatic setting remains poor despite therapeutic advances. In addition to chemotherapy, new drugs have recently been developed targeting signaling pathways involved in tumor growth, differentiation and angiogenesis. Aflibercept , a recombinant protein derived from VEGF receptors 1 and 2, also targets this angiogenesis pathway but via a different mechanism, acting as VEGF decoy, thus blocking other VEGFs., Areas Covered: A comprehensive review of preclinical studies with aflibercept in cell lines and xenografts of different tumor types is presented. Aflibercept safety, pharmacokinetics and pharmacodynamics data from Phase I studies in solid tumor patients are discussed. Implications of Phase II studies and the pivotal Phase III VELOUR trial of second-line treatment in metastatic CRC (mCRC) patients evaluating aflibercept alone or combined with chemotherapy are also described., Expert Opinion: In this challenging field, aflibercept offers a good option for oxaliplatin-refractory mCRC patients when combined with irinotecan and 5-fluorouracil irrespective of prior anti-angiogenic treatment. Therapeutic management may be further advanced by characterization of patients with predictive biomarkers and molecular profiles to improve benefit with this treatment.