January 25th, 2021 Hormone replacement therapy in cancer survivors

Summary

Improvements in oncology have led to an increased survival of cancer patients. Indeed, breast cancer patients live long enough to reach the natural age of menopause. In addition, in many of them, one of the main adverse effects of their received oncotherapy is premature ovarian failure caused by the cessation of gonadal function. Indicating menopausal hormone therapy (MHT) in these type of patients has become increasingly difficult as multiple clinical studies suggest an increased risk of recurrence and mortality with the use of MHT. The use of therapy must be supported according to oncological and endocrine factors, the oncotherapy received and the type of compound to be used: estrogen alone, estrogen plus progestogen and progestogen only, always balancing risk – benefit [1]. The pattern of expression of the estrogen receptor is not sufficient to predict the effect of estrogen or progesterone; since the biological effect depends on the tissue and type of tumor, the interaction with isoforms, growth factors, coactivators and corepressors.
Taking into account the aforementioned, MHT is chosen according to the type of cancer and its characteristics, risk factors of each patient and their preferences. In breast cancer survivors it is difficult to choose which is the best therapy, since according to the interpretation of the International Menopause Society "IMS", all hormonal therapy would be contraindicated. Hence, questions arise regarding molecules such as tibolone, the use of estrogens alone and local hormonal therapy, which could be considered according to the scenario of each patient and their history.
 
Commentary

The IMS guideline is clear in emphasizing that non-hormonal methods are preferred in receptor-negative or positive breast cancer survivors who have menopausal symptoms, and MHT is contraindicated. However, there is controversy in the literature in this regard: observational and case-control studies suggest that MHT does not increase disease recurrence [2,3]. Contrary to this, clinical studies such as the HABITS were suspended after 2.1 years because their results showed a higher risk of breast cancer recurrence (n = 434, 26 cases of recurrence in the MHT group compared to 7 cases in the group that did not receive MHT, hazard ratio [HR] 3.3) [4]. The 10-year follow-up results from the Stockholm trial also indicated an increased risk of breast cancer recurrence. In the study of Fahlen et al [5], a HR of 3.6 was detected for disease recurrence (n = 378, mean duration of MHT 26 months, recurrent rate among MHT users was 7.4% vs. non-users 2.1%) [5].
As an alternative, tibolone arises, a compound that is metabolized to an estrogenic, progestin and androgenic isomer and is used for the management of vasomotor symptoms. The LIFT study (Long-Term Intervention on Fractures with Tibolone) demonstrated that tibolone not only reduces the risk of fractures in an osteoporotic postmenopausal population, but also significantly reduces the risk of invasive breast cancer. However, the LIBERATE trial that evaluated the use of tibolone in breast cancer survivors was terminated prematurely due to the increased risk of breast cancer recurrence (n = 3,098, 3.1-year follow-up, breast cancer recurrence 15.2% among tibolone users versus 10.7% among placebo, HR: 1.4) [6]. It should be noted that the effect of tibolone can be modified by the presence of estrogen receptors and parallel endocrine oncotherapy: the risk of recurrence was high when the aromatase inhibitor (HR: 2.42) or the GnRH analog (HR: 2.29) were also used, but no significant increase in relative risk was observed in women estrogen receptor negative (HR: 1.15) and tamoxifen users (HR: 1.25). The differences can be explained by the different anti-estrogenic effects, which result in upregulation or downregulation or blocking of estrogen receptors with tibolone [5,7].
The route of administration has also shown relevance in terms of its effect among breast cancer survivors, finding: a recurrence risk with oral estrogen of 7.4% compared to 2.1% with local estrogen therapy [8].
 
Camilo Rueda
Universidad de la Sabana Chía
Colombia

 
References

  1. Deli T, Orosz M, Jakab A. Hormone Replacement Therapy in Cancer Survivors - Review of the Literature. Pathol Oncol Res. 2020 Jan;26(1):63-78.
    https://pubmed.ncbi.nlm.nih.gov/30617760/
  2. Cobleigh MA, Berris RF, Bush T, Davidson NE, Robert NJ, Sparano JA, Tormey DC, Wood WC. Estrogen replacement therapy in breast cancer survivors. A time for change. Breast Cancer Committees of the Eastern Cooperative Oncology Group. JAMA. 1994;272(7):540-5.
    https://pubmed.ncbi.nlm.nih.gov/8046809/
  3. O'Meara ES, Rossing MA, Daling JR, Elmore JG, Barlow WE, Weiss NS. Hormone replacement therapy after a diagnosis of breast cancer in relation to recurrence and mortality. J Natl Cancer Inst. 2001;93(10):754-62.
    https://pubmed.ncbi.nlm.nih.gov/11353785/
  4. Holmberg L, Anderson H; HABITS steering and data monitoring committees. HABITS (hormonal replacement therapy after breast cancer--is it safe?), a randomised comparison: trial stopped. Lancet. 2004;363(9407):453-5.
    https://pubmed.ncbi.nlm.nih.gov/14962527/
  5. Fahlén M, Fornander T, Johansson H, Johansson U, Rutqvist LE, Wilking N, von Schoultz E. Hormone replacement therapy after breast cancer: 10 year follow up of the Stockholm randomised trial. Eur J Cancer. 2013;49(1):52-9.
    https://pubmed.ncbi.nlm.nih.gov/22892060/
  6. Cummings SR, Ettinger B, Delmas PD, Kenemans P, Stathopoulos V, Verweij P, Mol-Arts M, Kloosterboer L, Mosca L, Christiansen C, Bilezikian J, Kerzberg EM, Johnson S, Zanchetta J, Grobbee DE, Seifert W, Eastell R; LIFT Trial Investigators. The effects of tibolone in older postmenopausal women. N Engl J Med. 2008;359(7):697-708. https://pubmed.ncbi.nlm.nih.gov/18703472/
  7. Lupo M, Dains JE, Madsen LT. Hormone Replacement Therapy: An Increased Risk of Recurrence and Mortality for Breast Cancer Patients? J Adv Pract Oncol. 2015;6(4):322-30.
    https://pubmed.ncbi.nlm.nih.gov/26705493/
  8. Durna EM, Wren BG, Heller GZ, Leader LR, Sjoblom P, Eden JA. Hormone replacement therapy after a diagnosis of breast cancer: cancer recurrence and mortality. Med J Aust. 2002;177(7):347-51.
    https://pubmed.ncbi.nlm.nih.gov/12358575/

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