BackgroundIn this study we aimed to evaluate the efficacy and safety of the PD-L1 inhibitor durvalumab across various mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H)... Show moreBackgroundIn this study we aimed to evaluate the efficacy and safety of the PD-L1 inhibitor durvalumab across various mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H) tumours in the Drug Rediscovery Protocol (DRUP). This is a clinical study in which patients are treated with drugs outside their labeled indication, based on their tumour molecular profile.Patients and methodsPatients with dMMR/MSI-H solid tumours who had exhausted all standard of care options were eligible. Patients were treated with durvalumab. The primary endpoints were clinical benefit ((CB): objective response (OR) or stable disease ≥16 weeks) and safety. Patients were enrolled using a Simon like 2-stage model, with 8 patients in stage 1, up to 24 patients in stage 2 if at least 1/8 patients had CB in stage 1. At baseline, fresh frozen biopsies were obtained for biomarker analyses.ResultsTwenty-six patients with 10 different cancer types were included. Two patients (2/26, 8%) were considered as non-evaluable for the primary endpoint. CB was observed in 13 patients (13/26, 50%) with an OR in 7 patients (7/26, 27%). The remaining 11 patients (11/26, 42%) had progressive disease. Median progression-free survival and median overall survival were 5 months (95% CI, 2-not reached) and 14 months (95% CI, 5-not reached), respectively. No unexpected toxicity was observed. We found a significantly higher structural variant (SV) burden in patients without CB. Additionally, we observed a significant enrichment of JAK1 frameshift mutations and a significantly lower IFN-γ expression in patients without CB.ConclusionDurvalumab was generally well-tolerated and provided durable responses in pre-treated patients with dMMR/MSI-H solid tumours. High SV burden, JAK1 frameshift mutations and low IFN-γ expression were associated with a lack of CB; this provides a rationale for larger studies to validate these findings. Show less
Colorectal cancer is one of the most frequent cancers in the Western world. Forty-five percent of symptomatic patients have metastatic disease. The overall prevalence of adenoma in an asymptomatic... Show moreColorectal cancer is one of the most frequent cancers in the Western world. Forty-five percent of symptomatic patients have metastatic disease. The overall prevalence of adenoma in an asymptomatic population is 25-30% at the age of 50 years and approximately two-thirds of all colonic polyps are adenomatous. Around 95% of CRCs evolve from an adenomatous polyp or sessile serrated lesion (SSL). Only 5% of all adenomatous polyps progress to CRC. To reduce both the incidence and mortality rate of CRC, a national bowel screening program started in January 2014. This thesis focussed on improving clinical care for patients with colorectal neoplasms. From identifying high risk persons/families through the national screening program to modifying a surgical technique to a minimal invasive organ-preserving technique for removal of colorectal neoplasms to the treatment of metastatic colorectal cancer. All studies are based on clinical questions arise from the daily practice. And is therefore also applicable in daily practice. Show less
A proportion of patients with endometrial carcinoma are currently over- or undertreated due to the lack of reproducibility of some of the traditional factors used to assess risk of recurrence and... Show moreA proportion of patients with endometrial carcinoma are currently over- or undertreated due to the lack of reproducibility of some of the traditional factors used to assess risk of recurrence and death due to the cancer, aswell as intrinsic differences in the biological background of tumours within the same risk category. This underlinesthe need for additional biomarkers for the improvement of current risk classification systems and adjuvant treatment selection. In this context, the molecular endometrial carcinoma classification offers an opportunity to categorize tumours according to their molecular background, resulting in more biologically homogeneous groups of patients, with a more precise prognostic and, possibly, predictive value. However, before clinical implementation is possible, information regarding the interpretation of non-hotspot POLE exonuclease domain mutations, aswell as the molecular background and clinical outcome of EC with more than one molecular classifying feature (multiple classifier EC) is needed in order to obtain a reproducible and accurate classification system. Additionally, the integration of the molecular subgroups with clinicopathological features has proven to have a strong prognostic value in intermediate tohigh-risk and unselected cohorts, highlighting its potential to refine prognosis in high-risk patients and perhaps its predictive value. Finally, not all women in the molecularlyprofiled EC cohorts published were staged by lymphadenectomy and most patients had received adjuvant treatment. These features could have influenced the prognostic value of the molecular subgroups. The aims of this thesis were:1) To refine the molecular profiling of endometrial carcinoma by addressing essential remaining questionson the interpretation of POLE variants and characterization of multiple classifier ECs.2) To elucidate the prognostic role of the molecular subgroups in high-risk patients.3) To evaluate the value of the molecular classification to guide adjuvant treatment decisions.4) To investigate the natural behaviour of the molecular EC subgroups among patients staged with lymphadenectomy or not receiving adjuvant treatment. Show less
Hodgkin lymphoma and testicular cancer survivors have an increased risk of developing second primary gastrointestinal malignancies. Whether the pathogenesis of the gastrointestinal malignancies in... Show moreHodgkin lymphoma and testicular cancer survivors have an increased risk of developing second primary gastrointestinal malignancies. Whether the pathogenesis of the gastrointestinal malignancies in cancer survivors differs from cancer in the general population is unknown. This thesis investigated the pathogenesis of gastrointestinal malignancies in Hodgkin lymphoma and testicular cancer survivors. Furthermore, the effectiveness of colorectal cancer surveillance is investigated in these cancer survivors. Additionally, this thesis will focus on mismatch repair deficiency, as identification of Lynch syndrome could have implications for the patients and implications for treatment choice. Show less
Helderman, N.C.; Elsayed, F.A.; Wezel, T. van; Terlouw, D.; Langers, A.M.J.; Egmond, D. van; ... ; Suerink, M. 2022
& nbsp;Small intestine-neuroendocrine tumors (SI-NETs) are one of the most common tumors of the small bowel. Despite an increasing incidence, the exact mechanisms driving underlying pathology... Show more& nbsp;Small intestine-neuroendocrine tumors (SI-NETs) are one of the most common tumors of the small bowel. Despite an increasing incidence, the exact mechanisms driving underlying pathology remain to be determined. Interestingly, recent studies linked the development of (SI-)NETs to both Lynch syndrome (LS) and MUTYH variants. If confirmed, these associations would have important consequences for treatment. In this study we therefore investigated the prevalence of mismatch repair (MMR) deficiency and MUTYH variants in 64 primary resected SI-NETs. Immunohistochemistry was used to assess the expression of the MMR genes, and competitive allele-specific PCR (KASPar) targeting two hotspot MUTYH variants [p.(Tyr179Cys), p.(Gly396Asp)] was performed to determine their prevalence in SI-NETs. Strikingly, all 64 SI-NETs stained positive for MSH6 and PMS2, indicating & nbsp;MMR proficiency. In addition, no MUTYH hotspot variant was found in any of the 64 SI-NETs. As such, these results do not support an association between SI-NET development and LS or MUTYH variants. In order to gain insight into SI-NET pathogenesis and optimally manage patients, future research should therefore focus on other candidate genes. (C) 2022 Published by Elsevier Inc Show less
Mismatch repair (MMR) testing is recommended in the Netherlands for all patients under 70 years of age with newly diagnosed colorectal cancer (CRC) in order to identify Lynch syndrome. T1 CRC can... Show moreMismatch repair (MMR) testing is recommended in the Netherlands for all patients under 70 years of age with newly diagnosed colorectal cancer (CRC) in order to identify Lynch syndrome. T1 CRC can be removed by local excision or oncological surgical resection. We evaluated the frequency of MMR testing in pT1 lesions within the Dutch CRC screening cohort. pT1 CRC diagnosed within the Dutch population-based screening program from 2016-2018 were identified by the Dutch pathology registry (PALGA). Pathology reports were evaluated, including registration of MMR testing (by immunohistochemistry and/or microsatellite instability PCR). Frequency of MMR testing was compared between pT1 tumors that were treated by local (endoscopic or transanal) excision and oncological surgical resections. A total of 3.692 pT1 CRCs were diagnosed (median age 63 years, 61.4% males). MMR testing was performed in 83% and uptake increased over time (71% in 2016 to 92% in 2018, p<0.01). MMR testing was significantly more often performed in younger patients and in academic hospitals. When pT1 CRC was treated by oncological surgical resection (n=1.132), MMR testing was performed in 89% of cases and was known prior to oncological resection in 51% of cases. MMR testing occurred significantly less often in case of local excision (80% of n=2.560) compared to oncological surgical resection (p<0.01). MMR testing was performed in 83% of T1 CRCs and uptake increased over time. MMR testing was more frequently performed in pT1 CRC resected by oncological surgical resection compared with local excision. Show less
