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Date of release: 20 April, 2009

Melanoma and HRT


A recent report from Koomen and colleagues in the Annals of Oncology [1] has reopened the discussion on the association between the development of cutaneous melanoma (CM) and hormones. 


The paper reports on a case–control study conducted in the Netherlands using two databases: PHARMO, a pharmacy database recording all prescriptions on an individual basis, and PALGA, the Dutch nationwide registry of histo- and cytopathology. The authors linked both databases for the use of oral contraception and hormone replacement therapy (HRT) (for at least 6 months) and a diagnosis of primary cutaneous melanoma. Inclusion criteria were women ≥ 18 years, complete records for the 3 years before CM diagnosis, and diagnosis of CM between 1991 and 2004. From 2053 female subjects with a CM diagnosis, 778 cases were included and matched with 4072 controls on age and geographical region. The mean ages of cases and controls were 53.6 and 54.6 years, respectively. Estrogens were used by 25.8% of the cases and 19.7% of the controls; dividing the data by use of oral contraceptives or HRT, oral contraceptives were used by 21.5% of the cases and 17.7% of the controls, and HRT was used by 4.2% of the cases and 2% of the controls. 


CM risk was significantly associated with estrogen use (adjusted odds ratio (OR) 1.42; 95% confidence interval (CI) 1.19–1.69). This effect was cumulative dose-dependent (p trend < 0.001). CM risk was also significantly associated with the use of HRT (OR 2.08; 95% CI 1.37–3.14) and oral contraceptives (OR 1.28; 95% CI 1.06–1.54).

Comment

The incidence of CM increases constantly, with a slower increase in mortality related to an earlier diagnosis. The increase of incidence is also related to external risk factors, mainly sun/ultraviolet light exposure.
It is thus important to evaluate other potential risk factors. Several epidemiological studies have investigated the association between oral contraceptive use and CM development. These studies show, however, predominantly negative results. 
A meta-analysis published in 1998 has pooled the data from 18 case–control studies that studied the association between oral contraceptives and CM [2]. Using either a ‘fixed effects’ or a ‘random effects’ model for the meta-analysis, the OR of 0.95 (95% CI 0.87–1.04) was not increased. Another more recent meta-analysis, pooling the data of a total of 2391 cases and 3199 controls, has not shown any increase in the risk (OR 0.86; 95% CI 0.74–1.01) and no increase with duration of oral contraception [3].
Concerning HRT, a Danish case–control study has shown no increase in the risk in 280 cases and 536 controls [4]. Similarly, a US case–control study did not see any increase in the risk in 308 cases and 232 controls [5].
An original study conducted in California Bay in 318 Caucasian women, who had experienced a modification in their naevi during pregnancy or under oral contraception or HRT between 1991 and 1992, reported no increase in the relative risk of CM under exogenous estrogens [6].
Clinical observations that suggest an increased risk of CM under exogenous estrogens are: the rare occurrence of CM prior to puberty, higher survival rates for women than men, and reproductive history-related factors, such as early age at first birth and higher parity, which have been associated with a lower risk of CM [7]. In addition, the presence of estrogen receptors (ERα and β) in the naevi and a possible decrease of expression in ERβ in a small number of invasive melanoma have been shown [8]. 
Form this survey of the literature, the evidence for an increased risk of CM induced by exogenous estrogens is not convincing. There are some limitations in the paper from Koomen and colleagues, in particular the requirement of a 3-year follow-up before the diagnosis of CM and thus a relative short time of use and record of oral contraception. If there is any increase in the risk with hormone use, it would increase with time and thus a cut-off at 3 years and not using the time-life exposure is somehow artificial. The total number of women who used HRT was 33; this number does not allow any conclusion to be drawn. The main objection is that sun exposure was not recorded and this was discussed by the authors. In addition, a bias of diagnosis is always possible and there are no data in this population to inform whether women using oral contraception/HRT are more likely to receive clinical examination in the Netherlands, but it is more than plausible.
An additional remark is that more than 50% of women had used non-steroidal anti-inflammatory drugs (NSAIDs). The potential association of NSAIDs with chemoprevention of melanoma has been investigated in a few studies which gave conflicting results [9]. We asked the authors of the current trial to address this issue, and this was their reply: ‘The high use of NSAIDs could be related to the age of the population’.
In conclusion, data concerning HRT and CM risk remain scarce and the paper by Koomen and colleagues provides additional information. The rough number of cases analyzed in the literature is extremely low. It is thus very difficult to conclude that there is any increase in the relative risk of cutaneous melanoma under exogenous estrogen exposure.

Comentario

Anne Gompel
Unité de Gynécologie Endocrinienne, Hôpital Hôtel-Dieu, Université Paris Descartes, Paris, France

M-F. Avril
Service de Dermatologie , Hôpital Cochin, Université Paris Descartes, Paris, France

    References

  1. Koomen ER, Joosse A, Herings RM, Casparie MK, Guchelaar HJ, Nijsten T. Estrogens, oral contraceptives and hormonal replacement therapy increase the incidence of cutaneous melanoma: a population-based casecontrol study. Ann Oncol 2009;20:358-64. Published February 2009.
    http://www.ncbi.nlm.nih.gov/pubmed/18725391

  2. Pfahlberg A, Hassan K, Wille L, Lausen B, Gefeller O. Systematic review of case-control studies: oral contraceptives show no effect on melanoma risk. Public Health Rev 1997;25:309-15.
    http://www.ncbi.nlm.nih.gov/pubmed/9553446

  3. Karagas MR, Stukel TA, Dykes J, et al. A pooled analysis of 10 case-control studies of melanoma and oral contraceptive use. Br J Cancer 2002;86:1085-92.
    http://www.ncbi.nlm.nih.gov/pubmed/11953854

  4. Osterlind A, Tucker MA, Stone BJ, Jensen OM. The Danish case-control study of cutaneous malignant melanoma. III. Hormonal and reproductive factors in women. Int J Cancer 1988;42:821-4.
    http://www.ncbi.nlm.nih.gov/pubmed/3192324

  5. Smith MA, Fine JA, Barnhill RL, Berwick M. Hormonal and reproductive influences and risk of melanoma in women. Int J Epidemiol 1998;27:751-7.
    http://www.ncbi.nlm.nih.gov/pubmed/9839729

  6. Lea CS, Holly EA, Hartge P, et al. Reproductive risk factors for cutaneous melanoma in women: a case-control study. Am J Epidemiol 2007;165:505-13.
    http://www.ncbi.nlm.nih.gov/pubmed/17158470

  7. Karagas MR, Zens MS, Stukel TA, et al. Pregnancy history and incidence in melanoma in women : a pooled analysis . Cancer Causes Control 2006;17:11-19.
    http://www.ncbi.nlm.nih.gov/pubmed/16411048

  8. de Giorgi V, Mavilia C, Massi D, et al. Estrogen receptor expression in cutaneous melanoma: a real-time reverse transcriptase-polymerase chain reaction and immunohistochemical study. Arch Dermatol 2009;145:30-6.
    http://www.ncbi.nlm.nih.gov/pubmed/19153340

  9. Asqari MM, Marati SS, White E, et al. A large cohort study of nonsteroidal anti-inflammatory drug use and melanoma incidence. J Natl Cancer Inst 2008;100:967-71.
    http://www.ncbi.nlm.nih.gov/pubmed/18577752