Title: Ovarian cancer and HRT

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This fact sheet has been produced in response to the ovarian cancer publication from the UK Million Women Study [1]. The study concluded that HRT taken over 5 years resulted in one extra ovarian cancer in roughly 2,500 HRT users and one extra ovarian cancer death in roughly 3,300 users. This figure was then extrapolated by those investigators from their 5-year study period to a time span of 14 years in order to claim that HRT had caused 1,000 deaths from ovarian cancer, thereby sensationalizing their findings. The aim is to put the figures in perspective.
Previous metanalyses have produced conflicting results with one showing a summary relative risk of 1.15 (95% CI 1.05 to 1.27) and another concluding that there was no statistically significant association between ever and never use (odds ratio 1.1, 95%CI 0.9 to 1.3) nor any evident dose-response relationship [2,3]. However, prospective studies have suggested a modest effect [4,5]. One study found a significant two-fold increased risk of ovarian cancer mortality in women who used estrogen alone for 10 or more years [5]. The randomized Women's Health Initiative found no significant increase with combined estrogen-progestogen HRT [6]. Furthermore ovarian cancer survival does not seem to be affected in HRT users [7].

Ovarian cancer figures in the UK
In 2003 there were 6,906 cases of ovarian cancer diagnosed in the UK and the disease accounts for about 4,400 deaths. The lifetime risk of developing ovarian cancer is approximately 1 in 48 for women in England and Wales [8].
Ovarian cancer is predominantly a disease of older, post-menopausal women with almost 85% of cases being diagnosed in women over 50 years (5,815 out of 6,906 cases). Incidence increases after the menopause. The highest incidence rates are for women aged 65 and over.

Risk factors for ovarian cancer
The most important risk factors for ovarian cancer are increasing age and certain gene mutations such as BRCA1 and BRCA2. In women with a known BRCA1 mutation, the cumulative lifetime risk of developing ovarian cancer has been estimated to be approximately 50% (95%CI 44.9 to 55.0%) compared with an approximate 1.7% lifetime risk in the general US population [9]. A woman in her 60s has double the risk of one in her forties.

1. Infertility and infertility treatment. While  women who have not had children (nulliparous) are at increased risk of ovarian cancer than women who have had one child or more (parous), (OR 2.42 95% CI 1.86-3.14) the evidence regarding infertile women and infertility treatments is conflicting.
2. Talc. While some epidemiological studies suggested an increased risk this has not been found in a meta-analysis.
3. Diet and body mass index. Here the evidence is conflicting but obesity may increase ovarian cancer risk.

Protective factors for ovarian cancer

1. Parity. Parous women have a lower risk of ovarian cancer than nulliparous women.
2. Breastfeeding. There is some evidence, albeit conflicting that breast feeding is protective.
3. Oral contraceptives. The use of oral contraceptives is protective, perhaps due to suppression of ovulation. The effect is prolonged lasting for up to 20 years after stopping therapy.
4. Sterilisation. Estimated reduction in risk is between 39% and 70%7. Hysterectomy may also reduce risk.
5. Medication usage There is some evidence that the use of aspirin and other non-steroidal anti-inflammatory drugs may reduce the risk of ovarian cancer but the evidence is inconclusive.

Conclusion
The design and analysis of the Million Women Study has been repeatedly criticized in many publications. In particular the characteristics of the women who took part in the study versus those who declined are difficult to control for. The increased risk found in the Million Women Study for ovarian cancer is not high in statistical terms and certainly not higher than that found in other studies. Thus women and health professionals should not be unnecessarily alarmed by this publication.

Margaret Rees
John Stevenson
30 April 2007 reviewed January 2008.

Whilst great care has been taken to ensure the accuracy of information contained in the fact sheets, the authors and the BMS cannot accept any responsibility for any errors omissions, mis-statements or mistakes or for any loss or damage arising from actions or decisions based on information contained in this publication. Ultimate responsibility for the treatment of patients and interpretation of published material lies with the medical practitioner. The opinions expressed are those of the authors, not necessarily those of the BMS. The inclusion in the publication of material relating to a particular product, method or technique does not amount to an endorsement of its value or quality, or of claims made by its manufacturer.
Margaret Rees and Sally Hope January 2008

References
1. Beral V; Million Women Study Collaborators, Bull D, Green J, Reeves G. Ovarian cancer and hormone replacement therapy in the Million Women Study. Lancet 2007;369:1703-10.
2. Garg PP, et al. Hormone replacement therapy and the risk of epithelial ovarian carcinoma: a meta-analysis. Obstet Gynecol 1998; 92: 472-9.
3. Coughlin SS, et al. A meta-analysis of estrogen replacement therapy and risk of epithelial ovarian cancer. J Clin Epidemiol 2000; 53: 367-75.
4. Riman T. Hormone replacement therapy and epithelial ovarian cancer: is there and association? J Br Menopause Soc 2003;9:61-8.
5. Rodriguez C, et al. Estrogen replacement therapy and ovarian cancer mortality in a large prospective study of US women. JAMA 2001; 285: 1460-5.
6. Anderson GL, et al. Effects of estrogen plus progestin on gynecologic cancers and associated diagnostic procedures: the Women's Health Initiative randomized trial. JAMA 2003; 290:1739-48.
7. Mascarenhas C, et al. Use of hormone replacement therapy before and after ovarian cancer diagnosis and ovarian cancer survival. Int J Cancer 2006;119:2907-15.
8. Ovarian Cancer. Cancer Research UK. http://info.cancerresearchuk.org/cancerstats/types/ovary/?a=5441
9. Brose MS., et al., Cancer risk estimates for BRCA1 mutation carriers identified in a risk evaluation program. J Natl Cancer Inst 2002; 94: 1365-72.

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