المؤلفون: Kirsten Kubler, Agostina Nardone, Shankara Anand, Daniel Gorvich, Marjolein Droog, Francisco Hermida-Prado, Tara Akshi, Avery S Feit, Gabriella Cohen, Gwen Dackus, Matthew Pun, Yanan Kuang, Justin Cha, Mendy Miller, William J Gibson, Cloud P Paweletz, Eliezer M Van Allen, Flora E van Leeuwen, Petra Nederlof, Harry Hollema, Quang-Dé Nguyen, Marian JE Mourits, Ignaty Leshchiner, Chip Stewart, Ursula A Matulonis, Wilbert Zwart, Yosef E Maruvka, Gad Getz, Rinath Jeselsohn

المصدر: Cancer Research. 82:GS2-09

مصطلحات موضوعية: Cancer Research, Oncology

الوصف: Tamoxifen is widely used in the adjuvant treatment of estrogen receptor–positive (ER+) breast cancer and is an important drug for pre-menopausal women and post-menopausal patients who cannot tolerate aromatase inhibitors. Despite the clear clinical benefit in improving relapse-free and overall survival in these patients, an adverse effect of tamoxifen is a 2- to 7-fold increased risk of uterine cancer (UC) after 2-5 years of treatment. To date, the mechanism of tamoxifen-driven tumorigenesis is not well understood, and preventive approaches are lacking. Here, to molecularly characterize tamoxifen-associated uterine cancers (TA-UCs) and gain insights into their unique evolution, we performed whole-exome sequencing of 21 TA-UCs (discovery cohort) and droplet digital PCR (ddPCR) of an additional 40 TA-UCs (validation cohort) obtained from the ‘Tamoxifen Associated Malignancies: Aspects of Risk’ (TAMARISK) study. In addition, we used in vivo mouse models to: (i) further investigate tamoxifen-activated molecular pathways that may be involved in TA-UC tumorigenesis; and (ii) offer mechanistic insights. Overall, we discovered that TA-UCs were genomically similar to non–TA-UCs from The Cancer Genome Atlas (TCGA) project, with one profound exception: TA-UCs are characterized by a lower-than-expected frequency of mutations in two highly prevalent UC driver genes in the PI3K pathway: PIK3CA (14% [3/21] vs 48% [265/554] in non–TA-UC; P=0.003, Fisher’s exact test; Q=0.02, Benjamini-Hochberg FDR) and PIK3R1 (0%, [0/21] vs 31% [174/554]; P=0.001; Q=0.01). We used ddPCR in the independent TA-UC validation cohort and confirmed the low frequency of mutations in PIK3CA (7.5% [3/40] vs 21% [144/685] in control UCs from the Dana-Farber contribution to the AACR GENIE project; P=0.04). We next performed mouse in vivo studies and demonstrated that tamoxifen activated the PI3K pathway and increased cell proliferation in normal mouse uterine tissue through paracrine and autocrine effects, both of which were abrogated by the PI3K inhibitor alpelisib. Taken together, we describe a distinct and novel pathway of carcinogenesis in which tamoxifen acts as a driver event in the uterus and promotes tumor development in a mutation-independent manner. Indeed, tamoxifen may increase the risk of UC by activating the PI3K pathway, which can substitute for the early acquisition of oncogenic PIK3CA or PIK3R1 mutations observed in non–TA-UC tumors. Furthermore, the ability of a PI3K inhibitor to reduce cell proliferation in our mouse model raises the possibility that downregulating the PI3K pathway may prevent or significantly reduce TA-UC development, offering a potential future therapeutic and prevention strategy for specific high-risk patients undergoing tamoxifen therapy. Citation Format: Kirsten Kubler, Agostina Nardone, Shankara Anand, Daniel Gorvich, Marjolein Droog, Francisco Hermida-Prado, Tara Akshi, Avery S Feit, Gabriella Cohen, Gwen Dackus, Matthew Pun, Yanan Kuang, Justin Cha, Mendy Miller, William J Gibson, Cloud P Paweletz, Eliezer M Van Allen, Flora E van Leeuwen, Petra Nederlof, Harry Hollema, Quang-Dé Nguyen, Marian JE Mourits, Ignaty Leshchiner, Chip Stewart, Ursula A Matulonis, Wilbert Zwart, Yosef E Maruvka, Gad Getz, Rinath Jeselsohn. Tamoxifen instigates uterine cancer development by activating PI3K signaling and supersedes PIK3CA driver mutations [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr GS2-09.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::6c533d1be37ca1b1d6a88816bc753271Test
https://doi.org/10.1158/1538-7445.sabcs21-gs2-09Test

المؤلفون: Mark Opdam, Sabine C. Linn, Michael Hauptmann, Harry Hollema, Lodewyk F. A. Wessels, Marian J.E. Mourits, Marjolein Droog, Koen D. Flach, Wilbert Zwart, Karianne Schuurman, Tesa M. Severson, Flora E. van Leeuwen, Patrycja Gradowska, Hester van Boven, Yongsoo Kim, Petra M. Nederlof, Gwen M. H. E. Dackus, Ekaterina Nevedomskaya

المساهمون: Targeted Gynaecologic Oncology (TARGON), Damage and Repair in Cancer Development and Cancer Treatment (DARE), Pathology, Epidemiology and Data Science, EMGO - Quality of care

المصدر: Droog, M, Kim, Y, Nevedomskaya, E, Severson, T, Flach, K D, Opdam, M, Schuurman, K, Gradowska, P, Hauptmann, M, Dackus, G, Hollema, H, Mourits, M, Nederlof, P, Van Boven, H, Linn, S C, Wessels, L, Van Leeuwen, F E & Zwart, W 2016, ' Comparative cistromics reveals genomic cross-talk between FOXA1 and ERα in tamoxifen-associated endometrial carcinomas ', Cancer Research, vol. 76, no. 13, pp. 3773-3784 . https://doi.org/10.1158/0008-5472.CAN-14-1813Test
Cancer Research, 76(13), 3773-3784. AMER ASSOC CANCER RESEARCH
Cancer Research, 76(13), 3773-3784. American Association for Cancer Research Inc.

مصطلحات موضوعية: 0301 basic medicine, Oncology, Cancer Research, FORKHEAD-BOX A1, Immunoenzyme Techniques, 0302 clinical medicine, PROGNOSTIC-SIGNIFICANCE, TRANSCRIPTION FACTOR, skin and connective tissue diseases, RISK, Reverse Transcriptase Polymerase Chain Reaction, Gene Expression Regulation, Neoplastic, 030220 oncology & carcinogenesis, Female, ESTROGEN-RECEPTOR-ALPHA, Signal Transduction, medicine.drug, Hepatocyte Nuclear Factor 3-alpha, EXPRESSION, Chromatin Immunoprecipitation, medicine.medical_specialty, Antineoplastic Agents, Hormonal, Breast Neoplasms, Biology, LUMINAL SUBTYPE, Real-Time Polymerase Chain Reaction, Response Elements, CELL-PROLIFERATION, 03 medical and health sciences, Breast cancer, Internal medicine, Biomarkers, Tumor, medicine, Humans, BREAST-CANCER, RNA, Messenger, Transcription factor, Endometrial cancer, Estrogen Receptor alpha, Cancer, medicine.disease, Endometrial Neoplasms, Tamoxifen, 030104 developmental biology, Cancer research, FOXM1, FOXA1, Estrogen receptor alpha, RESISTANCE

الوصف: Tamoxifen, a small-molecule antagonist of the transcription factor estrogen receptor alpha (ERα) used to treat breast cancer, increases risks of endometrial cancer. However, no parallels of ERα transcriptional action in breast and endometrial tumors have been found that might explain this effect. In this study, we addressed this issue with a genome-wide assessment of ERα-chromatin interactions in surgical specimens obtained from patients with tamoxifen-associated endometrial cancer. ERα was found at active enhancers in endometrial cancer cells as marked by the presence of RNA polymerase II and the histone marker H3K27Ac. These ERα binding sites were highly conserved between breast and endometrial cancer and enriched in binding motifs for the transcription factor FOXA1, which displayed substantial overlap with ERα binding sites proximal to genes involved in classical ERα target genes. Multifactorial ChIP-seq data integration from the endometrial cancer cell line Ishikawa illustrated a functional genomic network involving ERα and FOXA1 together with the enhancer-enriched transcriptional regulators p300, FOXM1, TEAD4, FNFIC, CEBP8, and TCF12. Immunohistochemical analysis of 230 primary endometrial tumor specimens showed that lack of FOXA1 and ERα expression was associated with a longer interval between breast cancer and the emergence of endometrial cancer, exclusively in tamoxifen-treated patients. Our results define conserved sites for a genomic interplay between FOXA1 and ERα in breast cancer and tamoxifen-associated endometrial cancer. In addition, FOXA1 and ERα are associated with the interval time between breast cancer and endometrial cancer only in tamoxifen-treated breast cancer patients. Cancer Res; 76(13); 3773–84. ©2016 AACR.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::36c889c8917664f080399220df564bdaTest
https://research.rug.nl/en/publications/23754f80-627e-40bc-a802-317a2a8d331fTest

المؤلفون: Jelle Wesseling, Marjanka K. Schmidt, Lindy L. Visser, Flora E. van Leeuwen, Lotte L. Elshof, Emma J. Groen, Esther H. Lips, Mathilde M. Almekinders, Koen Van de Vijver, Emiel J. Th. Rutgers, Michael Schaapveld

المصدر: Cancer Research. 77:4738-4738

مصطلحات موضوعية: Oncology, Cancer Research, education.field_of_study, medicine.medical_specialty, medicine.diagnostic_test, business.industry, medicine.medical_treatment, Population, Histology, Disease, Ductal carcinoma, medicine.disease, Breast cancer screening, Breast cancer, Internal medicine, medicine, Breast-conserving surgery, Immunohistochemistry, skin and connective tissue diseases, education, business, neoplasms

الوصف: INTRODUCTION. The wide spread adoption of population-based breast cancer screening has led to a substantial increase in diagnosis of ductal carcinoma in situ (DCIS). When detected, almost all DCIS is treated to prevent progression to invasive disease, even though the majority of DCIS will never progress. Yet, we are unable to discriminate harmless from potentially hazardous DCIS. Hence, there is an urgent need to find characteristics of DCIS and biomarkers that predict subsequent invasive tumor development. In this study, we compared primary DCIS lesions with their subsequent ipsilateral invasive breast cancer (iIBC), to explore how the initial DCIS lesion and its subsequent iIBC are related. PATIENTS AND METHODS. We used a population-based, nation-wide cohort consisting of 2,654 women who were treated for primary DCIS by breast conserving surgery (BCS) only. Within a median follow-up time of 10.7 years, 316 women developed a subsequent iIBC (12%). FFPE tissue blocks of both DCIS and subsequent iIBC could be collected for 158 of these 316 women. We assessed histology characteristics, tumor location, estrogen and progesterone receptor status, p16 expression, and HER2 and p53 overexpression. Additionally, DNA and RNA were simultaneously isolated from 100 DCIS and 100 matched subsequent iIBC specimens for extensive molecular profiling. RESULTS. More than 95% of the invasive recurrences were located at or near the site of the primary DCIS. Concordant histological grade was found in 94% of the matched pairs and identical immunohistochemical (IHC) marker expression in 58%. Of the 44 patients with HER2 positive DCIS, 36% developed HER2 negative iIBC. Furthermore, this change in HER2 status was also a main cause of a change in surrogate intrinsic subtype (based on ER, PR, HER2) between DCIS and iIBC, which was observed in 16% of the patients. These dissimilarities were not found when we compared invasive disease with synchronous DCIS (present in 83 of 158 patients). Molecular analyses is still ongoing. CONCLUSION. This is the first time that an unbiased comparison could be made between primary DCIS and its subsequent iIBC within such a large patient group, integrating clinical, histological and IHC data. Our results suggest that the majority of invasive breast cancers in our cohort reflect outgrowth of residual disease based on tumor location and histological grade. DCIS and iIBC are very similar when comparing histological grade, but frequently show differences on the IHC level. Remarkably, the dissimilarities in HER2 status and surrogate intrinsic subtype as seen in primary DCIS vs. iIBC are missing when comparing IBC with synchronous DCIS. As a next step, we will analyse the lesions on the molecular level, to verify these findings and to look for molecular characteristics of DCIS that could be associated with progression to invasive disease. Citation Format: Lindy L. Visser, Lotte L. Elshof, Koen van de Vijver, Emma J. Groen, Mathilde Almekinders, Marjanka K. Schmidt, Flora van Leeuwen, Emiel J. Rutgers, Michael Schaapveld, Esther H. Lips, Jelle Wesseling. Risk of ipsilateral invasive breast cancer after DCIS: a comparison of primary DCIS and subsequent invasive disease by morphological and immunohistochemical analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4738. doi:10.1158/1538-7445.AM2017-4738

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::44353a5469035ec8bc987a3b0fb6ab2fTest
https://doi.org/10.1158/1538-7445.am2017-4738Test

المؤلفون: Rob A. E. M. Tollenaar, Flora E. van Leeuwen, Alexandra J. van den Broek, Marjanka Mk Schmidt, Laura J. van't Veer

المصدر: Cancer Research. 73:1338-1338

مصطلحات موضوعية: Oncology, Cancer Research, medicine.medical_specialty, business.industry, Cancer, medicine.disease, Surgery, Breast cancer, Large breast, Internal medicine, Mutation (genetic algorithm), Cohort, medicine, Family history, skin and connective tissue diseases, business, Pathological, Cohort study

الوصف: The biological background and different pathological aspects of BRCA1-associated tumors support the hypothesis that patients carrying a BRCA1 and/or BRCA2 mutation might have a worse breast cancer prognosis compared to non-carriers. However, studies showed inconsistent results, possibly due to differences in study design, study size, study populations and methodological quality. We recently performed a systematic review taking into account the quality of all relevant studies published so far on BRCA1/2 mutation carriership and survival (n=63). Using a best-evidence synthesis, we found that there is only moderate evidence for a worse unadjusted recurrence-free survival for BRCA1 mutation carriers compared to non-carriers (pooled absolute survival difference of 10%) (to be submitted). The aim of the current study was to evaluate breast cancer outcome in a multicenter cohort of breast cancer patients with long-term follow-up, unselected for family history. We included invasive pathologically-confirmed breast cancers, diagnosed before Among 5518 breast cancer patients with a BRCA1/2 result we found 3.6% BRCA1 and 1.2% BRCA2 mutation carriers. The proportions of ER-positive breast cancers in non-BRCA, BRCA1 and BRCA2 mutation carriers were 86%, 29% and 81% respectively. Mean follow-up of the cohort was 11.3 years. Overall survival was worse for BRCA1 mutation carriers compared to non-carriers (HR-unadjusted 1.4 (95%CI: 1.1-1.7), p=0.003; HR-adjusted 1.2 (1-1.6), p=0.07); recurrence-free survival was also worse for BRCA1 mutation carriers (HR-adjusted 1.5 (1.1-1.9), p=0.004). We did not find evidence for a different survival of BRCA2 mutation carriers, except for a suggestion of a worse overall survival. These results are preliminary and further analyses including stratifications by tumor subtype and treatment will be presented at the AACR meeting. In one of the largest, unbiased, BRCA1/2 genotyped breast cancer cohort study, we found evidence for a significant worse overall and recurrence-free survival adjusted for clinico-pathological factors of BRCA1 mutation carriers. Citation Format: Marjanka MK Schmidt, Alexandra J. van den Broek, Rob AEM Tollenaar, Flora E. van Leeuwen, Laura J. Van ‘t Veer, on behalf of collaborators of 10 centers in the Netherlands. Breast cancer survival of BRCA1/2 carriers compared to non-BRCA1/2 carriers in a large breast cancer cohort. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1338. doi:10.1158/1538-7445.AM2013-1338

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::04f70dd5e3636f1132bee225de20b664Test
https://doi.org/10.1158/1538-7445.am2013-1338Test