The insulin receptor (INSR) and the insulin growth factor 1 receptor (IGF1R) play important roles in the etiology of both diabetes mellitus and breast cancer. We aimed to evaluate the expression of... Show moreThe insulin receptor (INSR) and the insulin growth factor 1 receptor (IGF1R) play important roles in the etiology of both diabetes mellitus and breast cancer. We aimed to evaluate the expression of hormone and insulin-related proteins within or related to the PI3K and MAPK pathway in breast tumors of women with or without diabetes mellitus, treated with or without insulin (analogues).\nImmunohistochemistry was performed on tumor tissue of 312 women with invasive breast cancer, with or without pre-existing diabetes mellitus, diagnosed in 2000-2010, who were randomly selected from a Danish breast cancer cohort. Women with diabetes were 2:1 frequency matched by year of birth and age at breast cancer diagnosis to those without diabetes. Tumor Microarrays were successfully stained for p-ER, EGFR, p-ERK1/2, p-mTOR, and IGF1R, and scored by a breast pathologist. Associations of expression of these proteins with diabetes, insulin treatment (human insulin and insulin analogues) and other diabetes medication were evaluated by multivariable logistic regression adjusting for menopause and BMI; effect modification by menopausal status, BMI, and ER status was assessed using interactions terms.\nWe found no significant differences in expression of any of the proteins in breast tumors of women with (n = 211) and without diabetes (n = 101). Among women with diabetes, insulin use (n = 53) was significantly associated with higher tumor protein expression of IGF1R (OR = 2.36; 95%CI:1.02-5.52; p = 0.04) and p-mTOR (OR = 2.35; 95%CI:1.13-4.88; p = 0.02), especially among women treated with insulin analogues. Menopause seemed to modified the association between insulin and IGF1R expression (p = 0.07); the difference in IGF1R expression was only observed in tumors of premenopausal women (OR = 5.10; 95%CI:1.36-19.14; p = 0.02). We found no associations between other types of diabetes medication, such as metformin, and protein expression of the five proteins evaluated.\nIn our study, breast tumors of women with pre-existing diabetes did not show an altered expression of selected PI3K/MAPK pathway-related proteins. We observed an association between insulin treatment and increased p-mTOR and IGF1R expression of breast tumors, especially in premenopausal women. This observation, if confirmed, might be clinically relevant since the use of IGF1R and mTOR inhibitors are currently investigated in clinical trials. Show less
Lam, S.W.; Noort, V. van der; Straaten, T. van der; Honkoop, A.H.; Peters, G.J.; Guchelaar, H.J.; E. boven 2018
Older women with breast cancer are underrepresented in the available evidence. Therefore, there is no solid evidence on how to treat older women with breast cancer. This thesis has three main... Show moreOlder women with breast cancer are underrepresented in the available evidence. Therefore, there is no solid evidence on how to treat older women with breast cancer. This thesis has three main conclusions: 1. There are large international differences in the treatment strategy of breast cancer among older women. These differences are not associated with a significant difference in prognosis. 2. The presence of comorbidity has an important impact on the general prognosis of older women with breast cancer. We did not show an important association between specific comorbidities or the use of co-medications and the breast cancer specific prognosis. 3. Concerning older women with breast cancer for research, there are very important methodological issues to take into account, including to avoidance of selection bias and the proper methodologies to take in to account the chance of dying from another cause of cancer: the competing risk of mortality. Future research should be done to create a tool which can assist in identifying the individualised treatment strategy for each older woman with breast cancer. This will have to take into consideration patient’s and tumour’s information, as well as the endpoints for each individual patient. Show less
Blok, E.J.; Bastiaannet, E.; Hout, W.B. van den; Liefers, G.J.; Smit, V.T.H.B.M.; Kroep, J.R.; Velde, C.J.H. van de 2018
This thesis deals with multiple aspects of breast cancer risk stratification after locoregional treatment. The first part of the thesis deals with the reproducibility of established... Show moreThis thesis deals with multiple aspects of breast cancer risk stratification after locoregional treatment. The first part of the thesis deals with the reproducibility of established pathological parameters that currently stratify breast cancer patients to low- or high risk, on the basis of which systemic therapies are considered. The reproducibility of estrogen receptor, progesterone receptor and HER2 is investigated. Additionally, prognostic implication of lymph vascular space invasion is assessed as well as its interobserver reproduciblity. Lastly, the reproducibility of Ki67 assays are determined. The second part of the thesis concerns investigations into the prognostic aspects of the tumor-associated stromal tissues. These tissues might be used to further improve breast cancer risk stratifications as well as help determine tumor susceptibility to systemic treatments. The prognostic implications of the tumor-stroma ratio is investigated. Proteomic studies into the tumor-associated stroma is described as well as a work-flow for investigating metabolic interactions between the tumor epithelium and tumor stroma. The prognostic significance of TGF-beta signaling is also investigated. Show less
The objective of the work presented in this thesis is to assess information provision about adjuvant systemic therapy during consultations between early-stage breast cancer patients and medical... Show moreThe objective of the work presented in this thesis is to assess information provision about adjuvant systemic therapy during consultations between early-stage breast cancer patients and medical oncologists in general. In this era of personalized medicine, prediction tools (e.g., Adjuvant!) are becoming an integral part of information provision during patient consultations. However, evidence is lacking about a) how prevalent the use of such tools is during patient consultations, and b) whether and how the use of such tools influences information provision. Therefore, this thesis in addition to assessing the availability and the quality of prediction tools for the early-stage breast cancer setting, also zooms in on the use of such tools during patient consultations and their impact on the content of consultations. Show less
Hamelinck, V.C.; Stiggelbout, A.M.; Velde, C.J.H. van de; Liefers, G.J.; Bastiaannet, E. 2017
Upon activation by estrogen, the Estrogen Receptor binds the chromatin and influences gene transcription. This ultimately leads to cell proliferation. About 75% of breast cancer patients... Show moreUpon activation by estrogen, the Estrogen Receptor binds the chromatin and influences gene transcription. This ultimately leads to cell proliferation. About 75% of breast cancer patients express this hormonal receptor. These patients are often treated with tamoxifen, which competitively inhibits the proliferative effects of estrogen in breast cancer cells. While tamoxifen inhibits the tumor growth of breast cancer, its effects in other Estrogen Receptor-positive tissues vary, as reviewed in chapter 1. Its most adverse side-effect is that it increases the risk for endometrial cancer. Chapters 2 and 3 describe the effects of tamoxifen on the DNA binding sites of the Estrogen Receptor in tamoxifen-associated endometrial cancer, and the similarities of these binding sites with those found in breast cancer. Unfortunately, there are Estrogen Receptor-positive breast cancer patients who do not respond to hormonal treatment. Chapter 4 reveals a key-role for activating transcription factor 2 on tamoxifen’s inhibitory response on cell proliferation. Chapter 5 discusses components of the Estrogen Receptor pathway and highlights their potential as biomarkers in hormonal response therapy. Finally, chapter 6 provides new questions invoked by this thesis, and discusses the importance of unraveling the Estrogen Receptor pathway in multiple tissues in order to develop tailor-made treatments. Show less
