1. Sri Puspita Amalia NP Lingga S Rienna Diansari Harsya DG WEEK 2 EBCR – 8A

2. Case Ilustration Mrs. X, 60 years old, complains a lump in her right breast since 4 weeks ago. The lump is not painful and getting bigger over time. It is fixated and has flat surface. There are some changes on her breast skin too. Mrs. X has been menopause since 7 years ago, and with the recommendation of her previous doctor, she has been taking estrogen therapy to prevent heart disease and osteoporosis. Her elder sister died 2 months ago from breast cancer and had a history of estrogen-progestin therapy. She asked whether the hormonal therapy could induce breast cancer..

3. Background In 2011, an estimated 230,480 new cases of invasive breast cancer were expected to be diagnosed in women in the U.S., along with 57,650 new cases of non-invasive (in situ) breast cancer. The second most common female cancer in Indonesia Risk factor: exposure to estrogen (hormone replacement therapy), family history, diet, oral contraceptive, breast changes, etc. Vogel VG. Breast Cancer. 2008. Merck & Co. Available at: http://www.merckmanuals.com/professional/gynecology_and_obstetrics/breast_disorders/breast_cancer.html http://www.merckmanuals.com/professional/gynecology_and_obstetrics/breast_disorders/breast_cancer.html Tjindarbumi D, Mangunkusumo R. Cancer in Indonesia, Present and Future. Jpn J Clin Oncol 2002; 32.

4. Estrogen and progesterone receptors, present in some breast cancers, are nuclear hormone receptors that promote DNA replication and cell division when the appropriate hormones bind to them. About two thirds of postmenopausal patients have an estrogen-receptor positive (ER+) tumor. Incidence of ER+ tumors is lower among premenopausal patients. Vogel VG. Breast Cancer. 2008. Merck & Co. Available at: http://www.merckmanuals.com/professional/gynecology_and_obstetrics/breast_disorders/breast_cancer.html http://www.merckmanuals.com/professional/gynecology_and_obstetrics/breast_disorders/breast_cancer.html

5. PICO Postmenopausal Women Patient /Problem Estrogen Therapy Intervention Estrogen-progestine therapy Comparison Breast cancer Outcome

6. Clinical Question In postmenopausal women, does estrogen therapy increase risk factor for breast cancer compared to estrogen-progestin therapy Type of Question Etiology

7. Methods

8. Search Strategy

9. post menopausal OR post-menopausal OR postmenopausal AND estrogen OR estrogen-induced OR estrogen induced OR estrogen therapy AND breast cancer OR breast neoplasm OR breast malignancy Ebsco Pubmed 2996 Inclusion: 10 years, human, female, systematic review, meta- analysis, english 60 Free full text availability 14 Screening title & abstract 114599 58 Useful 2 articles Search date: May 31 st, 2012 Major heading: Postmenopause, breast cancer, hormone replacement therapy Cochrane 95 1 1 0 0 Ebsco 0 Cochrane 0 Pubmed 2

11. What Questions did the Systematic Review Address? Is there any association between postmenopausal hormone therapy and increased of breast cancer event?

12. Is it unlikely that important & relevant studies were missed? Litearture search was done with Medline and Cancerlit database. Terms/Keyword: hormone replacement therapy, estrogen replacement, cancer and neoplasm.

13. The search limited to english language only. The search strategy include both MESH terms and text words. They used the reference lists from relevant studies But they did not pursue the unpublished data.

14. Were the criteria used to select articles for inclusion appropriate? The inclusion criteria for the subject is postmenopausal women. Data on cancer incidence. mortality, pathoogy or stage had to be reported. Inclusion criteria: 1. the study was observational or interventional with a comparison group 2. the study incorporated longitudinal ascertainment of exposure and disease 3. the study reported data on rates of cancer in at least two groups (“never” and “current” users), or the study included a summary estimate (eg, odds ratio, relative risk) with reported CIs or a precise P value 4. the study had to distinguish between noncontraceptive and contraceptive estrogen use in its presentation of results. 5. Reports selected for meta-analyses additionally had to provide estimates of risk for women using ET or CHT at study inception (current use). Exclusion criteria: editorials, letters, and nonsystematic reviews

15. Were the included studies sufficiently valid for the type of question asked? They selected most up-to-date results, longest follow up or most pertinent outcomes. They studies should at least have two group (never and current user of hormonal therapy)

16. Were the result similar from study to study? 8 cohort and 5 case-control studies addresed the association of estrogen therapy and breast cancer. Meta-analysis if these 13 studies including 701.160 women suggesting heterogeneity (P = 0.003 and I 2 = 53%) The potential sources of this heterogeneity did not detect a relation of the odds ratio to design (case control versus cohort), location (US versus Europe), enrollment or publication year, study size, quality rating (good versus poor/fair), years of follow-up, or adjustment for socioeconomic status.

17. IMPORTANCE Eight cohort and five case-control studies addressed the association of ET and breast cancer. Meta-analysis of these 13 studies including 701,160 women results in a pooled OR of 1.16 (95% CL 1.06, 1.28) with the Q test P = 0.003 suggesting heterogeneity and I 2 = 53% Nine studies provided estimates for less than 5 years of ET use: OR 1.16 (1.02, 1.32) with the Q test P = 0.09 and I2 = 27%. Ten studies provided data for 5 or more years of use: OR 1.20 (1.06, 1.37) with the Q test P < 0.001 and I2 = 70%.

18. We conducted a meta-analysis of observational studies of CHT and breast cancer (four cohort and four case-control studies). Meta-analysis of these eight studies with 655,559 women yields a pooled OR of 1.39 (95% CL 1.12, 1.72) with a heterogeneity P of < 0.001 and I2 = 87% (see Fig. 2). Six studies provided estimates for less than 5 years of CHT use: OR 1.35 (1.16, 1.57) with the Q test P = 0.17 and I2 = 11%. Five studies provided data for 5 or more years of use: OR 1.63 (1.22, 2.18) with the Q test P < 0.001 and I2 = 74%.

19. APPLICABILITY Is our patient so different from those in the study that its results cannot apply? NO What are our patient’s risks of benefit and harm from the agent? Cardiovascular, osteoporosis >< Breast ca What are our patient’s preferences, concerns, and expectations from this treatment? What alternatives treatments are availabe ? Lifestyle changes, physical exercise, diet, supplementation, prevention of HT

21. What Questions did the Systematic Review Address? What is the impact of menopausal hormone therapy (MHT) on the risk of incident invasive breast cancer

22. Is it unlikely that important & relevant studies were missed? Medline and the Cochrane Controlled Trials Register (http://www.cochranelibrary.com) From 1989 until August 2004 The search was restricted to studies conducted in the United States, Canada and European countries

23. “We used recent systematic reviews to potentially identify further studies and reference lists of pertinent studies, topic- specific reviews editorials, supplements, conference proceedings and abstract books” “In studies with multiple publications from the same population, we included only data from the most recent publication.” “In the case of double publication, we included only the data sets of the first publication”

24. Were the result similar from study to study? They included 15 cohort studies, 6 RCT studies, and 21 case control studies. Briefly, regarding the number of cases, age, duration of therapy, type of hormonal therapy and time of follow up, it varied widely. All studies show heterogeneity, except for the earlier period cohort/RCT studies

25. Importance Sistematik review terdiri dari 94 studi, yang distratifikasi berdasar tipe studi (case-control, cohort, dan RCT), tipe hormon (estrogen, estrogen-progestin, dan menopausal hormone therapy), dan waktu studi (sebelum dan sesudah 1992). setiap studi, ditampilkan data OR (Odds Ratio) dan RR (Relative Risk), 95% Confidence Interval. untuk melihat persamaan (similarity) dari hasil semua studi tersebut, digunakan forest plot. uji heterogenitas dilakukan dengan metode general variance-based dan Cochrane’s Q.

29. In conclusion, there is evidence that relative risks for BC risks by MHT, in particular EPT, and risks have been increasing in recent years. Given the widespread use of MHT, and often long duration, more detailed knowledge about differential BC risks of both estrogens and progestins are necessary to minimize BC risk in symptomatic women who consider MHT. We think that a potential lack of decrease of risk in past users of MHT calls for a pooled reanalysis of recent major epidemiological studies

30. APPLICABILITY Is our patient so different from those in the study that its results cannot apply? NO What are our patient’s risks of benefit and harm from the agent? Cardiovascular, osteoporosis >< Breast ca What are our patient’s preferences, concerns, and expectations from this treatment? What alternatives treatments are availabe ? Lifestyle changes, physical exercise, diet, supplementation, prevention of HT

31. Terima kasih