Upfront resection versus no resection of the primary tumor in patients with synchronous metastatic colorectal cancer: the randomized phase III CAIRO4 study conducted by the Dutch Colorectal Cancer Group and the Danish Colorectal Cancer Group.

BACKGROUND: Upfront primary tumor resection (PTR) has been associated with longer overall survival (OS) in patients with synchronous unresectable metastatic colorectal cancer (mCRC) in retrospective analyses. The aim of the CAIRO4 study was to investigate whether the addition of upfront PTR to systemic therapy resulted in a survival benefit in patients with synchronous mCRC without severe symptoms of their primary tumor. PATIENTS AND METHODS: This randomized phase III trial was conducted in 45 hospitals in The Netherlands and Denmark. Eligibility criteria included previously untreated mCRC, unresectable metastases, and no severe symptoms of the primary tumor. Patients were randomized (1 : 1) to upfront PTR followed by systemic therapy or systemic therapy without upfront PTR. Systemic therapy consisted of first-line fluoropyrimidine-based chemotherapy with bevacizumab in both arms. Primary endpoint was OS in the intention-to-treat population. The study was registered at ClinicalTrials.gov, NCT01606098. RESULTS: Between August 2012 and February 2021, 206 patients were randomized. In the intention-to-treat analysis, 204 patients were included (n = 103 without upfront PTR, n = 101 with upfront PTR) of whom 116 were men (57%) with median age of 65 years (interquartile range 59-71 years). Median follow-up was 69.4 months. Median OS in the arm without upfront PTR was 18.3 months (95% confidence interval 16.0-22.2 months) compared with 20.1 months (95% confidence interval 17.0-25.1 months) in the upfront PTR arm (P = 0.32). The number of grade 3-4 events was 71 (72%) in the arm without upfront PTR and 61 (65%) in the upfront PTR arm (P = 0.33). Three deaths (3%) possibly related to treatment were reported in the arm without upfront PTR and four (4%) in the upfront PTR arm. CONCLUSIONS: Addition of upfront PTR to palliative systemic therapy in patients with synchronous mCRC without severe symptoms of the primary tumor does not result in a survival benefit. This practice should no longer be considered standard of care.

Predicting response to neoadjuvant chemotherapy with liquid biopsies and multiparametric MRI in patients with breast cancer.

Accurate prediction of response to neoadjuvant chemotherapy (NAC) can help tailor treatment to individual patients' needs. Little is known about the combination of liquid biopsies and computer extracted features from multiparametric magnetic resonance imaging (MRI) for the prediction of NAC response in breast cancer. Here, we report on a prospective study with the aim to explore the predictive potential of this combination in adjunct to standard clinical and pathological information before, during and after NAC. The study was performed in four Dutch hospitals. Patients without metastases treated with NAC underwent 3 T multiparametric MRI scans before, during and after NAC. Liquid biopsies were obtained before every chemotherapy cycle and before surgery. Prediction models were developed using penalized linear regression to forecast residual cancer burden after NAC and evaluated for pathologic complete response (pCR) using leave-one-out-cross-validation (LOOCV). Sixty-one patients were included. Twenty-three patients (38%) achieved pCR. Most prediction models yielded the highest estimated LOOCV area under the curve (AUC) at the post-treatment timepoint. A clinical-only model including tumor grade, nodal status and receptor subtype yielded an estimated LOOCV AUC for pCR of 0.76, which increased to 0.82 by incorporating post-treatment radiological MRI assessment (i.e., the "clinical-radiological" model). The estimated LOOCV AUC was 0.84 after incorporation of computer-extracted MRI features, and 0.85 when liquid biopsy information was added instead of the radiological MRI assessment. Adding liquid biopsy information to the clinical-radiological resulted in an estimated LOOCV AUC of 0.86. In conclusion, inclusion of liquid biopsy-derived markers in clinical-radiological prediction models may have potential to improve prediction of pCR after NAC in breast cancer.

MRI to assess response after neoadjuvant chemotherapy in breast cancer subtypes: a systematic review and meta-analysis.

This meta-analysis aimed to estimate and compare sensitivity, specificity, positive- (PPV) and negative predictive value (NPV) of magnetic resonance imaging (MRI) for predicting pathological complete remission (pCR) after neoadjuvant chemotherapy (NAC) in patients with early-stage breast cancer. We stratified for molecular subtype by immunohistochemistry (IHC) and explored the impact of other factors. Two researchers systematically searched PUBMED and EMBASE to select relevant studies and extract data. For meta-analysis of sensitivity and specificity, we used bivariate random-effects models. Twenty-six included studies contained 4497 patients. There was a significant impact of IHC subtype on post-NAC MRI accuracy (p = 0.0082) for pCR. The pooled sensitivity was 0.67 [95% CI 0.58-0.74] for the HR-/HER2-, 0.65 [95% CI 0.56-0.73] for the HR-/HER2+, 0.55 [95% CI 0.45-0.64] for the HR+/HER2- and 0.60 [95% CI 0.50-0.70] for the HR+/HER2+ subtype. The pooled specificity was 0.85 [95% CI 0.81-0.88] for the HR-/HER2-, 0.81 [95% CI 0.74-0.86] for the HR-/HER2+, 0.88[95% CI 0.84-0.91] for the HR+/HER2- and 0.74 [95% CI 0.63-0.83] for the HR+/HER2+ subtype. The PPV was highest in the HR-/HER2- subtype and lowest in the HR+/HER2- subtype. MRI field strength of 3.0 T was associated with a higher sensitivity compared to 1.5 T (p = 0.00063). The accuracy of MRI for predicting pCR depends on molecular subtype, which should be taken into account in clinical practice. Higher MRI field strength positively impacts accuracy. When intervention trials based on MRI response evaluation are designed, the impact of IHC subtype and field strength on MR accuracy should be considered.

Population-based estimates of overtreatment with adjuvant systemic therapy in early breast cancer patients with data from the Netherlands and the USA.

PURPOSE: Although adjuvant systemic therapy (AST) helps increase breast cancer-specific survival (BCSS), there is a growing concern for overtreatment. By estimating the expected BCSS of AST using PREDICT, this study aims to quantify the number of patients treated with AST without benefit to provide estimates of overtreatment. METHODS: Data of all non-metastatic unilateral breast cancer patients diagnosed in 2015 were retrieved from cancer registries from The Netherlands and the USA. The PREDICT tool was used to estimate AST survival benefit. Overtreatment was defined as the proportion of patients that would have survived regardless of or died despite AST within 10 years. Three scenarios were evaluated: actual treatment, and recommendations by the Dutch or USA guidelines. RESULTS: 59.5% of Dutch patients were treated with AST. 6.4% (interquartile interval [IQI] = 2.5, 8.2%) was expected to survive at least 10 years due to AST, leaving 93.6% (IQI = 91.8, 97.5%) without AST benefit (overtreatment). The lowest expected amount of overtreatment was in the targeted and chemotherapy subgroup, with 86.5% (IQI = 83.4, 89.6%) overtreatment, and highest in the only endocrine treatment subgroup, with 96.7% (IQI = 96.0, 98.1%) overtreatment. Similar results were obtained using data from the USA, and guideline recommendations. CONCLUSION: Based on PREDICT, AST prevents 10-year breast cancer death in 6.4% of the patients treated with AST. Consequently, AST yields no survival benefit to many treated patients. Especially improved personalization of endocrine therapy is relevant, as this therapy is widely used and is associated with the highest amount of overtreatment.

89Zr-pembrolizumab imaging as a non-invasive approach to assess clinical response to PD-1 blockade in cancer.

BACKGROUND: Programmed cell death protein 1 (PD-1) antibody treatment is standard of care for melanoma and non-small-cell lung cancer (NSCLC). Accurately predicting which patients will benefit is currently not possible. Tumor uptake and biodistribution of the PD-1 antibody might play a role. Therefore, we carried out a positron emission tomography (PET) imaging study with zirconium-89 (89Zr)-labeled pembrolizumab before PD-1 antibody treatment. PATIENTS AND METHODS: Patients with advanced or metastatic melanoma or NSCLC received 37 MBq (1 mCi) 89Zr-pembrolizumab (∼2.5 mg antibody) intravenously plus 2.5 or 7.5 mg unlabeled pembrolizumab. After that, up to three PET scans were carried out on days 2, 4, and 7. Next, PD-1 antibody treatment was initiated. 89Zr-pembrolizumab tumor uptake was calculated as maximum standardized uptake value (SUVmax) and expressed as geometric mean. Normal organ uptake was calculated as SUVmean and expressed as a mean. Tumor response was assessed according to (i)RECIST v1.1. RESULTS: Eighteen patients, 11 with melanoma and 7 with NSCLC, were included. The optimal dose was 5 mg pembrolizumab, and the optimal time point for PET scanning was day 7. The tumor SUVmax did not differ between melanoma and NSCLC (4.9 and 6.5, P = 0.49). Tumor 89Zr-pembrolizumab uptake correlated with tumor response (P trend = 0.014) and progression-free (P = 0.0025) and overall survival (P = 0.026). 89Zr-pembrolizumab uptake at 5 mg was highest in the spleen with a mean SUVmean of 5.8 (standard deviation ±1.8). There was also 89Zr-pembrolizumab uptake in Waldeyer's ring, in normal lymph nodes, and at sites of inflammation. CONCLUSION: 89Zr-pembrolizumab uptake in tumor lesions correlated with treatment response and patient survival. 89Zr-pembrolizumab also showed uptake in lymphoid tissues and at sites of inflammation.

Improving clinical management of colon cancer through CONNECTION, a nation-wide colon cancer registry and stratification effort (CONNECTION II trial): rationale and protocol of a single arm intervention study.

BACKGROUND: It is estimated that around 15-30% of patients with early stage colon cancer benefit from adjuvant chemotherapy. We are currently not capable of upfront selection of patients who benefit from chemotherapy, which indicates the need for additional predictive markers for response to chemotherapy. It has been shown that the consensus molecular subtypes (CMSs), defined by RNA-profiling, have prognostic and/or predictive value. Due to postoperative timing of chemotherapy in current guidelines, tumor response to chemotherapy per CMS is not known, which makes the differentiation between the prognostic and predictive value impossible. Therefore, we propose to assess the tumor response per CMS in the neoadjuvant chemotherapy setting. This will provide us with clear data on the predictive value for chemotherapy response of the CMSs. METHODS: In this prospective, single arm, multicenter intervention study, 262 patients with resectable microsatellite stable cT3-4NxM0 colon cancer will be treated with two courses of neoadjuvant and two courses of adjuvant capecitabine and oxaliplatin. The primary endpoint is the pathological tumor response to neoadjuvant chemotherapy per CMS. Secondary endpoints are radiological tumor response, the prognostic value of these responses for recurrence free survival and overall survival and the differences in CMS classification of the same tumor before and after neoadjuvant chemotherapy. The study is scheduled to be performed in 8-10 Dutch hospitals. The first patient was included in February 2020. DISCUSSION: Patient selection for adjuvant chemotherapy in early stage colon cancer is far from optimal. The CMS classification is a promising new biomarker, but a solid chemotherapy response assessment per subtype is lacking. In this study we will investigate whether CMS classification can be of added value in clinical decision making by analyzing the predictive value for chemotherapy response. This study can provide the results necessary to proceed to future studies in which (neo) adjuvant chemotherapy may be withhold in patients with a specific CMS subtype, who show no benefit from chemotherapy and for whom possible new treatments can be investigated. TRIAL REGISTRATION: This study has been registered in the Netherlands Trial Register (NL8177) at 11-26-2019, https://www.trialregister.nl/trial/8177 . The study has been approved by the medical ethics committee Utrecht (MEC18/712).

Correction to: [89Zr]Zr-cetuximab PET/CT as biomarker for cetuximab monotherapy in patients with RAS wild-type advanced colorectal cancer.

Missing Electronic Supplementary Materials.

[89Zr]Zr-cetuximab PET/CT as biomarker for cetuximab monotherapy in patients with RAS wild-type advanced colorectal cancer.

PURPOSE: One-third of patients with RAS wild-type mCRC do not benefit from anti-EGFR monoclonal antibodies. This might be a result of variable pharmacokinetics and insufficient tumor targeting. We evaluated cetuximab tumor accumulation on [89Zr]Zr-cetuximab PET/CT as a potential predictive biomarker and determinant for an escalating dosing strategy. PATIENTS AND METHODS: PET/CT imaging of [89Zr]Zr-cetuximab (37 MBq/10 mg) after a therapeutic pre-dose (500 mg/m2 ≤ 2 h) cetuximab was performed at the start of treatment. Patients without visual tumor uptake underwent dose escalation and a subsequent [89Zr]Zr-cetuximab PET/CT. Treatment benefit was defined as stable disease or response on CT scan evaluation after 8 weeks. RESULTS: Visual tumor uptake on [89Zr]Zr-cetuximab PET/CT was observed in 66% of 35 patients. There was no relationship between PET positivity and treatment benefit (52% versus 80% for PET-negative, P = 0.16), progression-free survival (3.6 versus 5.7 months, P = 0.15), or overall survival (7.1 versus 9.4 months, P = 0.29). However, in 67% of PET-negative patients, cetuximab dose escalation (750-1250 mg/m2) was applied, potentially influencing outcome in this group. None of the second [89Zr]Zr-cetuximab PET/CT was positive. Eighty percent of patients without visual tumor uptake had treatment benefit, making [89Zr]Zr-cetuximab PET/CT unsuitable as a predictive biomarker. Tumor SUVpeak did not correlate to changes in tumor size on CT (P = 0.23), treatment benefit, nor progression-free survival. Cetuximab pharmacokinetics were not related to treatment benefit. BRAF mutations, right-sidedness, and low sEGFR were correlated with intrinsic resistance to cetuximab. CONCLUSION: Tumor uptake on [89Zr]Zr-cetuximab PET/CT failed to predict treatment benefit in patients with RAS wild-type mCRC receiving cetuximab monotherapy. BRAF mutations, right-sidedness, and low sEGFR correlated with intrinsic resistance to cetuximab.

The Changing Role of Gene-Expression Profiling in the Era of De-escalating Adjuvant Chemotherapy in Early-Stage Breast Cancer.

PURPOSE: We assessed the recent trends in the administration of adjuvant chemotherapy thereby evaluating the role of the 70-gene signature (70-GS) testing in decision-making in the systemic treatment of patients with lymph node negative (N0) and lymph node positive (N+) breast cancer. METHODS: Patients with a national guideline directed indication for 70-GS use treated between 2013 and 2016 were selected from the Netherlands Cancer Registry. Time trends in the administration of adjuvant chemotherapy were evaluated within guideline- and age-delineated subgroups. The influence of the 70-GS on chemotherapy use was assessed with logistic regression. RESULTS: During the study period, the overall administration of adjuvant chemotherapy decreased from 49 to 23% and 70-GS use increased from 24 to 51%. The 70-GS was not associated with a decreased likelihood for N0 patients to receive chemotherapy (odds ratio [OR] 1.0; 95% confidence interval [CI] 0.86-1.17), as the proportion of N0 patients who received chemotherapy in the absence of 70-GS use decreased during the study period. In patients with N1a disease, 70-GS testing was associated with a decreased likelihood to receive chemotherapy (OR 0.21; 95% CI 0.15-0.29). In patients < 50 years and 50-59 years of age, 70-GS use was associated with a consistent lower proportion of patients receiving chemotherapy throughout the study period (OR 0.17; 95% CI 0.13-0.23 and OR 0.53; 95% CI 0.43-0.65, respectively). CONCLUSIONS: In this population-based study, the administration of adjuvant chemotherapy in ER+ breast cancer strongly declined. For node-positive and younger patients, 70-GS use was associated with a decreased probability for patients to receive adjuvant chemotherapy.

Organoids from colorectal peritoneal metastases as a platform for improving hyperthermic intraperitoneal chemotherapy.

BACKGROUND: Patients with peritoneal metastases from colorectal cancer have a poor prognosis. If the intraperitoneal tumour load is limited, patients may be eligible for cytoreductive surgery followed by hyperthermic intraperitoneal chemotherapy (HIPEC). This treatment has improved overall survival, but recurrence rates are high. The aim of this study was to create a preclinical platform for the development of more effective intraperitoneal chemotherapy strategies. METHODS: Using organoid technology, five tumour cultures were generated from malignant ascites and resected peritoneal metastases. These were used in an in vitro HIPEC model to assess sensitivity to mitomycin C (MMC) and oxaliplatin, the drugs used most commonly in HIPEC. The model was also used to test a rational combination treatment involving MMC and inhibitors of the checkpoint kinase ATR. RESULTS: MMC was more effective in eliminating peritoneal metastasis-derived organoids than oxaliplatin at clinically relevant concentrations. However, the drug concentrations required to eliminate 50 per cent of the tumour cells (IC50) were higher than the median clinical dose in two of five organoid lines for MMC, and all five lines for oxaliplatin, indicating a general resistance to monotherapy. ATR inhibition increased the sensitivity of all peritoneal metastasis-derived organoids to MMC, as the IC50 decreased 2·6-12·4-fold to well below concentrations commonly attained in clinical practice. Live-cell imaging and flow cytometric analysis showed that ATR inhibition did not release cells from MMC-induced cell cycle arrest, but caused increased replication stress and accelerated cell death. CONCLUSION: Peritoneal metastasis-derived organoids can be used to evaluate existing HIPEC regimens on an individual-patient level and for development of more effective treatment strategies. Surgical relevance Cytoreductive surgery followed by hyperthermic intraperitoneal chemotherapy (HIPEC) has improved prognosis of patients with peritoneal metastases from colorectal cancer, but disease recurrence is common. More effective and personalized HIPEC is urgently needed. Organoid technology is frequently used for drug screens, as patient-derived organoids can accurately predict clinical therapeutic response in vitro. A panel of organoids was established from peritoneal metastases from colorectal cancer and used to develop a model for testing HIPEC regimens in vitro. Patient-derived organoids differed in sensitivity to commonly used chemotherapeutics, in line with variable clinical outcomes following cytoreductive surgery-HIPEC. Combining MMC with an ATR inhibitor improved the efficacy of MMC. Peritoneal metastasis-derived organoids can be used as a platform to test novel (combination) strategies that increase HIPEC efficacy. In the future, organoids could be used to select patent-tailored HIPEC regimens.

ANTECEDENTES: Los pacientes con metástasis peritoneales (peritoneal metastasis, PM) de cáncer colorrectal tienen un mal pronóstico. Si la carga tumoral intraperitoneal es reducida, los pacientes pueden ser candidatos a cirugía citorreductora seguida de quimioterapia intraperitoneal hipertérmica (hyperthermic intraperitoneal chemotherapy, HIPEC). Este tratamiento ha mejorado la supervivencia global, pero las tasas de recidiva son altas. El objetivo de este estudio fue crear una plataforma preclínica para el desarrollo de las estrategias de quimioterapia intraperitoneal más efectivas. MÉTODOS: Mediante la utilización de la tecnología de organoides, se generaron cinco cultivos tumorales a partir de ascitis maligna y PM resecadas. Se utilizó un modelo de HIPEC in vitro para evaluar la sensibilidad a la mitomicina C (mitomycin C, MMC) y al oxaliplatino, los fármacos más utilizados en la HIPEC. El modelo también se usó para probar un tratamiento combinado de MMC e inhibidores de control inmunitario de la quinasa ATR. RESULTADOS: A concentraciones clínicamente relevantes, la MMC fue más efectiva que el oxaliplatino para eliminar los organoides derivados de PM. Sin embargo, las concentraciones de fármaco necesarias para eliminar el 50% de las células tumorales (IC50) fueron más elevadas que la mediana de la dosis clínica en 2/5 (MMC) o 5/5 (oxaliplatino) de las líneas de organoides, lo que indica una resistencia general a la monoterapia. La inhibición de ATR aumentó la sensibilidad a MMC de todos los organoides derivados de PM, ya que la IC50 disminuyó (2,6-12,4 veces) a concentraciones muy por debajo de las que se alcanzan comúnmente en la práctica clínica. Los análisis de viabilidad celular y de citometría de flujo (FACS) mostraron que la inhibición de ATR no liberaba células tras la detención del ciclo celular inducida por la MMC, sino que causaba un aumento en el estrés replicativo y muerte celular acelerada. CONCLUSIÓN: Se pueden usar los organoides derivados de PM para evaluar los regímenes HIPEC existentes a nivel del paciente individual y para desarrollar estrategias terapéuticas más efectivas.

Histopathological and molecular classification of colorectal cancer and corresponding peritoneal metastases.

BACKGROUND: Patients with colorectal peritoneal carcinomatosis have a very poor prognosis. The recently developed consensus molecular subtype (CMS) classification of primary colorectal cancer categorizes tumours into four robust subtypes, which could guide subtype-targeted therapy. CMS4, also known as the mesenchymal subtype, has the greatest propensity to form distant metastases. CMS4 status and histopathological features of colorectal peritoneal carcinomatosis were investigated in this study. METHODS: Fresh-frozen tissue samples from primary colorectal cancer and paired peritoneal metastases from patients who underwent cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy were collected. Histopathological features were analysed, and a reverse transcriptase-quantitative PCR test was used to assess CMS4 status of all collected lesions. RESULTS: Colorectal peritoneal carcinomatosis was associated with adverse histopathological characteristics, including a high percentage of stroma in both primary tumours and metastases, and poor differentiation grade and high-grade tumour budding in primary tumours. Furthermore, CMS4 was significantly enriched in primary tumours with peritoneal metastases, compared with unselected stage I-IV tumours (60 per cent (12 of 20) versus 23 per cent; P = 0.002). The majority of peritoneal metastases (75 per cent, 21 of 28) were also classified as CMS4. Considerable intrapatient subtype heterogeneity was observed. Notably, 15 of 16 patients with paired tumours had at least one CMS4-positive tumour location. CONCLUSION: Significant enrichment for CMS4 was observed in colorectal peritoneal carcinomatosis. Surgical relevance Cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) improves survival of selected patients with colorectal peritoneal carcinomatosis, but recurrence is common. Histopathological and molecular analysis of colorectal peritoneal carcinomatosis could provide clues for development of novel therapies. In this study, colorectal peritoneal carcinomatosis was found to be enriched for tumours with high stromal content and CMS4-positive status. To further improve prognosis for patients with colorectal peritoneal carcinomatosis, therapies that target tumour-stroma interaction could be added to CRS-HIPEC.

Endoscopic resection of high-risk T1 colorectal carcinoma prior to surgical resection has no adverse effect on long-term outcomes.

OBJECTIVE: It is difficult to predict the presence of histological risk factors for lymph node metastasis (LNM) before endoscopic treatment of T1 colorectal cancer (CRC). Therefore, endoscopic therapy is propagated to obtain adequate histological staging. We examined whether secondary surgery following endoscopic resection of high-risk T1 CRC does not have a negative effect on patients' outcomes compared with primary surgery. DESIGN: Patients with T1 CRC with one or more histological risk factors for LNM (high risk) and treated with primary or secondary surgery between 2000 and 2014 in 13 hospitals were identified in the Netherlands Cancer Registry. Additional data were collected from hospital records, endoscopy, radiology and pathology reports. A propensity score analysis was performed using inverse probability weighting (IPW) to correct for confounding by indication. RESULTS: 602 patients were eligible for analysis (263 primary; 339 secondary surgery). Overall, 34 recurrences were observed (5.6%). After adjusting with IPW, no differences were observed between primary and secondary surgery for the presence of LNM (OR 0.97; 95% CI 0.49 to 1.93; p=0.940) and recurrence during follow-up (HR 0.97; 95% CI 0.41 to 2.34; p=0.954). Further adjusting for lymphovascular invasion, depth of invasion and number of retrieved lymph nodes did not alter this outcome. CONCLUSIONS: Our data do not support an increased risk of LNM or recurrence after secondary surgery compared with primary surgery. Therefore, an attempt for an en-bloc resection of a possible T1 CRC without evident signs of deep invasion seems justified in order to prevent surgery of low-risk T1 CRC in a significant proportion of patients.

Maintenance treatment with capecitabine and bevacizumab versus observation in metastatic colorectal cancer: updated results and molecular subgroup analyses of the phase 3 CAIRO3 study.

BACKGROUND: The phase 3 CAIRO3 study showed that capecitabine plus bevacizumab (CAP-B) maintenance treatment after six cycles capecitabine, oxaliplatin, and bevacizumab (CAPOX-B) in metastatic colorectal cancer (mCRC) patients is effective, without compromising quality of life. In this post hoc analysis with updated follow-up and data regarding sidedness, we defined subgroups according to RAS/BRAF mutation status and mismatch repair (MMR) status, and investigated their influence on treatment efficacy. PATIENTS AND METHODS: A total of 558 patients with previously untreated mCRC and stable disease or better after six cycles CAPOX-B induction treatment were randomised to either CAP-B maintenance treatment (n = 279) or observation (n = 279). Upon first progression, patients were to receive CAPOX-B reintroduction until second progression (PFS2, primary end point). We centrally assessed RAS/BRAF mutation status and MMR status, or used local results if central assessment was not possible. Intention-to-treat stratified Cox models adjusted for baseline covariables were used to examine whether treatment efficacy was modified by RAS/BRAF mutation status. RESULTS: RAS, BRAF mutations, and MMR deficiency were detected in 240/420 (58%), 36/381 (9%), and 4/279 (1%) patients, respectively. At a median follow-up of 87 months (IQR 69-97), all mutational subgroups showed significant improvement from maintenance treatment for the primary end point PFS2 [RAS/BRAF wild-type: hazard ratio (HR) 0.57 (95% CI 0.39-0.84); RAS-mutant: HR 0.74 (0.55-0.98); V600EBRAF-mutant: HR 0.28 (0.12-0.64)] and secondary end points, except for the RAS-mutant subgroup regarding overall survival. Adjustment for sidedness instead of primary tumour location yielded comparable results. Although right-sided tumours were associated with inferior prognosis, both patients with right- and left-sided tumours showed significant benefit from maintenance treatment. CONCLUSIONS: CAP-B maintenance treatment after six cycles CAPOX-B is effective in first-line treatment of mCRC across all mutational subgroups. The benefit of maintenance treatment was most pronounced in patients with RAS/BRAF wild-type and V600EBRAF-mutant tumours. CLINICALTRIALS.GOV NUMBER: NCT00442637.

Neoadjuvant chemotherapy affects molecular classification of colorectal tumors.

The recent discovery of 'molecular subtypes' in human primary colorectal cancer has revealed correlations between subtype, propensity to metastasize and response to therapy. It is currently not known whether the molecular tumor subtype is maintained after distant spread. If this is the case, molecular subtyping of the primary tumor could guide subtype-targeted therapy of metastatic disease. In this study, we classified paired samples of primary colorectal carcinomas and their corresponding liver metastases (n=129) as epithelial-like or mesenchymal-like, using a recently developed immunohistochemistry-based classification tool. We observed considerable discordance (45%) in the classification of primary tumors and their liver metastases. Discordant classification was significantly associated with the use of neoadjuvant chemotherapy. Furthermore, gene expression analysis of chemotherapy-exposed versus chemotherapy naive liver metastases revealed expression of a mesenchymal program in pre-treated tumors. To explore whether chemotherapy could cause gene expression changes influencing molecular subtyping, we exposed patient-derived colonospheres to six short cycles of 5-fluorouracil. Gene expression profiling and signature enrichment analysis subsequently revealed that the expression of signatures identifying mesenchymal-like tumors was strongly increased in chemotherapy-exposed tumor cultures. Unsupervised clustering of large cohorts of human colon tumors with the chemotherapy-induced gene expression program identified a poor prognosis mesenchymal-like subgroup. We conclude that neoadjuvant chemotherapy induces a mesenchymal phenotype in residual tumor cells and that this may influence the molecular classification of colorectal tumors.

The influence of socioeconomic status and ethnicity on adjuvant systemic treatment guideline adherence for early-stage breast cancer in the Netherlands.

BACKGROUND: We aimed to assess whether socioeconomic status (SES) and ethnicity affect adjuvant systemic therapy (AST) guideline adherence in early breast cancer patients in a health care setting with assumed equal access to care. METHODS: Data from all female patients surgically treated for primary unifocal early breast cancer between January 2005 and December 2014 were retrieved from the Netherlands Cancer Registry. We assessed the association between SES, ethnicity and non-adherence to adjuvant chemotherapy (CT) or endocrine therapy (ET) guideline indications with Poisson regression models, adjusting for clinicopathological variables. RESULTS: A total of 104 201 patients were included in the current analysis. Of patients without an indication, 4% and 13% received adjuvant CT or ET (overtreatment), whereas 39% and 14% of patients with an indication did not receive CT or ET (undertreatment). Medium and low SES patients were 1.01 (95% CI 1.00-1.01) and 1.01 (95% CI 1.00-1.01) times more likely to be undertreated and 0.85 (95% CI 0.76-0.94) and 0.67 (95% CI 0.60-0.75) times more likely to be overtreated with CT compared with high SES patients [resulting in an overall relative risk of CT use of 0.94 (95% CI 0.92-0.96) and 0.85 (95% CI 0.83-0.87), respectively]. No association between SES and ET guideline adherence or ethnicity and CT/ET guideline adherence was observed. CONCLUSION: In the Netherlands, minimal SES disparities in CT guideline adherence were observed: low SES patients are less likely be overtreated and marginally more likely to be undertreated with CT resulting in an overall decreased risk of receiving CT. No ethnical disparities in AST guideline adherence were observed.

Imatinib treatment of poor prognosis mesenchymal-type primary colon cancer: a proof-of-concept study in the preoperative window period (ImPACCT).

BACKGROUND: The identification of four Consensus Molecular Subtypes (CMS1-4) of colorectal cancer forms a new paradigm for the design and evaluation of subtype-directed therapeutic strategies. The most aggressive subtype - CMS4 - has the highest chance of disease recurrence. Novel adjuvant therapies for patients with CMS4 tumours are therefore urgently needed. CMS4 tumours are characterized by expression of mesenchymal and stem-like genes. Previous pre-clinical work has shown that targeting Platelet-Derived Growth Factor Receptors (PDGFRs) and the related KIT receptor with imatinib is potentially effective against mesenchymal-type colon cancer. In the present study we aim to provide proof for the concept that imatinib can reduce the aggressive phenotype of primary CMS4 colon cancer. METHODS: Tumour biopsies from patients with newly diagnosed stage I-III colon cancer will be analysed with a novel RT-qPCR test to pre-select patients with CMS4 tumours. Selected patients (n = 27) will receive treatment with imatinib (400 mg per day) starting two weeks prior to planned tumour resection. To assess treatment-induced changes in the aggressive CMS4 phenotype, RNA sequencing will be performed on pre- and post-treatment tissue samples. DISCUSSION: The development of effective adjuvant therapy for primary colon cancer is hindered by multiple factors. First, new drugs that may have value in the prevention of (early) distant recurrence are almost always first tested in patients with heavily pre-treated metastatic disease. Second, measuring on-target drug effects and biological consequences in tumour tissue is not commonly a part of the study design. Third, due to the lack of patient selection tools, clinical trials in the adjuvant setting require large patient populations. Finally, the evaluation of recurrence-prevention requires a long-term follow-up. In the ImPACCT trial these issues are addressed by including newly diagnosed pre-selected patients with CMS4 tumours prior to primary tumour resection, rather than non-selected patients with late-stage disease. By making use of the pre-operative window period, the biological effect of imatinib treatment on CMS4 tumours can be rapidly assessed. Delivering proof-of-concept for drug action in early stage disease should form the basis for the design of future trials with subtype-targeted therapies in colon cancer patients. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02685046 . Registration date: February 9, 2016.

Adjuvant systemic therapy in early breast cancer: impact of guideline changes and clinicopathological factors associated with nonadherence at a nation-wide level.

Over recent years, adjuvant systemic treatment guidelines (AST) for early-stage breast cancer have changed considerably. We aimed to assess the impact of these guideline changes on the administration of AST in early-stage breast cancer patients and to what extent these guidelines are adhered to at a nation-wide level. We used Netherlands Cancer Registry data to describe trends in AST prescription, adherence to AST guidelines, and to identify clinicopathological determinants of nonadherence. Between 1990 and 2012, 231,648 Dutch patients were diagnosed with early breast cancer, of whom 124,472 received AST. Adjuvant endocrine treatment (ET) use increased from 23 % of patients (1990) to 56 % (2012), and chemotherapy from 11 to 44 %. In 2009-2012, 8 % of patients received ET and 3 % received chemotherapy without guideline indication. Conversely, 10-29 % of patients did not receive ET and chemotherapy, respectively, despite a guideline indication. Unfavorable clinicopathological characteristics generally decreased the chance of undertreatment and increased the chance for overtreatment. Remarkable was the increased chance of ET undertreatment in younger women (RR < 35 vs 60-69 years 1.79; 95 % CI 1.30-2.47) and in women with HER2+ disease (RR 1.64; 95 % CI 1.46-1.85). Over the years, AST guidelines expanded resulting in much more Dutch early breast cancer patients receiving AST. In the majority of cases, AST administration was guideline concordant, but the high frequency of chemotherapy undertreatment in some subgroups suggests limited AST guideline support in these patients.

Endoscopic mucosal resection (EMR) versus endoscopic submucosal dissection (ESD) for resection of large distal non-pedunculated colorectal adenomas (MATILDA-trial): rationale and design of a multicenter randomized clinical trial.

BACKGROUND: Endoscopic mucosal resection (EMR) is currently the most used technique for resection of large distal colorectal polyps. However, in large lesions EMR can often only be performed in a piecemeal fashion resulting in relatively low radical (R0)-resection rates and high recurrence rates. Endoscopic submucosal dissection (ESD) is a newer procedure that is more difficult resulting in a longer procedural time, but is promising due to the high en-bloc resection rates and the very low recurrence rates. We aim to evaluate the (cost-)effectiveness of ESD against EMR on both short (i.e. 6 months) and long-term (i.e. 36 months). We hypothesize that in the short-run ESD is more time consuming resulting in higher healthcare costs, but is (cost-) effective on the long-term due to lower patients burden, a higher number of R0-resections and lower recurrence rates with less need for repeated procedures. METHODS: This is a multicenter randomized clinical trial in patients with a non-pedunculated polyp larger than 20 mm in the rectum, sigmoid, or descending colon suspected to be an adenoma by means of endoscopic assessment. Primary endpoint is recurrence rate at follow-up colonoscopy at 6 months. Secondary endpoints are R0-resection rate, perceived burden and quality of life, healthcare resources utilization and costs, surgical referral rate, complication rate and recurrence rate at 36 months. Quality-adjusted-life-year (QALY) will be estimated taking an area under the curve approach and using EQ-5D-indexes. Healthcare costs will be calculated by multiplying used healthcare services with unit prices. The cost-effectiveness of ESD against EMR will be expressed as incremental cost-effectiveness ratios (ICER) showing additional costs per recurrence free patient and as ICER showing additional costs per QALY. DISCUSSION: If this trial confirms ESD to be favorable on the long-term, the burden of extra colonoscopies and repeated procedures can be prevented for future patients. TRIAL REGISTRATION: NCT02657044 (Clinicaltrials.gov), registered January 8, 2016.

Changes over time in the impact of gene-expression profiles on the administration of adjuvant chemotherapy in estrogen receptor positive early stage breast cancer patients: A nationwide study.

Ten years ago gene-expression profiles were introduced to aid adjuvant chemotherapy decision making in breast cancer. Since then subsequent national guidelines gradually expanded the indication area for adjuvant chemotherapy. In this nation-wide study the evolution of the proportion of patients with estrogen-receptor positive (ER+) tumors receiving adjuvant chemotherapy in relation to gene-expression profile use in patient groups that became newly eligible for chemotherapy according to national guideline changes over time is assessed. Data on all surgically treated early breast cancer patients diagnosed between 2004-2006 and 2012-2014 were obtained from the Netherlands Cancer Registry. ER+/Her2- patients with tumor-characteristics making them eligible for gene-expression testing in both cohorts and a discordant chemotherapy recommendation over time (2004 guideline not recommending and 2012 guideline recommending chemotherapy) were identified. We identified 3,864 patients eligible for gene-expression profile use during both periods. Gene-expression profiles were deployed in 5% and 35% of the patients in the respective periods. In both periods the majority of patients was assigned to a low genomic risk-profile (67% and 69%, respectively) and high adherence rates to the test result were observed (86% and 91%, respectively). Without deploying a gene-expression profile 8% and 52% (p <0.001) of the respective cohorts received chemotherapy while 21% and 28% of these patients received chemotherapy when a gene-expression profile was used (p 0.191). In conclusion, in ER+/Her2- early stage breast cancer patients gene-expression profile use was associated with a consistent proportion of patients receiving chemotherapy despite an adjusted guideline-based recommendation to administer chemotherapy.

Using a gene expression signature when controversy exists regarding the indication for adjuvant systemic treatment reduces the proportion of patients receiving adjuvant chemotherapy: a nationwide study.

PURPOSE: The Dutch national guideline advises use of gene-expression signatures, such as the 70-gene signature (70-GS), in case of ambivalence regarding the benefit of adjuvant chemotherapy (CT). In this nationwide study, the impact of 70-GS use on the administration of CT in early breast cancer patients with a dubious indication for CT is assessed. METHODS: Patients within a national guideline directed indication area for 70-GS use who were surgically treated between November 2011 and April 2013 were selected from the Netherlands Cancer Registry database. The effect of 70-GS use on the administration of CT was evaluated in guideline- and age-delineated subgroups addressing potential effect of bias by linear mixed-effect modeling and instrumental variable (IV) analyses. RESULTS: A total of 2,043 patients within the indicated area for 70-GS use were included, of whom 298 received a 70-GS. Without use of the 70-GS, 45% of patients received CT. The 70-GS use was associated with a 9.5% decrease in CT administration (95% confidence interval (CI): -15.7 to -3.3%) in linear mixed-effect model analyses and IV analyses showed similar results (-9.9%; 95% CI: -19.3 to -0.4). CONCLUSION: In patients in whom the Dutch national guidelines suggest the use of a gene-expression profile, 70-GS use is associated with a 10% decrease in the administration of adjuvant CT.Genet Med 18 7, 720-726.Genetics in Medicine (2016); 18 7, 720-726. doi:10.1038/gim.2015.152.