INTRODUCTION:The rising incidence of early-onset gastrointestinal (GI) cancer has made the impact of treatment-related gonadal toxicity increasingly significant. While there is ample evidence on oncofertility outcomes in breast cancer and hematological malignancies, data in GI cancers remain limited. We sought to evaluate oncofertility perspectives from the viewpoint of young GI cancer survivors across Europe. METHODS:A cross-sectional 60-item electronic survey regarding oncofertility practices was distributed via patient digital platforms. The target population was survivors treated for GI cancers before the age of 45 or 50 years (women/men). Statistical analysis was performed on country, gender, and tumor type. RESULTS:One hundred and forty survivors from 19 countries completed the survey (78F/62M), median age at diagnosis was 36.9/35.6 years (F/M), the majority had colorectal cancer, treated with chemotherapy (88%/89%) and radiotherapy (34%/48%). Fertility impact was discussed in 66% of women and 71% of men, but fewer were referred for fertility preservation (43%/57%), and fewer underwent preservation (18%/61%), with variability between countries. The main reason for not preserving fertility was lack of desire of future offspring (women) or lack of referral (men). Sexual health counseling was conducted in less than 50% of patients. Among women, 46% reported persistent amenorrhea and 64% menopausal symptoms. Significant sexual dysfunction was indicated by 69% of women and 83% of men. CONCLUSION:Anti-cancer treatment has substantial impact on fertility and sexual function in young GI cancer survivors. Counseling, referral, and uptake vary across countries. Gonadal-related issues remain an unmet need in GI oncology, requiring improved counseling and clinical practice.

BACKGROUND:The peritoneum is the third most prevalent location for metastases of colorectal cancer. In patients with resectable disease, cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) is the preferred treatment in the Netherlands, achieving median overall survival (OS) of 36-42 months. However, during explorative laparotomy, CRS-HIPEC may appear unfeasible. Evidence on how such non-therapeutic laparotomies affect prognosis is limited. METHODS:This retrospective cohort study included all non-therapeutic laparotomies performed between 01 and 01-2010 and 01-01-2022 in two Dutch tertiary HIPEC-centers. Patient, tumor and treatment characteristics, postoperative morbidity, and survival outcomes were analyzed and compared to existing literature. RESULTS:In total, 108 patients underwent a non-therapeutic laparotomy (discontinued CRS-HIPEC). The main reason was that peritoneal disease was too extensive (56%). Severe postoperative complications (Clavien-Dindo ≥ 3) occurred in 9%. Following a non-therapeutic procedure, 55% of patients received tumor-directed palliative treatment. Median OS of the entire cohort was 6.5 months (95% CI 5.1-8.0). Palliative systemic therapy was the only factor significantly associated with improved OS (12.6 vs. 2.9 months, p < 0.001). CONCLUSIONS:Non-therapeutic laparotomies are associated with decreased survival in patients with extensive peritoneal metastases. Reducing their occurrence is essential. Advances in diagnostic modalities, including MRI, FAPI-PET, artificial intelligence, and developments in bidirectional treatments, may improve preoperative selection and offer alternative therapeutic options. Further research is required.

Patients with metastatic colorectal cancer (mCRC) undergoing systemic treatment often experience toxicities. Although exercise may improve physical fitness and quality of life and counteract treatment toxicity, knowledge in patients with mCRC is limited. The ongoing randomized controlled AMICO trial evaluates the effects of supervised exercise on clinical outcomes. The present qualitative study was a pre-planned part of this trial aiming to capture adherence, satisfaction, and perceived effects of exercise among patients with mCRC. Patients with mCRC receiving first-line systemic treatment were randomized (1:1:1) to a control group or one of two supervised exercise arms including continuous aerobic exercise with either resistance exercises or high-intensity interval training. Semi-structured interviews with patients in the exercise arms were transcribed verbatim and thematically analyzed. Descriptive data on adherence (exercise logs) and satisfaction (questionnaire) was collected to complement and contextualize the qualitative findings. Twenty-one patients were interviewed. Median exercise attendance was 67

Background: For patients with small-size colorectal liver metastases, growing evidence suggests thermal ablation to be associated with fewer adverse events and faster recovery than resection while also challenging resection in terms of local control and overall survival. This study assessed the potential non-inferiority of thermal ablation compared with surgical resection in patients with small-size resectable colorectal liver metastases. Methods: Adult patients (aged >= 18 years) from 14 centres in the Netherlands, Belgium, and Italy with ten or fewer small-size (<= 3 cm) colorectal liver metastases, no extrahepatic metastases, and an Eastern Cooperative Oncology Group performance status of 0-2, were stratified per centre, and according to their disease burden, into low, intermediate, and high disease burden subgroups and randomly assigned 1:1 to receive either thermal ablation (experimental group) or surgical resection (control group) of all target colorectal liver metastases using the web-based module Castor electronic data capture with variable block sizes of 4, 6, and 8. Although at the operator's discretion, a minimally invasive approach in both treatment groups was recommended. The primary endpoint was overall survival, assessed in the intention-to-treat population. A hazard ratio (HR) of 130 was considered the upper limit of non-inferiority for the primary endpoint. A preplanned interim analysis with predefined stopping rules for futility (conditional power to prove the null hypothesis <20%) and early benefit (conditional power >90%, superior safety outcomes for the experimental group, and no difference or superiority regarding local control for the experimental group) was done 12 months after enrolment of 50% of the planned sample size. Safety was assessed per treatment group. This trial is registered with ClinicalTrials.gov, NCT03088150. Findings: Between Aug 7, 2017, and Feb 14, 2024, 300 patients were randomly assigned to the experimental group (n=148, 100 male [68%] and 48 female [32%]; median age 679 years [IQR 292-857]) or to the control group (n=148, 107 male [72%] and 41 female [28%]; median age 651 [IQR 314-874]); four patients (two in each treatment group) were excluded after randomisation because they were found to have other disease pathology. Median follow-up at the prespecified interim analysis was 289 months (IQR 03-778). The trial was stopped early for meeting the predefined stopping rules: (1) a conditional likelihood to prove non-inferiority for overall survival of 905% (median overall survival not reached in both groups; HR 105; 95% CI 069-158; p=083), (2) a non-inferior local control (median local control not reached in both groups; HR 013, 95% CI 002-106; p=0057), and (3) a superior safety profile for the experimental group. Patients in the experimental group had fewer adverse events than those in the control group (28 [19%] vs 67 [46%]; p<00001). Serious adverse events occurred in 11 (7%) of 148 patients in the experimental group and 29 (20%) of 146 in the control group, mostly periprocedural haemorrhage requiring intervention (one [1%] vs eight [5%]), and infectious complications requiring intervention (six [4%] vs 11 [8%]). There were no treatment-related deaths in the experimental group and three treatment-related deaths (2%) in the control group (two due to postoperative cardiac complications and one due to sepsis and liver failure). Interpretation: The assumption that thermal ablation should be reserved for unresectable colorectal liver metastases requires re-evaluation and the preferred treatment should be individualised and based on clinical characteristics and available expertise.

BACKGROUND:Patients with metastatic colorectal cancer often have poor or short responses to currently available therapies. Drug repurposing with alternative dosing schedules may offer unexpected clinical benefit, even for agents that previously failed for this indication. METHODS:We explored a high-dose treatment strategy for sunitinib, assessing its potential for both cancer cell killing and inducing immunogenic cell death in patient-derived tumor organoids (PDTOs) of metastatic colorectal cancer (mCRC). In a randomized clinical trial, we studied the efficacy of high-dose intermittent sunitinib (700 mg once every 2 weeks) in patients with advanced CRC compared to standard therapy with trifluridine/tipiracil. The primary outcome measure was progression-free survival (PFS); secondary outcomes included overall survival, safety and tolerability, quality of life, and exploratory biomarker analyses. RESULTS:While high, intermittent dosing was found to effectively kill PDTOs in vitro, no support for immunogenic cell death was found. In our clinical trial, among a total of 63 evaluable patients, median PFS was 2.8 months (95% CI 0.9-4.7) for the investigation arm compared to 1.9 months (95% CI 1.6-2.3) for the trifluridine/tipiracil group (P = .78, HR 1.22; 95% CI 0.73-2.04). The trial was halted prematurely due to toxicities: in particular, hemorrhage, fever and gastrointestinal adverse events. CONCLUSION:High-dose intermittent sunitinib treatment did not improve PFS for patients with heavily pretreated mCRC compared to standard 3rd or 4th-line treatment with trifluridine/tipiracil, whereas significant toxicity was observed. In addition, this approach provoked no relevant immunological responses in vitro, discouraging further research for potential combinations with immunotherapeutics. IDENTIFIER:NCT03909724.

To describe trends in incidence of early-onset colorectal cancer in the Netherlands. Observational research. We selected colorectal cancer patients aged 15 to 49 years, diagnosed between 1989-2023, from the Netherlands Cancer Registry (NCR). We calculated incidence rates and determined changes in trends using Joinpoint regression analyses. Furthermore, we made a prediction of the number of early-onset colorectal cancer patients in 2035. The number of new early-onset colorectal cancer patients has increased; from 6.3 per 100,000 in 1998 to 9.3 per 100,000 in 2023 (Annual Percentage Change 1.41% (95% confidence interval 1.18-1.71)). This incidence is expected to increase further in the future, reaching between 629 and 871 cases by 2035. There is an increase in the incidence of early-onset colorectal cancer in the Netherlands which appears to persist over the next 10 years. Further research is needed to identify the causes of this increase.

Recent advances in single cell sequencing and multi-omics techniques have significantly improved our understanding of biological phenomena and our capacity to model them. Despite combined capture of data modalities showing similar progress, notably single cell transcriptomics and proteomics, simultaneous multi-omics level probing still remains challenging. As an alternative to combined capture of biological data, in this review, we explore current and upcoming methods for post-hoc network inference and integration with an emphasis on single cell transcriptomics and proteomics. By examining various approaches, from probabilistic models to graph-based algorithms, we outline the challenges and potential strategies for effectively combining biological data types while simultaneously highlighting the importance of model validation. With this review, we aim to inform readers of the breadth of tools currently available for the purpose-specific generation of heterogeneous multi-layer networks.

INTRODUCTION:This study aimed to assess whether total tumor volume (TTV) outperforms RECIST1.1 for treatment response assessment in patients with colorectal liver metastases (CRLM), and to investigate TTV as a predictive biomarker for the optimal systemic treatment regimen for individual patients with initially unresectable CRLM. METHODS:Patients with initially unresectable liver-only CRLM from the phase 3 CAIRO5 trial (NCT02162563) were included. All patients received induction systemic treatment. Baseline TTV and changes in TTV and RECIST1.1 in response to systemic treatment were calculated using the CT scans before systemic treatment and at first follow-up, and were assessed for their prognostic and predictive value with multivariable Cox regression models. Results In total, 425 patients were included. In multivariable analyses, baseline TTV (adjusted HR [aHR] for 100 mL vs 10 mL, 2.44 [95 % CI, 1.25-4.76]; P = 0.006) and relative change in TTV were the strongest predictors for OS (aHR for 0 % change vs 50 % decrease, 2.57 [1.83-3.60]; P < 0.0001). In contrast, RECIST1.1 was not independently associated with OS (aHR for partial response vs progressive disease, 0.63 [95 % CI, 0.33-1.20]). Higher baseline TTV predicted a stronger treatment benefit of FOLFOX-/FOLFIRI-bevacizumab vs FOLFOX-/FOLFIRI-panitumumab on OS (Pinteraction=0.017). CONCLUSION:This study demonstrates that TTV (i) outperforms traditional risk factors for OS prognostication, and (ii) may be a more accurate and sensitive treatment response assessment method compared to the currently used RECIST1.1 system in patients with initially unresectable CRLM. Moreover, TTV assessment is a promising approach for individualized clinical decision-making between bevacizumab and panitumumab.

BRCA1/2 are crucial in the homologous recombination repair (HRR) pathway, with loss-of-function (LoF) alterations predicting sensitivity to PARP-inhibitors (PARPi). Whether other HRR-gene alterations confer PARPi sensitivity remains unclear. In the Drug Rediscovery Protocol, patients receive off-label drugs matched to their tumor molecular profile. Here, olaparib efficacy and safety were evaluated in adult patients with treatment-refractory, progressive malignancies harboring LoF alterations in ATM (cohort A) or other HRR-genes including CDK12, PPP2R2A, CHEK1/2, and RAD51B (cohort B). Primary endpoints were clinical benefit (CB: confirmed objective response or stable disease ≥16 weeks) and safety. Pre-treatment biopsies were analyzed by whole-genome sequencing (WGS) for target validation. CB was observed in 8/25 patients (32%) in cohort A (prostate cancer: n = 6, adenoid cystic carcinoma: n = 1, endometrial cancer: n = 1). No effectiveness was seen in patients with colorectal cancer (n = 8). Median progression-free survival (PFS) and overall survival (OS) were 3.4 months (95% CI 1.8-5.3) and 9.2 months (95% CI 5.2-21.3), respectively. In cohort B, the CB rate was 41.7% (10/24) with median PFS and OS of 3.5 months (95% CI 3.4-6.6) and 8.1 months (95% CI 6.6-14.2), respectively. CB was observed in CKD12 (n = 7), RAD51B (n = 2), and CHEK2-altered tumors (n = 1), but not in PPP2R2A (n = 6) or CHEK1-altered tumors (n = 1). No unexpected toxicities occurred. WGS confirmed inclusion target in 84% of tested patients. In conclusion, PARPi sensitivity varies across HRR-genes, indicating that relying solely on an altered common mechanistic pathway is insufficient to predict response. Future studies should target specific HRR-genes to assess subgroup-specific benefits and determine proper use of molecular diagnostics.

Background:Despite a generally poor prognosis of patients with brain metastases of colorectal cancer (CRC-BM), local treatment of BM might be beneficial in selected patients. The aim of this study was to characterize patient and clinicopathological characteristics of CRC-BM and to identify patients who benefit most from local treatment of CRC-BM. Methods:In this retrospective cohort study, clinicopathological characteristics, including treatment response and survival, were collected from 100 patients who were treated for CRC-BM at the Netherlands Cancer Institute between 2001 and 2021. All analyses were performed using SPSS. Results:Median overall survival (OS) from CRC diagnosis and diagnosis of BM was 47.3 and 5.2 months, respectively. Median brain metastasis-free interval (BMFI) was 39.0 months. Median OS of patients with metachronous extracranial metastases (ECM) and subsequent BM was 5.7 months compared to 2.8 months in patients with synchronous ECM and subsequent BM (P = .08). In the latter group, the diameter of BM and liver metastases negatively influenced survival. OS of patients with CRC-BM improved over time (9.0 vs 4.0 months in 2016-2021 vs 2001-2015, respectively (P = .002)) and was better in patients able to receive systemic therapy after diagnosis of CRC-BM compared to patients who did not (19.4 months vs 4.7 months; P = .005). Conclusions:Although the development of BM in patients with CRC is a late event resulting in a poor prognosis, outcome improved over time. OS was significantly longer in patients who still have systemic treatment options. This can be taken into account in the decision for local treatment of patients with CRC-BM.

Two decades after the genomics revolution, oncology is rapidly transforming into a genome-driven discipline, yet routine cancer diagnostics is still mainly microscopy based, except for tumor type-specific predictive molecular tests. Pathology laboratories struggle to quickly validate and adopt biomarkers identified by genomics studies of new targeted therapies. Consequently, clinical implementation of newly approved biomarkers suffers substantial delays, leading to unequal patient access to these therapies. Whole-genome sequencing (WGS) can successfully address these challenges by providing a stable molecular diagnostic platform that allows detection of a multitude of genomic alterations in a single cost-efficient assay and facilitating rapid implementation, as well as by the development of new genomic biomarkers. Recently, the Whole-genome sequencing Implementation in standard Diagnostics for Every cancer patient (WIDE) study demonstrated that WGS is a feasible and clinically valid technique in routine clinical practice with a turnaround time of 11 workdays. As a result, WGS was successfully implemented at the Netherlands Cancer Institute as part of routine diagnostics in January 2021. The success of implementing WGS has relied on adhering to a comprehensive protocol including recording patient information, sample collection, shipment and storage logistics, sequencing data interpretation and reporting, integration into clinical decision-making and data usage. This protocol describes the use of fresh-frozen samples that are necessary for WGS but can be challenging to implement in pathology laboratories accustomed to using formalin-fixed paraffin-embedded samples. In addition, the protocol outlines key considerations to guide uptake of WGS in routine clinical care in hospitals worldwide.

AIM:This study aimed to determine the consequences of the new definition of rectal cancer for decision-making in multidisciplinary team meetings (MDT). The new definition of rectal cancer, the lower border of the tumour is located below the sigmoid take-off (STO), was implemented in the Dutch guideline in 2019 after an international Delphi consensus meeting to reduce interhospital variations. METHOD:All patients with rectal cancer according to the local MDT, who underwent resection in 2016 in the Netherlands were eligible for this nationwide collaborative cross-sectional study. MRI-images were rereviewed, and the tumours were classified as above or on/below the STO. RESULTS:This study registered 3107 of the eligible 3178 patients (98%), of which 2784 patients had an evaluable MRI. In 314 patients, the tumour was located above the STO (11%), with interhospital variation between 0% and 36%. Based on TN-stage, 175 reclassified patients with colon cancer (6%) would have received different treatment (e.g., omitting neoadjuvant radiotherapy, candidate for adjuvant chemotherapy). Tumour location above the STO was independently associated with lower risk of 4-year locoregional recurrence (HR 0.529; p = 0.030) and higher 4-year overall survival (HR 0.732; p = 0.037) compared to location under the STO. CONCLUSION:By using the STO, 11% of the prior MDT-based diagnosis of rectal cancer were redefined as sigmoid cancer, with potential implications for multimodality treatment and prognostic value. Given the substantial interhospital variation in proportion of redefined cancers, the use of the STO will contribute to standardisation and comparability of outcomes in both daily practice and trial settings.

Colorectal cancer (CRC) raises considerable clinical challenges, including a high mortality rate once the tumor spreads to distant sites. At this advanced stage, more accurate prediction of prognosis and treatment outcome is urgently needed. The role of cancer immunity in metastatic CRC (mCRC) is poorly understood. Here, we explore cellular immune cell status in patients with multi-organ mCRC. We analyzed T cell infiltration in primary tumor sections, surveyed the lymphocytic landscape of liver metastases, and assessed circulating mononuclear immune cells. Besides asking whether immune cells are associated with survival at this stage of the disease, we investigated correlations between the different tissue types; as this could indicate a dominant immune phenotype. Taken together, our analyses corroborate previous observations that higher levels of CD8+ T lymphocytes link to better survival outcomes. Our findings therefore extend evidence from earlier stages of CRC to indicate an important role for cancer immunity in disease control even after metastatic spreading to multiple organs. This finding may help to improve predicting outcome of patients with mCRC and suggests a future role for immunotherapeutic strategies.

LBA3502 Background: The phase-3, investigator-initiated, ORCHESTRA trial (NCT01792934) was conducted to prospectively evaluate overall survival (OS) benefit from tumor debulking in addition to standard palliative systemic therapy in patients with multiorgan metastatic colorectal cancer (mCRC). Local therapy of metastases is increasingly discussed as part of the treatment plan for patients with multiorgan mCRC in analogy to selected patients with oligometastatic disease for whom this is standard of care. Treatment decisions are made on a daily base in multidisciplinary teams (MDT) worldwide, but evidence of superiority for additional local therapy over systemic therapy alone based on a head-to-head comparison is lacking. Methods: Between May 2013 and May 2023, 454 patients were enrolled in 28 hospitals. Patients with multiorgan mCRC as described in Table, were eligible if at least 80% tumor debulking was deemed feasible by resection, radiotherapy and/or thermal ablative therapy at the start of first-line palliative systemic therapy according to the MDT. Upon clinical benefit after 3 or 4 cycles of respectively capecitabine or 5-fluorouracil/leucovorin and oxaliplatin ± bevacizumab, 382 patients were randomized 1:1 to continuation with systemic therapy alone in the standard arm or to tumor debulking followed by restart of the systemic therapy in the experimental arm. The primary endpoint was OS, from the date of inclusion to the date of death. Secondary endpoints included progression free survival (PFS) and treatment related adverse events. OS and PFS were analyzed by means of multivariable Cox proportional hazards regression analysis where the variables used in the randomization process were included as covariates. Results: 382 patients were randomized to either receive standard palliative systemic therapy in the standard arm (N=192) or to receive additional tumor debulking to palliative systemic therapy in the experimental arm (N=190). Baseline characteristics of patients were in standard arm versus (vs) experimental arm: median age 64 vs 64 years, male 69% vs 67%, >2 organs involved 38% vs 40%, baseline LDH >250 U/L 17% vs 16%, baseline CEA >200 ng/ml 5% vs 8%. At data cut-off on April 4th, 2024, a total of 153 OS events were observed in the standard arm and 155 OS events in the experimental arm. Median follow up was 32.3 months. Median OS in the standard arm was 27.5 months versus 30.0 months in the experimental arm (adjusted HR 0.88 [95% CI 0.70-1.10] p=0.225). Median PFS in the standard arm was 10.4 months versus 10.5 months in the experimental arm (adjusted HR 0.83 [95% CI 0.67-1.02], p=0.076). Details on local treatment modalities being applied, including rate of successful radical debulking and related adverse events, will be presented at the meeting. Conclusions: Additional tumor debulking to standard first-line palliative systemic therapy failed to improve overall survival for patients with multiorgan metastatic colorectal cancer. The increasing use of local therapies for patients with mCRC needs further consideration. Clinical trial information: NCT01792934 . [Table: see text]

Importance Neoadjuvant short-course radiotherapy was routinely applied for nonlocally advanced rectal cancer (cT1-3N0-1M0 with >1 mm distance to the mesorectal fascia) in the Netherlands following the Dutch total mesorectal excision trial. This policy has shifted toward selective application after guideline revision in 2014. Objective To determine the association of decreased use of neoadjuvant radiotherapy with cancer-related outcomes and overall survival at a national level. Design, Setting, and Participants This multicenter, population-based, nationwide cross-sectional cohort study analyzed Dutch patients with rectal cancer who were treated in 2011 with a 4-year follow-up. A similar study was performed in 2021, analyzing all patients that were surgically treated in 2016. From these cohorts, all patients with cT1-3N0-1M0 rectal cancer and radiologically unthreatened mesorectal fascia were included in the current study. The data of the 2011 cohort were collected between May and October 2015, and the data of the 2016 cohort were collected between October 2020 and November 2021. The data were analyzed between May and October 2022. Main Outcomes and Measures The main outcomes were 4-year local recurrence and overall survival rates. Results Among the 2011 and 2016 cohorts, 1199 (mean [SD] age, 68 [11] years; 430 women [36%]) of 2095 patients (57.2%) and 1576 (mean [SD] age, 68 [10] years; 547 women [35%]) of 3057 patients (51.6%) had cT1-3N0-1M0 rectal cancer and were included, with proportions of neoadjuvant radiotherapy of 87% (2011) and 37% (2016). Four-year local recurrence rates were 5.8% and 5.5%, respectively (P = .99). Compared with the 2011 cohort, 4-year overall survival was significantly higher in the 2016 cohort (79.6% vs 86.4%; P < .001), with lower non-cancer-related mortality (13.8% vs 6.3%; P < .001). Conclusions and Relevance The results of this cross-sectional study suggest that an absolute 50% reduction in radiotherapy use for nonlocally advanced rectal cancer did not compromise cancer-related outcomes at a national level. Optimizing clinical staging and surgery following the Dutch total mesorectal excision trial has potentially enabled safe deintensification of treatment.

3116 Background: BRCA1/2are crucial genes in the homologous recombination repair (HRR) pathway, and loss-of-function mutations in these genes are associated with response to PARP-inhibitors (PARPi). However, it remains unclear to which extent patients with alterations in other HRR-pathway associated genes may benefit from PARPi. In the Drug Rediscovery Protocol (DRUP, NCT02925234), patients receive off-label drugs based on their tumor molecular profile. Here, we present the results from two separate DRUP-cohorts to evaluate the efficacy and safety of olaparib in patients with tumors harboring mutations in ATM, CKD12, PPP2R2A, CHEK1/2 or RAD51B. Methods: Adult patients with progressive, treatment-refractory tumors with loss-of-function mutations in ATM (cohort A) or other HRR-pathway associated genes as described above (cohort B), and measurable disease according to RECISTv1.1 were eligible for inclusion. Patients received olaparib (300mg) twice daily, until disease progression (assessments every 8 weeks) or unmanageable toxicity. The primary endpoints of DRUP are clinical benefit (CB: defined as confirmed objective response (OR) or stable disease (SD) ≥16 weeks) and safety. Per protocol, patients were enrolled using a Simon-like two-stage model. Whole genome sequencing (WGS) was performed on pre-treatment biopsies to identify potential biomarkers for CB. Results: A total of 25 evaluable patients with 10 different tumor types (n = 10 prostate cancer; n = 5 colorectal cancer; n = 2 non-small cell lung cancer; n = 2 adenoid cystic carcinoma; n = 6 other) were enrolled in cohort A. CB was observed in 8/25 patients (32%; 95% CI 14.9%-53%); one patient achieved an OR (4%). Median progression-free (PFS) and overall survival (OS) were 3.4 months (95% CI 1.8-5.3) and 9.2 months (95% CI 5.2-21.3), respectively. In cohort B, 24 evaluable patients with 4 different tumor types (n = 18 prostate cancer; n = 3 ovarian cancer; n = 2 pancreatic; n = 1 breast cancer) were included. These patients harbored loss-of-function mutations in CDK12 (n = 9), PPP2R2A (n = 6), CHEK1/2 (n = 5), and RAD51B (n = 4). CB was observed in 10/24 patients (41.7%; 95% CI 22.1%-63.4%), with loss-of-function mutations in CDK12 (n = 7), RAD51B (n = 2) and CHEK2 (n = 1). Median PFS and OS were 3.5 months (95% CI 3.4-6.6) and 8.1 months (95% CI 6.6-14.2), respectively. Overall, no unexpected toxicities were observed. Biomarker analysis (HR-deficiency core, loss of heterozygosity, telomeric allelic imbalance and large-scale transitions) is currently ongoing. Conclusions: Olaparib has clinical benefit in patients with progressive, treatment-refractory tumors harboring mutations in ATM, CDK12, CHEK2 or RAD51B. The ongoing biomarker analysis aims to identify potential biomarkers that can help refining patient selection and thereby improving clinical benefit rate. Clinical trial information: NCT02925234 .

ObjectiveTo improve sustainability of a patient decision aid for systemic treatment of metastatic colorectal cancer, we evaluated real-world experiences and identified ways to optimize decision aid content and future implementation.MethodsSemi-structured interviews with patients and medical oncologists addressed two main subjects: user experience and decision aid content. Content analysis was applied. Fifteen experts discussed the results and devised improvements based on experience and literature review.ResultsThirteen users were interviewed. They confirmed the relevance of the decision aid for shared decision making. Areas for improvement of content concerned; 1) outdated and missing information, 2) an imbalance in presentation of treatment benefits and harms, and 3) medical oncologists' expressed preference for a more center-specific or patient individualized decision aid, presenting a selection of the guideline recommended treatment options. Key points for improvement of implementation were better alignment within the care pathway, and clear instruction to users.ConclusionWe identified relevant opportunities for improvement of an existing decision aid and developed an updated version and accompanying implementation strategy accordingly.InnovationThis paper outlines an approach for continued decision aid and implementation strategy development which will add to sustainability. Implementation success of the improved decision aid is currently being studied in a multi-center mixed-methods implementation study.

Background: The simultaneous presence of colorectal liver metastases (CRLMs) and extrahepatic metastases in patients with colorectal cancer (CRC) can be considered a relative contraindication for local treatment with curative intent. This study aims to assess the survival outcomes of patients with CRLMs and extrahepatic metastases after comprehensive local treatment of all metastatic sites. Methods: Patients with CRLMs who received local treatment of all metastatic sites were extracted from the prospective AmCORE registry database and subdivided into two groups: CRLM only vs. CRLM and extrahepatic metastasis. To address potential confounders, multivariate analysis was performed. The primary endpoint was overall survival (OS). Results: In total, 881 patients with CRLM only and 60 with CRLM and extrahepatic disease were included, and the median OS was 55.7 months vs. 42.7 months, respectively. Though OS was significantly lower in patients with concomitant extrahepatic metastases (HR 1.477; 95% CI 1.029–2.121; p = 0.033), the survival curve plateaued after 6.2 years. Extrahepatic manifestations were pulmonary (43.3%), peritoneal (16.7%) and non-regional lymph node metastases (10.0%). In patients with pulmonary and non-regional lymph node metastases, OS did not significantly differ from patients with CRLM-only disease; concomitant peritoneal metastases showed an inferior OS (HR 1.976; 95% CI 1.017–3.841, p = 0.041). Conclusions: In this comparative series, OS was inferior for patients with multi-organ metastatic CRC versus patients with CRLMs alone. Nonetheless, the long-term survival curve plateau seemed to justify local treatment in a subset of patients with multi-organ metastatic CRC, especially for patients with CRLMs and pulmonary or lymph node metastases.

3576 Background: The use of anti-Epidermal Growth Factor Receptor monoclonal antibody therapy (anti-EGFR mAb) for patients with metastatic colorectal cancer (mCRC) is ongoing subject of research. Initially, absence of mutations in KRASand NRAS oncogenes was identified as biomarker for response, however, not all patients benefitted. Molecular imaging to assess metabolic response could serve as an early biomarker for treatment response. We evaluated the predictive performance of early evaluation of metabolic rate with [18F]FDG PET/CT and baseline and after 1 intravenous anti-EGFR mAb administration to distinguish patients with and without clinical benefit. Methods: The multicenter IMPACT-CRC study (NCT02117466) prospectively included patients with RASwild-type mCRC starting treatment with biweekly monotherapy anti-EGFR mAb (cetuximab or panitumumab) as second or third line treatment. Clinical benefit was defined as partial, response (PR)complete response (CR) and stable disease (SD) according to RECIST (version 1.1) with CT-imaging at 8 weeks. Patients underwent an [18F]FDG PET/CT at baseline and 2 weeks after start therapy prior to the second treatment cycle. Change in sum Total Lesion Glycolysis (TLG, defined as metabolic active tumor volume (MATV) times mean standard uptake value corrected for lean body mass (SULmean)) of 5 lesions according to van Helden et al (PLoS One 2016 May 19;11(5):e0155178) was evaluated as a predictive biomarker for clinical benefit using a predetermined data-driven threshold. Tumor sidedness and BRAF mutations were determined. Results: Seventy-five out of 80 participating patients were evaluable for metabolic response: The mean change in sum TLG was -58% (SD 19%) for patient with clinical benefit (n=57) versus -1·9% (SD 36%) without clinical benefit (n=18); P =0·003. A threshold of < -15% change in sum TLG had a 100% negative predictive value for clinical benefit. Metabolic responders had a longer progression-free survival (PFS) compared to metabolic non-responders (6.5 versus 1·7 months ( P<0·001)). Sixty-five (out of 80) patients had RAS/BRAF wild-type (wt) left-sided mCRC, with a 91% clinical benefit rate (30% PR and 61% SD) and a median PFS of 5·7 months (95% CI 5·2 – 10). Conclusions: Early [18F]FDG PET/CT after a single dose of anti-EGFR mAb therapy demonstrates a 100% negative predictive value for clinical benefit. Selection of patients with left-sided RASwt/ BRAFwt mCRC successfully identifies the majority (91%) of patients with clinical benefit from anti-EGFR monotherapy. For mCRC patients with inconclusive mutational screens early [18F]FDG PET/CT evaluation may have clinical value to predict treatment benefit. Clinical trial information: NCT02117466 .

Introduction: Clear guidelines for colorectal lung metastasis (LM) treatment are not available. This study aimed to provide insight into the treatment strategies and efficacy of local and systemic therapy in patients with LM eligible for (potentially) curative treatment. Methods: This was a retrospective study of patients with <= 5 LM discussed in two tertiary referral centers. Patient and tumor characteristics were compared between treatment groups. Treatment strategies were compared between centers and survival data between treatment groups, local treatment modalities, and treating centers. Results: Ninety-two patients (median 2 LMs) were included. Seventy-one (77%) patients underwent local treatment (17 surgery, 13 ablation, 38 radiotherapy, 3 combination of local treatments) and 21 (23%) with systemic therapy alone. The latter group more frequently had extrapulmonary metastases (81.0% vs. 26.8%, p < 0.001) and synchronous presentation of LM (23.8% vs. 7.0%, p = 0.045). Choice of local versus systemic therapy and time to start treatment after diagnosis (median 109 days, IQR 44-240 vs. 88 days, IQR 53-168) were comparable between centers. Three-year survival rates did not differ between treatment groups, local treatment modalities, or treating centers. Conclusion: Treatment strategies and oncological outcomes were rather similar between centers. Survival outcomes were not different between locally and systemically treated patients.