Cancer recurrence and mortality in women using hormone replacement therapy after breast cancer: Meta-analysis

,

Original Research

Cancer recurrence and mortality in women using hormone replacement therapy after breast cancer: Meta-analysis

J Fam Pract. 2002 December;51(12):1056-1062

PDF Download

References

1. Schairer C, Lubin J, Troisi R, Sturgeon S, Brinton L. Menopausal estrogen and estrogen–progestin replacement therapy and breast cancer risk. JAMA 2000;283:485-91.

2. Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women. JAMA 2002;288:321-33.

3. Bluming AZ, Waisman JR, Dosik GM, et al. Hormone replacement therapy (ERT) in women with previously treated primary breast cancer. Update VII. Proc ASCO 2001;20:12b.-

4. DiSaia PJ, Brewster WR. Hormone replacement therapy in breast cancer survivors. Am J Obstet Gynecol 2000;183:517.-

5. Brewster WR, DiSaia PJ, Grosen EA, McGonigle KF, Kuykendall JL, Creasman WT. An experience with estrogen replacement therapy in breast cancer survivors. Int J Fertil Womens Med 1999;44(4):186-92.

6. DiSaia PJ, Odicino F, Grosen EA, Cowan B, Pecorelli S, Wile AG. Hormone replacement therapy in breast cancer. Lancet 1993;342:1232.-

7. Decker D, Cox T, Burdakin J, Jaiyesimi I, Pettinga J, Benitez P. Hormone replacement therapy (ERT) in breast cancer survivors. Proc ASCO 1996;15:208.-

8. Guidozzi F. Estrogen replacement therapy in breast cancer survivors. Int J Gynaecol Obstet 1999;64:59-63.

9. Powles TJ, Hickish T, Casey S, O’Brien M. Hormone replacement after breast cancer. Lancet 1993;342:60-1.

10. Vassilopoulou-Sellin R, Theriault R, Klein MJ. Estrogen replacement therapy in women with prior diagnosis and treatment for breast cancer. Gynecol Oncol 1997;65:89-93.

11. Wile AG, Opfell RW, Margileth DA. Hormone replacement therapy in previously treated breast cancer patients. Am J Surg 1993;165:372-5.

12. DiSaia PJ, Grosen EA, Odicino F, et al. Replacement therapy for breast cancer survivors. A pilot study. Cancer 1995;76(suppl):2075-8.

13. Espie M, Gorins A, Perret F, et al. Hormone replacement therapy (ERT) in patients treated for breast cancer: Analysis of a cohort of 120 patients [abstract]. Proc ASCO 1999;18:586a.-

14. Peters GN, Jones SE. Estrogen replacement therapy in breast cancer patients: a time for change? [abstract]. J Clin Oncol 1996;15:121.-

15. Dew J, Eden J, Beller E, et al. A cohort study of hormone replacement therapy given to women previously treated for breast cancer. Climacteric 1998;1:137-42.

16. DiSaia PJ, Grosen EA, Kurosaki T, Gildea M, Cowan B, Anton-Culver H. Hormone replacement therapy in breast cancer survivors: a cohort study [see comments]. Am J Obstet Gynecol 1996;174:1494-8.

17. DiSaia PJ, Brewster WR, Ziogas A, Anton-Culver H. Breast cancer survival and hormone replacement therapy: a cohort analysis. Am J Clin Oncol 2000;23:541-5.

18. Eden J, Bush T, Natrajan PK, Wren B. A case-control study of combined continuous estrogen–progestin replacement therapy among women with a personal history of breast cancer. Menopause 1995;2:67-72.

19. Marsden J, Whitehead M, A’Hern R, Baum M, Sacks N. Are randomized trials of hormone replacement therapy in symptomatic women with breast cancer feasible? Fertil Steril 2000;73:292-9.

20. Natrajan PK, Soumakis K, Gambrell RD, Jr. Estrogen replacement therapy in women with previous breast cancer. Am J Obstet Gynecol 1999;181:288-95.

21. Vassilopoulou-Sellin R, Asmar L, Hortobagyi GN, et al. Estrogen replacement therapy after localized breast cancer: clinical outcome of 319 women followed prospectively. J Clin Oncol 1999;17:1482-7.

22. Wile AG, Opfell RW, Margileth DA, Anton-Culver H. Hormone replacement therapy does not effect breast cancer outcome. Proc ASCO 1991;10:58.-

23. Habel LA, Daling JR, Newcoomb PA, et al. Risk of recurrence after ductal carcinoma in situ of the breast. Cancer Epidemiol Biomarkers Prev 1998;7:689-96.

24. Ursic-Vrscaj M, Bebar S. A case-control study of hormone replacement therapy after primary surgical breast cancer treatment. Eur J Surg Oncol 1999;25:146-51.

25. Beckmann MW, Jap D, Djahansouzi S, et al. Hormone replacement therapy after treatment of breast cancer: effects on postmenopausal symptoms, bone mineral density and recurrence rates. Oncology 2001;60:199-206.

26. Col NF, Hirota LK, Orr RK, Erban JK, Wong JB, Lau J. Hormone replacement therapy after breast cancer: a systematic review and quantitative assessment of risk. J Clin Oncol 2001;19:2357-63.

27. Cobleigh MA. Hormone replacement therapy and nonhormonal control of menopausal symptoms in breast cancer survivors. In: Biological and Hormonal Therapies of Cancer. Foon Ka, Muss HB (eds.): Kluwer Academic Publishers, Boston, 1998;209-230.

28. Steinberg KK, Smith SJ, Thacker SB, Stroup DF. Breast cancer risk and duration of estrogen use: the role of study design in meta-analysis. Epidemiology 1994;5:415-21.

Validity assessment

All included studies were assessed for validity by 2 independent reviewers, blinded to study results, for the following characteristics: (1) prospective data collection, (2) clear subject inclusion criteria, (3) reliability of exposure, (4) similarity between exposed and unexposed groups, (5) loss to follow-up, and (6) reliability of outcome assessment. When threats to study validity were identified, attempts were made to determine whether these threats were likely to significantly influence the results of the study and to estimate the direction of the influence of these threats on the resulting data. Because baseline differences between the study groups are such an important threat to the validity of these studies, the studies were graded as higher quality and lower quality based on whether significant differences in known prognostic factors existed.

Data management and analysis

A data extraction form was created to aid consistent recording of data from all studies, and both investigators extracted data independently. Any discrepancies in data interpretation or abstraction were resolved through consensus. Study characteristics and results for single-arm cohort studies were presented descriptively. For controlled studies, data were entered as dichotomous variables into Review Manager 4.1 software, as distributed by the Cochrane Collaboration. Summary relative risk (RR) estimates were calculated by using a fixed effects model (Mantel-Haenszel method) unless the results were found to be statistically heterogeneous (P < .1) through the use of a Q statistic, in which case the more conservative random effects model (DerSimonian-Laird method) was used. A subanalysis was performed based on the quality ratings, with a lower rating given to studies in which the exposed and unexposed groups differed significantly on important prognostic factors such as age, tumor stage, and time since diagnosis. Funnel plots were constructed to identify possible publication bias.

Results

Description of studies

The original search yielded 24 relevant reports, including 1 unpublished report (Bluming AZ, personal communication, 2000) with 2 separate studies. One of these and 12 published single-arm cohort studies^3-14 were excluded because they lacked a control group, but a summary of these studies can be found online (Table W1, available on the JFP Web site: www.jfponline.com). Twelve reports^15-25 met the inclusion criteria and provided data comparing the rates of recurrence or mortality among patients who used ERT after the diagnosis of breast cancer and users vs controls. Among these studies were 8 independent cohort studies from the published literature,^{15-17,20,21,23-25} one set of unpublished data from Bluming et al, and one 6-month pilot randomized controlled trial.¹⁹ One matched cohort study¹⁸ presented recurrence data for 90 patients and 180 controls who were later included in a larger, non-matched study reporting recurrence and mortality.¹⁵ Another small study²² reported only deaths from breast cancer from a data set included at least in part in another report¹⁶ and was therefore excluded. Overall, the included studies accounted for 717 subjects who used hormone replacement therapy at some time after their diagnosis of breast cancer compared with 2545 nonusers. Characteristics of included studies are summarized in the Table.

TABLE
Characteristics of included studies

Study	Design (matched variables, when applicable)	ERT/ controls, no.	Disease, stage included	Median DFI, mo*	Median ERT use, mo*	Median follow-up for users/ controls, mo*	groups similar at baseline^†	Recurrence	Death
Beckmann et al²⁵	Cohort study; local controls	64/121	0–III	NR	33 (3–60)	37 (3–60)/ 42 (3–60)	No	Yes	Yes
Bluming et al (personal communication)	Cohort study; local controls	95/64	T1N0	60 (NR)	46 (1–88)	107 (3–400)/ 206 (17–251)	No	Yes	0
Dew et al¹⁵	Cohort study; local controls	167/1305	Anyl	36 (0–312)	19 (3–264)	NR	No	No	Yes
DiSaia et al¹⁶	Matched cohort; population controls (age, stage, year of diagnosis)	41/82	0–III	NR	NR	NR NR (6–114)	Yes	Yes	Yes
DiSaia et al¹⁷	Matched cohort; population controls (age, stage, year of diagnosis)	125/362	0–IV	46 (0–401)*	22 (NR)*	NR	Yes	No	Yes
Eden et al¹⁸	Matched cohort; local controls (age, year of diagnosis, DFI, nodes, tumor size)	90/180	0–IV	60 (0–300)	18 (4–144)	84 (4–360)/ 72 (4–348)	Yes	Yes	Yes
Habel et al²³	Retrospective cohort; population sample; exposure identified through mailed survey	64/222	DCIS only	NR	24 (NR)	NR	No	Yes	No
Marsden et al¹⁹	RCT	51/49	0–II	40 (2–215)	6 (6)	6 (6)	Yes	Yes	0
Natrajan et al²⁰	Cohort study; local controls	50/18	I–II	NR	65 (6–384)*	83 (6–384)/ 50 (6–120)*	No	Yes	Yes
Ursic-Vrscaj and Bebar²⁴	Matched cohort; local controls (age, year of diagnosis, DFI, nodes, tumor size)	21/42	I–III	62 (1–180)	28 (3–72)	100 (18–234)/ 100 (18–230)	Yes	Yes	Yes
Vassilopoulou-Sellin et al²¹	Prospective cohort study; local controls	39/280	I–II	114	NR (24–234)	40 (24–99)	Yes	Yes	0
*Values presented as mean (range).
^†Based on matching or demonstrated similarity in age at diagnosis, disease stage, and DFI. Estrogen receptor status not available for most subjects, and race was not reported in any study.
0, no deaths occurred; DCIS, ductal carcinoma in situ; DFI, disease-free interval, or number of months between the diagnosis of breast cancer and the initiation of ERT; ERT; estrogen replacement therapy; NR, not reported; RCT, randomized controlled trial.

Methodologic quality

The quality of the studies was variable. The only randomized controlled trial¹⁹ was a 6-month pilot study, after which the allocation code was broken and patients were free to choose whether to be on treatment. Of the cohort studies, only 1 trial²¹ began with an inception cohort that combined data from 62 patients who elected to be part of a randomized controlled trial with that from another 257 who declined to be randomized but chose on their own whether to take ERT.²¹ One study was clearly retrospective²³ ; patients with ductal carcinoma in situ were identified through a cancer registry, and their exposures and recurrences were determined through a mailed questionnaire. The remaining studies used clinic records to identify patients who had been prescribed ERT and compared those recurrence and mortality rates with those of a control group comprising the remaining clinic patients^{15,18,20,24,25} or matched subjects selected from a regional cancer surveillance database.^15,16 Although the matching process controlled for some important prognostic factors (age, stage, and time since diagnosis), post-diagnosis ERT use was not recorded in the surveillance database, so these control groups may have contained patients who took ERT at some time, thereby diluting any differences that might be observed. Conversely, none of the cohort studies reported means confirming that those for whom HRT had been prescribed actually took it regularly.