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Background: Surgery improves long-term survival for resectable, liver-only metastatic colorectal cancer (mCRC). With no consensus definition of "resectable" disease, decisions regarding resectability are reliant on the expertise and judgement of the treating clinician working in consultation with a multidisciplinary team (MDT). This study examines the clinical outcome versus initial assessment of resectability in an Australian population with mCRC., Patients and Methods: Patients with liver-only mCRC diagnosed January 2009 to December 2022 were identified from the Treatment of Recurrent and Advanced Colorectal Cancer (TRACC) registry. Patients were classified based on prospectively documented treatment assessment as "resectable," "potentially resectable," or "unresectable." The correlation between initial assessment of resectability and clinical outcome, and any impact of clinicopathologic factors were examined. Kaplan-Meier analysis assessed overall survival based on initial resectability assessment and resection status., Results: Of 4437 patients with mCRC identified through TRACC, 1250 (28%) had liver-only disease at presentation, with 497 (43%), 277 (24%), and 374 (33%) classified as "unresectable," "potentially resectable," and "resectable," respectively. In total, 516 (41%) ultimately underwent surgical resection, including 30 (6%) of the "initially unresectable," 148 (53%) of the "potentially resectable," and 338 (90%) of the "resectable" at a median of 9.5, 5.9, and 2.4 months from the diagnosis of liver metastases, respectively. Resection in the "unresectable" patient population was associated with younger age (mean age 63 vs. 69, P = .0006), better performance status (ECOG 0-1 100% vs. 74%, P = .0017), and fewer comorbidities (Charlson index 0-3 in 73% vs. 53%, P = .0296) compared with no resection. Median overall survival was longer for resected versus nonresected patients across all categories: "unresectable" (59.2 vs. 17.6 months, P < .0001), "potentially resectable" (57.2 vs. 22.8 months, P < .0001), and "resectable" (108 vs. 55 months, P < .0001)., Conclusions: This real-world study demonstrates the potential for "initially unresectable" patients to become surgical candidates following systemic therapy, more likely in younger and fitter patients, with overall excellent survival outcomes in resected patients. This highlights the value of routine, repeated MDT assessments for patients with liver-only disease who are continuing to respond to systemic therapy, even for those initially considered never to be surgical candidates., Competing Interests: Disclosure None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: To determine whether the addition of durvalumab (anti-PD-L1) and oleclumab (anti-CD73) to standard-of-care treatment (FOLFOX and bevacizumab) enhances the anti-tumour effect in patients with metastatic colorectal cancer (mCRC)., Methods: COLUMBIA-1 (NCT04068610) was a Phase Ib (feasibility; Part 1)/Phase II (randomised; Part 2) trial in patients with treatment-naïve microsatellite stable mCRC. Patients in Part 2 were randomised to receive standard-of-care (control arm) or standard-of-care plus durvalumab and oleclumab (experimental arm). Primary objectives included safety and efficacy., Results: Seven patients were enrolled in Part 1 and 52 in Part 2 (n = 26 in each arm). Grade ≥3 treatment-emergent adverse events (TEAE) occurred in 80.8% and 65.4% of patients in the control and experimental arms of Part 2, respectively, with 26.9% and 46.3% experiencing serious TEAEs. The confirmed objective response rate (ORR) was numerically higher in the experimental arm compared with the control arm (61.5% [95% confidence interval (CI), 40.6-79.8] vs 46.2% [95% CI, 26.6-66.6]) but did not meet the statistically significant threshold in either arm., Conclusion: The safety profile of FOLFOX and bevacizumab in combination with durvalumab and oleclumab was manageable; however, the efficacy results do not warrant further development of this combination in patients with microsatellite stable mCRC., Registration: NCT04068610., (© 2024. The Author(s).)

BRAF V600E -mutant metastatic colorectal cancer represents a distinct molecular phenotype known for its aggressive biological behavior, resistance to standard therapies, and poor survival rates. Improved understanding of the biology of the BRAF oncogene has led to the development of targeted therapies that have paved the way for a paradigm shift in managing this disease. However, despite significant recent advancements, responses to targeted therapies are short-lived, and several challenges remain. In this review, we discuss how progress in treating BRAF V600E -mutant metastatic colorectal cancer has been made through a better understanding of its unique biological and clinical features. We provide an overview of the evidence to support current treatment approaches and discuss critical areas of need and future research strategies that hold the potential to refine clinical practice further. We also discuss some challenging aspects of managing this disease, particularly the complexity of acquired resistance mechanisms that develop under the selective pressure of targeted therapies and rational strategies being investigated to overcome them., Competing Interests: Disclosure Oliver Piercey - OP has received educational travel reimbursement from MSD, educational speaker fees from BMS, medical writing support from Pierre-Fabre. Jeanne Tie - JT reports receiving honorarium for consultancy/advisory role from Astra Zeneca, Haystack Oncology, Merck Serono, Merck Sharp & Dohme, Pierre Fabre, Bristol Myers Squibb, Servier, Daiichi Sankyo, Gilead, Beigene, Illumina, Takeda; research funding (institutional) from Pfizer, Daiichi Sankyo, Bristol Myers Squibb, Genentech, Grail, Zentalis, IGM Biosciences. Frederic Hollande - None. John Mariadason - None. Hui-Li Wong - None. Jayesh Desai - JD has served as a consultant and as an advisory board or steering committee member for Amgen, Axelia, Bayer, BeiGene, Boehringer Ingelheim, Daiichi Sankyo, Ellipses, GSK, IQVIA, Merck KGaA, Novartis, Pfizer, Pierre Fabre, and Roche/Genentech; and reports institutional research funding from Amgen, AstraZeneca, BeiGene, Bristol Myers Squibb, GSK, Novartis, and Roche/Genentech., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: A substantial proportion of patients with stage III colorectal cancer (CRC) are older than 70 years. Optimal adjuvant chemotherapy (AC) for older patients (OP) continues to be debated, with subgroup analyses of randomized trials not demonstrating a survival benefit from the addition of oxaliplatin to a fluoropyrimidine backbone., Patients and Methods: We analyzed the multisite Australian ACCORD registry, which prospectively collects patient, tumor and treatment data along with long term clinical follow-up. We compared OP (≥70) with stage III CRC to younger patients ([YP] <70), including the proportion recommended AC and any reasons for not prescribing AC. AC administration, regimen choice, completion rates, and survival outcomes were also examined., Results: One thousand five hundred twelve patients enrolled in the ACCORD registry from 2005 to 2018 were included. Median follow-up was 57.0 months. Compared to the 827 YP, the 685 OP were less likely to be offered AC (71.5% vs. 96.5%, P < .0001) and when offered, were more likely to decline treatment (15.1% vs. 2.8%, P < .0001). Ultimately, 60.0% of OP and 93.7% of YP received AC (P < .0001). OP were less likely to receive oxaliplatin (27.5% vs. 84.7%, P < .0001) and to complete AC (75.9% vs. 85.7%, P < .0001). The probability of remaining recurrence-free was significantly higher in OP who received AC compared to those not treated (HR 0.73, P = .04) but not significantly improved with the addition of oxaliplatin (HR 0.75, P = .18)., Conclusion: OP were less likely than YP to receive AC. Receipt of AC reduced recurrences in OP, supporting its use, although no significant benefit was observed from the addition of oxaliplatin., Competing Interests: Disclosure Oliver Piercey: OP has received travel expenses from MSD and an educational speaker fee from BMS; Valerie Heong: VH has received consulting fees or honoraria from AstraZeneca, Novartis, MSD, DKSH and receives grant funding from an NTF HIP grant and an LKC-NHG grant; Jeanne Tie: JT has received consulting fees or honoraria from Haystack Oncology, Seres Therapeutics, Amgen, Servier, Beigene, Novartis, Astra Zeneca, Merck Serono, MSD, Pierre Fabre, BMS, Daichii Sankyo, Illumina, Takeda and Gilead. All other authors report no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: There is accumulating evidence supporting the clinical use of circulating tumor DNA (ctDNA) in solid tumors, especially in different types of gastrointestinal cancer. As such, appraisal of the current and potential clinical utility of ctDNA is needed to guide clinicians in decision-making to facilitate its general applicability., Content: In this review, we firstly discuss considerations surrounding specimen collection, processing, storage, and analysis, which affect reporting and interpretation of results. Secondly, we evaluate a selection of studies on colorectal, esophago-gastric, and pancreatic cancer to determine the level of evidence for the use of ctDNA in disease screening, detection of molecular residual disease (MRD) and disease recurrence during surveillance, assessment of therapy response, and guiding targeted therapy. Lastly, we highlight current limitations in the clinical utility of ctDNA and future directions., Summary: Current evidence of ctDNA in gastrointestinal cancer is promising but varies depending on its specific clinical role and cancer type. Larger prospective trials are needed to validate different aspects of ctDNA clinical utility, and standardization of collection protocols, analytical assays, and reporting guidelines should be considered to facilitate its wider applicability., (© Association for Diagnostics & Laboratory Medicine 2024. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Horizon scanning (HS) is the systematic identification of emerging therapies to inform policy and decision-makers. We developed an agile and tailored HS methodology that combined multi-criteria decision analysis weighting and Delphi rounds. As secondary objectives, we aimed to identify new medicines in melanoma, non-small cell lung cancer and colorectal cancer most likely to impact the Australian government's pharmaceutical budget by 2025 and to compare clinician and consumer priorities in cancer medicine reimbursement., Method: Three cancer-specific clinician panels (total n = 27) and a consumer panel (n = 7) were formed. Six prioritisation criteria were developed with consumer input. Criteria weightings were elicited using the Analytic Hierarchy Process (AHP). Candidate medicines were identified and filtered from a primary database and validated against secondary and tertiary sources. Clinician panels participated in a three-round Delphi survey to identify and score the top five medicines in each cancer type., Results: The AHP and Delphi process was completed in eight weeks. Prioritisation criteria focused on toxicity, quality of life (QoL), cost savings, strength of evidence, survival, and unmet need. In both curative and non-curative settings, consumers prioritised toxicity and QoL over survival gains, whereas clinicians prioritised survival. HS results project the ongoing prevalence of high-cost medicines. Since completion in October 2021, the HS has identified 70 % of relevant medicines submitted for Pharmaceutical Benefit Advisory Committee assessment and 60% of the medicines that received a positive recommendation., Conclusion: Tested in the Australian context, our method appears to be an efficient and flexible approach to HS that can be tailored to address specific disease types by using elicited weights to prioritise according to incremental value from both a consumer and clinical perspective., Policy Summary: Since HS is of global interest, our example provides a reproducible blueprint for adaptation to other healthcare settings that integrates consumer input and priorities., Competing Interests: Declaration of Competing Interest MA has received financial support to attend conferences and meetings by AstraZeneca and serves on the advisory board for Pfizer and Bristol Myers Squibb. PAA has/had a consultant/advisory role for Bristol Myers Squibb, Roche-Genentech, Merck Sharp & Dohme, Novartis, Merck Serono, Pierre-Fabre, AstraZeneca, Sun Pharma, Canofi, Idera, Sandoz, Immunocore, 4SC, Italfarmaco, Nektar, Boehringer-Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Pfizer, Oncosec, Nouscom, Lunaphore, Seagen, iTeos, Medicenna, Bio-Al Health, ValoTX, Replimmune. He has received research funding grants from Bristol Myers Squibb, Roche-Genentech, Pfizer, Sanofi. He has received travel support from Pfizer. SA has served uncompensated on the boards of Health Issues Centre, Australia, Victorian Agency for Health Information, and Safer Care Victoria. MPB has received honoraria from BNS Australia, USD Oncology, and Novartis. He holds an advisory role for Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, and Cartherics for which his institution receives reimbursements. His institution has also received reimbursement for research support from Bristol Myers Squibb, Merck Sharp & Dohme, Pharmaust, Zucero Therapeutics, and CStone Pharmaceuticals. MB has received compensation and research support as an advisor and consultant to Pierre Fabre, MSD, GSK, Servier, and AstraZeneca. MI is on the advisory boards of Pfizer, Roche, Takeda, BeiGene, Amgen, Merck, and MSD and has received honoraria from Pfizer, Roche, Takeda, Novartis, as well as research funding from Pfizer. TJ reports consulting fees from AstraZeneca and MSD, and advisory boards and committees for AstraZeneca, Amgen, Bristol Myers Squibb, Merck & Co., MSD, Gilead, Puma, Pfizer Inc., Roche AG, Specialised Therapeutics, and Takeda Pharmaceutical, outside the submitted work. SK reports honoraria to institution from Astra Zeneca, Roche, Pfizer, Bristol Myers Squibb, MSD and Takeda; consulting fees from AstraZeneca, Pfizer, MSD, Novartis, Roche, Takeda, Amgen; and research funding to institution from Astra Zeneca. MK reports institutional grants from Nordic Farma, Merck-Serono, Pierre Fabre, Servier, Bayer, Bristol Myers Squibb, Merck, and Roche; and consulting fees and honoraria paid to institution from Pierre Fabre and Servier. BTL has served as an uncompensated advisor and consultant to Amgen, AstraZeneca, Boehringer Ingelheim, Bolt Biotherapeutics, Daiichi Sankyo, Genentech, and Lilly. He has received research grants to his institution from Amgen, AstraZeneca, Bolt Biotherapeutics, Daiichi Sankyo, Genentech, Hengrui USA, and Lilly. He has received academic travel support from Amgen, Jiangsu Hengrui Medicine and MORE Health. He is an inventor on two institutional patents at MSK (US62/685,057, US62/514,661) and has intellectual property rights as a book author at Karger Publishers and Shanghai Jiao Tong University Press. BTL is supported by the Memorial Sloan Kettering Cancer Centre Support Grant P30 CA008748 and Research Project Grant R01CA249666 from the National Institutes of Health. GVL is consultant advisor for Agenus, Amgen, Array Biopharma, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Evaxion, Hexal AG (Sandoz Company), Highlight Therapeutics S.L., Innovent Biologics USA, Merck Sharpe & Dohme, Novartis, OncoSec, PHMR Ltd, Pierre Fabre, Provectus, Qbiotics, Regeneron. JML receives research support from Ipsen Pharmaceuticals, Novartis and Amgen, and reports consulting fees and/or honoraria from Amgen, Ipsen, Taiho, Novartis, SAGA Diagnostics and Natera. BM is on the advisory boards of Amgen, MSD, Bristol Myers Squibb, Beigene and AstraZeneca. GAM has received research support from Bristol Myers Squibb and as Principal Investigator his institution has received reimbursement of trial costs from Roche-Genentech. TMM reports consulting fees and participation on advisory boards for Bristol Myers Squibb, MSD, Merck, AstraZeneca, Novartis, GSK, Eisai, and honoraria from AstraZeneca. TMM has received support to attend meetings from Bristol Myers Squibb and AstraZeneca. LN has received institutional consulting fees from Bristol Myers Squibb, Pfizer, and Merck Sharp & Dohme, and reports support to attend a research meeting from AstraZeneca. NP has served on advisory boards or received personal honoraria from Boehringer Ingelheim, MSD, Merck, Bristol-Myers Squib, Astra Zeneca, Takeda, Pfizer, Roche, Novartis, Ipsen and Bayer and has received research funding to his institution from Bayer, Pfizer and Roche. TMP has received research support from Roche and Pfizer, and holds a consulting or advisory role for Merck, Bristol Myers Squibb, Novartis, Sanofi/Regeneron, and Pfizer. SP is compensated consultant to Amgen, AstraZeneca, Bayer, Blueprint, BMS, Boehringer Ingelheim, Daiichi Sankyo, EQRx, GSK, Guardant Health, Incyte, Janssen, Lilly, Merck Serono, MSD, Novartis, Roche, Takeda, Pfizer, Seattle Genetics, Turning Point Therapeutics, declares expert testimony to Roche and Merck Serono, and travel support from Janssen and Roche.BJS is on the Advisory Boards/Honoraria for Pfizer, Novartis, Roche, AstraZeneca, Merck, Bristol Myers Squibb, Eli Lilly, Amgen, BeiGene, Janssen, Takeda. JAS has received support for conference attendance from MSD (virtual registration ASCO). JT has received consulting fees or honoraria from Haystack Oncology, Servier, Pierre Fabre, MSD, Merck Serono, Amgen, Novartis, Seres and AstraZeneca. JT is on the advisory boards of Beigene, Daiichi Sankyo, Gilead, Illumina, Novartis, BMS, and MSD. WX has received research support from Merck, honoraria from MSD, Merck and AstraZeneca, and support for attending meetings from MSD (virtual registration ASCO) and Eli Lilly (virtual registration SABCS). WX is on the advisory boards of MSD, Merck and Novartis, and holds unpaid positions as Chair of the Melanoma and Skin Cancer trials group and Australasian Merkel Cell Carcinoma interest group.DY has received institutional payments for his role on advisory boards for AstraZeneca, Servier, Specialised Therapeutics, MSD and BayerJZ serves in an advisory/consultancy role for Merck Sharp & Dohme, Specialised Therapeutics, CEND, Deciphera, Revolution Medicine, FivePHusion, Genorbio, 1Global, Novotech, Alloplex Biotherapeutics, NOUS Consulting, and Oncology Republic; owns stock in Biomarin, Ophthea, Amarin, Concert Pharmaceuticals, Frequency Therapeutics, Gilead, Madrigal Pharmaceuticals, UniQure, Zogenix, Orphazyme, Moderna Therapeutics, TWST, Novavax, and Teladoc; has received honoraria from Gilead Sciences, MSD Oncology, and Viatris; and his institution has received research funding from Bristol-Myers Squibb, AstraZeneca, Pfizer, IQvia, Mylan, Ipsen, Eisai, Medtronic, MSD Oncology and Servier; and has received travel, accommodations, expenses from ICON Group, MSD Oncology, and PRAXIS., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Importance: Thromboprophylaxis for individuals receiving systemic anticancer therapies has proven to be effective. Potential to maximize benefits relies on improved risk-directed strategies, but existing risk models underperform in cohorts with lung and gastrointestinal cancers., Objective: To assess clinical benefits and safety of biomarker-driven thromboprophylaxis and to externally validate a biomarker thrombosis risk assessment model for individuals with lung and gastrointestinal cancers., Design, Setting, and Participants: This open-label, phase 3 randomized clinical trial (Targeted Thromboprophylaxis in Ambulatory Patients Receiving Anticancer Therapies [TARGET-TP]) conducted from June 2018 to July 2021 (with 6-month primary follow-up) included adults aged 18 years or older commencing systemic anticancer therapies for lung or gastrointestinal cancers at 1 metropolitan and 4 regional hospitals in Australia. Thromboembolism risk assessment based on fibrinogen and d-dimer levels stratified individuals into low-risk (observation) and high-risk (randomized) cohorts., Interventions: High-risk patients were randomized 1:1 to receive enoxaparin, 40 mg, subcutaneously daily for 90 days (extending up to 180 days according to ongoing risk) or no thromboprophylaxis (control)., Main Outcomes and Measures: The primary outcome was objectively confirmed thromboembolism at 180 days. Key secondary outcomes included bleeding, survival, and risk model validation., Results: Of 782 eligible adults, 328 (42%) were enrolled in the trial (median age, 65 years [range, 30-88 years]; 176 male [54%]). Of these participants, 201 (61%) had gastrointestinal cancer, 127 (39%) had lung cancer, and 132 (40%) had metastatic disease; 200 (61%) were high risk (100 in each group), and 128 (39%) were low risk. In the high-risk cohort, thromboembolism occurred in 8 individuals randomized to enoxaparin (8%) and 23 control individuals (23%) (hazard ratio [HR], 0.31; 95% CI, 0.15-0.70; P = .005; number needed to treat, 6.7). Thromboembolism occurred in 10 low-risk individuals (8%) (high-risk control vs low risk: HR, 3.33; 95% CI, 1.58-6.99; P = .002). Risk model sensitivity was 70%, and specificity was 61%. The rate of major bleeding was low, occurring in 1 participant randomized to enoxaparin (1%), 2 in the high-risk control group (2%), and 3 in the low-risk group (2%) (P = .88). Six-month mortality was 13% in the enoxaparin group vs 26% in the high-risk control group (HR, 0.48; 95% CI, 0.24-0.93; P = .03) and 7% in the low-risk group (vs high-risk control: HR, 4.71; 95% CI, 2.13-10.42; P < .001)., Conclusions and Relevance: In this randomized clinical trial of individuals with lung and gastrointestinal cancers who were stratified by risk score according to thrombosis risk, risk-directed thromboprophylaxis reduced thromboembolism with a desirable number needed to treat, without safety concerns, and with reduced mortality. Individuals at low risk avoided unnecessary intervention. The findings suggest that biomarker-driven, risk-directed primary thromboprophylaxis is an appropriate approach in this population., Trial Registration: ANZCTR Identifier: ACTRN12618000811202.

Cell-free DNA (cfDNA) concentrations from patients with cancer are often elevated compared with those of healthy controls, but the sources of this extra cfDNA have never been determined. To address this issue, we assessed cfDNA methylation patterns in 178 patients with cancers of the colon, pancreas, lung, or ovary and 64 patients without cancer. Eighty-three of these individuals had cfDNA concentrations much greater than those generally observed in healthy subjects. The major contributor of cfDNA in all samples was leukocytes, accounting for ∼76% of cfDNA, with neutrophils predominating. This was true regardless of whether the samples were derived from patients with cancer or the total plasma cfDNA concentration. High levels of cfDNA observed in patients with cancer did not come from either neoplastic cells or surrounding normal epithelial cells from the tumor's tissue of origin. These data suggest that cancers may have a systemic effect on cell turnover or DNA clearance., Significance: The origin of excess cfDNA in patients with cancer is unknown. Using cfDNA methylation patterns, we determined that neither the tumor nor the surrounding normal tissue contributes this excess cfDNA-rather it comes from leukocytes. This finding suggests that cancers have a systemic impact on cell turnover or DNA clearance. See related commentary by Thierry and Pisareva, p. 2122. This article is featured in Selected Articles from This Issue, p. 2109., (©2023 American Association for Cancer Research.)

Liquid biopsies that detect circulating tumour DNA (ctDNA) have the potential to revolutionise the personalised management of colorectal cancer. For patients with early-stage disease, emerging clinical applications include the assessment of molecular residual disease after surgery, the monitoring of adjuvant chemotherapy efficacy, and early detection of recurrence during surveillance. In the advanced disease setting, data highlight the potential of ctDNA levels as a prognostic marker and as an early indicator of treatment response. ctDNA assessment can complement standard tissue-based testing for molecular characterisation, with the added ability to monitor emerging mutations under the selective pressure of targeted therapy. Here we provide an overview of the evidence supporting the use of ctDNA in colorectal cancer, the studies underway to address some of the outstanding questions, and the barriers to widespread clinical uptake., Competing Interests: Declaration of Interests PG has received consulting fees from Haystack Oncology and honoraria from Amgen, Roche, Servier, Merck, Pierre-Fabre, and MSD. JT has received consulting fees from Haystack Oncology and Seres Therapeutics, honoraria from Astra Zeneca, Amgen, and Servier, support for attending meetings from Roche, participated on advisory boards for Beigene, Novartis, Astra Zeneca, Merck, Serono, MSD, Pierre Fabre, BMS, Daichii Sankyo, Takeda, Illumina, and Gilead, and has a leadership role on AGITG and ESMO. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Competing Interests: I report receiving consulting fees or honoraria from Haystack Oncology, Seres Therapeutics, Amgen, Servier, Beigene, Novartis, Astra Zeneca, Merck Serono, MSD, Pierre Fabre, BMS, Daichii Sankyo, Illumina, Takeda, and Gilead.

Purpose: BRAF V600E mutant metastatic colorectal cancer represents a significant clinical problem, with combination approaches being developed clinically with oral BRAF inhibitors combined with EGFR-targeting antibodies. While compelling preclinical data have highlighted the effectiveness of combination therapy with vemurafenib and small-molecule EGFR inhibitors, gefitinib or erlotinib, in colorectal cancer, this therapeutic strategy has not been investigated in clinical studies., Patients and Methods: We conducted a phase Ib/II dose-escalation/expansion trial investigating the safety/efficacy of the BRAF inhibitor vemurafenib and EGFR inhibitor erlotinib., Results: Thirty-two patients with BRAF V600E positive metastatic colorectal cancer (mCRC) and 7 patients with other cancers were enrolled. No dose-limiting toxicities were observed in escalation, with vemurafenib 960 mg twice daily with erlotinib 150 mg daily selected as the recommended phase II dose. Among 31 evaluable patients with mCRC and 7 with other cancers, overall response rates were 32% [10/31, 16% (5/31) confirmed] and 43% (3/7), respectively, with clinical benefit rates of 65% and 100%. Early ctDNA dynamics were predictive of treatment efficacy, and serial ctDNA monitoring revealed distinct patterns of convergent genomic evolution associated with acquired treatment resistance, with frequent emergence of MAPK pathway alterations, including polyclonal KRAS, NRAS, and MAP2K1 mutations, and MET amplification., Conclusions: The Erlotinib and Vemurafenib In Combination Trial study demonstrated a safe and novel combination of two oral inhibitors targeting BRAF and EGFR. The dynamic assessment of serial ctDNA was a useful measure of underlying genomic changes in response to this combination and in understanding potential mechanisms of resistance., (©2023 The Authors; Published by the American Association for Cancer Research.)

The management of locally advanced rectal cancer (LARC) requires multimodality treatment, typically with neoadjuvant chemoradiotherapy (CRT) followed by total mesorectal excision. However, the treatment landscape is rapidly evolving with total neoadjuvant therapy and non-operative management for selected patients emerging as other novel treatment approaches. With so many treatment options, there is a need for biomarkers to direct a more personalised treatment strategy for patients with LARC. In this review, we summarise the available data regarding the use of circulating tumour DNA (ctDNA) in patients with LARC, as both a marker of treatment response to neoadjuvant therapy and as a marker of minimal residual disease (MRD) after patients have completed definitive local treatment. To date, the ability of ctDNA status to predict for pathologic complete response at any timepoint during multimodality treatment has been variably reported. The most consistent finding across available studies is the ability of ctDNA to detect MRD after CRT and surgery, the presence of which confers a significantly poor prognosis, with increased risk of cancer recurrence and worse overall survival. It is yet to be determined if providing additional therapies to patients with MRD improves outcomes. The available studies assessing the potential utility of ctDNA in LARC are limited by significant heterogeneity in the choice of ctDNA assay, timepoint at which ctDNA was collected, treatment that patients received and length of follow-up, leading to uncertainties about how to implement it into daily clinical practice. As the treatment landscape evolves, larger randomised trials assessing the role of ctDNA in LARC are needed., Competing Interests: A/Prof Jeanne Tie has the following financial relationships to disclose: • Consultant/advisor: Haystack Oncology, Amgen, Novartis, Astra Zeneca, Merck Serono, Merck Sharp & Dohme, Pierre Fabre, Bristol Myers Squibb • Speaker’s Bureau: Limbic Digital Media, Medla Education, Physician’s Education Resource • Grant/Research support (institutional): Astra Zeneca, Pfizer, Daiichi Sankyo, Novartis, Marcus Foundation, (© The Author(s), 2023.)

Competing Interests: JT is a clinical advisor for Haystack Oncology; receives honorarium for presentations from Servier, Pierre Fabre, Amgen, Merck Serono, Merck Sharp & Dohme; receives support for attending meetings from Roche; and is a part of the advisory board for Pierre Fabre, Novartis, Merck Sharp & Dohme, Bristol Myers Squibb, and Astra Zeneca. HLW declares no competing interests.

Background: Cytoreductive surgery (CRS) with or without hyperthermic intraperitoneal chemotherapy (HIPEC) is a well-recognised treatment option for the management of colorectal peritoneal metastases (CRPM). However, incorporating the routine use of neoadjuvant chemotherapy (NAC) into this management plan is controversial., Methods: A systematic review and meta-analysis were conducted to evaluate the impact of neoadjuvant chemotherapy on perioperative morbidity and mortality, and long-term survival of patients with CRPM undergoing CRS and HIPEC., Results: Twelve studies met the inclusion criteria (n = 2,463 patients). Ten were retrospective cohort, one was prospective cohort, and one was a prospective randomised by design. Patients who received NAC followed by CRS and HIPEC experienced no difference in major perioperative morbidity and mortality compared with patients who underwent surgery first (SF). There was no difference in overall survival at 3 years, but at 5 years NAC patients had superior survival (relative risk [RR] 1.31; 95% confidence interval [CI] 1.11-1.54, P < 0.001). There were no differences in 1- and 3-year, disease-free survival (DFS) between groups. Study heterogeneity was generally high across all outcome measures., Conclusions: Patients who received neoadjuvant chemotherapy did not experience any increase in perioperative morbidity or mortality. The potential improvement in 5-year overall survival in patients receiving NAC is based on limited confidence due to several limitations in the data, but not sufficiently enough to curtail its use. The practice of NAC in this setting will remain heterogeneous and guided by retrospective evidence until prospective, randomised data are reported., (© 2022. The Author(s).)

Background: Stratification of patients with colorectal peritoneal metastases (CRPM) using RAS/BRAF mutational status may refine patient selection for cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). This study aimed to analyse the association of RAS/BRAF status and their variants, with clinicopathological variables and survival outcomes in patients who have undergone CRS ± HIPEC., Methods: A single centre, peritonectomy database was interrogated for patients with CRPM who underwent peritonectomy procedures between 2010 and 2020., Results: During the study period, 174 patients were included. Molecular status was obtained on 169 patients, with 68 (40.5%) KRAS, 25 (14.8%) BRAF and 6 (3.6%) NRAS mutations detected. Patients with BRAF mutations were more likely to be mismatch repair deficient (dMMR) (BRAF 20%, KRAS 4.4%, wild type 8.6%, p = 0.015). Most common BRAF and KRAS variants were, V600E (80%) and G12D (39.7%), respectively. BRAF V600E was independently associated with worse overall (median: 28 months, multivariate: HR 2.29, p = 0.026) and disease-free survival (median: 8 months, multivariate: HR 1.8, p = 0.047). KRAS G12V was a strong prognostic factor associated with disease-free survival (median: 9 months, HR 2.63, p = 0.016). dMMR patients (14/161, 8.7%) exhibited worse median overall survival compared to those with proficient MMR (dMMR 27 months, pMMR 29 months p = 0.025)., Conclusion: This study highlights the importance of molecular analysis in CRPM stratification. BRAF V600E mutations predict poor outcomes post CRS and HIPEC and may help refine patient selection for this procedure. Molecular analysis should be performed preoperatively to characterise prognosis and guide perioperative therapeutic options., 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 © 2022 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Circulating tumor DNA (ctDNA) is tumor-derived fragmented DNA in the bloodstream that has come from primary or metastatic cancer sites. Neoplasm-specific genetic and epigenetic abnormalities are increasingly being identified through liquid biopsy: a novel, minimally invasive technique used to isolate and analyze ctDNA in the peripheral circulation. Liquid biopsy and other emerging ctDNA technologies represent a paradigm shift in cancer diagnostics because they allow for the detection of minimal residual disease in patients with early-stage disease, improve risk stratification, capture tumor heterogeneity and genomic evolution, and enhance ctDNA-guided adjuvant and palliative cancer therapy. Moreover, ctDNA can be used to monitor the tumor response to neoadjuvant and postoperative therapy in patients with metastatic disease. Using clearance of ctDNA as an endpoint for escalation/de-escalation of adjuvant chemotherapy for patients considered to have high-risk disease has become an important area of research. The possibility of using ctDNA as a surrogate for treatment response-including for overall survival, progression-free survival, and disease-free survival-is an attractive concept; this surrogate will arguably reduce study duration and expedite the development of new therapies. In this review, we summarize the current evidence on the applications of ctDNA for the diagnosis and management of gastrointestinal tumors. Gastrointestinal cancers-including tumors of the esophagus, stomach, colon, liver, and pancreas-account for one-quarter of global cancer diagnoses and contribute to more than one-third of cancer-related deaths. Given the prevalence of gastrointestinal malignancies, ctDNA technology represents a powerful tool to reduce the global burden of disease.

Locally advanced rectal cancers (LARC) are the subject of a rapidly evolving treatment paradigm. The critical timepoints where management decisions are required during the care of the LARC patient are: prior to the institution of any treatment, post neoadjuvant therapy and post-surgery. This article reviews the clinical, imaging, blood-based, tissue-based, and molecular biomarkers that can assist clinicians at these timepoints in the patient's management, in prognosticating for their LARC patients or in predicting responses to therapy in the multi-modality neoadjuvant treatment era., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Detection of minimal residual disease in patients with cancer, who are in complete remission with no cancer cells detectable, has the potential to improve recurrence-free survival through treatment selection. Studies analyzing circulating tumor DNA (ctDNA) in patients with solid tumors suggest the potential to accurately predict and detect relapse, enabling treatment strategies that may improve clinical outcomes. Over the past decade, assays for ctDNA detection in plasma samples have steadily increased in sensitivity and specificity. These are applied for the detection of residual disease after treatment and for earlier detection of recurrence. Novel clinical trials are now assessing how assays for "residual disease and recurrence" (RDR) may influence current treatment paradigms and potentially change the landscape of risk classification for cancer recurrence. In this review, we appraise the progress of RDR detection using ctDNA and consider the emerging role of liquid biopsy in the monitoring and management of solid tumors., Competing Interests: Declaration of interests J.C.M.W. and N.R. are inventors/contributors on patents covering methods for ctDNA detection (including WO/2020/104670). P.R. reports institutional research funding from Novartis, Grail/Illumina, ArcherDx/Invitae, Inivata, Epic Sciences, and Tempus; advisory board/honoraria from Novartis, AstraZeneca, Foundation Medicine, Pfizer, Epic Sciences, Inivata, and Natera; and consulting for Tempus. Y.-S.Y. reports honoraria/consultancy from Novartis, Lilly, Pfizer, AstraZeneca, Eisai, MSD, and Specialised Therapeutics and travel support from Pfizer, Eisai, and Roche. S.-J.D. has received research funding from Roche Genentech and Cancer Therapeutics (CTx) CRC and has been an advisory board member for AstraZeneca and Inivata. S.K. serves on the advisory board and is a consultant for Inivata and Natera. N.R. and C.D.M. are officers of Inivata. T.I.M., P.R., E.L.M., R.G., I.T., Y.-S.Y., W.A.R., B.B., A.B., and J.T. served on the advisory board and consulted for Inivata., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Introduction: The optimal management of isolated distant lymph node metastases (IDLNM) from a colorectal primary, is not clearly established. We aimed to analyze the outcomes of patients with IDLNM treated with systemic therapies plus locoregional therapy with curative intent versus systemic therapies with palliative intent., Materials & Methods: Clinical data were collected and reviewed from the Treatment of Recurrent and Advanced Colorectal Cancer registry, a prospective, comprehensive registry for metastatic colorectal cancer (mCRC) treated at multiple tertiary hospitals across Australia. Clinicopathological characteristics, treatment modalities and survival outcomes were analyzed in patients with IDLNM and compared to patients with disease at other sites., Results: Of 3408 mCRC patients diagnosed 2009 to 2020, with median follow-up of 38.0 months, 93 (2.7%) were found to have IDLNM. Compared to mCRC at other sites, patients with IDLNM were younger (mean age: 62.1 vs. 65.6 years, P = .02), more likely to have metachronous disease (57.0% vs. 38.9%, P < .01), be KRAS wild-type (74.6% vs. 53.9%, P< .01) and BRAF mutant (12.9% vs. 6.2%, P = .01). Amongst mCRC patients with IDLNM, 24 (25.8%) received treatment with curative intent and had a significantly better overall median survival than those treated with palliative intent (73.5 months vs. 23.2 months, P = .01). These 24 patients had an overall median survival similar (62.7 months, P = .82) to patients with isolated liver or lung metastases also treated with curative intent., Conclusion: Curative treatment strategies (radiotherapy or surgery), with or without systemic therapy, should be considered for mCRC patients with IDLNM where appropriate as assessed by the multidisciplinary team., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose of Review: Improving outcomes for patients with colorectal cancer in both the adjuvant and metastatic setting has been challenging. Here, we review the current and future directions for using ctDNA in clinical practice., Recent Findings: Circulating tumour DNA (ctDNA) with its ability to detect minimal residual disease is beginning to refine the way we assess recurrence risk in the adjuvant setting. We can potentially tailor treatments to reduce recurrence risk and minimize treatment toxicity. In the metastatic setting, ctDNA can provide a less invasive method of detecting clinically important genetic changes to guide molecularly targeted treatment and to identify mechanisms of molecular resistance. ctDNA can be a surrogate marker for treatment response and help guide the timing of anti-EGFR rechallenge. We await the results of the randomized clinical trials assessing clinical utility of ctDNA in both the adjuvant and metastatic setting before incorporating ctDNA into clinical practice., (© 2021. Crown.)

Background: Total neoadjuvant therapy in rectal cancer refers to the administration of chemoradiotherapy plus chemotherapy before surgery. Recent studies have shown improved pathological complete response and disease-free survival with this approach. However, survival benefits remain unproven. Our objective is to present a metaanalysis of oncological outcomes of total neoadjuvant therapy in locally advanced rectal cancer., Patients and Methods: A comprehensive search was performed on PubMed, Medline, and Google Scholars. Studies comparing total neoadjuvant therapy with standard neoadjuvant chemoradiotherapy were included. Data extracted from the individual studies were pooled and a metaanalysis performed. The outcomes of interest are the rate of complete pathological response, nodal response, resection margin, anal preservation, anastomotic leak, local recurrence, distant recurrence, disease-free survival, and overall survival., Results: There were 15 comparative studies with 2437 patients in the neoadjuvant chemoradiotherapy group and 2284 in the total neoadjuvant therapy group. The pooled complete pathological response was 22.3% in the total neoadjuvant therapy group, compared with 14.2% in the standard neoadjuvant chemoradiotherapy group (p < 0.001). Even though there was no difference in local recurrence rate, there was a significantly lower rate of distant recurrence (OR 0.81, p = 0.02), and better 3-year disease-free survival (70.6% vs. 65.3%, respectively, p < 0.001) and overall survival (84.9% vs. 82.3%, respectively, p = 0.006), favoring the total neoadjuvant therapy group. Due to significant heterogeneity in the study protocols, there remains uncertainty on the ideal chemotherapy/radiotherapy sequence., Conclusions: This study provides supporting evidence on the favorable immediate and intermediate oncological outcomes with the use of total neoadjuvant therapy for locally advanced rectal cancer., (© 2021. Crown.)

Rectal bleeding occurs in about 40% of pregnant women, and is predominantly attributed to benign perianal pathology (haemorrhoids or anal fissures). More sinister causes of rectal bleeding may be heralded by key red flag clinical and biochemical features. These features should be evaluated in all women with rectal bleeding. Imaging investigations or flexible sigmoidoscopy may be warranted. The latter can be performed safely by experienced operators in pregnant women. Women with evidence of haemodynamic compromise, elevated inflammatory markers, significant anaemia, signs of intestinal obstruction or compromise to the fetus should be evaluated urgently. Providers must be mindful of the changes in normal ranges for common haematological and biochemical parameters in pregnancy compared with the non-pregnant state. Faecal calprotectin is an established tool for identification of intestinal inflammation and is valid in pregnancy. An elevated faecal calprotectin level (≥ 50 µg/g) signifies a need for further diagnostic evaluation. Inflammatory bowel disease may present initially, or with worsening disease activity, in pregnancy. Expedient diagnosis with the use of faecal calprotectin, sigmoidoscopy with or without intestinal ultrasound, exclusion of alternative or compounding infective aetiologies, and institution of appropriate therapy are critical. Medical therapies for management of inflammatory bowel disease can be safely instituted in pregnancy. Colorectal cancer incidence is increasing in younger age groups, but fortunately remains rare. When diagnosed in pregnancy, colorectal cancer can be successfully and safely managed with a collaborative multidisciplinary team approach. Early diagnosis is key to optimising outcomes., (© 2021 AMPCo Pty Ltd.)

Background: In patients with resectable colorectal liver metastases (CRLM), the role of pre- and postoperative systemic therapy continues to be debated. Previous studies have shown that circulating tumor DNA (ctDNA) analysis, as a marker of minimal residual disease, is a powerful prognostic factor in patients with nonmetastatic colorectal cancer (CRC). Serial analysis of ctDNA in patients with resectable CRLM could inform the optimal use of perioperative chemotherapy. Here, we performed a validation study to confirm the prognostic impact of postoperative ctDNA in resectable CRLM observed in a previous discovery study., Methods and Findings: We prospectively collected plasma samples from patients with resectable CRLM, including presurgical and postsurgical samples, serial samples during any pre- or postoperative chemotherapy, and serial samples in follow-up. Via targeted sequencing of 15 genes commonly mutated in CRC, we identified at least 1 somatic mutation in each patient's tumor. We then designed a personalized assay to assess 1 mutation in plasma samples using the Safe-SeqS assay. A total of 380 plasma samples from 54 patients recruited from July 2011 to Dec 2014 were included in our analysis. Twenty-three (43%) patients received neoadjuvant chemotherapy, and 42 patients (78%) received adjuvant chemotherapy after surgery. Median follow-up was 51 months (interquartile range, 31 to 60 months). At least 1 somatic mutation was identified in all patients' tumor tissue. ctDNA was detectable in 46/54 (85%) patients prior to any treatment and 12/49 (24%) patients after surgery. There was a median 40.93-fold (19.10 to 87.73, P < 0.001) decrease in ctDNA mutant allele fraction with neoadjuvant chemotherapy, but ctDNA clearance during neoadjuvant chemotherapy was not associated with a better recurrence-free survival (RFS). Patients with detectable postoperative ctDNA experienced a significantly lower RFS (HR 6.3; 95% CI 2.58 to 15.2; P < 0.001) and overall survival (HR 4.2; 95% CI 1.5 to 11.8; P < 0.001) compared to patients with undetectable ctDNA. For the 11 patients with detectable postoperative ctDNA who had serial ctDNA sampling during adjuvant chemotherapy, ctDNA clearance was observed in 3 patients, 2 of whom remained disease-free. All 8 patients with persistently detectable ctDNA after adjuvant chemotherapy have recurred. End-of-treatment (surgery +/- adjuvant chemotherapy) ctDNA detection was associated with a 5-year RFS of 0% compared to 75.6% for patients with an undetectable end-of-treatment ctDNA (HR 14.9; 95% CI 4.94 to 44.7; P < 0.001). Key limitations of the study include the small sample size and the potential for false-positive findings with multiple hypothesis testing., Conclusions: We confirmed the prognostic impact of postsurgery and posttreatment ctDNA in patients with resected CRLM. The potential utility of serial ctDNA analysis during adjuvant chemotherapy as an early marker of treatment efficacy was also demonstrated. Further studies are required to define how to optimally integrate ctDNA analyses into decision-making regarding the use and timing of adjuvant therapy for resectable CRLM., Trial Registration: ACTRN12612000345886., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: BV, KWK, & NP are founders of, and hold equity in Thrive Earlier Detection and Personal Genome Diagnostics. KWK & NP are on the Board of Directors of, and consultants to, Thrive Earlier Detection. KWK & BV are consultants to Sysmex, Eisai, Personal Genome Diagnostics and CAGE Pharma and hold equity in CAGE Pharma. KWK, BV, and NP are consultants to and hold equity in NeoPhore. BV is a consultant to and holds equity in Catalio Capital Management. NP is an advisor to and holds equity in CAGE Pharma. The companies named above, as well as other companies, have licensed previously described technologies related to the work described in this paper from Johns Hopkins University. BV, KWK, and NP are inventors on some of these technologies. Licenses to these technologies are or will be associated with equity or royalty payments to the inventors as well as to Johns Hopkins University. CT and the University are entitled to royalty distributions related to technology licensed to Thrive Earlier Detection. CT is a consultant to Thrive. The terms of all these arrangements are being managed by Johns Hopkins University in accordance with its conflict of interest policies. All other authors declare no competing interests.

Background: The management of metastatic colorectal cancer patients with a poor performance status (PS) continues to be a clinical dilemma, with the potential activity and safety of treating this population remaining poorly understood. Few of these patients are enrolled onto clinical trials, and poor PS is often multifactorial., Patients and Methods: We analyzed the Treatment of Recurrent and Advanced Colorectal Cancer registry to describe treatment practices and outcomes in poor (Eastern Cooperative Oncology Group [ECOG] PS 2) and very poor PS (ECOG PS > 2) patients to explore the relationship between age, tumor burden, comorbidities, and PS, and to evaluate the benefit of systemic therapy. Standard descriptive statistical methods, Kaplan-Meier analysis, and a multivariate Cox regression model were used., Results: Of 2769 registry patients (diagnosed January 2009 to June 2018), 329 (12%) and 182 (7%) patients had a poor and very poor PS, respectively. Good PS patients were more likely to receive systemic therapy than poor and very poor PS patients (85%, 55%, and 21.5%, P < .0001), but clinician assessed response was observed in all subsets (53%, 41%, and 29%, P = .0003). Treatment with chemotherapy was associated with longer median overall survival across PS groups. Exploratory analysis based on comorbidity score and tumor burden subgroups demonstrated a consistently positive overall survival association with treatment. Benefit was observed where poor overall survival was attributable to medical comorbidities and to tumor burden., Conclusion: In routine clinical care, a substantial proportion of poor and very poor PS patients receive active treatment, which is often associated with meaningful clinical benefit., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: B-Raf proto-oncogene (BRAF)-V600E mutations (BRAFmt) in colorectal cancer (CRC) predominantly occur in right-side (RS) primaries. In metastatic CRC (mCRC), there is substantial overlap between the reported features of BRAFmt and of an RS primary., Objectives: To explore the significance of BRAFmt in a left-side (LS) primary, we analysed data from a multi-site mCRC registry. Tumours distal to the splenic flexure were considered LS., Results: Of 3380 patients enrolled from June 2009 to June 2020, 214 (13%) of 1657 with known status were BRAFmt: 127 (24%) of 524 RS and 87 (8%) of 1133 LS. LS versus RS BRAFmt were younger (mean 59.5 vs. 65.1 years; p = 0.01), whereas sex (48 vs. 59% female; p = 0.13), mismatch repair-deficiency (dMMR) (16 vs. 21%; p = 0.47), and overall survival (OS) (median 15.1 vs. 17.7 months; p = 0.98) were similar. LS BRAFmt versus LS BRAF wildtype (wt) were of similar age (59.5 vs. 61.3 years; p = 0.28) with more females (48 vs. 37%; p = 0.04), more dMMR (16 vs. 1%; p < 0.0001), and inferior OS (median 15.1 vs. 36.6 months; p < 0.0001). Initial treatment with chemotherapy plus an epidermal growth factor receptor inhibitor produced median progression-free survival (PFS) of 4.3 versus 12.3 months (p = 0.20) for LS BRAFmt (n = 9) versus LS BRAFwt (n = 104). Initial chemotherapy and bevacizumab produced a median PFS of 7.6 versus 11.6 months (p = 0.02) for LS BRAFmt (n = 36) versus LS BRAFwt (n = 438), respectively., Conclusion: LS BRAFmt cancers share many features with RS BRAFmt cancers, including poor survival outcomes. Mature data on the activity of BRAF-targeted therapies in the first-line setting are eagerly awaited.

We report a sensitive PCR-based assay called Repetitive Element AneupLoidy Sequencing System (RealSeqS) that can detect aneuploidy in samples containing as little as 3 pg of DNA. Using a single primer pair, we amplified ∼350,000 amplicons distributed throughout the genome. Aneuploidy was detected in 49% of liquid biopsies from a total of 883 nonmetastatic, clinically detected cancers of the colorectum, esophagus, liver, lung, ovary, pancreas, breast, or stomach. Combining aneuploidy with somatic mutation detection and eight standard protein biomarkers yielded a median sensitivity of 80% in these eight cancer types, while only 1% of 812 healthy controls scored positive., Competing Interests: Competing interest statement: K.W.K., N.P., and B.V. are founders of, hold equity in, and are consultants to Thrive and Personal Genome Diagnostics. K.W.K. and N.P. are on the Board of Directors of Thrive. K.W.K. and B.V. are consultants to Sysmex, Eisai, and CAGE Pharma. B.V. is also a consultant to Nexus, and K.W.K., N.P., and B.V. are consultants to Neophore. C.B. is a consultant to Depuy-Synthes. C.T. is a paid consultant to Thrive and Bayer. C.D. is a consultant to Thrive. The companies named above as well as other companies have licensed previously described technologies related to the work described in this paper from Johns Hopkins University. C.D., J.D.C., R.K., C.B., K.W.K., N.P., and B.V. are inventors on some of these technologies. Licenses to these technologies are or will be associated with equity or royalty payments to the inventors as well as to Johns Hopkins University. Additional patent applications on the work described in this paper may be filed by Johns Hopkins University. The terms of all of these arrangements are being managed by Johns Hopkins University in accordance with its conflict of interest policies. N.R. is a cofounder and Chief Scientific Officer of Inivata.

Background: Colorectal cancer is the second leading cause of cancer-related mortality worldwide. Peritoneal metastases carry the worst prognosis among all sites of colorectal cancer metastases. In recent years, the advent and acceptance of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy have greatly improved survival for selected patients with low-volume peritoneal metastases., Objective: Here, we report the evolution of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for colorectal peritoneal metastases at a statewide tertiary referral center over an 8-year period., Design: This is a retrospective study from 2009 to 2017., Setting: The study was conducted at a single center over 8 years., Patients: Patients with colorectal peritoneal metastases undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy were included., Main Outcomes: Main outcomes included evaluation of grade III/IV morbidity rate, mortality rate, overall and relapse-free survival, and prognostic factors influencing survival on a Cox multivariate analysis model., Results: One hundred one cytoreductive surgeries were undertaken on 96 patients during this time for colorectal peritoneal metastases. The median patient age was 60 years with 55.2% being female. The median Peritoneal Carcinomatosis Index was 9, with complete cytoreduction achieved in 76 (75.2%) cases. Grade III or IV complications occurred in 26 cases (25.7%) with 2 (2%) perioperative mortalities. Median overall survival for the entire cohort was 32 months, with a 3-year survival of 38%. For patients who achieved a complete cytoreduction, median overall survival was 37 months, with a relapse-free survival of 13 months and a 3-year survival of 54%. Complete cytoreduction and nonmucinous histology were key factors independently associated with improved overall survival., Limitations: The main limitation this study is its retrospective nature., Conclusion: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for isolated low-volume colorectal peritoneal metastases is safe and effective, with low morbidity. It offers selected patients a highly favorable overall and relapse-free survival. See Video Abstract at http://links.lww.com/DCR/B2. EVOLUCIÓN DE LA CIRUGÍA CITORREDUCTIVA Y QUIMIOTERAPIA INTRAPERITONEAL HIPERTÉRMICA (HIPEC) PARA METÁSTASIS PERITONEALES COLORRECTALES: EXPERIENCIA INSTITUCIONAL DE 8 AÑOS: El cáncer colorrectal es la segunda causa de mortalidad relacionada con el cáncer en todo el mundo. Las metástasis peritoneales tienen el peor pronóstico entre todos los sitios de metástasis del cáncer colorrectal. En los últimos años, el advenimiento y la aceptación de la cirugía citorreductiva y la quimioterapia intraperitoneal hipertérmica ha mejorado enormemente la supervivencia de pacientes seleccionados con metástasis peritoneales de bajo volumen., Objetivo: Aquí, informamos sobre la evolución de la cirugía citorreductiva y la quimioterapia intraperitoneal hipertérmica para las metástasis peritoneales colorrectales en un centro de referencia terciario para todo el estado durante un período de ocho años. DISEÑO:: Estudio retrospectivo del 2009 a 2017. CONFIGURACIÓN:: Centro único a lo largo de ocho años., Pacientes: Pacientes con metástasis peritoneales colorrectales sometidos a cirugía citorreductiva y quimioterapia intraperitoneal hipertérmica., Resultados Principales: Los resultados principales incluyeron la evaluación de la tasa de morbilidad de grado III / IV, la tasa de mortalidad, la supervivencia general y libre de recaída y los factores pronósticos que influyen en la supervivencia en el modelo de análisis multivariado Cox., Resultados: Se realizaron el ciento uno cirugías citorreductivas en noventa y seis pacientes durante este tiempo por metástasis peritoneales colorrectales. La edad media de los pacientes fue de 60 años, con un 55.2% de mujeres. El Índice de Carcinomatosis Peritoneal mediano fue de 9, con una citorreducción completa lograda en 76 (75.2%) casos. Las complicaciones de grado III o IV ocurrieron en 26 casos (25.7%) con dos (2%) de mortalidad perioperatoria. La supervivencia mediana general para toda la cohorte fue de 32 meses, con una supervivencia de 3 años del 38%. Para los pacientes que lograron una citorreducción completa, la supervivencia global media fue de 37 meses, con una supervivencia sin recaída de 13 meses y una supervivencia de 3 años del 54%. La citorreducción completa y la histología no mucinosa fueron factores clave asociados de forma independiente con una mejor supervivencia general., Limitaciones: La principal limitación es la naturaleza retrospectiva del estudio. CONCLUSIÓN:: La cirugía citorreductiva y la quimioterapia intraperitoneal hipertérmica para las metástasis peritoneales colorrectales aisladas de bajo volumen son seguras y eficaces, con baja morbilidad. Ofrece a los pacientes seleccionados una supervivencia global altamente favorable y libre de recaída. Vea el Resumen del video en http://links.lww.com/DCR/B2.

Aim: Current efforts to understand patient management in clinical practice are largely based on clinician surveys with uncertain reliability. The TRACC (Treatment of Recurrent and Advanced Colorectal Cancer) database is a multisite registry collecting comprehensive treatment and outcome data on consecutive metastatic colorectal cancer (mCRC) patients at multiple sites across Australia. This study aims to determine the accuracy of oncologists' impressions of real-word practice by comparing clinicians' estimates to data captured by TRACC., Methods: Nineteen medical oncologists from nine hospitals contributing data to TRACC completed a 34-question survey regarding their impression of the management and outcomes of mCRC at their own practice and other hospitals contributing to the database. Responses were then compared with TRACC data to determine how closely their impressions reflected actual practice., Results: Data on 1300 patients with mCRC were available. Median clinician estimated frequency of KRAS testing within 6 months of diagnosis was 80% (range: 20-100%); the TRACC documented rate was 43%. Clinicians generally overestimated the rates of first-line treatment, particularly in patients over 75 years. Estimate for bevacizumab in first line was 60% (35-80%) versus 49% in TRACC. Estimated rate for liver resection varied substantially (5-35%), and the estimated median (27%) was inconsistent with the TRACC rate (12%). Oncologists generally felt their practice was similar to other hospitals., Conclusions: Oncologists' estimates of current clinical practice varied and were discordant with the TRACC database, often with a tendency to overestimate interventions. Clinician surveys alone do not reliably capture contemporary clinical practices in mCRC., (© 2017 John Wiley & Sons Australia, Ltd.)

Earlier detection is key to reducing cancer deaths. Here, we describe a blood test that can detect eight common cancer types through assessment of the levels of circulating proteins and mutations in cell-free DNA. We applied this test, called CancerSEEK, to 1005 patients with nonmetastatic, clinically detected cancers of the ovary, liver, stomach, pancreas, esophagus, colorectum, lung, or breast. CancerSEEK tests were positive in a median of 70% of the eight cancer types. The sensitivities ranged from 69 to 98% for the detection of five cancer types (ovary, liver, stomach, pancreas, and esophagus) for which there are no screening tests available for average-risk individuals. The specificity of CancerSEEK was greater than 99%: only 7 of 812 healthy controls scored positive. In addition, CancerSEEK localized the cancer to a small number of anatomic sites in a median of 83% of the patients., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Aim: Precision oncology involves molecularly matching patients to targeted agents usually in early drug development (EDD) programs. Molecular profiling (MP) identifies actionable targets. Comprehensive commercial MP platforms are costly and in resource limited environments, a more practical approach to MP is necessary to support EDD and precision oncology. We adopted a clinician-directed, tailored approach to MP to enrol patients onto molecularly targeted trials. We report the feasibility of this approach., Methods: All patients referred to the Royal Melbourne Hospital (RMH) EDD between September 2013 and September 2015 were identified in a prospective database. Key captured data included clinicopathological data, MP platform ordered (if any), molecular targets identified and subsequent enrolment onto clinical trials. EDD-clinician decisions to order MP and the platform utilized was guided by patient consultation, tumor type, trial availability and requirement for molecular information., Results: We identified 377 patients referred to RMH EDD. A total of 216 (57%) had MP ordered. The remainder had known actionable targets (19%), or were inappropriate for clinical trials (24%). In those undergoing MP, 187 genetic aberrations were found in 113 patients with 98 considered actionable targets in 86 patients. Ninety-eight (25%) patients were enrolled onto a clinical trial, including 40 (11%) receiving molecularly matched treatments. Median progression-free survival was improved in patients enrolled onto molecularly matched trials compared to those on unmatched trials (3.6 months vs 1.9 months, HR 0.58 [0.38-0.89], P  =  0.013)., Conclusion: A clinician-directed, tailored approach to the use of MP is feasible, resulting in 11% of patients enrolled onto molecularly matched trials., (© 2017 John Wiley & Sons Australia, Ltd.)

The earlier diagnosis of cancer is one of the keys to reducing cancer deaths in the future. Here we describe our efforts to develop a noninvasive blood test for the detection of pancreatic ductal adenocarcinoma. We combined blood tests for KRAS gene mutations with carefully thresholded protein biomarkers to determine whether the combination of these markers was superior to any single marker. The cohort tested included 221 patients with resectable pancreatic ductal adenocarcinomas and 182 control patients without known cancer. KRAS mutations were detected in the plasma of 66 patients (30%), and every mutation found in the plasma was identical to that subsequently found in the patient's primary tumor (100% concordance). The use of KRAS in conjunction with four thresholded protein biomarkers increased the sensitivity to 64%. Only one of the 182 plasma samples from the control cohort was positive for any of the DNA or protein biomarkers (99.5% specificity). This combinatorial approach may prove useful for the earlier detection of many cancer types., Competing Interests: Conflict of interest statement: C.M.S. and M.T.Y.-S. are founders and coowners of B9, Inc. and have no conflicts of interest with respect to the new technology described in this article. N.P., K.W.K., and B.V. are founders of Personal Genome Diagnostics, Inc. and PapGene, Inc. K.W.K. and B.V. are members of the Scientific Advisory Board of Sysmex-Inostics and Morphotek. B.V. is also a member of the Scientific Advisory Board of Exelixis GP. These companies and others have licensed technologies from Johns Hopkins, including those related to early diagnostics. N.P., K.W.K., and B.V. are the inventors of some of these technologies and receive equity or royalties from their licenses. The terms of these arrangements are being managed by the university in accordance with its conflict of interest policies. N.P., K.W.K., and B.V. have no conflicts of interest with respect to the new technology described in this article, as defined by the Johns Hopkins University policy on conflict of interest.

Background: Debate continues regarding the benefits versus risks of initial resection of the primary tumor in metastatic colorectal cancer (mCRC) patients with an asymptomatic primary tumor. Although the benefit of the anti-vascular endothelial growth factor agent bevacizumab alongside first-line chemotherapy in mCRC is established, the impact of bevacizumab on the intact primary tumor (IPT) is less well understood., Methods: Data from an Australian mCRC registry were used to assess the impact of bevacizumab-based regimens in the presence of an IPT, to see if this differs from effects in resected primary tumor (RPT) patients and to understand the safety profile of bevacizumab in patients with IPT. Progression-free survival (PFS), overall survival (OS) and safety endpoints were analyzed., Results: Of 1204 mCRC patients, 826 (69%) were eligible for inclusion. Bevacizumab use was similar in both arms (IPT (64%) versus RPT (70%)); compared with chemotherapy alone, bevacizumab use was associated with significantly longer PFS (IPT: 8.5 months vs 4.7 months, P = 0.017; RPT: 10.8 months vs 5.8 months, P < 0.001) and OS (IPT: 20 months vs 14.8 months, P = 0.005; RPT: 24.4 months vs 17.3 months, P = 0.004)). 1 Bevacizumab use in an IPT was associated with more GI perforations (4.5% vs 1.8%, P = 0.210) but less frequent bleeding (1.5% vs 5.3%, P = 0.050) and thrombosis (1.5% vs 2.7%, P = 0.470), versus chemotherapy alone. Median survival was equivalent between patients that did or did not experience bevacizumab-related adverse events - 20.0 months versus 19.9 months, hazard ratio = 0.98, P = 0.623. 1 CONCLUSIONS: The addition of bevacizumab significantly improved survival outcomes in mCRC with an IPT. The occurrence of bevacizumab-related adverse events did not significantly impact survival outcomes., (© 2016 John Wiley & Sons Australia, Ltd.)

Purpose: Prognostic markers that identify patients with stage II colon cancers who are at the risk of recurrence are essential to personalize therapy. We evaluated the potential of GIV/Girdin as a predictor of recurrence risk in such patients., Experimental Design: Expression of full-length GIV was evaluated by IHC using a newly developed mAb together with a mismatch repair (MMR)-specific antibody panel in three stage II colon cancer patient cohorts, that is, a training (n = 192), test (n = 317), and validation (n = 181) cohort, with clinical follow-up data. Recurrence risk stratification models were established in the training cohort of T3, proficient MMR (pMMR) patients without chemotherapy and subsequently validated., Results: For T3 pMMR tumors, GIV expression and the presence of lymphovascular invasion (LVI) were the only factors predicting recurrence in both training (GIV: HR, 2.78, P = 0.013; LVI: HR, 2.54, P = 0.025) and combined test and validation (pooled) cohorts (GIV: HR, 1.85, P = 0.019; LVI: HR, 2.52, P = 0.0004). A risk model based on GIV expression and LVI status classified patients into high- or low-risk groups; 3-year recurrence-free survival was significantly lower in the high-risk versus low-risk group across all cohorts [Training: 52.3% vs. 84.8%; HR, 3.74, 95% confidence interval (CI), 1.50-9.32; Test: 85.9% vs. 97.9%, HR, 7.83, 95% CI, 1.03-59.54; validation: 59.4% vs. 84.4%, HR, 3.71, 95% CI, 1.24-11.12]., Conclusions: GIV expression status predicts recurrence risk in patients with T3 pMMR stage II colon cancer. A risk model combining GIV expression and LVI status information further enhances prediction of recurrence. Further validation studies are warranted before GIV status can be routinely included in patient management algorithms. Clin Cancer Res; 22(14); 3488-98. ©2016 AACR., (©2016 American Association for Cancer Research.)

Paraneoplastic neurological syndromes (PNS) are rare complications of cancer and may be the presenting sign of an occult malignancy. Diagnosis of PNS is often challenging and treatment of the underlying tumour remains the best therapeutic option for preventing further neurological damage. We report on a patient who developed a rapidly progressive cerebellar ataxia and underwent extensive investigations before a paraneoplastic aetiology was confirmed by detection of an underlying malignancy.