First-line palliative systemic therapy alternated with oxaliplatin-based pressurized intraperitoneal aerosol chemotherapy for unresectable colorectal peritoneal metastases: A single-arm phase II trial (CRC-PIPAC-II).

BACKGROUND: Palliative systemic therapy alternated with electrostatic precipitation oxaliplatin-based pressurized intraperitoneal aerosol chemotherapy (ePIPAC) has never been prospectively investigated in patients with unresectable colorectal peritoneal metastases (CPM). The CRC-PIPAC-II study aimed to assess safety, feasibility and efficacy of such bidirectional therapy. METHODS: This two-center, single-arm, phase II trial enrolled chemotherapy-naïve patients to undergo three treatment cycles, consisting of systemic therapy (CAPOX, FOLFOX, FOLFIRI, or FOLFOXIRI, all with bevacizumab) and oxaliplatin-based ePIPAC (92 mg/m2) with intravenous leucovorin (20 mg/m2) and 5-fluorouracil (400 mg/m2). Primary outcome were major treatment-related adverse events. Secondary outcomes included minor events, tumor response, progression-free survival (PFS) and overall survival (OS). RESULTS: Twenty patients completed 52 treatment cycles. Fifteen major events occurred in 7 patients (35 %): 5 events (33 %) related to systemic therapy; 5 (33 %) related to ePIPAC; and 5 (33 %) were biochemical events. No treatment-related deaths occurred. All patients experienced minor events, mostly abdominal pain, nausea and peripheral sensory neuropathy. After treatment, radiological, pathological, cytological, and biochemical response was observed in 0 %, 88 %, 38 %, and 31 % of patients respectively. Curative surgery was achieved in one patient. Median PFS was 10.0 months (95 % confidence interval [CI] 8.0-13.0) and median OS was 17.5 months (95 % CI 13.0-not reached). CONCLUSIONS: Combining palliative systemic therapy with oxaliplatin-based ePIPAC in patients with unresectable CPM was feasible and showed an acceptable safety profile. Treatment-induced response and survival are promising, yet further research is required to determine the additional value of ePIPAC to systemic therapy.

Effect of optical diagnosis training on recognition and treatment of submucosal invasive colorectal cancer in community hospitals: a prospective multicenter intervention study.

BACKGROUND: Recognition of submucosal invasive colorectal cancer (T1 CRC) is difficult, with sensitivities of 35 %-60 % in Western countries. We evaluated the real-life effects of training in the OPTICAL model, a recently developed structured and validated prediction model, in Dutch community hospitals. METHODS: In this prospective multicenter study (OPTICAL II), 383 endoscopists from 40 hospitals were invited to follow an e-learning program on the OPTICAL model, to increase sensitivity in detecting T1 CRC in nonpedunculated polyps. Real-life recognition of T1 CRC was then evaluated in 25 hospitals. Endoscopic and pathologic reports of T1 CRCs detected during the next year were collected retrospectively, with endoscopists unaware of this evaluation. Sensitivity for T1 CRC recognition, R0 resection rate, and treatment modality were compared for trained vs. untrained endoscopists. RESULTS: 1 year after e-learning, 528 nonpedunculated T1 CRCs were recorded for endoscopies performed by 251 endoscopists (118 [47 %] trained). Median T1 CRC size was 20 mm. Lesions were mainly located in the distal colorectum (66 %). Trained endoscopists recognized T1 CRCs more frequently than untrained endoscopists (sensitivity 74 % vs. 62 %; mixed model analysis odds ratio [OR] 2.90, 95 %CI 1.54-5.45). R0 resection rate was higher for T1 CRCs detected by trained endoscopists (69 % vs. 56 %; OR 1.73, 95 %CI 1.03-2.91). CONCLUSION: Training in optical recognition of T1 CRCs in community hospitals was associated with increased recognition of T1 CRCs, leading to higher en bloc and R0 resection rates. This may be an important step toward more organ-preserving strategies.

Dynamic Prediction of Advanced Colorectal Neoplasia in Inflammatory Bowel Disease.

BACKGROUND & AIMS: Colonoscopic surveillance is recommended in patients with colonic inflammatory bowel disease (IBD) given their increased risk of colorectal cancer (CRC). We aimed to develop and validate a dynamic prediction model for the occurrence of advanced colorectal neoplasia (aCRN, including high-grade dysplasia and CRC) in IBD. METHODS: We pooled data from 6 existing cohort studies from Canada, The Netherlands, the United Kingdom, and the United States. Patients with IBD and an indication for CRC surveillance were included if they underwent at least 1 follow-up procedure. Exclusion criteria included prior aCRN, prior colectomy, or an unclear indication for surveillance. Predictor variables were selected based on the literature. A dynamic prediction model was developed using a landmarking approach based on Cox proportional hazard modeling. Model performance was assessed with Harrell's concordance-statistic (discrimination) and by calibration curves. Generalizability across surveillance cohorts was evaluated by internal-external cross-validation. RESULTS: The surveillance cohorts comprised 3731 patients, enrolled and followed-up in the time period from 1973 to 2021, with a median follow-up period of 5.7 years (26,336 patient-years of follow-up evaluation); 146 individuals were diagnosed with aCRN. The model contained 8 predictors, with a cross-validation median concordance statistic of 0.74 and 0.75 for a 5- and 10-year prediction window, respectively. Calibration plots showed good calibration. Internal-external cross-validation results showed medium discrimination and reasonable to good calibration. CONCLUSIONS: The new prediction model showed good discrimination and calibration, however, generalizability results varied. Future research should focus on formal external validation and relate predicted aCRN risks to surveillance intervals before clinical application.

Oncologic outcomes of screen-detected and non-screen-detected T1 colorectal cancers.

BACKGROUND: The incidence of T1 colorectal cancer (CRC) has increased with the implementation of CRC screening programs. It is unknown whether the outcomes and risk models for T1 CRC based on non-screen-detected patients can be extrapolated to screen-detected T1 CRC. This study aimed to compare the stage distribution and oncologic outcomes of T1 CRC patients within and outside the screening program. METHODS: Data from T1 CRC patients diagnosed between 2014 and 2017 were collected from 12 hospitals in the Netherlands. The presence of lymph node metastasis (LNM) at diagnosis was compared between screen-detected and non-screen-detected patients using multivariable logistic regression. Cox proportional hazard regression was used to analyze differences in the time to recurrence (TTR), metastasis-free survival (MFS), cancer-specific survival (CSS), and overall survival. Additionally, the performance of conventional risk factors for LNM was evaluated across the groups. RESULTS: 1803 patients were included (1114 [62%] screen-detected), with median follow-up of 51 months (interquartile range 30). The proportion of LNM did not significantly differ between screen- and non-screen-detected patients (12.6% vs. 8.9%; odds ratio 1.41; 95%CI 0.89-2.23); a prediction model for LNM performed equally in both groups. The 3- and 5-year TTR, MFS, and CSS were similar for patients within and outside the screening program. However, overall survival was significantly longer in screen-detected T1 CRC patients (adjusted hazard ratio 0.51; 95%CI 0.38-0.68). CONCLUSIONS: Screen-detected and non-screen-detected T1 CRCs have similar stage distributions and oncologic outcomes and can therefore be treated equally. However, screen-detected T1 CRC patients exhibit a lower rate of non-CRC-related mortality, resulting in longer overall survival.

Organoids as a biomarker for personalized treatment in metastatic colorectal cancer: drug screen optimization and correlation with patient response.

BACKGROUND: The inability to predict treatment response of colorectal cancer patients results in unnecessary toxicity, decreased efficacy and survival. Response testing on patient-derived organoids (PDOs) is a promising biomarker for treatment efficacy. The aim of this study is to optimize PDO drug screening methods for correlation with patient response and explore the potential to predict responses to standard chemotherapies. METHODS: We optimized drug screen methods on 5-11 PDOs per condition of the complete set of 23 PDOs from patients treated for metastatic colorectal cancer (mCRC). PDOs were exposed to 5-fluorouracil (5-FU), irinotecan- and oxaliplatin-based chemotherapy. We compared medium with and without N-acetylcysteine (NAC), different readouts and different combination treatment set-ups to capture the strongest association with patient response. We expanded the screens using the optimized methods for all PDOs. Organoid sensitivity was correlated to the patient's response, determined by % change in the size of target lesions. We assessed organoid sensitivity in relation to prior exposure to chemotherapy, mutational status and sidedness. RESULTS: Drug screen optimization involved excluding N-acetylcysteine from the medium and biphasic curve fitting for 5-FU & oxaliplatin combination screens. CellTiter-Glo measurements were comparable with CyQUANT and did not affect the correlation with patient response. Furthermore, the correlation improved with application of growth rate metrics, when 5-FU & oxaliplatin was screened in a ratio, and 5-FU & SN-38 using a fixed dose of SN-38. Area under the curve was the most robust drug response curve metric. After optimization, organoid and patient response showed a correlation coefficient of 0.58 for 5-FU (n = 6, 95% CI -0.44,0.95), 0.61 for irinotecan- (n = 10, 95% CI -0.03,0.90) and 0.60 for oxaliplatin-based chemotherapy (n = 11, 95% CI -0.01,0.88). Median progression-free survival of patients with resistant PDOs to oxaliplatin-based chemotherapy was significantly shorter than sensitive PDOs (3.3 vs 10.9 months, p = 0.007). Increased resistance to 5-FU in patients with prior exposure to 5-FU/capecitabine was adequately reflected in PDOs (p = 0.003). CONCLUSIONS: Our study emphasizes the critical impact of the screening methods for determining correlation between PDO drug screens and mCRC patient outcomes. Our 5-step optimization strategy provides a basis for future research on the clinical utility of PDO screens.

Correlation between Histopathological Prognostic Tumor Characteristics and [18F]FDG Uptake in Corresponding Metastases in Newly Diagnosed Metastatic Breast Cancer.

BACKGROUND: In metastatic breast cancer (MBC), [18F]fluorodeoxyglucose positron emission tomography/computed tomography ([18F]FDG-PET/CT) can be used for staging. We evaluated the correlation between BC histopathological characteristics and [18F]FDG uptake in corresponding metastases. PATIENTS AND METHODS: Patients with non-rapidly progressive MBC of all subtypes prospectively underwent a baseline histological metastasis biopsy and [18F]FDG-PET. Biopsies were assessed for estrogen, progesterone, and human epidermal growth factor receptor 2 (ER, PR, HER2); Ki-67; and histological subtype. [18F]FDG uptake was expressed as maximum standardized uptake value (SUVmax) and results were expressed as geometric means. RESULTS: Of 200 patients, 188 had evaluable metastasis biopsies, and 182 of these contained tumor. HER2 positivity and Ki-67 ≥ 20% were correlated with higher [18F]FDG uptake (estimated geometric mean SUVmax 10.0 and 8.8, respectively; p = 0.0064 and p = 0.014). [18F]FDG uptake was lowest in ER-positive/HER2-negative BC and highest in HER2-positive BC (geometric mean SUVmax 6.8 and 10.0, respectively; p = 0.0058). Although [18F]FDG uptake was lower in invasive lobular carcinoma (n = 31) than invasive carcinoma NST (n = 146) (estimated geometric mean SUVmax 5.8 versus 7.8; p = 0.014), the metastasis detection rate was similar. CONCLUSIONS: [18F]FDG-PET is a powerful tool to detect metastases, including invasive lobular carcinoma. Although BC histopathological characteristics are related to [18F]FDG uptake, [18F]FDG-PET and biopsy remain complementary in MBC staging (NCT01957332).

A prediction model for response to immune checkpoint inhibition in advanced melanoma.

Predicting who will benefit from treatment with immune checkpoint inhibition (ICI) in patients with advanced melanoma is challenging. We developed a multivariable prediction model for response to ICI, using routinely available clinical data including primary melanoma characteristics. We used a population-based cohort of 3525 patients with advanced cutaneous melanoma treated with anti-PD-1-based therapy. Our prediction model for predicting response within 6 months after ICI initiation was internally validated with bootstrap resampling. Performance evaluation included calibration, discrimination and internal-external cross-validation. Included patients received anti-PD-1 monotherapy (n = 2366) or ipilimumab plus nivolumab (n = 1159) in any treatment line. The model included serum lactate dehydrogenase, World Health Organization performance score, type and line of ICI, disease stage and time to first distant recurrence-all at start of ICI-, and location and type of primary melanoma, the presence of satellites and/or in-transit metastases at primary diagnosis and sex. The over-optimism adjusted area under the receiver operating characteristic was 0.66 (95% CI: 0.64-0.66). The range of predicted response probabilities was 7%-81%. Based on these probabilities, patients were categorized into quartiles. Compared to the lowest response quartile, patients in the highest quartile had a significantly longer median progression-free survival (20.0 vs 2.8 months; P < .001) and median overall survival (62.0 vs 8.0 months; P < .001). Our prediction model, based on routinely available clinical variables and primary melanoma characteristics, predicts response to ICI in patients with advanced melanoma and discriminates well between treated patients with a very good and very poor prognosis.

The prognostic potential of mammographic growth rate of invasive breast cancer in the Nijmegen breast cancer screening cohort.

OBJECTIVES: Insight into the aggressiveness of potential breast cancers found in screening may optimize recall decisions. Specific growth rate (SGR), measured on mammograms, may provide valuable prognostic information. This study addresses the association of SGR with prognostic factors and overall survival in patients with invasive carcinoma of no special type (NST) from a screened population. METHODS: In this historic cohort study, 293 women with NST were identified from all participants in the Nijmegen screening program (2003-2007). Information on clinicopathological factors was retrieved from patient files and follow-up on vital status through municipalities. On consecutive mammograms, tumor volumes were estimated. After comparing five growth functions, SGR was calculated using the best-fitting function. Regression and multivariable survival analyses described associations between SGR and prognostic factors as well as overall survival. RESULTS: Each one standard deviation increase in SGR was associated with an increase in the Nottingham prognostic index by 0.34 [95% confidence interval (CI): 0.21-0.46]. Each one standard deviation increase in SGR increased the odds of a tumor with an unfavorable subtype (based on histologic grade and hormone receptors; odds ratio 2.14 [95% CI: 1.45-3.15]) and increased the odds of diagnosis as an interval cancer (versus screen-detected; odds ratio 1.57 [95% CI: 1.20-2.06]). After a median of 12.4 years of follow-up, 78 deaths occurred. SGR was not associated with overall survival (hazard ratio 1.12 [95% CI: 0.87-1.43]). CONCLUSIONS: SGR may indicate prognostically relevant differences in tumor aggressiveness if serial mammograms are available. A potential association with cause-specific survival could not be determined and is of interest for future research.

EGFR-targeted fluorescence molecular imaging for intraoperative margin assessment in oral cancer patients: a phase II trial.

Inadequate surgical margins occur frequently in oral squamous cell carcinoma surgery. Fluorescence molecular imaging (FMI) has been explored for intraoperative margin assessment, but data are limited to phase-I studies. In this single-arm phase-II study (NCT03134846), our primary endpoints were to determine the sensitivity, specificity and positive predictive value of cetuximab-800CW for tumor-positive margins detection. Secondary endpoints were safety, close margin detection rate and intrinsic cetuximab-800CW fluorescence. In 65 patients with 66 tumors, cetuximab-800CW was well-tolerated. Fluorescent spots identified in the surgical margin with signal-to-background ratios (SBR) of ≥2 identify tumor-positive margins with 100% sensitivity, 85.9% specificity, 58.3% positive predictive value, and 100% negative predictive value. An SBR of ≥1.5 identifies close margins with 70.3% sensitivity, 76.1% specificity, 60.5% positive predictive value, and 83.1% negative predictive value. Performing frozen section analysis aimed at the fluorescent spots with an SBR of ≥1.5 enables safe, intraoperative adjustment of surgical margins.

Smoking and colorectal neoplasia in patients with inflammatory bowel disease: Dose-effect relationship.

BACKGROUND AND AIMS: Prior studies on the effect of smoking on the risk of colitis-associated colorectal neoplasia (CRN) have reported conflicting results. We aimed to further elucidate the association between smoking, including possible dose-effects, and the development of colorectal neoplasia in patients with inflammatory bowel disease (IBD). METHODS: We performed a prospective multicenter cohort study including patients with colonic IBD enrolled in a surveillance program in four academic hospitals between 2011 and 2021. The effects of smoking status and pack-years at study entry on subsequent recurrent events of CRN (including indefinite, low- and high-grade dysplasia, and colorectal cancer [CRC]) were evaluated using uni- and multivariable Prentice, Williams, and Peterson total-time Cox proportional hazard models. Adjustment was performed for extensive disease, prior/index dysplasia, sex, age, first-degree relative with CRC, primary sclerosing cholangitis, and endoscopic inflammation. RESULTS: In 501 of the enrolled 576 patients, at least one follow-up surveillance was performed after the study index (median follow-up 5 years). CRN occurred at least once in 105 patients. Ever smoking was not associated with recurrent CRN risk (adjusted hazard ratio [aHR] 1.04, 95% confidence interval [CI] 0.75-1.44), but an increasing number of pack-years was associated with an increased risk of recurrent CRN (aHR per 10 pack-years 1.17, 95% CI 1.03-1.32; p < 0.05). Separate analyses per IBD type did not reveal differences. CONCLUSIONS: This study found that an increase in pack-years is associated with a higher risk of recurrent CRN in patients with IBD, independent of established CRN risk factors (NCT01464151).

Co-cultures of colon cancer cells and cancer-associated fibroblasts recapitulate the aggressive features of mesenchymal-like colon cancer.

Background: Poor prognosis in colon cancer is associated with a high content of cancer-associated fibroblasts (CAFs) and an immunosuppressive tumor microenvironment. The relationship between these two features is incompletely understood. Here, we aimed to generate a model system for studying the interaction between cancer cells and CAFs and their effect on immune-related cytokines and T cell proliferation. Methods: CAFs were isolated from colon cancer liver metastases and were immortalized to prolong lifespan and improve robustness and reproducibility. Established medium and matrix compositions that support the growth of patient-derived organoids were adapted to also support CAF growth. Changes in growth pattern and cellular re-organization were assessed by confocal microscopy, live cell imaging, and immunofluorescence. Single cell RNA sequencing was used to study CAF/organoid co-culture-induced phenotypic changes in both cell types. Conditioned media were used to quantify the production of immunosuppressive factors and to assess their effect on T cell proliferation. Results: We developed a co-culture system in which colon cancer organoids and CAFs spontaneously organize into superstructures with a high capacity to contract and stiffen the extracellular matrix (ECM). CAF-produced collagen IV provided a basement membrane supporting cancer cell organization into glandular structures, reminiscent of human cancer histology. Single cell RNA sequencing analysis showed that CAFs induced a partial epithelial-to-mesenchymal-transition in a subpopulation of cancer cells, similar to what is observed in the mesenchymal-like consensus molecular subtype 4 (CMS4) colon cancer. CAFs in co-culture were characterized by high expression of ECM components, ECM-remodeling enzymes, glycolysis, hypoxia, and genes involved in immunosuppression. An expression signature derived from CAFs in co-culture identified a subpopulation of glycolytic myofibroblasts specifically residing in CMS1 and CMS4 colon cancer. Medium conditioned by co-cultures contained high levels of the immunosuppressive factors TGFß1, VEGFA and lactate, and potently inhibited T cell proliferation. Conclusion: Co-cultures of organoids and immortalized CAFs recapitulate the histological, biophysical, and immunosuppressive features of aggressive mesenchymal-like human CRC. The model can be used to study the mechanisms of immunosuppression and to test therapeutic strategies targeting the cross-talk between CAFs and cancer cells. It can be further modified to represent distinct colon cancer subtypes and (organ-specific) microenvironments.

Towards Response ADAptive Radiotherapy for organ preservation for intermediate-risk rectal cancer (preRADAR): protocol of a phase I dose-escalation trial.

INTRODUCTION: Organ preservation is associated with superior functional outcome and quality of life (QoL) compared with total mesorectal excision (TME) for rectal cancer. Only 10% of patients are eligible for organ preservation following short-course radiotherapy (SCRT, 25 Gy in five fractions) and a prolonged interval (4-8 weeks) to response evaluation. The organ preservation rate could potentially be increased by dose-escalated radiotherapy. Online adaptive magnetic resonance-guided radiotherapy (MRgRT) is anticipated to reduce radiation-induced toxicity and enable radiotherapy dose escalation. This trial aims to establish the maximum tolerated dose (MTD) of dose-escalated SCRT using online adaptive MRgRT. METHODS AND ANALYSIS: The preRADAR is a multicentre phase I trial with a 6+3 dose-escalation design. Patients with intermediate-risk rectal cancer (cT3c-d(MRF-)N1M0 or cT1-3(MRF-)N1M0) interested in organ preservation are eligible. Patients are treated with a radiotherapy boost of 2×5 Gy (level 0), 3×5 Gy (level 1), 4×5 Gy (level 2) or 5×5 Gy (level 3) on the gross tumour volume in the week following standard SCRT using online adaptive MRgRT. The trial starts on dose level 1. The primary endpoint is the MTD based on the incidence of dose-limiting toxicity (DLT) per dose level. DLT is a composite of maximum one in nine severe radiation-induced toxicities and maximum one in three severe postoperative complications, in patients treated with TME or local excision within 26 weeks following start of treatment. Secondary endpoints include the organ preservation rate, non-DLT, oncological outcomes, patient-reported QoL and functional outcomes up to 2 years following start of treatment. Imaging and laboratory biomarkers are explored for early response prediction. ETHICS AND DISSEMINATION: The trial protocol has been approved by the Medical Ethics Committee of the University Medical Centre Utrecht. The primary and secondary trial results will be published in international peer-reviewed journals. TRIAL REGISTRATION NUMBER: WHO International Clinical Trials Registry (NL8997; https://trialsearch.who.int).

Patient-derived head and neck cancer organoids allow treatment stratification and serve as a tool for biomarker validation and identification.

BACKGROUND: Organoids are in vitro three-dimensional structures that can be grown from patient tissue. Head and neck cancer (HNC) is a collective term used for multiple tumor types including squamous cell carcinomas and salivary gland adenocarcinomas. METHODS: Organoids were established from HNC patient tumor tissue and characterized using immunohistochemistry and DNA sequencing. Organoids were exposed to chemo- and radiotherapy and a panel of targeted agents. Organoid response was correlated with patient clinical response. CRISPR-Cas9-based gene editing of organoids was applied for biomarker validation. FINDINGS: A HNC biobank consisting of 110 models, including 65 tumor models, was generated. Organoids retained DNA alterations found in HNC. Comparison of organoid and patient response to radiotherapy (primary [n = 6] and adjuvant [n = 15]) indicated potential for guiding treatment options in the adjuvant setting. In organoids, the radio-sensitizing potential of cisplatin and carboplatin could be validated. However, cetuximab conveyed radioprotection in most models. HNC-targeted treatments were tested on 31 models, indicating possible novel treatment options with the potential for treatment stratification in the future. Activating PIK3CA mutations did not predict alpelisib response in organoids. Protein arginine methyltransferase 5 (PRMT5) inhibitors were identified as a potential treatment option for cyclin-dependent kinase inhibitor 2A (CDKN2A) null HNC. CONCLUSIONS: Organoids hold potential as a diagnostic tool in personalized medicine for HNC. In vitro organoid response to radiotherapy (RT) showed a trend that mimics clinical response, indicating the predictive potential of patient-derived organoids. Moreover, organoids could be used for biomarker discovery and validation. FUNDING: This work was funded by Oncode PoC 2018-P0003.

Fibroblast Activation Protein Inhibitor-PET Imaging in Colorectal Cancer.

Fibroblast activation protein inhibitor (FAPI)-PET imaging holds great promise for improving the clinical management of colorectal cancer. High fibroblast activation protein expression is particularly observed in lymph node metastases, in the aggressive Consensus Molecular Subtype 4, in peritoneal metastases, and in tumors that respond poorly to immunotherapy. We have defined six clinical dilemmas in the diagnosis and treatment of colorectal cancer, which FAPI-PET may help solve. Future clinical trials should include patients undergoing tumor resection, allowing correlation of FAPI-PET signals with in-depth histopathological, cellular, and molecular tissue analyses.

CT radiomics compared to a clinical model for predicting checkpoint inhibitor treatment outcomes in patients with advanced melanoma.

INTRODUCTION: Predicting checkpoint inhibitors treatment outcomes in melanoma is a relevant task, due to the unpredictable and potentially fatal toxicity and high costs for society. However, accurate biomarkers for treatment outcomes are lacking. Radiomics are a technique to quantitatively capture tumour characteristics on readily available computed tomography (CT) imaging. The purpose of this study was to investigate the added value of radiomics for predicting clinical benefit from checkpoint inhibitors in melanoma in a large, multicenter cohort. METHODS: Patients who received first-line anti-PD1±anti-CTLA4 treatment for advanced cutaneous melanoma were retrospectively identified from nine participating hospitals. For every patient, up to five representative lesions were segmented on baseline CT, and radiomics features were extracted. A machine learning pipeline was trained on the radiomics features to predict clinical benefit, defined as stable disease for more than 6 months or response per RECIST 1.1 criteria. This approach was evaluated using a leave-one-centre-out cross validation and compared to a model based on previously discovered clinical predictors. Lastly, a combination model was built on the radiomics and clinical model. RESULTS: A total of 620 patients were included, of which 59.2% experienced clinical benefit. The radiomics model achieved an area under the receiver operator characteristic curve (AUROC) of 0.607 [95% CI, 0.562-0.652], lower than that of the clinical model (AUROC=0.646 [95% CI, 0.600-0.692]). The combination model yielded no improvement over the clinical model in terms of discrimination (AUROC=0.636 [95% CI, 0.592-0.680]) or calibration. The output of the radiomics model was significantly correlated with three out of five input variables of the clinical model (p < 0.001). DISCUSSION: The radiomics model achieved a moderate predictive value of clinical benefit, which was statistically significant. However, a radiomics approach was unable to add value to a simpler clinical model, most likely due to the overlap in predictive information learned by both models. Future research should focus on the application of deep learning, spectral CT-derived radiomics, and a multimodal approach for accurately predicting benefit to checkpoint inhibitor treatment in advanced melanoma.

Long-term Survival in Breast Cancer Patients Is Associated with Contralateral Parenchymal Enhancement at MRI: Outcomes of the SELECT Study.

Background Several single-center studies found that high contralateral parenchymal enhancement (CPE) at breast MRI was associated with improved long-term survival in patients with estrogen receptor (ER)-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Due to varying sample sizes, population characteristics, and follow-up times, consensus of the association is currently lacking. Purpose To confirm whether CPE is associated with long-term survival in a large multicenter retrospective cohort, and to investigate if CPE is associated with endocrine therapy effectiveness. Materials and Methods This multicenter observational cohort included women with unilateral ER-positive HER2-negative breast cancer (tumor size ≤50 mm and ≤three positive lymph nodes) who underwent MRI from January 2005 to December 2010. Overall survival (OS), recurrence-free survival (RFS), and distant RFS (DRFS) were assessed. Kaplan-Meier analysis was performed to investigate differences in absolute risk after 10 years, stratified according to CPE tertile. Multivariable Cox proportional hazards regression analysis was performed to investigate whether CPE was associated with prognosis and endocrine therapy effectiveness. Results Overall, 1432 women (median age, 54 years [IQR, 47-63 years]) were included from 10 centers. Differences in absolute OS after 10 years were stratified according to CPE tertile as follows: 88.5% (95% CI: 88.1, 89.1) in tertile 1, 85.8% (95% CI: 85.2, 86.3) in tertile 2, and 85.9% (95% CI: 85.4, 86.4) in tertile 3. CPE was independently associated with OS, with a hazard ratio (HR) of 1.17 (95% CI: 1.0, 1.36; P = .047), but was not associated with RFS (HR, 1.11; P = .16) or DRFS (HR, 1.11; P = .19). The effect of endocrine therapy on survival could not be accurately assessed; therefore, the association between endocrine therapy efficacy and CPE could not reliably be estimated. Conclusion High contralateral parenchymal enhancement was associated with a marginally decreased overall survival in patients with estrogen receptor-positive and human epidermal growth factor receptor 2-negative breast cancer, but was not associated with recurrence-free survival (RFS) or distant RFS. Published under a CC BY 4.0 license. Supplemental material is available for this article. See also the editorial by Honda and Iima in this issue.

Time interval from primary melanoma to first distant recurrence in relation to patient outcomes in advanced melanoma.

Since the introduction of BRAF(/MEK) inhibition and immune checkpoint inhibition (ICI), the prognosis of advanced melanoma has greatly improved. Melanoma is known for its remarkably long time to first distant recurrence (TFDR), which can be decades in some patients and is partly attributed to immune-surveillance. We investigated the relationship between TFDR and patient outcomes after systemic treatment for advanced melanoma. We selected patients undergoing first-line systemic therapy for advanced melanoma from the nationwide Dutch Melanoma Treatment Registry. The association between TFDR and progression-free survival (PFS) and overall survival (OS) was assessed by Cox proportional hazard regression models. The TFDR was modeled categorically, linearly, and flexibly using restricted cubic splines. Patients received anti-PD-1-based treatment (n = 1844) or BRAF(/MEK) inhibition (n = 1618). For ICI-treated patients with a TFDR <2 years, median OS was 25.0 months, compared to 37.3 months for a TFDR >5 years (P = .014). Patients treated with BRAF(/MEK) inhibition with a longer TFDR also had a significantly longer median OS (8.6 months for TFDR <2 years compared to 11.1 months for >5 years, P = .004). The hazard of dying rapidly decreased with increasing TFDR until approximately 5 years (HR 0.87), after which the hazard of dying further decreased with increasing TFDR, but less strongly (HR 0.82 for a TFDR of 10 years and HR 0.79 for a TFDR of 15 years). Results were similar when stratifying for type of treatment. Advanced melanoma patients with longer TFDR have a prolonged PFS and OS, irrespective of being treated with first-line ICI or targeted therapy.

Development and validation of risk calculators for people with "thin" melanomas on their skin to predict the likelihood that their cancer will return: a plain language summary of publication.

WHAT IS THIS SUMMARY ABOUT?: This is a summary of an article describing the development of risk calculators for use in people who develop a type of melanoma on their skin called "thin" melanoma to predict the likelihood that their cancer will return. The article was originally published in the Journal of Clinical Oncology in 2021. HOW WERE THE CALCULATORS DEVELOPED?: Calculations were performed to predict the chance of people with thin melanomas surviving without their melanoma recurring. Three graphical prediction calculators (called nomograms) were developed, along with easy-to-use online calculators using the same underlying calculation methods. The model was developed using data for 25,930 Dutch people diagnosed with thin melanomas (called the "development set"). To test its ability to predict melanoma recurrence, it was then compared with data for 2,968 Australian people with melanoma (the "validation set"). The calculators developed in the Dutch patients were found to accurately predict the risk of melanoma recurring for people with melanoma in the Australian "validation" group. WHAT DO THE RESULTS MEAN?: The calculators provide estimates of the risk of the melanoma returning for people with thin melanomas. The easy-to-use online calculators are freely available on a smartphone, tablet or computer, and will assist in providing accurate estimates of recurrence risks for individuals with thin melanomas, allowing more intensive follow-up of those whose predicted risk of their melanoma returning is high.

Predicting early extrahepatic recurrence after local treatment of colorectal liver metastases.

BACKGROUND: Patients who develop early extrahepatic recurrence (EHR) may not benefit from local treatment of colorectal liver metastases (CRLMs). This study aimed to develop a prediction model for early EHR after local treatment of CRLMs using a national data set. METHODS: A Cox regression prediction model for EHR was developed and validated internally using data on patients who had local treatment for CRLMs with curative intent. Performance assessment included calibration, discrimination, net benefit, and generalizability by internal-external cross-validation. The prognostic relevance of early EHR (within 6 months) was evaluated by landmark analysis. RESULTS: During a median follow-up of 35 months, 557 of the 1077 patients had EHR and 249 died. Median overall survival was 19.5 (95 per cent c.i. 15.6 to 23.0) months in patients with early EHR after CRLM treatment, compared with not reached (45.3 months to not reached) in patients without an early EHR. The EHR prediction model included side and stage of the primary tumour, RAS/BRAFV600E mutational status, and number and size of CRLMs. The range of 6-month EHR predictions was 5.9-56.0 (i.q.r. 12.9-22.0) per cent. The model demonstrated good calibration and discrimination. The C-index through 6 and 12 months was 0.663 (95 per cent c.i. 0.624 to 0.702) and 0.661 (0.632 to 0.689) respectively. The observed 6-month EHR risk was 6.5 per cent for patients in the lowest quartile of predicted risk compared with 32.0 per cent in the highest quartile. CONCLUSION: Early EHR after local treatment of CRLMs can be predicted.

Comparison between de novo and metachronous metastatic breast cancer: the presence of a primary tumour is not the only difference-a Dutch population-based study from 2008 to 2018.

PURPOSE: The aim of this study was to compare characteristics and survival of patients with de novo and metachronous metastatic breast cancer. METHODS: Data of patients with metastatic breast cancer were obtained from the Netherlands Cancer Registry. Patients were categorized as having de novo metastatic breast cancer (n = 8656) if they had distant metastases at initial presentation, or metachronous metastatic disease (n = 2374) in case they developed metastases within 5 or 10 years after initial breast cancer diagnosis. Clinicopathological characteristics and treatments of these two groups were compared, after which multiple imputation was performed to account for missing data. Overall survival was compared for patients treated with systemic therapy in the metastatic setting, using Kaplan Meier curves and multivariable Cox proportional hazards models. The hazard ratio for overall survival of de novo versus metachronous metastases was assessed accounting for time-varying effects. RESULTS: Compared to metachronous patients, patients with de novo metastatic breast cancer were more likely to be ≥ 70 years, to have invasive lobular carcinoma, clinical T3 or T4 tumours, loco-regional lymph node metastases, HER2 positivity, bone only disease and to have received systemic therapy in the metastatic setting. They were less likely to have triple negative tumours and liver or brain metastases. Patients with de novo metastases survived longer (median 34.7 months) than patients with metachronous metastases (median 24.3 months) and the hazard ratio (0.75) varied over time. CONCLUSIONS: Differences in clinicopathological characteristics and survival between de novo and metachronous metastatic breast cancer highlight that these are distinct patients groups.