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- Gapstur, S. M., et al.
(författare)
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Menopausal hormone use and ovarian cancer risk: individual participant meta-analysis of 52 epidemiological studies
- 2015
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Ingår i: The Lancet. - 1474-547X. ; 385:9980, s. 1835-1842
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Tidskriftsartikel (refereegranskat)abstract
- Background Half the epidemiological studies with information about menopausal hormone therapy and ovarian cancer risk remain unpublished, and some retrospective studies could have been biased by selective participation or recall. We aimed to assess with minimal bias the effects of hormone therapy on ovarian cancer risk. Methods Individual participant datasets from 52 epidemiological studies were analysed centrally. The principal analyses involved the prospective studies (with last hormone therapy use extrapolated forwards for up to 4 years). Sensitivity analyses included the retrospective studies. Adjusted Poisson regressions yielded relative risks (RRs) versus never-use. Findings During prospective follow-up, 12 110 postmenopausal women, 55% (6601) of whom had used hormone therapy, developed ovarian cancer. Among women last recorded as current users, risk was increased even with <5 years of use (RR 1.43, 95% CI 1.31-1.56; p<0.0001). Combining current-or-recent use (any duration, but stopped <5 years before diagnosis) resulted in an RR of 1.37 (95% CI 1.29-1.46; p<0.0001); this risk was similar in European and American prospective studies and for oestrogen-only and oestrogen-progestagen preparations, but differed across the four main tumour types (heterogeneity p<0.0001), being definitely increased only for the two most common types, serous (RR 1.53, 95% CI 1.40-1.66; p<0.0001) and endometrioid (1.42, 1.20-1.67; p<0.0001). Risk declined the longer ago use had ceased, although about 10 years after stopping long-duration hormone therapy use there was still an excess of serous or endometrioid tumours (RR 1.25, 95% CI 1.07-1.46, p=0.005). Interpretation The increased risk may well be largely or wholly causal; if it is, women who use hormone therapy for 5 years from around age 50 years have about one extra ovarian cancer per 1000 users and, if its prognosis is typical, about one extra ovarian cancer death per 1700 users.
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- Lokkegaard, Sanne, et al.
(författare)
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MCM3 upregulation confers endocrine resistance in breast cancer and is a predictive marker of diminished tamoxifen benefit
- 2021
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Ingår i: npj Breast Cancer. - : NATURE RESEARCH. - 2374-4677. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- Resistance to endocrine therapy in estrogen receptor-positive (ER+) breast cancer is a major clinical problem with poorly understood mechanisms. There is an unmet need for prognostic and predictive biomarkers to allow appropriate therapeutic targeting. We evaluated the mechanism by which minichromosome maintenance protein 3 (MCM3) influences endocrine resistance and its predictive/prognostic potential in ER+ breast cancer. We discovered that ER+ breast cancer cells survive tamoxifen and letrozole treatments through upregulation of minichromosome maintenance proteins (MCMs), including MCM3, which are key molecules in the cell cycle and DNA replication. Lowering MCM3 expression in endocrine-resistant cells restored drug sensitivity and altered phosphorylation of cell cycle regulators, including p53(Ser(315,33)), CHK1(Ser(317)), and cdc25b(Ser(323)), suggesting that the interaction of MCM3 with cell cycle proteins is an important mechanism of overcoming replicative stress and anti-proliferative effects of endocrine treatments. Interestingly, the MCM3 levels did not affect the efficacy of growth inhibitory by CDK4/6 inhibitors. Evaluation of MCM3 levels in primary tumors from four independent cohorts of breast cancer patients receiving adjuvant tamoxifen mono-therapy or no adjuvant treatment, including the Stockholm tamoxifen (STO-3) trial, showed MCM3 to be an independent prognostic marker adding information beyond Ki67. In addition, MCM3 was shown to be a predictive marker of response to endocrine treatment. Our study reveals a coordinated signaling network centered around MCM3 that limits response to endocrine therapy in ER+ breast cancer and identifies MCM3 as a clinically useful prognostic and predictive biomarker that allows personalized treatment of ER+ breast cancer patients.
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- Pedersen, A. T., et al.
(författare)
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Impact of recent studies on attitudes and use of hormone therapy among Scandinavian gynaecologists
- 2007
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Ingår i: Acta Obstet Gynecol Scand. - 1600-0412. ; 86:12, s. 1490-5
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Climacteric medicine has been in focus during the last 2 decades, and an intensive debate has been ongoing regarding the positive and negative aspects of postmenopausal hormone therapy (HT). Recent randomised controlled studies have been unable to confirm data from observational studies of primary or secondary preventive effects of HT on coronary heart disease, and other studies have indicated an increased risk of breast cancer, stroke and venous thromboembolism among HT users. In 2001, we reported on knowledge, attitudes, management strategies and use of HT among Scandinavian gynaecologists. The aim of the present study was to re-assess the same parameters concerning HT among Scandinavian gynaecologists in 2002-2003, and compare the results with the data collected in 1995-1997. METHODS: All practicing gynaecologists in Denmark, Sweden and Norway were invited by letter to complete and return a questionnaire regarding their knowledge, attitudes and management strategies concerning HT. Female gynaecologists were questioned if they were currently using HT, and the same question was posed concerning spouses of male gynaecologists. RESULTS: The questionnaire was completed and returned by 60, 76 and 72%, respectively of gynaecologists in Denmark, Sweden and Norway. Of the 1,591 physicians who responded, 13% thought that all women should be offered HT provided there were no contraindications, while 86% recommended HT only to selected women after considering the individual advantages and disadvantages of the treatment. Of the gynaecologists, 37% considered HT to be without relevance in the primary prevention of osteoporosis in healthy women. As for duration of the treatment, 40% of the gynaecologists would recommend HT for <5 years for the treatment of climacteric complaints, and only 8% would recommend HT for >10 years. The prevalence of HT use among the menopausal female gynaecologists varied between 71 and 74%. Among the menopausal spouses of male gynaecologists, 68-72% were current users of HT. CONCLUSION: During the last years of ongoing debate, gynaecologists from Denmark, Sweden and Norway have become more modest in their recommendations of postmenopausal HT. Scandinavian specialists are more cautious in prescribing hormones for women with symptomatic CVD or previously treated for breast cancer, however, their personal use of HT has not changed dramatically and still reflects a positive attitude.
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