Clinical Review

HRT and cancer: quantifying the risk

OBG Manag. 2002 December;14(12):53-64

Until recently, hormone replacement therapy was hailed for its many benefits in postmenopausal women, but findings from the Women’s Health Initiative and other trials have altered the landscape. Here, the authors sift the data on HRT and the risk of various cancers.

PDF Download

References

1. Greendale GA, Reboussin BA, Sie A, et al. for the Postmenopausal Estrogen/Progestin Interventions (PEPI) Investigators. Effects of estrogen and estrogen-progestin on mammographic parenchymal density. Ann Intern Med. 1999;130:262-269.

2. Saftlas AF, Hoover RN, Brinton LA, Szklo M, Olson DR, Salane M. Mammographic densities and risk of breast cancer. Cancer. 1991;67:2833-2838.

3. Boyd NF, Byng JW, Jong RA, et al. Quantitative classification of mammographic densities and breast cancer risk: results from the Canadian National Breast Screening Study. J Natl Cancer Inst. 1995;87:670-675.

4. Cauley JA, Lucas FL, Kuller LH, Vogt MT, Browner WS, Cummings SR. for the Study of Osteoporotic Fractures Research Group. Bone mineral density and risk of breast cancer in older women: the Study of Osteoporotic Fractures. JAMA. 1996;276:1404-1408.

5. Lippman M, Bolan G, Huff K. The effects of estrogens and antiestrogens on hormone-responsive human breast cancer in long-term tissue culture. Cancer Res. 1976;36:4595-4601.

6. Gapstur SM, Morrow M, Sellers TA. Hormone replacement therapy and risk of breast cancer with a favorable histology: results of the Iowa Women’s Health Study. JAMA. 1999;281:2091-2097.

7. Holli K, Isola J, Cuzick J. Low biologic aggressiveness in breast cancer in women using hormone replacement therapy. J Clin Oncol. 1998;16:3115-3120.

8. Colditz GA, Hankinson SE, Hunter DJ, et al. The use of estrogens and progestins and the risk of breast cancer in postmenopausal women. N Engl J Med. 1995;332:1589-1593.

9. Schairer C, Lubin J, Troisi R, Sturgeon S, Brinton L, Hoover R. Menopausal estrogen and estrogen-progestin replacement therapy and breast cancer risk. JAMA. 2000;283:485-491.

10. Pike MC, Ross RK. Progestins and menopause: epidemiological studies of risks of endometrial and breast cancer. Steroids. 2000;65:659-664.

11. The Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA. 2002;288:321-333.

12. Lando JF, Heck KE, Brett KM. Hormone replacement therapy and breast cancer risk in a nationally representative cohort. Am J Prev Med. 1999;17:176-180.

13. Stanford JL, Weiss NS, Voigt LF, Daling JR, Habel LA, Rossing MA. Combined estrogen and progestin hormone replacement therapy in relation to risk of breast cancer in middle-aged women. JAMA. 1995;274:137-142.

14. 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;93:754-762.

15. Willis DB, Calle EE, Miracle-McMahill HL, Heath CW, Jr. Estrogen replacement therapy and risk of fatal breast cancer in a prospective cohort of postmenopausal women in the United States. Cancer Causes Control. 1996;7:449-457.

16. Bush TL, Whiteman M, Flaws JA. Hormone replacement therapy and breast cancer: a qualitative review. Obstet Gynecol. 2001;98:498-508.

17. Barrett-Connor E, Stuenkel CA. Hormone replacement therapy (HRT)—risks and benefits. Int J Epidemiol. 2001;30:423-426.

18. LaVecchia C, Brinton LA, McTiernan A. Menopause, hormone replacement therapy and cancer. Maturitas. 2001;39:97-115.

19. Rodriguez C, Patel AV, Calle EE, Jacob EJ, Thun MJ. Estrogen replacement therapy and ovarian cancer mortality in a large prospective study of US women. JAMA. 2001;285:1460-1465.

20. Rodriguez C, Calle EE, Coates RJ, Miracle-McMahill HL, Thun MJ, Heath CW, Jr. Estrogen replacement therapy and fatal ovarian cancer. Am J Epidemiol. 1995;141:828-835.

21. Purdie DM, Bain CJ, Siskind V, et al. Hormone replacement therapy and risk of epithelial ovarian cancer. Br J Cancer. 1999;81:559-563.

22. Risch HA. Estrogen replacement therapy and risk of epithelial ovarian cancer. Gynecol Oncol. 1996;63:254-257.

23. Kaufman DW, Kelly JP, Welch WR, et al. Noncontraceptive estrogen use and epithelial ovarian cancer. Am J Epidemiol. 1989;130:1142-1151.

24. Hempling RE, Wong C, Piver S, Natarajan N, Mettlin CJ. Hormone replacement therapy as a risk factor for epithelial ovarian cancer: results of a case-control study. Obstet Gynecol. 1997;89:1012-1016.

25. Whittemore AS, Harris R, Itnyre J. and the Collaborative Ovarian Cancer Group. Characteristics relating to ovarian cancer risk: collaborative analysis of 12 US case-control studies. Am J Epidemiol. 1992;136:1184-1203.

26. Booth M, Beral V, Smith P. Risk factors for ovarian cancer: a case-control study. Br J Cancer. 1989;60:592-598.

27. Garg PP, Kerlikowske K, Subak L, Grady D. Hormone replacement therapy and the risk of epithelial ovarian carcinoma: a meta-analysis. Obstet Gynecol. 1998;92:472-479.

28. Negri E, Tzonou A, Beral V, et al. Hormonal therapy for menopause and ovarian cancer in a collaborative re-analysis of European studies. Int J Cancer. 1999;80:848-851.

29. Guidozzi F, Daponte A. Estrogen replacement therapy for ovarian carcinoma survivors: a randomized controlled trial. Cancer. 1999;86:1013-1018.

30. Ursic-Vrscaj M, Bebar S, Zakelj MP. Hormone replacement therapy after invasive ovarian serous cystadenocarcinoma treatment: the effect on survival. Menopause. 2001;8(1):70-75.

31. Troisi R, Schairer C, Chow WH, Schatzkin A, Brinton LA, Fraumeni JF, Jr. A prospective study of menopausal hormones and risk of colorectal cancer (United States). Cancer Causes Control. 1997;8:130-138.

32. Grodstein F, Martinez ME, Platz EA, et al. Postmenopausal hormone use and risk for colorectal cancer and adenoma. Ann Intern Med. 1998;128:705-712.

33. Fernandez E, LaVecchia C, D’Avanzo B, Franceschi S, Negri E, Parazzini F. Oral contraceptives, hormone replacement therapy and the risk of colorectal cancer. Br J Cancer. 1996;73:1431-1435.

34. Kampman E, Potter JD, Slattery ML, Caan BJ, Edwards S. Hormone replacement therapy, reproductive history, and colon cancer: a multicenter, case-control study in the United States. Cancer Causes Control. 1997;8:146-158.

35. Chute CG, Willett WC, Colditz GA, Stampfer MJ, Rosner B, Speizer FE. A prospective study of reproductive history and exogenous estrogens on the risk of colorectal cancer in women. Epidemiology. 1991;2:201-207.

36. Risch HA, Howe GR. Menopausal hormone use and colorectal cancer in Saskatchewan: a record linkage cohort study. Cancer Epidemiol Biom Preven. 1995;4:21-28.

37. Calle EE. Hormone replacement therapy and colorectal cancer: interpreting the evidence. Cancer Causes Control. 1997;8:127-129.

38. The Writing Group for the PEPI Trial. Effects of hormone replacement therapy on endometrial histology in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. JAMA. 1996;275:370-375.

39. Kurman RJ, Kaminski PF, Norris HJ. The behavior of endometrial hyperplasia: a long-term study of “untreated” hyperplasia in 170 patients. Cancer. 1985;56:403-412.

40. Grady D, Gebretsadik T, Kerlikowske K, Ernster V, Petitti D. Hormone replacement therapy and endometrial cancer risk: a meta-analysis. Obstet Gynecol. 1995;85:304-313.

41. Brinton LA, Hoover RN. and the Endometrial Cancer Collaborative Group. Estrogen replacement therapy and endometrial cancer risk: unresolved issues. Obstet Gynecol. 1993;81:265-271.

42. Beresford SA, Weiss NS, Voigt LF, McKnight B. Risk of endometrial cancer in relation to use of oestrogen combined with cyclic progestagen therapy in post-menopausal women. Lancet. 1997;349:458-461.

43. Hill DA, Weiss NS, Beresford SA, et al. Continuous combined hormone replacement therapy and risk of endometrial cancer. Am J Obstet Gynecol. 2000;183:1456-1461.

44. Sturdee DW, Ulrich LG, Barlow DH. The endometrial response to sequential and continuous combined oestrogen-progestagen replacement therapy. Br J Obstet Gynaecol. 2000;107:1392-1400.

45. Hargrove JT, Maxson WS, Wentz AC, Burnett LS. Menopausal hormone replacement therapy with continuous daily oral micronized estradiol and progesterone. Obstet Gynecol. 1989;73:606-612.

46. Luciano AA, Turksoy RN, Carleo J, Hendrix JW. Clinical and metabolic responses of menopausal women to sequential versus continuous estrogen and progestin replacement therapy. Obstet Gynecol. 1988;71:39-43.

47. Clisham PR, de Ziegler D, Lozano K, Judd HL. Comparison of continuous versus sequential estrogen and progestin therapy in postmenopausal women. Obstet Gynecol. 1991;77:241-246.

48. Weinstein L, Bewtra C, Gallagher JC. Evaluation of a continuous combined low-dose regimen of estrogen-progestin for treatment of the menopausal patient. Am J Obstet Gynecol. 1990;162:1534-1542.

49. Tseng L, Tseng JK, Mann WJ, et al. Endocrine aspects of human uterine sarcoma: a preliminary study. Am J Obstet Gynecol. 1986;155(1):95-101.

50. Wade K, Quinn MA, Hammond I, Williams K, Cauchi M. Uterine sarcoma: steroid receptors and response to hormonal therapy. Gynecol Oncol. 1990;39(3):364-367.

51. Schwartz SM, Weiss NS, Daling JR, et al. Exogenous sex hormone use, correlates of endogenous hormone levels, and the incidence of histologic types of sarcoma of the uterus. Cancer. 1996;77:717-724.

52. McGonigle KF, Karlan BY, Barbuto DA, Leuchter RS, LaGasse LD, Judd HL. Development of endometrial cancer in women on estrogen and progestin hormone replacement therapy. Gynecol Oncol. 1994;55:126-132.

53. Mahavni V, Sood AK. Hormone replacement therapy and cancer risk. Curr Opin Oncol. 2001;13:384-389.

54. Pilon D, Castillous AM, LeLorier J. Estrogen replacement therapy: determinants of persistence with treatment. Obstet Gynecol. 2001;97:97-100.

55. Marsh JV, Brett KM, Miller LC. Racial differences in hormone replacement therapy prescriptions. Obstet Gynecol. 1999;93:999-1003.

KEY POINTS

Hormone replacement therapy (HRT) may be associated with an increased risk of breast cancer.
Although the increased risk of breast cancer with HRT use is minimal, it may be advisable for some women to avoid this therapy altogether, especially those at high risk of breast cancer.
The long-term use of unopposed estrogen is associated with epithelial ovarian cancer.
The data on the risk of colorectal cancer with HRT use demonstrate a protective effect.
Unopposed estrogen use is associated with the development of endometrial carcinoma.

To say that the body of research on hormone replacement therapy (HRT) and the risk of cancer in postmenopausal women is rife with ambiguity is an understatement. Not only have recent studies challenged earlier findings, but the popular press often has generalized highly specific data into ubiquitous truths. Even so, we are gradually discerning who should and should not take the therapy, particularly in regard to the increased risk of cancer or its recurrence. With this article, we aim to objectively cite what is known about HRT in menopause and offer guidelines on how this information can be individualized to patients.

HRT and breast cancer

The most controversial risk associated with HRT is developing or aggravating breast cancer. Estrogen therapy—alone or in combination with progesterone—has been shown to increase production of the estrogen and progesterone receptors in breast tissue.¹ When activated, these receptors enhance breast density. In fact, a relationship between increasing breast density and breast cancer has been detected in several studies.^2,3

Endogenous hormones also may heighten the risk of breast cancer. Risk factors such as early menarche, late menopause, and high postmenopausal serum estradiol levels appear to be significantly associated with the development of breast cancer, as does obesity that persists after menopause (with presumed high estrogen levels secondary to peripheral androgen conversion to estrogen).⁴ In addition, an in vitro study suggests that breast-cell growth is stimulated with low doses of estrogen (but restricted at high doses).⁵

A recent prospective study found a significantly higher risk of invasive breast carcinoma among women who had ever used HRT (5 or more years).⁶ No association was noted between use of HRT and ductal carcinoma in situ (DCIS) or invasive ductal or lobular carcinoma. Nor was any association found between current HRT use and DCIS or invasive ductal or lobular carcinoma, regardless of the duration of use. Holli and colleagues corroborate these findings.⁷

In the Nurses’ Health Study, Colditz et al detected a significant association between breast cancer and the use of unopposed estrogen, estrogen in combination with progesterone, or progesterone alone.⁸ Current HRT users who were 55 to 59 years of age had a significantly increased risk of breast cancer, as did women age 60 to 64 who had taken HRT more than 5 years. The authors recommended that the use of any form of HRT be considered carefully, on a patient-by-patient basis, especially after 55 years of age.

In the Breast Cancer Detection Demonstration Project, Schairer et al found that the risk of breast cancer increased with the duration of HRT use among postmenopausal women.⁹ With unopposed estrogen, the risk of breast cancer in nonobese women increased after 8 or more years of use. With estrogen-progesterone, the risk was elevated after 4 years of use. When Schairer and colleagues analyzed different types of breast cancer, they found estrogen-progesterone was associated with a significantly increased risk of ductal and/or lobular disease with 4 or more years of use. In contrast, unopposed estrogen was associated with an increase in ductal and/or lobular disease after 8 to 16 years of use. Pike and Ross also found a statistically significant association between the risk of breast cancer and the use of estrogen-progesterone, compared with the use of estrogen alone.¹⁰

Researchers found a significant association between HRT use of 5 to 10 years and the development of invasive breast cancer, but no significance for prior use exceeding 10 years.

We now have data from the estrogen-progestin arm of the Women’s Health Initiative (WHI), which was halted after a mean follow-up of 5.2 years.¹¹ One reason this arm of the trial was interrupted was the emerging evidence that combination HRT is associated with invasive breast cancer. Researchers found a significant association between HRT use of 5 to 10 years and the development of invasive breast cancer (confidence interval [CI], 1.01-21.02). However, prior use exceeding 10 years was not significantly associated with breast cancer (CI, 0.60-5.43). This trial involved only 1 form and dose of HRT: conjugated equine estrogen 0.625 mg and medroxyprogesterone acetate 2.5 mg. It did not consider the use of lower doses of estrogen and progesterone or different formulations.