Academic dissertation

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Τάκης Πολίτης
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1 Academic dissertation

2 ISBN (paperback) ISBN (PDF)

4 Table of contents List of original publications Abbreviations Abstract Introduction Review of the literature Aims of the study Subjects and methods 4

5 Results Discussion Conclusions Acknowledgements References Original publications 5

6 List of original publications 6

7 Abbreviations 7

8 Abstract Background Subjects and methods 8

9 Results Conclusions 9

10 Introduction 10

11 11

12 Review of the literature Ovaries Figure 1. Illustration of anatomical parts of ovary and fallopian tube. 12

13 Ovarian cancer Table 1. Features and mutations associated with different histological types of epithelial ovarian cancers. Modified according to reviews by Fleming 2006, and Jayson et al High-grade serous Low-grade serous Endometroid (high- and lowgrade) Clear cell Mucinous Possible origin Fimbriae of fallopian tubes Benign cysts or borderline ovarian tumors Endometrium/ endometriosis Endometrium/ endometriosis Benign cysts or borderline ovarian tumors Behaviour Aggressive Indolent Depend on grade Aggressive Indolent Sensitivity to chemotherapy sensitive less sensitive less sensitive non-sensitive less sensitive Some typical gene mutations TP53, BRCA1/2 KRAS, BRAF ARID1A, P13KCA, PTEN ARID1A, P13KCA, PTEN KRAS, ERBB2 amplifications Incidence 13

14 14

15 Theories on etiology 15

16 16

17 17

18 Genetic predisposition 18

19 Protective and risk factors 19

20 Table 2. Factors associated with ovarian cancer. A relative risk <1 means protective effect and relative risk >1 means increased risk. Modified from the studies by Annegers et al. 1979, Booth et al. 1989, Risch et al. 1994, 1996, Auranen et al. 1996, Ness et al. 2002, Hinkula et al. 2006, Beral et al. 2008, a review by Sueblinvong and Carney 2009, Domcheck et al. 2010, and meta-analyses by Cibula et al and Rice et al Factor Relative risk Parity Oral contraceptive use Hysterectomy Tubal ligation Breast feeding Family history of ovarian cancer BRCA 1/2 mutations Infertility Table 3. Risk and protective factors for four main histological types of ovarian cancer. risk increase, risk decrease, no effect. Modified according to the studies of Risch et al. 1996, Kurian et al. 2005, Nagle et al. 2008, Gates et al and Yang et al Risk factors Serous Endometroid Mucinous Clear cell Parity Oral contraceptive use Hysterectomy Tubal ligation Endometriosis Tobacco smoking Body mass index >25 kg/m 2 Breastfeeding 20

21 Diagnosis Management and survival 21

22 22

23 Fallopian tubes 23

24 24

25 Primary fallopian tube carcinoma Incidence Protective and risk factors 25

26 Table 4. Possible protective and risk factors for primary fallopian tube carcinoma (PFTC). Modified according to studies of Riska et al. 2007a, Jordan et al and a review by Kalampokas et al Factor Impact on PFTC risk Parity Protective Oral contraceptive use Protective Tubal ligation Protective Chronic tubal inflammation Risk increasing BRCA-mutations Risk increasing Infertility Risk increasing Diagnosis, management and survival 26

27 27

28 Menopause Immediate symptoms Long-term consequences 28

29 Postmenopausal hormone therapies Estrogen therapy 29

30 Table 5. Type, mode and route of administration and daily dose of estrogen in regimens used in Finland since Regimen Administration Daily dose (mg) Estradiol Oral 1, 2 Transdermal patch Transdermal gel 0.5, 1, Vaginal tablet Vaginal ring Estriol Vaginal suppository 0.5 Vaginal creme

31 Progestins and estrogen-progestin therapies Table 6. The binding of different progestins and tibolone metabolites to various steroid receptors. Modified according to reviews by Kuhl 2005 and Stanczyk 2013, based mainly on animal studies. ++ strong effect, + effect, (+) weak effect, - no effect,? effect is unknown. The progestins used in Finland are included. Progestin Antiestrogenic Estrogenic Androgenic Antiandrogenic Glucocor- Antiminera ticoid locorticoid Progesterone (+) + + Cyproterone acetate Medroxyprogesterone acetate + - (+) Medrogestone ? - Dydrogesterone ? (+) Norethisterone Levonorgestrel Gestodene (+) + Norgestimate ?? Δ4 tibolone Drospirenone Trimegestrone (+) - (+) Promegestrone Nomegestrol acetate

32 Table 7. Type, mode, daily dose and route of administration of progestins used in combination with estradiol in postmenopausal hormone regimens in Finland since Progestin regimen Administration Daily dose (mg) Sequential, Oral norethisterone acetate oral 1 medroxyprogesterone acetate oral 10, 20 levonorgestrel oral 0.25 dydrogesterone oral 10, 20 medroxyprogesterone oral 5, 10 megesterole acetate oral 10 trimegesterone oral 2 progesterone oral lynesterol oral 5 trimegesterone oral 0.5 Sequential, Transdermal norethisterone acetate patch 0.17, 025 levonorgestrel patch 0.01, 0.02 Continuous, Oral norethisterone acetate oral 0.5, 0.7, 1 medroxyprogesterone acetate oral 2.5, 5 dydrogesterone oral 5 drospirenone oral 2 Continuous, Transdermal norethisterone acetate patch 0.17, 0.25 Continuous, Intrauterine levonorgestrel intrauterine system 0.02 Levonorgestrel-releasing intrauterine system 32

33 Tibolone Others 33

34 Effects of postmenopausal hormone therapy Benefits 34

35 Adverse effects Influence of administration routes 35

36 Postmenopausal hormone therapy and general risk of cancer 36

37 Hormone therapy and ovarian cancer Hormone therapy and primary fallopian tube carcinoma 37

38 Table 11. Some studies on ovarian cancer risk in users of postmenopausal hormone therapy (HT) (estrogen-only therapy, ET or estrogen-progestin therapy, EPT). RR, risk ratio; OR, odds ratio; CI, confidence interval. * All relative risks are for HT use 5 years if not marked otherwise. * Only randomized placebo-controlled trial ** Published after the initiation of my thesis. Study Design Years conducted Study population/ number of subjects Regimen Relative risk by RR, or and 95% CI for HT use 5 years* Cramer et al Case-control /173 ET OR for ET 2.83 ( ) (cases/controls) Lee et al Case-control /1,210 ET OR for ET use 6 years 1.7 ( ) (cases/controls) Hartge et al Cohort /244 ET RR for ET use >2.5 years 0.4 ( ) (cases/controls) Booth et al Case-control /451 ET OR for ever-use of ET 1.5 ( ) (cases/controls) Whittemore et al Case-control ,197/8,893 ET RR for ET 1.0 ( ) (cases/controls) Parazzini et al Case-control /2,503 ET OR for ET use 2 years 1.7 ( ) (cases/controls) Risch et al Case-control Hempling et al Case-control Purdie et al Case-control Lacey et al Cohort Riman et al Case-control Anderson et al. 2003* Randomized trial Pike et al Case-control Moorman et al Case-control Lacey et al Cohort Danforth et al Cohort Beral et al Cohort Rossing et al Case-control Mørch et al. 2009** Cohort Hildebrand et al. 2010** Cohort Tsilidis et al. 2011** Cohort Trabert et al. 2012** Cohort /564 (cases/controls) 491/741 (cases/controls) 732/784 (cases/controls) 233/44,241 (cancers/cohort) 655/3,899 (cases/controls) 32/16,608 (cancers/cohort) 477/660 (cases/controls) 364/370 (cases/controls) 214/97,638 (cancers/cohort) 389/82,905 (cancers/cohort) 2,273/287,143 (cancers/cohort of current users) ET and EPT HT not specified ET and EPT OR for any HT 1.05 ( ) only nonmucinous tumors included OR for HT 5 years 0.6 ( ) OR for ET 0.94 ( ) OR for EPT >3years of use 1.33 ( ) RR for ET 1.20 ( ) RR for EPT 0.93 ( ) OR for ever-use of ET 1.43 ( ) OR for ever-use of EPT 1.54 ( ) ET and EPT ET and EPT EPT RR for EPT 2.42 ( ) ET and EPT ET and EPT ET and EPT ET and EPT ET, EPT and tibolone 299/614 (cases/controls) ET and EPT 2,681/909,946 (epithelial ET and ovarian cancers/cohort) EPT 297/ 22,721 (cancers/cohort of everand current users) 424/37,630 (cancers/cohort of current users) 426/50,397 (cancers/cohort of current users) ET and EPT ET, EPT and Tibolone ET and EPT OR for ET 1.13 ( ) OR for EPT 1.00 ( ) OR for ET use of 5 years 1.5 ( ) and 10 years 2.2 ( ) OR for EPT use of 5 year 1.1 ( ) and 10 years 1.0 ( ) RR for ET 1.33 ( ) RR for sequential EPT 3.09 ( ) and RR for continuous EPT 1.82 ( ) RR for ET 1.25 ( ) RR for EPT 1.04 ( ) RR for ET 1.53 ( ) RR for EPT 1.17 ( ) RR for tibolone 1.07 ( ) OR for ET 1.4 ( ) OR for EPT 1.00 ( ) RR for ET 1.31 ( ) RR for EPT 1.50 ( ) RRs for any duration RR for ET 1-<10 years 1.70 ( ) RR for EPT 5 years 1.30 ( ) RR for ever-use of ET 1.63 ( ) RR for ever-use of EPT 1.20 ( ) RR for ever-use of tibolone 2.19 ( ) RR for ET 10 years 2.15 ( ) RR for EPT 10 years 1.68 ( ) 38

39 Aims of the study 39

40 Subjects and methods Permissions Registers used in the studies 40

41 Table 12. The nation-wide registers employed in the studies I-IV. Register Register Keeper Used in Studies Medical reimbursement National Social register Insurance Institution Cancer Registry Institute for Health and Welfare Hospital care register Institute for Health and Welfare Finnish population register Population Register Centre Sterilization register Institute for Health and Welfare Complete nationwide data available from I, II, III, IV I, II, III, IV I, II, III, IV II, IV IV Study populations Cohort studies 41

42 42

43 Case-control studies 43

44 Use of hormone therapy Cohort studies Case-control-studies 44

45 Statistical methods Cohort studies 45

46 Case-control studies Table 13. The study populations, design, follow-up, hormone therapies and registers used in the studies I-IV. Study Design Study Period Subjects Follow-up Hormone therapies Cencoring event (Excluded) Registers used I Cohort ,015 women 602 incident ovarian cancers , 1,591,201 women-years mean follow-up 7 years EPT Hysterectomy n=23,371 Cancer registry, Medical reimbursement register, Patient care register III Cohort ,601 women 160 incident PFTCs , 1,0009,358 womenyears (ET-users), 2,145,659 women-years (EPT-users) mean follow-up 9 years in both groups ET, EPT Salpingectomy n=18,310 Cancer registry, Medical reimbursement register, Patient care register II Casecontrol ,958 ovarian cancer cases 11,325 controls ET, EPT, E+LNG- IUS, tibolone Oophorectomy n=506 Cancer registry, Medical reimbursement register, Patient care register, Population register IV Casecontrol PFTC cases 3,442 controls ET, EPT, E+LNG- IUS, tibolone Salpingectomy n=158 Cancer Registry, Medical reimbursement register, Patient care register, Population register, Sterilization register 46

47 Results Features of hormone therapy use 47

48 Ovarian cancer risk Cohort study (study I) Table 14. Ovarian cancer risk in estradiol-progestin therapy (EPT) users during (study I). SIR, Standardized incidence ratio; CI confidence interval. EPT Observed Expexted SIR 95% CI >6 months<5 years years years Ever-use of EPT Table 15. Ovarian cancer risk in users of sequential and continuous estradiol-progestin therapy (EPT) (study I). SIR, Standardized incidence ratio; CI confidence interval. EPT Observed Expected SIR 95% CI Sequential <5 years Continuous <5years Sequential 5years Continuous 5years

49 Table 16. Ovarian cancer risk in users of medroxyprogesterone acetate (MPA) and norethisterone acetate (NETA) as parts of estradiol-progestin therapy (EPT ), (study I). SIR, Standardized incidence ratio; CI confidence interval. Progestin and duration Observed Expected SIR 95% CI MPA <5years MPA 5years NETA <5years NETA 5years Case-control study (study II) 49

50 Table 17. Risk of ovarian cancer, the type of postmenopausal hormone therapy (HT) and duration of exposure. A woman may be included in more than one category of hormone therapy. Adjusted for parity, age at births of children and hysterectomy (study II). ET, estradiol-only therapy; EPT, estradiol-progestin therapy; OR, odds ratio; CI, confidence interval; LNG-IUS, levonorgestrel-releasing intrauterine system. Hormone therapy and duration Cases Controls OR 95% CI p-value ET <1 year ET 1-5 years ET >5 years P-value for trend = EPT sequential <1 year EPT sequential 1-5 years EPT sequential >5 years P-value for trend = EPT continuous <1 year EPT continuous 1-5 years EPT continuous >5 years P-value for trend = estradiol+ LNG-IUS 5 years estradiol+ LNG-IUS >5 years tibolone <1 year tibolone >1 year unspecified type of HT <5 years unspecified type of HT 5-10 years unspecified type of HT >10 years P-value for trend =

51 Table 18. Risk of ovarian cancer by histological type, the type of postmenopausal hormone therapy and duration of exposure. A woman may be included in more than one category of hormone therapy. Adjusted for parity, age at births of children and hysterectomy (study II). ET, estradiol-only therapy; EPT, estradiolprogestin therapy; OR, odds ratio; CI, confidence interval. Histology and hormone therapy Cases Controls OR 95% CI p-value Serous (48%) 1,903 5,430 ET <1year ET 1-5 years ET >5 years < P-value for trend < EPT sequential <1 year EPT sequential 1-5 years EPT sequential >5 years P-value for trend =0.004 EPT continuous <1 year EPT continuous 1-5 years EPT continuous >5years P-value for trend =0.218 Endometroid (19%) 748 2,153 ET <1 year ET 1-5 years ET >5 years P-value for trend =0.248 EPT Sequential <1 year EPT Sequential 1-5 years EPT Sequential >5 years P-value for trend =0.041 EPT continuous <1 year EPT continuous 1-5 years EPT continuous >5 years P-value for trend =0.062 Mucinous (11%) 417 1,194 ET <1 year ET 1-5 years ET >5 years P-value for trend <0.001 EPT Sequential <1 year EPT Sequential 1-5 years EPT Sequential >5 years P-value for trend =0.172 EPT continuous <1 year EPT continuous 1-5 years EPT continuous >5 years P-value for trend =0.03 Clear Cell (4%) ET <1 year ET 1-5 years ET >5 years P-value for trend =0.087 EPT Sequential <1 year

52 EPT Sequential 1-5 years EPT Sequential >5 years P-value for trend =0.928 EPT continuous <1 year EPT continuous 1-5 years EPT continuous >5 years P-value for trend =0.149 Other (18%) 735 2,107 ET <1 year ET 1-5 years ET >5 years P-value for trend =0.305 EPT Sequential <1 year EPT Sequential 1-5 years EPT Sequential >5 years P-value for trend =0.400 EPT continuous <1 year EPT continuous 1-5 years EPT continuous > 5 years P-value for trend =

53 Primary fallopian tube carcinoma risk Cohort study (study III) Table 19. Primary fallopian tube carcinoma (PFTC) risk in users of hormone therapy during (study III). ET, estradiol-only therapy; EPT, estradiol-progestin therapy; SIR, Standardized incidence ratio; CI confidence interval. ET Observed Expected SIR 95% CI >6 months<5 years years years Ever-Use of ET EPT Observed Expected SIR 95% CI >6 months<5 years years years Ever-Use of EPT

54 Table 20. Primary fallopian tube carcinoma risk in users of sequential and continuous estradiol-progestin therapy (EPT) and medroxyprogesterone acetate (MPA) and norethisterone acetate (NETA) as parts of EPT (study III). SIR, Standardized incidence ratio; CI confidence interval. EPT Observed Expected SIR 95% CI Sequential <5 years Sequential 5years Continuous <5 years Continuous 5years MPA <5 years MPA 5years MPA 10years NETA <5 years NETA 5years NETA 10years Case-control study (study IV) 54

55 Table 21. Risk of primary fallopian tube carcinoma according to the type and duration of postmenopausal hormone therapy. A woman may be included in more than one category of hormone therapy. Adjusted for parity, age at last delivery, hysterectomy and sterilization (study IV). ET, estradiol-only therapy; EPT, estradiol-progestin therapy; LNG- IUS, levonorgestrel-releasing intrauterine system; OR, odds ratio; CI confidence interval. Hormone therapy and duration Cases Controls OR 95% CI p-value ET <1 year ET 1-5 years ET >5 years P-value for trend = EPT sequential <1 year EPT sequential 1-5 years EPT sequential >5 years < P-value for trend < EPT continuous <1 year EPT continuous 1-5 years EPT continuous >5 years P-value for trend =0.074 estradiol+ LNG-IUS 5 years 0 4 NA NA estradiol+ LNG-IUS >5 years P-value for trend =0.088 tibolone <1 year tibolone >1 year P-value for trend =

56 Other factors Table 22. Ovarian cancer risk according to parity, age at births and hysterectomy. Adjusted for HT use (study II). OR, odds ratio; CI confidence interval. Parity and age at first and last birth Cases Controls OR 95% CI p-value nulliparity reference 1 2 children, first birth <25, last birth <35 1,017 2, children, first birth <25, last birth children, first birth 25, last birth < , children, first birth 25, last birth < children, first birth <25, last birth < , < children, first birth <25, last birth < children, first birth 25, last birth < < children, first birth 25, last birth <0.001 Hysterectomy <0.001 Table 23. Risk of Primary fallopian tube carcinoma according to parity, age at last delivery, hysterectomy and sterilization. Adjusted for hormone therapy use (study IV). OR, odds ratio; CI confidence interval. Parity and age at last delivery Cases Controls OR 95% CI p-value Nulliparity reference 1-3 children, age at last delivery < children age at last delivery children, age at last delivery < children age at last delivery < Hysterectomy Sterilization

57 Discussion 57

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64 Conclusions 64

65 Acknowledgements 65

66 66

67 References 67

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83 Original publications 83

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