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Purpose: High densities of tumor infiltrating CD3 and CD8 T-cells are associated with superior prognosis in colorectal cancer (CRC). Their value as predictors of benefit from adjuvant chemotherapy is uncertain., Patients and Methods: Tumor tissue from 868 patients in the QUASAR trial (adjuvant fluorouracil/folinic acid v observation in stage II/III CRC) was analyzed by CD3 and CD8 immunohistochemistry. Pathologists, assisted by artificial intelligence, calculated CD3 and CD8 cell densities (cells/mm 2 ) in the core tumor (CT) and invasive margin (IM). Participants were randomly partitioned into training and validation sets. The primary outcome was recurrence-free interval (RFI), 2-year RFI for assessment of biomarker-treatment interactions. Maximum-likelihood methods identified optimal high-risk/low-risk group cutpoints in the training set. Prognostic analyses were repeated in the validation set., Results: In the training set, the recurrence rate in the high-risk group was twice that in the low-risk group for all measures (CD3-CT: rate ratio [RR], 2.00, P = .0008; CD3-IM: 2.38, P < .00001; CD8-CT: 2.17, P = .0001; CD8-IM: 2.13, P = .0001). This was closely replicated in the validation set (RR, 1.96, 1.79, 1.72, 1.72, respectively). In multivariate analyses, prognostic effects were similar in colon and rectal cancers, and in stage II and III disease. Proportional reductions in recurrence with adjuvant chemotherapy were of similar magnitude in the high- and low-recurrence risk groups. Combining information from CD3-IM and CD3-CT (CD3 Score) generated high-, intermediate-, and low-risk groups with numbers needed to treat (NNTs) to prevent one disease recurrence being 11, 21, and 36, respectively., Conclusion: Recurrence rates in the high-risk CD3/CD8 groups are twice those in the low-risk groups. Proportional reductions with chemotherapy are similar, allowing NNTs derived in QUASAR to be updated using contemporary, nonrandomized data sets.

Approximately 15% of locally advanced colorectal cancers (CRC) have DNA mismatch repair deficiency (dMMR), resulting in high microsatellite instability and a high tumour mutational burden. These cancers are frequently sensitive to therapy with immune-checkpoint inhibitors (ICIs) in the metastatic setting. This sensitivity seems to be even more pronounced in locally advanced disease, and organ preservation has become a realistic aim in ongoing clinical trials involving patients with dMMR rectal cancer. By contrast, metastatic CRCs with proficient DNA mismatch repair (pMMR) are generally resistant to ICIs, although a proportion of locally advanced pMMR tumours seem to have a high degree of sensitivity to ICIs. In this Review, we describe the current and emerging clinical evidence supporting the use of neoadjuvant ICIs in patients with dMMR and pMMR CRC, and the potential advantages (based on a biological rationale) of such an approach. We discuss how neoadjuvant 'window-of-opportunity' trials are being leveraged to progress biomarker discovery and we provide an overview of potential predictive biomarkers of response to ICIs, exploring the challenges faced when evaluating such biomarkers in biopsy-derived samples. Lastly, we describe how these discoveries might be used to drive a rational approach to trialling novel immunotherapeutic strategies in patients with pMMR CRC, with the ultimate aim of disease eradication and the generation of long-term immunosurveillance., (© 2024. Springer Nature Limited.)

Background: Immunotherapy is used routinely for treating deficient mismatch repair (dMMR) colon cancer (CC). This case series highlights an emerging safety issue, where patients develop bowel obstruction associated with immunotherapy response., Patients and Methods: Patients with dMMR CC who developed bowel obstruction while responding to immunotherapy were retrospectively identified. Data on patient, disease, treatment, and response-specific factors were explored for potential risk factors. Overall treatment numbers were used to estimate incidence., Results: Nine patients from eight European centres were included. Common features were hepatic flexure location (5/9), T4 radiological staging (6/9), annular shape (8/9), radiological stricturing (5/9), and endoscopic obstruction (6/9). All received pembrolizumab and obstructed between 45 and 652 days after starting treatment. Seven patients underwent surgical resection; one was managed with a defunctioning stoma; and one was managed conservatively. One patient died from obstruction. Radiological response was seen in eight patients, including two complete responses. Pathological response was seen in all seven who underwent resection, including four complete responses. The overall incidence of immunotherapy response-related obstruction in these centres was 1.51%., Conclusions: Bowel obstruction associated with immunotherapy response may represent a rare treatment-related complication in dMMR CC. Clinicians must recognise this safety signal and share experience to maintain patient safety., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: Mismatch repair (MMR) deficient (dMMR) colon cancer (CC) is distinct from MMR proficient (pMMR) CC, yet the impact of MMR status on radiological staging is unclear. The purpose of this study was to investigate how MMR status impacts CC CT staging., Methods: We retrospectively compared CT staging accuracy between dMMR and pMMR CC patients undergoing curative resection. Accuracy was assessed as individual tumour (T)/nodal (N) stages and as dichotomous "statuses" (T1/2 vs T3/4; N0 vs N1/2). Patient characteristics were analysed for factors to support staging., Results: There was no significant difference in overall staging accuracy between the dMMR (44 patients) and pMMR (57 patients) groups. dMMR tumours with incorrect N stage/"status" were more likely to be overstaged than pMMR tumours (90% vs 59%; p = 0.023 for "N status"). Platelet count, CRP and neutrophil count (AUC 0.76 ( p = 0.0078), 0.75 ( p = 0.034) and 0.70 ( p = 0.044), respectively) were associated with "N status" in dMMR tumours., Conclusion: Whilst overall staging accuracy was similar between groups, incorrectly N staged dMMR tumours were more likely to be overstaged than pMMR tumours, risking inappropriate surgical or neoadjuvant treatment. We describe novel relationships between several inflammatory markers and pathological "N status" in dMMR CC, which if integrated into routine practice may improve CT staging accuracy., Advances in Knowledge: Compared to pMMR CC, dMMR CC is at significant risk of N overstaging. Platelet count, CRP and neutrophil count are higher in dMMR CC patients with nodal metastases than those without, and their role in refining clinical staging requires further investigation.

Aim: The international FOxTROT trial, recently published in the Journal of Clinical Oncology is the first randomized controlled trial testing neoadjuvant chemotherapy (NAC) with oxaliplatin and 5-fluorouracil in locally advanced, but operable, colon cancer. The trial met its primary endpoint with fewer patients experiencing recurrent or residual disease at 2 years with NAC compared with the control (16.8% vs. 21.2%, risk ratio = 0.74, p  = 0.042). Translating the findings of the FOxTROT trial into improved patient outcomes is dependent on implementation of new neoadjuvant chemotherapy (NAC) pathways in colorectal cancer., Method: We describe our experience implementing a novel neoadjuvant treatment pathway in colorectal cancer at a large UK teaching hospital., Results: To date 64 patients have been commenced on the novel pathway following presentation and adoption of the FOxTROT trial results. We present key lessons and strategies developed across the multidisciplinary team to minimize impact on person hours, service capacity and budget, whilst building patient safety and confidence., Conclusion: Use of NAC for locally advanced colon cancer has been shown to improve surgical outcomes and longer term cancer outcomes. Provision of NAC requires some modifications to current treatment pathways but can be delivered with team working and without the requirement for additional resources., (© 2022 The Authors. Colorectal Disease published by John Wiley & Sons Ltd on behalf of Association of Coloproctology of Great Britain and Ireland.)

Treating older adults with cancer is increasingly important in modern oncology practice. However, we currently lack the high-quality evidence needed to guide optimal management of this heterogeneous group. Principally, historic under-recruitment of older adults to clinical trials limits our understanding of how existing evidence can be applied to this group. Such uncertainty is particularly prevalent in the management of colon cancer (CC). With CC being most common in older adults, many patients also suffer from frailty, which is recognised as being strongly associated with poor clinical outcomes. Conducting clinical trials in older adults presents several major challenges, many of which impact the clinical relevance of results to a real-world population. When considering this heterogeneous group, it may be difficult to define the target population, recruit participants effectively, choose an appropriate trial design, and ensure participants remain engaged with the trial during follow-up. Furthermore, after overcoming these challenges, clinical trials tend to enrol highly selected patient cohorts that comprise only the fittest older patients, which are not representative of the wider population. FOxTROT1 was the first phase III randomised controlled trial to illustrate the benefit of neoadjuvant chemotherapy (NAC) in the treatment of CC. Patients receiving NAC had greater 2-year disease-free survival compared to those proceeding straight to surgery. Outcomes for older adults in FOxTROT1 were similarly impressive when compared to their younger counterparts. Yet, this group inevitably represents a fitter subgroup of the older patient population. FOxTROT2 has been designed to investigate NAC in a full range of older adults with CC, including those with frailty. In this review, we describe the key challenges to conducting a robust clinical trial in this heterogeneous patient group, highlight our strategies for overcoming these challenges in FOxTROT2, and explain how we hope to provide clarity on the optimal treatment of CC in older adults., Competing Interests: Disclosure ZC has received grants from Celgene, MSD, Amgen, and Takeda (via institution). MS has received a grant from Yorkshire Cancer Research to support provision of a clinical trial (via institution). MB has received payment/honoraria from Laboratoires Pierre Fabre, Amgen, and Servier, is Co-lead of Audit for the National Bowe Cancer Audit (England and Wales), and author of the National Institute for Health and Care Excellence (NICE) Colorectal Cancer Guideline. JR has received grants from Bristol Meyers Squibb, Laboratoires Pierre Fabre, Servier, HUB Organoids, and Cleara Biotech (via institution), consulting fees from Bayer, Bristol Meyers Squibb, Merck-Serono, Laboratoires Pierre Fabre, and Servier (via institution), payment/honoraria from Bristol Meyers Squibb, Laboratoires Pierre Fabre, and Servier (via institution), and support for attending meetings from Servier. JR is also a member of advisory boards for the PelvEx and MEND-IT trials, and a member of the ONCODE clinical advisory board. CP has received consulting fees from Nordic Pharma (via institution). JT has received payment/honoraria from Astellas Pharma Inc., Bristol Meyers Squibb, MSD, Merck & Co., Roche, Laboratoires Pierre Fabre, Novartis, and Servier, support for attending meetings from Laboratoires Pierre Fabre, MSD, and Servier, and is a member of advisory boards for Bristol Meyers Squibb, MSD, Merck & Co., Roche, Laboratoires Pierre Fabre, Novartis, and Servier. JB has received grants from Cancer Research UK, the National Institute for Health and Care Research, Medical Research Council, and Roche, and is Chair of the advisory board for the NIHR By-Band-Sleeve trial and the NIHR Health Technology Assessment General Funding Committee. DAC has received grants from Yorkshire Cancer Research (via institution) and support for attending meetings from Celgene. JFS has received consulting fees from Seagen, payment/honoraria from Laboratoires Pierre Fabre, Merck-Serono, and Servier, and support for attending meetings from Servier and Bristol Meyers Squibb. JFS is also a member of advisory boards for Elevation Oncology, Laboratoires Pierre Fabre, and Zentalis Pharmaceuticals. JFS, JB, and DM have received support from Yorkshire Cancer Research for the FOxTROT 2 trial, on which this manuscript is based (via institution). All other authors have declared no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Despite extensive randomized evidence supporting the use of treatment breaks in metastatic colorectal cancer (mCRC), they are not universally offered to patients despite improvements in quality of life without detriment to overall survival (OS). FOCUS4-N was set up to explore the impact of oral maintenance therapy in patients who are responding to first-line therapy., Methods: FOCUS4 was a molecularly stratified trial program that registered patients with newly diagnosed mCRC. The FOCUS4-N trial was offered to patients in whom a targeted subtrial was unavailable or biomarker tests failed. Patients were randomly assigned using a 1:1 ratio between maintenance capecitabine and active monitoring (AM). The primary outcome was progression-free survival (PFS) with secondary outcomes including OS toxicity and tolerability., Results: Between March 2014 and March 2020, 254 patients were randomly assigned (127 to capecitabine and 127 to AM) across 88 UK sites. Baseline characteristics were balanced. There was strong evidence of efficacy for PFS (hazard ratio = 0.40; 95% CI, 0.21 to 0.75; P < .0001), but no significant improvement in OS (hazard ratio, 0.93; 95% CI, 0.69 to 1.27; P = .66) was observed. Compliance with treatment was good, and toxicity from capecitabine versus AM was as expected with grade ≥ 2 fatigue (25% v 12%), diarrhea (23% v 13%), and hand-foot syndrome (26% v 3%). Quality of life showed little difference between the groups., Conclusion: Despite strong evidence of disease control with maintenance therapy, OS remains unaffected and FOCUS4-N provides additional evidence to support the use of treatment breaks as safe management alternatives for patients who are stable or responding to first-line treatment for mCRC. Capecitabine without bevacizumab may be used to extend PFS in the interval after 16 weeks of first-line therapy., Competing Interests: Richard A. AdamsHonoraria: Merck Serono, Servier, AmgenConsulting or Advisory Role: Merck Serono, Amgen, Servier, BayerSpeakers' Bureau: Merck SeronoResearch Funding: Merck Sharp & DohmeTravel, Accommodations, Expenses: Servier, Amgen, Merck Serono, AstraZeneca Janet GrahamHonoraria: Merck Serono, Bristol Myers Squibb, Nucana, BayerConsulting or Advisory Role: Merck KGaATravel, Accommodations, Expenses: Nucana Jenny F. SeligmannHonoraria: Pierre Fabre, Merck Serono, ServierConsulting or Advisory Role: Pierre Fabre, Roche Molecular DiagnosticsTravel, Accommodations, Expenses: Bristol Myers Squibb/Medarex Matthew SeymourResearch Funding: Amgen, AstraZeneca Richard KaplanResearch Funding: AstraZeneca Mahesh ParmarResearch Funding: AstraZeneca, Astellas Pharma, Janssen, Clovis Oncology Philip QuirkeHonoraria: RocheConsulting or Advisory Role: Roche, Adlai Nortye, Avacta Life Sciences, Amgen, BayerResearch Funding: Roche, GeneFirst, ONIPatents, Royalties, Other Intellectual Property: Roche have filed a patent jointly with my UniversityTravel, Accommodations, Expenses: Roche, Bayer, Amgen Rachel ButlerSpeakers' Bureau: Bayer, Pfizer, Roche, AstraZeneca, MSD, Illumina, Lilly, Novartis, Amgen, Boehringer Ingelheim Ewan BrownResearch Funding: MSD Oncology Fiona CollinsonResearch Funding: Bristol Myers Squibb Stephen FalkStock and Other Ownership Interests: GlaxoSmithKlineSpeakers' Bureau: Merck Serono, Servier, AmgenResearch Funding: Gilead SciencesTravel, Accommodations, Expenses: CelgeneOther Relationship: Servier Harpreet WasanHonoraria: Merck KGaA, Celgene, Sirtex Medical, Servier, Array BioPharma, Roche/Genentech, ERYTECH Pharma, Incyte, ZymeworksConsulting or Advisory Role: Roche Pharma AG, ERYTECH Pharma, Shire, Incyte, Sirtex Medical, Pierre Fabre, Pfizer, BayerSpeakers' Bureau: Sirtex Medical, Celgene, Merck KGaA, Servier, IncyteResearch Funding: Sirtex Medical, Merck KGaA, Pfizer, Merck Sharp & Dohme Kai-Keen ShiuHonoraria: Merck Serono, MSD Oncology, Innovent Biologics, Servier, Daiichi Sankyo Europe GmbHConsulting or Advisory Role: MSD Oncology, Roche, Mirati TherapeuticsResearch Funding: MSD Oncology, Roche Gary MiddletonConsulting or Advisory Role: BMS, D2G, MSDSpeakers' Bureau: Roche, BMS, Servier, PierreFabre, AZTravel, Accommodations, Expenses: BMS Leslie SamuelHonoraria: ServierConsulting or Advisory Role: MerckResearch Funding: Merck, Array BioPharma, Tesaro, Servier, Hutchison MediPharma Richard H. WilsonHonoraria: Servier, Amgen, Bristol Myers SquibbConsulting or Advisory Role: Amgen, CV6 Therapeutics, Pierre Fabre, Amphista Therapeutics, NucanaTravel, Accommodations, Expenses: Amgen, Pierre Fabre Louise C. BrownResearch Funding: AstraZeneca Timothy S. MaughanConsulting or Advisory Role: AstraZeneca, Vertex, Pierre FabreResearch Funding: AstraZeneca, PsiOxus Therapeutics, Merck KgAA, Almac DiagnosticsNo other potential conflicts of interest were reported.

Purpose: Outcomes in RAS -mutant metastatic colorectal cancer (mCRC) remain poor and patients have limited therapeutic options. Adavosertib is the first small-molecule inhibitor of WEE1 kinase. We hypothesized that aberrations in DNA replication seen in mCRC with both RAS and TP53 mutations would sensitize tumors to WEE1 inhibition., Methods: Patients with newly diagnosed mCRC were registered into FOCUS4 and tested for TP53 and RAS mutations. Those with both mutations who were stable or responding after 16 weeks of chemotherapy were randomly assigned 2:1 between adavosertib and active monitoring (AM). Adavosertib (250 mg or 300 mg) was taken orally once on days 1-5 and days 8-12 of a 3-week cycle. The primary outcome was progression-free survival (PFS), with a target hazard ratio (HR) of 0.5 and 80% power with a one-sided 0.025 significance level., Results: FOCUS4-C was conducted between April 2017 and Mar 2020 during which time 718 patients were registered; 247 (34%) were RAS/TP53 -mutant. Sixty-nine patients were randomly assigned from 25 UK hospitals (adavosertib = 44; AM = 25). Adavosertib was associated with a PFS improvement over AM (median 3.61 v 1.87 months; HR = 0.35; 95% CI, 0.18 to 0.68; P = .0022). Overall survival (OS) was not improved with adavosertib versus AM (median 14.0 v 12.8 months; HR = 0.92; 95% CI, 0.44 to 1.94; P = .93). In prespecified subgroup analysis, adavosertib activity was greater in left-sided tumors (HR = 0.24; 95% CI, 0.11 to 0.51), versus right-sided (HR = 1.02; 95% CI, 0.41 to 2.56; interaction P = .043). Adavosertib was well-tolerated; grade 3 toxicities were diarrhea (9%), nausea (5%), and neutropenia (7%)., Conclusion: In this phase II randomized trial, adavosertib improved PFS compared with AM and demonstrates potential as a well-tolerated therapy for RAS/TP53 -mutant mCRC. Further testing is required in this sizable population of unmet need., Competing Interests: Jenny F. SeligmannHonoraria: Pierre Fabre, Merck Serono, ServierConsulting or Advisory Role: Pierre Fabre, Roche Molecular DiagnosticsTravel, Accommodations, Expenses: Bristol Myers Squibb/Medarex Louise C. BrownResearch Funding: AstraZeneca Richard A. AdamsHonoraria: Merck Serono, Servier, AmgenConsulting or Advisory Role: Merck Serono, Amgen, Servier, BayerSpeakers' Bureau: Merck Serono, AstraZeneca, Merck Sharp & DohmeTravel, Accommodations, Expenses: Servier, Amgen, Merck Serono, AstraZeneca Janet GrahamHonoraria: Merck Serono, Bristol Myers Squibb, Nucana, BayerConsulting or Advisory Role: Merck KGaATravel, Accommodations, Expenses: Nucana Philip QuirkeHonoraria: RocheConsulting or Advisory Role: Roche, Adlai Nortye, Avacta Life Sciences, Amgen, BayerResearch Funding: Roche, GeneFirst, ONIPatents, Royalties, Other Intellectual Property: Roche has filed a patent jointly with my University; I may receive income but none to dateTravel, Accommodations, Expenses: Roche, Bayer, Amgen Rachel ButlerSpeakers' Bureau: Bayer, Pfizer, Roche, AstraZeneca, MSD, Illumina, Lilly, Novartis, Amgen, Boehringer Ingelheim Michael BraunHonoraria: Servier, Amgen, Pierre FabreTravel, Accommodations, Expenses: Servier Fiona CollinsonResearch Funding: Bristol Myers Squibb Rob JonesHonoraria: Astellas Pharma, Janssen, AstraZeneca, MSD Oncology, Bristol Myers Squibb, Pfizer, Novartis, Ipsen, Seattle Genetics, Sanofi, Bayer, Roche/Genentech, EUSA Pharma, Pharmacyclics, Clovis Oncology, Merck Serono, EisaiConsulting or Advisory Role: Clovis OncologyResearch Funding: Roche, Astellas Pharma, AstraZeneca, Pfizer, Novartis, Exelixis, Clovis Oncology, BayerTravel, Accommodations, Expenses: Ipsen, Bayer, Janssen, Astellas Pharma, MSD Ewan BrownResearch Funding: MSD Oncology Timothy C. HumphreyResearch Funding: Debiopharm Group Mahesh ParmarResearch Funding: AstraZeneca, Astellas Pharma, Janssen, Clovis Oncology Richard KaplanResearch Funding: AstraZeneca Richard WilsonHonoraria: Servier, Amgen, Bristol Myers SquibbConsulting or Advisory Role: Amgen, CV6 Therapeutics, Pierre Fabre, Amphista Therapeutics, NucanaTravel, Accommodations, Expenses: Amgen, Pierre Fabre Matthew SeymourResearch Funding: Amgen, AstraZeneca Timothy S. MaughanConsulting or Advisory Role: AstraZeneca, Vertex, Pierre FabreResearch Funding: AstraZeneca, PsiOxus Therapeutics, Merck KgAA, Almac DiagnosticsNo other potential conflicts of interest were reported.

Purpose: High tumor mRNA levels of the EGFR ligands amphiregulin (AREG) and epiregulin (EREG) are associated with anti-EGFR agent response in metastatic colorectal cancer (mCRC). However, ligand RNA assays have not been adopted into routine practice due to issues with analytic precision and practicality. We investigated whether AREG/EREG IHC could predict benefit from the anti-EGFR agent panitumumab., Experimental Design: Artificial intelligence algorithms were developed to assess AREG/EREG IHC in 274 patients from the PICCOLO trial of irinotecan with or without panitumumab (Ir vs. IrPan) in RAS wild-type mCRC. The primary endpoint was progression-free survival (PFS). Secondary endpoints were RECIST response rate (RR) and overall survival (OS). Models were repeated adjusting separately for BRAF mutation status and primary tumor location (PTL)., Results: High ligand expression was associated with significant PFS benefit from IrPan compared with Ir [8.0 vs. 3.2 months; HR, 0.54; 95% confidence interval (CI), 0.37-0.79; P = 0.001]; whereas low ligand expression was not (3.4 vs. 4.4 months; HR, 1.05; 95% CI, 0.74-1.49; P = 0.78). The ligand-treatment interaction was significant ( P interaction = 0.02) and remained significant after adjustment for BRAF -mutation status and PTL. Likewise, RECIST RR was significantly improved in patients with high ligand expression (IrPan vs. Ir: 48% vs. 6%; P < 0.0001) but not those with low ligand expression (25% vs. 14%; P = 0.10; P interaction = 0.01). The effect on OS was similar but not statistically significant., Conclusions: AREG/EREG IHC identified patients who benefitted from the addition of panitumumab to irinotecan chemotherapy. IHC is a practicable assay that may be of use in routine practice., (©2021 American Association for Cancer Research.)

Analysis of routine population-based data has previously shown that patterns of surgical treatment for colorectal cancer can vary widely, but there is limited evidence available to determine if such variation is also seen in the use of chemotherapy. This study quantified variation in adjuvant chemotherapy across both England using cancer registry data and in more detail across the representative Yorkshire and Humber regions. Individuals with Stages II and III colorectal cancer who underwent major resection from 2014 to 2015 were identified. Rates of chemotherapy were calculated from the Systemic Anticancer Treatment database using multilevel logistic regression. Additionally, questionnaires addressing different clinical scenarios were sent to regional oncologists to investigate the treatment preferences of clinicians. The national adjusted chemotherapy treatment rate ranged from 2% to 46% (Stage II cancers), 19% to 81% (Stage III cancers), 24% to 75% (patients aged <70 years) and 5% to 46% (patients aged ≥70 years). Regionally, the rates of treatment and the proportions of treated patients receiving combination chemotherapy varied by stage (Stage II 4%-26% and 0%-55%, Stage III 48%-71% and 40%-84%) and by age (<70 years 35%-68% and 49%-91%; ≥70 years 15%-39% and 6%-75%). Questionnaire responses showed significant variations in opinions for high-risk Stage II patients with both deficient and proficient mismatch repair tumours and Stage IIIB patients aged ≥70 years. Following a review of the evidence, open discussion in our region has enabled a consensus agreement on an algorithm for colorectal cancer that is intended to reduce variation in practice., (© 2020 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of Union for International Cancer Control.)

Aims: Brain (central nervous system; CNS) metastases occur in 30-50% of patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC). A substantive evidence base for treatment is lacking, but activity with lapatinib plus capecitabine (lap-cap) has been reported. We compared lap-cap with trastuzumab plus capecitabine (tras-cap) in patients with HER2-positive MBC with CNS metastases previously treated with trastuzumab., Materials and Methods: This open-label randomised phase II screening trial aimed to randomise 130 participants over 2 years to receive lap-cap or tras-cap. Eligible patients had HER2-positive MBC with newly diagnosed or recently progressed CNS metastases; previous, or current, treatment included: trastuzumab, a taxane or anthracycline and recent completion of local cranial therapy. The primary end point was time to progression of CNS metastases within the 24-week trial period. Secondary objectives included CNS response rate, progression-free survival, steroid use for CNS symptoms and feasibility of recruitment to a large phase III trial., Results: Between September 2011 and October 2013, 30 participants were randomised, 16 to lap-cap and 14 to tras-cap. Recruitment to a large phase III trial was determined not to be feasible. At 24 weeks, CNS disease progression was 41.8% (95% confidence interval 16.1-67.5%) in lap-cap and 41.2% (95% confidence interval 12.8-69.6%) in tras-cap arms; progression-free survival was 44.4% (95% confidence interval 18.1-70.8%) in lap-cap and 50.0% (95% confidence interval 20.9-79.1%) in tras-cap arms., Conclusion: Poor recruitment confirmed that a larger phase III trial would not be feasible and prohibited a preliminary evaluation of the superiority of lap-cap over tras-cap. Descriptive statistics are presented to inform the limited evidence base and future study design., (Copyright © 2020 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Background: Primary tumour location (PTL) is being adopted by clinicians to guide treatment decisions in metastatic colorectal cancer (mCRC). Here we test PTL as a predictive marker for panitumumab efficacy, and examine its relationship with an extended biomarker profile. We also examine rectal tumours as a separate location., Patients and Methods: mCRC patients from the second-line PICCOLO trial of irinotecan versus irinotecan/panitumumab (IrPan). PTL was classified as right-PTL, left-PTL or rectal-PTL. PTL was assessed as a predictive biomarker for IrPan effect in RAS-wild-type (RAS-wt) patients (compared with irinotecan alone), then tested for independence alongside an extended biomarker profile (BRAF, epiregulin/amphiregulin (EREG/AREG) and HER3 mRNA expression)., Results: PTL data were available for 1180 patients (98.5%), of whom 558 were RAS-wt. High HER3 expression was independently predictive of panitumumab overall survival improvement, but PTL and EREG/AREG were not. IrPan progression-free survival (PFS) improvement compared with irinotecan was seen in left-PTL [hazard ratio (HR) = 0.61, P = 0.002) but not right-PTL (HR = 0.98, P = 0.90) (interaction P = 0.05; RAS/BRAF-wt interaction P = 0.10), or in rectal-PTL (HR = 0.82, P = 0.20) (interaction P = 0.14 compared with left-PTL; RAS/BRAF-wt interaction P = 0.04). Patients with right-PTL and high EREG/AREG or HER3 expression, had IrPan PFS improvement (high EREG/AREG HR = 0.20, P = 0.04; high HER3 HR = 0.33, P = 0.10) compared with irinotecan. Similar effect was seen for rectal-PTL patients (high EREG/AREG HR = 0.44, P = 0.03; high HER3 HR = 0.34, P = 0.05)., Conclusions: RAS-wt patients with left-PTL are more likely to have panitumumab PFS advantage than those with right-PTL or rectal-PTL. However, an extended biomarker panel demonstrated significant heterogeneity in panitumumab PFS effect within a tumour location. AREG/EREG and HER3 mRNA expression identifies patients with right-PTL or rectal-PTL who achieve similar PFS effect with panitumumab as left-colon patients. Testing could provide a more reliable basis for clinical decision making. Further validation and development of these biomarkers is required to optimise routine patient care., Clinical Trial Registration: ISRCTN identifier: ISRCTN93248876., Competing Interests: Disclosure JS has received speaker fees from Merck Serono and has served on advisory committees for Roche and Pierre Fabre. The other authors have declared no conflict of interest., (Copyright © 2020. Published by Elsevier Ltd.)

The presence of peritoneal metastases in patients with advanced colorectal cancer is associated with poor prognosis but the mechanisms for this are unclear. This review summarises the current knowledge of the pathophysiology, clinical features, prevalence, prognosis, and molecular biology of peritoneal metastases and the risk factors for the development of peritoneal metastases following resection of a primary colorectal tumour. Furthermore, the evidence for treatment strategies are described including cytoreductive surgery, hyperthermic intraperitoneal chemotherapy, early post-operative intraperitoneal chemotherapy, sequential post-operative intraperitoneal chemotherapy and emerging novel strategies. Active areas of research should include the identification of individuals at high risk of peritoneal metastases after curative resection of primary tumour, development of a surveillance program for high-risk patients, optimisation of systematic therapies and further investigation of the use of intraperitoneal chemotherapy., Competing Interests: Declaration of competing interest JS – speaker fees Merck Serono; advisory board - Pierre Fabre, Roche; CME – GI Connect. NPW - consultancy fees from Eisai., (Copyright © 2019. Published by Elsevier Ltd.)

Importance: Epidermal growth factor receptor (EGFR) (HER1) signaling depends on ligand binding and dimerization with itself or other HER receptors. We previously showed in a randomized trial that high EGFR ligand expression is predictive of panitumumab benefit in advanced colorectal cancer. Tumor expression of HER3 may further refine the RAS wild-type (wt) population benefitting from anti-EGFR agents., Objective: To examine HER3 messenger RNA expression as a prognostic and predictive biomarker for anti-EGFR therapy in a randomized clinical trial of panitumumab., Design, Setting, and Participants: The study was a prospectively planned retrospective biomarker study of pretreatment samples from the PICCOLO trial that tested the addition of panitumumab to irinotecan therapy in patients with KRAS wt advanced colorectal cancer who experienced failure with prior fluoropyrimidine treatment. HER3 was assessed as a prognostic marker, then as a predictive biomarker in patients with RAS wt, first as a continuous variable and then as a binary (high vs low) variable. Relationship with MEK-AKT pathway mutations and EGFR ligands epiregulin and amphiregulin (EREG/AREG) were also assessed., Main Outcomes and Measures: Primary end point was progression-free survival (PFS); secondary end points were response rate and overall survival (OS)., Results: In 308 patients (mean age at randomization, 61.6 years; 193 men) higher HER3 was weakly prognostic for OS (hazard ratio [HR] per 2-fold change, 0.91; 95% CI, 0.83-0.99; P = .04) but not PFS (HR, 0.93; 95% CI, 0.83-1.05; P = .25). Higher HER3 was predictive, being associated with prolonged PFS on irinotecan plus panitumumab (IrPan) (HR, 0.71; 95% CI, 0.61-0.82; P < .001), but not irinotecan (HR, 0.96; 95% CI, 0.82-1.13; P = .65) in patients with RAS wt, with significant interaction between biomarker and treatment (P = .001). Similar interaction was seen for OS (P = .004). In an exploratory binary model, dividing the population at the 66th percentile, HER3 was predictive of panitumumab benefit: in patients with high HER3 expression, median PFS was 8.2 months (IrPan) vs 4.4 months (irinotecan) (HR, 0.33; 95% CI, 0.19-0.58; P < .001). Patients with low HER3 expression gained no benefit in PFS: 3.3 months (IrPan) vs 4.3 months (irinotecan) (HR, 0.96; 95% CI, 0.67-1.38; P = .84), with significant interaction (P = .002). The binary model was also predictive for OS, with significant interaction (P = .01). Combining HER3 and ligand data, patients with HER3-high, AREG/EREG-high tumors gained markedly from panitumumab (PFS HR, 0.24; 95% CI, 0.11-0.51; P < .005 and OS HR, 0.36; 95% CI, 0.18-0.73; P = .004). Conversely, patients with HER3-low, AREG/EREG-low tumors did not benefit (PFS HR, 1.14; 95% CI, 0.73-1.79; P = .57 and OS HR, 1.44; 95% CI, 0.92-2.26; P = .11)., Conclusions and Relevance: High HER3 expression identified patients with RAS wt who gained markedly from panitumumab, and those who did not, with statistically significant biomarker-treatment interactions for PFS and OS. This finding provides insight into the mechanism of anti-EGFR agents and is of potential clinical utility.

Background: To improve strategies for the treatment of BRAF-mutant advanced colorectal cancer (aCRC) patients, we examined individual data from patients treated with chemotherapy alone in three randomised trials to identify points on the treatment pathway where outcomes differ from BRAF wild-types., Patients and Methods: 2530 aCRC patients were assessed from three randomised trials. End-points were progression-free survival, response rate, disease control rate, post-progression survival (P-PS) and overall survival. Treatments included first-line oxaliplatin/fluorouracil (OxFU) and second-line irinotecan. Clinicians were unaware of BRAF-status., Results: 231 patients (9.1%) had BRAF-mutant tumours. BRAF-mutation conferred significantly worse survival independent of associated clinicopathological factors known to be prognostic. Compared with wild-type, BRAF-mutant patients treated with first-line OxFU had similar DCR (59.2% versus 72%; adjusted OR = 0.76, P = 0.24) and PFS (5.7 versus 6.3 months; adjusted HR = 1.14, P = 0.26). Following progression on first-line chemotherapy, BRAF-mutant patients had a markedly shorter P-PS (4.2 versus 9.2 months, adjusted HR = 1.69, P < 0.001). Fewer BRAF-mutant patients received second-line treatment (33% versus 51%, P < 0.001), but BRAF-mutation was not associated with inferior second-line outcomes (RR adjusted OR = 0.56, P = 0.45; PFS adjusted HR = 1.01, P = 0.93). Significant clinical heterogeneity within the BRAF-mutant population was observed: a proportion (24.3%) had good first-line PFS and P-PS (both >6 months; OS = 24.0 months); however, 36.5% progressed rapidly through first-line chemotherapy and thereafter, with OS = 4.7 months., Conclusions: BRAF-mutant aCRC confers a markedly worse prognosis independent of associated clinicopathological features. Chemotherapy provides meaningful improvements in outcome throughout treatment lines. Post-progression survival is markedly worse and vigilance is required to ensure appropriate delivery of treatment after first-line progression., (© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Importance: RAS wild-type (wt) status is necessary but not sufficient for response to anti-epidermal growth factor receptor (EGFR) agents in advanced colorectal cancer (aCRC). RNA expression of EGFR ligands epiregulin (EREG) and amphiregulin (AREG) may correlate with EGFR-targeted therapy efficacy in aCRC, so may represent a much-needed additional predictive marker for these drugs., Objective: To examine a novel ligand model in a randomized clinical trial of panitumumab, irinotecan, and ciclosporin in colorectal cancer (PICCOLO) with with the a priori hypothesis that high tumor expression of either AREG or EREG would predict panitumumab therapy benefit in RAS-wt patients; and low expression, lack of efficacy., Design, Setting, and Participants: Prospectively planned retrospective biomarker study from the PICCOLO trial, which tested the addition of panitumumab to irinotecan therapy in patients with KRAS wt aCRC who experienced failure with prior fluoropyrimidine treatment. The analysis was conducted between 2012 and 2014. A predefined dichotomous model classified tumors as "high expressor" (either EREG or AREG in top tertile for messenger RNA level) or "low expressor" (neither EREG nor AREG in top tertile). Ligand expression was assessed as a prognostic and predictive biomarker. Expression of AREG/EREG and RAS and BRAF mutations were assessed in archival tumor tissue., Main Outcomes and Measures: Primary end point was progression-free survival (PFS); secondary end points were response rate and overall survival (OS)., Results: Of the 696 PICCOLO trial patients in the irinotecan-vs-irinotecan with panitumumab randomization, 331 had sufficient tumor tissue available and measurement of ligand expression was successful in 323. High ligand expression was not prognostic for OS (hazard ratio [HR], 0.79 [95% CI, 0.58-1.09]; P = .15) or PFS (HR, 0.93 [95% CI, 0.68-1.27]; P = .64). The primary population had RAS wt aCRC (n = 220); for RAS wt patients with high ligand expression, median (interquartile range [IQR]) PFS was 8.3 [4.0-11.0] months (irinotecan with panitumumab) vs 4.4 [2.8-6.7] months (irinotecan alone); HR, 0.38 [95% CI, 0.24-0.61]; P < .001). In RAS wt patients with low ligand expression, median (IQR) PFS was 3.2 [2.7-8.1] months (irinotecan with panitumumab) vs 4.0 [2.7-7.5] months (irinotecan); HR, 0.93 [95% CI, 0.64-1.37]; P = .73; interaction test results were significant [P = .01]). Less marked effects were seen for response rate (interaction P = .17) and OS (interaction P = .11)., Conclusions and Relevance: High ligand expression is a predictive marker for panitumumab therapy benefit on PFS in RAS wt patients; conversely, patients with low ligand expression gained no benefit. The current "opt-in" strategy for anti-EGFR therapy in all patients with RAS wt aCRC should be questioned. Expression of EREG/AREG is a useful biomarker for anti-EGFR therapy; optimization for clinical use is indicated., Trial Registration: isrctn Identifier: ISRCTN93248876.

Background: Therapeutic antibodies targeting EGFR have activity in advanced colorectal cancer, but results from clinical trials are inconsistent and the population in which most benefit is derived is uncertain. Our aim was to assess the addition of panitumumab to irinotecan in pretreated advanced colorectal cancer., Methods: In this open-label, randomised trial, we enrolled patients who had advanced colorectal cancer progressing after fluoropyrimidine treatment with or without oxaliplatin from 60 centres in the UK. From December, 2006 until June, 2008, molecularly unselected patients were recruited to a three-arm design including irinotecan (control), irinotecan plus ciclosporin, and irinotecan plus panitumumab (IrPan) groups. From June 10, 2008, in response to new data, the trial was amended to a prospectively stratified design, restricting panitumumab randomisation to patients with KRAS wild-type tumours; the results of the comparison between the irinotcan and IrPan groups are reported here. We used a computer-generated randomisation sequence (stratified by previous EGFR targeted therapy and then minimised by centre, WHO performance status, previous oxaliplatin, previous bevacizumab, previous dose modifications, and best previous response) to randomly allocate patients to either irinotecan or IrPan. Patients in both groups received 350 mg/m(2) intravenous irinotecan every 3 weeks (300 mg/m(2) if aged ≥70 years or a performance status of 2); patients in the IrPan group also received intravenous panitumumab 9 mg/kg every 3 weeks. The primary endpoint was overall survival in KRAS wild-type patients who had not received previous EGFR targeted therapy, analysed by intention to treat. Tumour DNA was pyrosequenced for KRASc.146, BRAF, NRAS, and PIK3CA mutations, and predefined molecular subgroups were analysed for interaction with the effect of panitumumab. This study is registered, number ISRCTN93248876., Results: Between Dec 4, 2006, and Aug 31, 2010, 1198 patients were enrolled, of whom 460 were included in the primary population of patients with KRASc.12-13,61 wild-type tumours and no previous EGFR targeted therapy. 230 patients were randomly allocated to irinotecan and 230 to IrPan. There was no difference in overall survival between groups (HR 1·01, 95% CI 0·83-1·23; p=0·91), but individuals in the IrPan group had longer progression-free survival (0·78, 0·64-0·95; p=0·015) and a greater number of responses (79 [34%] patients vs 27 [12%]; p<0·0001) than did individuals in the irinotecan group. Grade 3 or worse diarrhoea (64 [29%] of 219 patients vs 39 [18%] of 218 patients), skin toxicity (41 [19%] vs none), lethargy (45 [21]% vs 24 [11%]), infection (42 [19%] vs 22 [10%]) and haematological toxicity (48 [22%] vs 27 [12%]) were reported more commonly in the IrPan group than in the irinotecan group. We recorded five treatment-related deaths, two in the IrPan group and three in the irinotecan group., Interpretation: Adding panitumumab to irinotecan did not improve the overall survival of patients with wild-type KRAS tumours. Further refinement of molecular selection is needed for substantial benefits to be derived from EGFR targeting agents., Funding: Cancer Research UK, Amgen Inc., (Copyright © 2013 Elsevier Ltd. All rights reserved.)