BackgroundWe aimed to study the pharmacokinetics and -dynamics of tamoxifen in older women with non-metastatic breast cancer.MethodsData for this analysis were derived from the CYPTAM study ... Show moreBackgroundWe aimed to study the pharmacokinetics and -dynamics of tamoxifen in older women with non-metastatic breast cancer.MethodsData for this analysis were derived from the CYPTAM study (NTR1509) database. Patients were stratified by age (age groups < 65 and 65 and older). Steady-state trough concentrations were measured of tamoxifen, N-desmethyltamoxifen, 4-hydroxy-tamoxifen, and endoxifen. CYP2D6 and CYP3A4 phenotypes were assessed for all patients by genotyping. Multiple linear regression models were used to analyze tamoxifen and endoxifen variability. Outcome data included recurrence-free survival at time of tamoxifen discontinuation (RFSt) and overall survival (OS).Results668 patients were included, 141 (21%) were 65 and older. Demographics and treatment duration were similar across age groups. Older patients had significantly higher concentrations of tamoxifen 129.4 ng/ml (SD 53.7) versus 112.2 ng/ml (SD 42.0) and endoxifen 12.1 ng/ml (SD 6.6) versus 10.7 ng/ml (SD 5.7, p all < 0.05), independently of CYP2D6 and CYP3A4 gene polymorphisms. Age independently explained 5% of the variability of tamoxifen (b = 0.95, p < 0.001, R-2 = 0.051) and 0.1% of the variability in endoxifen concentrations (b = 0.45, p = 0.12, R-2 = 0.007). Older patients had worse RFSt (5.8 versus 7.3 years, p = 0.01) and worse OS (7.8 years versus 8.7 years, p = 0.01). This was not related to differences in endoxifen concentration (HR 1.0, 95% CI 0.96-1.04, p = 0.84) or CYP polymorphisms.ConclusionSerum concentrations of tamoxifen and its demethylated metabolites are higher in older patients, independent of CYP2D6 or CYP3A4 gene polymorphisms. A higher bioavailability of tamoxifen in older patients may explain the observed differences. However, clinical relevance of these findings is limited and should not lead to a different tamoxifen dose in older patients. Show less
Endometrial cancer (EC) is the most common gynaecological cancer in developed countries. Standard treatment consists of surgery (hysterectomy and bilateral salpingo-oophorectomy) followed by either... Show moreEndometrial cancer (EC) is the most common gynaecological cancer in developed countries. Standard treatment consists of surgery (hysterectomy and bilateral salpingo-oophorectomy) followed by either no adjuvant treatment, vaginal brachytherapy (VBT) or external beam radiotherapy (EBRT) with or without chemotherapy. The type of adjuvant treatment is based on clinicopathologic risk factors as age, FIGO-stage, histologic type and grade, myometrial invasion and lymph-vascular space invasion. In the recent years, knowledge has been gained on molecular risk factors in EC and four different molecular subgroups with distinct prognosis have been defined. The implementation of these subgroups into the treatment guidelines is being investigated in the PORTEC-4a trial. In this trial women with high-intermediate risk EC are randomised to either VBT versus an experimental arm in which a molecular-integrated risk profile is used to guide adjuvant treatment. With the improved patient selection women with favourable prognosis can be spared unnecessary treatment, while those with unfavourable prognosis are treated with more intensive treatment (EBRT). Besides the improvement of patient selection, radiotherapy techniques have developed as well. Modern radiotherapy techniques can increasingly spare healthy tissues with comparable outcomes and less toxicity. These developments will lead to better results and higher(er) quality-of-life for women with EC. Show less
Approximately 15–20% of women with endometrial cancer have high-risk disease features and are at increased risk of distant metastases. Standard treatment after surgery is pelvic radiotherapy to... Show moreApproximately 15–20% of women with endometrial cancer have high-risk disease features and are at increased risk of distant metastases. Standard treatment after surgery is pelvic radiotherapy to reduce the risk of recurrence. In the international PORTEC-3 trial we have investigated the added value of adjuvant chemotherapy during and after radiotherapy in terms of efficacy, toxicity and quality of life. It was found that both overall and recurrence-free survival were significantly improved with the addition of chemotherapy to radiotherapy, especially for women with more advanced disease (stage 3) or with serous histological type. This comes however at the expense of increased and more serious toxicity and an impaired quality of life during and in the first 6 months after treatment. About 25% of women treated with chemotherapy still reported tingling and numbness of hands and/or feet at 2 years after treatment. It is therefore important to discuss the benefits and costs of the addition of chemotherapy in shared decision making, for which the results discussed in this thesis provide valuable information. Currently molecular analysis of the PORTEC-3 tissue samples is done to evaluate which patients benefit most from added chemotherapy. Show less
Somatic mutations in the proofreading domain of DNA polymerase epsilon denote a distinct molecular subgroup of endometrial cancer, characterized by an exceptionally high mutational burden.... Show moreSomatic mutations in the proofreading domain of DNA polymerase epsilon denote a distinct molecular subgroup of endometrial cancer, characterized by an exceptionally high mutational burden. Despite this so-called ‘ultramutated’ phenotype, POLE-mutant endometrial cancers have an excellent prognosis with very few recurrences. This thesis provides insights into somatic POLE exonuclease domain mutations in endometrial cancer and especially into the underlying mechanisms by which these POLE mutations contribute to the favorable clinical outcome. Studies in this thesis focus on the immune response in POLE-mutant endometrial cancers and show that these tumors are characterized by an intratumoral T cell response. This response correlates with an enrichment of neo-epitopes, providing a plausible mechanisms for the excellent prognosis of these cancers. We demonstrate that increased sensitivity to adjuvant treatment cannot explain the good clinical outcome. Furthermore, we show that somatic POLE mutations are early, and probably initiating events in endometrial and colorectal carcinogenesis. These insights provide a deeper understanding of the molecular mechanisms underlying this group of endometrial cancers and may facilitate the implementation of POLE mutation screening in routine clinical practice. This would be an important step towards a more tailored treatment approach in endometrial cancer. Show less
Velde, C.J.H. van de; Boelens, P.G.; Borras, J.M.; Coebergh, J.W.; Cervantes, A.; Blomqvist, L.; ... ; Valentini, V. 2014
