Relation of Regimens of Combined Hormone Replacement Therapy to Lobular, Ductal, and Other Histologic Types of Breast Carcinoma

Transcription

1 2455 Relation of Regimens of Combined Hormone Replacement Therapy to Lobular, Ductal, and Other Histologic Types of Breast Carcinoma Janet R. Daling, Ph.D. 1,2 Kathleen E. Malone, Ph.D. 1,2 David R. Doody, M.S. 1 Lynda F. Voigt, Ph.D. 1 Leslie Bernstein, Ph.D. 3 Ralph J. Coates, Ph.D. 4 Polly A. Marchbanks, Ph.D. 5 Sandra A. Norman, Ph.D. 6 Linda K. Weiss, Ph.D. 7 Giske Ursin, M.D., Ph.D. 3 Jesse A. Berlin, Sc.D. 6 Ronald T. Burkman, M.D. 8 Dennis Deapen, Dr.P.H. 3 Suzanne G. Folger, Ph.D. 5 Jill A. McDonald, Ph.D. 5 Michael S. Simon, M.D., M.P.H. 9 Brian L. Strom, M.D., M.P.H. 6 Phyllis A. Wingo, Ph.D. 10 Robert Spirtas, Dr.P.H Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington. BACKGROUND. The incidence of invasive lobular carcinoma has been increasing among postmenopausal women in some parts of the United States. Part of this may be due to changes in classification over time. However, the use of combined (estrogen and progestin) hormone replacement therapy (CHRT) also has increased during the last decade and may account in part for the increase in invasive lobular breast carcinoma. METHODS. A large, multicenter case control study of Caucasian and African- American women who were diagnosed at age 65 years with their first invasive breast tumor from July 1, 1994 through April 30, 1998 was conducted. In-person interviews were conducted with 1749 postmenopausal patients, and their responses were compared with the responses of 1953 postmenopausal control women identified through random-digit dialing who met the study criteria of being postmenopausal at the time of diagnosis. Polytomous logistic regression was used to calculate the odds ratio (OR) as an estimate of the relative risk and to compute the 95% confidence interval (95%CI) associated with the use of various regimens of hormone replacement therapy (HRT) among women diagnosed with ductal breast carcinoma, lobular (or mixed lobular and ductal) breast carcinoma, and a grouping of other histologic types of breast carcinoma. RESULTS. Ever use of unopposed estrogen therapy (ERT) was not associated with an increase in the risk of any histologic type of breast carcinoma. The risk of invasive lobular breast carcinoma and the risk of breast carcinoma of the grouping of other histologies increased among women currently using CHRT (OR, 2.2; 2 Department of Epidemiology, School of Public Health and Community Medicine, University of Washington, Seattle, Washington. 3 Department of Preventive Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, California. 4 Cancer Division, Centers for Disease Control and Prevention, Atlanta, Georgia. 5 Division of Reproductive Health, Centers for Disease Control and Prevention, Atlanta, Georgia. 6 Center for Clinical Epidemiology and Biostatistics and Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania. 7 Division of Epidemiology, Karmanos Cancer Institute at Wayne State University, Detroit, Michigan. 8 Department of Obstetrics and Gynecology, Bay State Medical Center, Springfield, Massachusetts. 9 Division of Hematology and Oncology, Karmanos Cancer Institute at Wayne State University, Detroit, Michigan. 10 Department of Epidemiology and Surveillance Research, American Cancer Society, Atlanta, Georgia. 11 Contraception and Reproductive Health Branch, Center for Population Research, National Institute of Child Health and Human Development, Bethesda, Maryland. Supported by the National Institute of Child Health and Human Development, with additional support from the National Cancer Institute, through contracts with Emory University (N01 HD ), the Fred Hutchinson Cancer Research Center (N01 HD ), Karmanos Cancer Institute at Wayne State University (N01 HD ), the University of Pennsylvania (N01 HD ), and the University of Southern California (N01 HD ) and through an intraagency agreement with the Centers for Disease Control and Prevention (Y01 HD 7022). Also supported by the Surveillance, Epidemiology, and End Results Programs (N01 CN 0532, N01 CN 65064, N01 PC 67010, and N01 PC 67006). The authors thank the study participants for their generous contributions to this study. Brian L. Strom is a consultant for Wyeth-Ayerst Pharmaceuticals on other issues. Robert Spirtas is an employee of the federal government agency that sponsored this study. Linda K. Weiss s current address is National Cancer Institute, Bethesda, Maryland. Phyllis A. Wingo s current address is Division of Center Prevention and Control, Centers for Disease Control and Prevention, Atlanta, Georgia. Address for reprints: Janet R. Daling, Ph.D., Division of Public Health Sciences, Fred Hutchinson Cancer Research Center; 1100 Fairview Avenue North (MP 381), P.O. Box 19024, Seattle, WA ; Fax: (206) ; jdaling@fhcrc.org Received June 4, 2002; revision received July 18, 2002; accepted July 26, *This article is a US Government work and, as such, is in the public domain in the United States of America. Published 2002 by the American Cancer Society*

2 2456 CANCER December 15, 2002 / Volume 95 / Number 12 The incidence of invasive lobular breast carcinoma has increased steadily since 1977 among postmenopausal women in some parts of the United States, whereas the incidence of invasive ductal breast carcinoma has remained essentially constant since Of the lobular breast carcinomas, pure lobular carcinoma has almost doubled over this period, whereas mixed lobular and ductal carcinoma has increased about 6-fold. 2 The use of combined (estrogen plus progestin) hormone replacement therapy (CHRT) has increased since the mid-1980s, and three reports indicate that the use of this therapy may be related to the incidence of lobular breast carcinoma. 3 5 Few other published studies have assessed the relation between the use of hormone replacement therapy (HRT) and risks of breast carcinoma of different histologic types. It was reported previously that the use of any type of HRT had a stronger association with tumors with histologies that indicated a favorable prognosis compared with the association with combined lobular and ductal tumors in a comparison group. 6 That study did not ascertain the types of postmenopausal hormones used (i.e., CHRT vs. unopposed estrogen therapy [ERT]). In addition, ductal and lobular breast carcinoma may be distinct etiologically, and women with lobular histology have a better prognosis compared with women who have ductal breast carcinoma. 7 Using data from the National Institute of Child Health and Human Development Women s Contraceptive and Reproductive Experiences (CARE) Study a large, multicenter, case control breast carcinoma study of Caucasian and African-American women we assessed the relation between HRT and histologic types of invasive breast carcinoma, focusing on specific drug regimens as well as duration and recency of use. 95%CI, ; and OR, 1.9; 95%CI, , respectively). The risk increase was greater for the mixed lobular-ductal type than for the pure lobular type of breast carcinoma, although the difference was not statistically significant. There was some indication that 5 years of continuous CHRT ( 25 days per month of progestin) was associated with a higher risk of lobular breast carcinoma (OR, 2.5; 95%CI, ) compared with sequential CHRT ( 25 days per month of progestin; OR, 1.5; 95%CI, ). Current use of continuous CHRT was only moderately associated with risk of ductal breast carcinoma. CONCLUSIONS. Postmenopausal women who take CHRT appear to be at an increased risk of lobular breast carcinoma. Data from this study suggest that neither ERT use nor CHRT substantially increase the risk of ductal breast carcinoma among women age 65 years. Cancer 2002;95: Published 2002 by the American Cancer Society.* DOI /cncr KEYWORDS: histologic types of breast carcinoma, combined hormone replacement therapy, regimens of hormone replacement therapy, ductal, lobular. MATERIALS AND METHODS A detailed description of the methods used in the Women s CARE Study appears elsewhere. 8 Briefly, the study was conducted in five geographic areas: Atlanta, Detroit, Los Angeles, Philadelphia, and Seattle. The Centers for Disease Control served as the data coordinating center. Protocols were approved by the Institutional Review Committees of each center. Cases Women age years who resided in one of the five geographic areas and who had no history of in situ or invasive breast carcinoma when they were diagnosed with invasive breast carcinoma between July 1, 1994 and April 30, 1998, were eligible as cases. The Surveillance, Epidemiology, and End Results (SEER) Registry at each site (except Philadelphia) was used to identify cases. In Philadelphia, cases were ascertained by field staff contacting the hospitals in the study area. Because one goal of the study was to maximize the number of African-American women participating in the study, African-American women were oversampled. Caucasian women were selected randomly to provide approximately equal numbers of women in each 5-year age category, if possible. Only patients who were born in the United States were considered eligible. Of 5982 eligible patients who were identified and selected, 4575 patients (76.5%) were interviewed. Controls Random-digit dialing was used to identify women from the same geographic areas to serve as controls. Unclustered equal probability sampling of phone numbers with automated elimination of nonworking numbers was used. Approximately 82% of residential households called were successfully screened. Women

3 Combined HRT Use and Breast Carcinoma/Daling et al for the control group were selected randomly from those identified by the telephone screener by frequency matching women to the age, race, and geographic location of the patients in the case population. Control participants were eligible if they were born in the United States. Of 5956 eligible women who were selected as controls, 4682 women (78.6%) were interviewed, for an overall response rate of 64.5%. Data Collection In-person interviews were conducted with all study participants, usually in the woman s home. We asked questions about menstrual, contraceptive, and reproductive histories; body size; and medical history, including family history of cancer. Demographic data and information on smoking status, alcohol use, and exercise were collected. We also obtained a detailed history of all episodes of hormone use, including beginning and ending dates, total duration, brand, dose, and pattern of use (number of days per month) for each formulation. A life events calendar and a photo book of HRT medications marketed in the United States were used to enhance recall. Analysis Women were considered eligible to be included in this analysis if they met the following criteria for being postmenopausal: 1) natural menopause, defined as the last menstrual period (LMP) 12 months prior to the reference date, or a 12-month gap between LMP and first use of HRT, or LMP 12 months prior to hysterectomy or bilateral oophorectomy; 2) induced menopause through bilateral oophorectomy, chemotherapy, or radiation prior to natural menopause; 3) known menopause but type unclear, defined as bilateral oophorectomy prior to the reference date, with either a hysterectomy 1 year before or use of HRT in the entire 12-month period prior to oophorectomy; and 4) assumed natural menopause, including women age 55 years, either using HRT and still having periods or with a partial hysterectomy prior to natural menopause, and women whose periods stopped 12 months prior to the reference date for miscellaneous reasons unrelated to menopause (such as trauma). A total of 2651 cases and 2653 controls were excluded, including premenopausal women (2116 cases and 2061 controls), women with unknown menopausal status (53 cases and 66 controls), and women age 55 years with unclear menopausal status at the reference date (482 cases and 526 controls). We also excluded women who had only taken HRT in the form of creams, shots, implants, or suppositories or who had used only unopposed progestin (51 cases and 76 controls). For analysis, the tumors were grouped into three histologic groups: 1) ductal carcinoma (n 1386 patients; International Classification of Diseases for Oncology [ICD-O] code 8500); 2) lobular carcinoma (n 148 patients; ICD-O code 8520) or mixed lobular and ductal breast carcinoma (n 115 patients; ICD-O code 8522); and 3) other specific histologies (n 100 patients), including papillary breast carcinoma (ICD-O codes 8050, 8260, and 8503), tubular breast carcinoma (ICD-O 8211), mucinous breast carcinoma (ICD-O codes 8480 and 8481), and medullary breast carcinoma (ICD-O codes 8510 and 8512). This last group was formed to replicate the previous analysis by Gapstur et al. 6 Women with tumor types other than those described above (n 121 patients) were excluded from the analyses. Women who used estrogen and who took progestin 25 days per month were considered sequential CHRT (S-CHRT) users, whereas women who used estrogen and took progestin 25 days per month were considered continuous CHRT (C-CHRT) users. Polytomous logistic regression analysis was used to calculate odds ratios (ORs) as an estimate of the relative risk and to compute 95% confidence intervals (95%CIs). The following variables were evaluated as potential confounders: family history of breast carcinoma (first-degree relative or no first-degree relative), education (less than high school, high school graduate, technical school or some college, college graduate or higher), and type of menopause and age at menopause (5-year categories with imputation for those with unknown age at menopause). Age at menopause was imputed for women with unknown or unclear age at menopause. Imputed age at menopause was defined as age at bilateral oophorectomy for women who had an unclear type of menopause and age at first HRT use for women whose age at menopause was obscured by HRT use or whose first use of HRT occurred after hysterectomy (without bilateral oophorectomy). Age at menopause was imputed as the age at last menstrual period for all other women with unknown or unclear age at menopause. Also evaluated were age at menarche ( 11 years, years, years, or 15 years), parous (yes or no), age at first full-term ( 26 weeks) pregnancy (never pregnant, years, years, years, or 30 years), prior breast biopsy (yes or no), body mass index (BMI) 5 years prior to reference date (quartiles of control population), alcohol use 2 years prior to the reference date (average number of drinks per week: none, 7, or 7), oral contraceptive use (never, 6 months, 6 months to 5 years, or 5 years), smoking status (never, former, or current), and screening mammograms in the 2 years before reference date (0, 1, 2, or

4 2458 CANCER December 15, 2002 / Volume 95 / Number 12 3). Only adjustment for type of menopause changed the risk estimates of the ORs of interest by more than 10%. Further adjustment for age at menopause did not alter the estimates. Therefore, all analyses were adjusted for age (continuous), race, study site, and type of menopause. A subanalysis was performed splitting the lobular group into 1) pure lobular carcinoma (ICD-O code 8520) and 2) mixed lobular-ductal carcinoma (ICD-O code 8522). In the collaborative reanalysis of data from 51 studies on postmenopausal hormones and breast carcinoma, 9 the authors presented analyses showing that the risk of breast carcinoma associated with HRT was underestimated if there was inadequate control for the confounding factor: age at menopause. Pike et al. 10 provided a theoretical basis for this and indicated that the inclusion of women who undergo simple hysterectomy prior to natural menopause in analyses of HRT use and breast carcinoma should be avoided. To assess this potential bias, we performed a subanalysis that was restricted to the women with known age at menopause (841 women with ductal carcinoma, 145 women with lobular carcinoma, and 1210 control women). Due to the small number of women among the group with other histologies (n 57 patients), this grouping was not included in the current analysis. RESULTS Women with ductal breast carcinoma were somewhat younger compared with women who had tumors of lobular or other histologic types (Table 1). Women with lobular breast carcinoma were more likely to be white, to have a college education, to have an earlier age at menarche, to be nulliparous, to have a lower BMI, and to consume more alcohol compared with women in the control group or women in the other case groups. Women with breast carcinoma of other histologic types were more likely to be African American, to not have a first-degree family history of breast carcinoma, to not have undergone bilateral oophorectomy, and to be in the highest quartile of BMI compared with women who had ductal or lobular breast carcinoma. Ever use of unopposed estrogens (ERT) was not associated with an increased risk of breast carcinoma for any of the histologic groups (Table 2), and there was no increase in risk with duration of use. There was a slight reduction in the risk of ductal breast carcinoma associated with ever use of ERT (OR, 0.8; 95%CI, ) (Table 2). When we restricted the analyses to women who had only used ERT and had never used combined therapy, the risk estimates remained the same. These results also were unchanged when we confined our analysis to the 841 patients with ductal breast carcinoma, the 145 patients with lobular breast carcinoma, and the 1210 women in the control group with known age at menopause (Table 3). There was no increase in the risk of ductal breast carcinoma associated with ever use, only use, or duration of use of CHRT (Table 2). Like ERT, there was some indication of a reduced risk of ductal breast carcinoma among women who used CHRT for 6 months. However, women who had ever used CHRT for 6 months were at increased risk of lobular breast carcinoma (OR, 1.8; 95%CI, ). Compared with never users of HRT, women who used CHRT for 6 months to 5 years had a 1.6-fold greater risk of lobular carcinoma (95%CI, ), and women with 5 years of CHRT use had a 2.0-fold greater risk of lobular carcinoma (95%CI, ). Although some of the estimates of risk exceeded one for the other breast carcinoma histologies, all risk estimates were imprecise. The increased risk of lobular breast carcinoma associated with use of CHRT was somewhat more pronounced among women who used progestin continuously for 25 days per month (C-CHRT), particularly among women who used C-CHRT for 5 years (OR, 2.5; 95%CI, ) (Table 2). When we confined our analysis to the women with known age at menopause and adjusted for age at menopause, the risks for ductal and lobular carcinoma were 1.6 (95%CI, ) and 3.2 (95%CI, ), respectively (Table 3). The majority of women using CHRT were current users (Table 4), which limited our ability to assess the effect of time since last use on risk. Current users of C-CHRT had a 2.4-fold greater risk of developing lobular breast carcinoma (95%CI, ) compared with hormone nonusers. This relative risk diminished to 1.6 (95%CI, ) after 5 years from last use, but only 6 cases and 39 controls were in this former user group. There was some indication that women who were current users of S-CHRT also were at increased risk for breast carcinoma of other histologies (OR, 2.7; 95%CI, ). Current use of C-CHRT was associated modestly with excess risk of ductal carcinoma (OR, 1.3; 95%CI, ) and breast carcinoma of other histologies (OR, 1.7; 95%CI, ); however, these associations were imprecise. We also conducted analyses separately for pure lobular carcinoma and mixed lobular-ductal carcinoma. The relative risk estimates were stronger for mixed lobular-ductal carcinoma (i.e., for 5 years of C-CHRT use [mixed lobular-ductal breast carcinoma: OR, 2.9; 95%CI, ; pure lobular breast carcinoma: OR, 1.6; 95%CI, ] data not shown). DISCUSSION Some limitations should be considered when interpreting the results of our study. We were only able to

5 Combined HRT Use and Breast Carcinoma/Daling et al TABLE 1 Characteristics of Study Population According to Histologic Type of Breast Carcinoma Control group (n 1953) Type of breast carcinoma Ductal (n 1386) Lobular (n 263) Other (n 100) a Characteristic No. % No. % No. % No. % Age (yrs) Race White African American Study site Atlanta Detroit Los Angeles Philadelphia Seattle Education Less than high school High school graduate Technical school College graduate First-degree family history No Yes Unknown Age at menopause (yrs) b Unknown/unclear Body mass index (quartiles) Unknown Average weekly alcohol consumption None drinks drinks Unknown Smoking status Never Former Current Age at menarche (yrs) Unknown Parous No Yes Unknown (continued)

6 2460 CANCER December 15, 2002 / Volume 95 / Number 12 TABLE 1 (continued) Control group (n 1953) Type of breast carcinoma Ductal (n 1386) Lobular (n 263) Other (n 100) a Characteristic No. % No. % No. % No. % Age at first full-term pregnancy (yrs) Never pregnant Unknown History of breast biopsy Never Ever Type of menopause Known menopausal, natural Known menopausal, induced Known menopausal, unknown type Assumed natural menopause No. of screening mammograms in 2 yrs before reference date Unknown a Lobular includes both lobular and mixed lobular and ductal carcinoma; other includes papillary, tubular, mucinous, and medullary carcinoma. b Known age at menopause. Excludes women with imputed age at menopause. interview 76.5% of all eligible cases. In addition, only 82% of residential households were screened successfully, and only 78.6% of potential controls identified in this way were interviewed, for an overall response rate of 64.5%. If the women we were unable to interview differed from those who did participate with regard to type or patterns of hormone use, then our results would be biased to some degree. Another limitation of our study is that we relied on a woman s ability to recall the types of HRT used as well as the timing and duration of use. Studies have shown good agreement between women s reports and physicians reports or medical records. 11 The majority of women who used CHRT in our study were current users (78.8% of cases and 68.3% of controls), which would increase their ability to report accurately on the specific regimens used. In addition, because some women changed not only the type of HRT (i.e., ERT and CHRT) but also the number of days per month that they used progestin, a portion of women had used more than one regimen and fell into more than one regimen category. However, when we restricted our analyses to women who had only used one regimen, the results did not change. Finally, we did not conduct a pathology review of the tumors to ensure a consistent assessment of histology. Therefore, we relied on the diagnoses made by the numerous pathologists serving the five geographic areas included in the study. This may have resulted in some misclassification of tumors with respect to histology. The incidence of both lobular carcinoma and mixed lobularductal carcinoma has increased over the past 20 years, with mixed lobular-ductal carcinoma increasing 6-fold during this period. 2 It is unclear whether this is real or simply an artifact due to changes in histologic classification criteria over time. It also is unclear to what extent there are variations between laboratories in making this classification. In our study, the strongest findings were observed for the type of tumor that has observed the greatest increase in incidence over time, tumors of the mixed lobular-ductal type. If the diagnosis of either lobular carcinoma or mixed lobular breast carcinoma is more likely to occur in laboratories where samples from C-CHRT users are sent, then it is possible that we may have overestimated the risks associated with HRT in this histologic grouping. The proportion of the breast carcinomas that were classified as the lobular type varied by study site. This is not surprising if our study results are

7 Combined HRT Use and Breast Carcinoma/Daling et al TABLE 2 Relation of Hormone Replacement Therapy to Risk of Histologic Types of Breast Carcinoma by Regimen and Duration Control group (n 1953) Type of breast carcinoma Ductal (n 1386) Lobular (n 263) Other (n 100) a HRT regimen No. % No. % OR b 95%CI No. % OR b 95%CI No. % OR b 95%CI Never used HRT c Ref Ref Ref. Unopposed estrogen pill/patch Duration 6 months Only used ( 6 months) d e Ever used ( 6 months) e months to 5 yrs yrs e Estrogen and progestin pill/patch Duration 6 months e Only used ( 6 months) d Ever used ( 6 months) months to 5 yrs yrs Sequential estrogen and progestin pill/patch f Duration 6 months Only used ( 6 months) d Ever used ( 6 months) months to 5 yrs yrs Continuous combined estrogen and progestin pill/patch g Duration 6 months Only used ( 6 months) d Ever used ( 6 months) months to 5 yrs yrs HRT: hormone replacement therapy OR: odds ratio; 95%CI: 95% confidence interval; Ref. reference. a Lobular includes lobular and mixed lobular and ductal carcinoma; other includes papillary, tubular, mucinous, and medullary carcinoma. b The OR was adjusted for age, race, study site, and type of menopause. c Never used any HRT. d Exclusively used this specified regimen. e 95%CI does not include 1.0. f Progestin was added 25 days per month. g Progestin was added 25 days per month. accurate. CHRT use is more common on the west coast and is less common among African-American women. The results of our study apply only to women age 65 years at the time they are diagnosed with breast carcinoma. Hence, our results cannot be compared directly with studies that included older women who may have used HRT for longer durations or who may have experienced a longer time since first use. Nonetheless, the results of our study are in agreement with those of Li et al. 4 and Newcomer et al., 3 who observed an increase in risk of lobular breast carcinoma among current users of CHRT (OR, 2.6; 95%CI, ; and OR, 3.1; 95%CI, , respectively). Those studies did not find any increased risk of ductal breast carcinoma in users of either ERT or CHRT. Chen et al., 5 who studied women age years, restricted their analyses to women who had used HRT in the 5 years prior to the reference date and grouped their cases into two histologic categories: lobular and nonlobular. Those authors did not find any significant correlations between the use of either ERT or CHRT and nonlobular breast carcinoma. However, the use of ERT and CHRT for 60 months was related to an increased risk of lobular breast carcinoma (ERT: OR, 3.68; 95%CI, ; CHRT: OR, 2.91; 95%CI, ). They found some indication that C-CHRT was related more strongly to the risk of breast carcinoma compared with S-CHRT; however, the number of exposed cases was limited. Their findings are consistent with our results. Four other studies 6,12 14 have reported on the relation of HRT and histologic types of breast carcinoma. None of those studies evaluated the risk asso-

8 2462 CANCER December 15, 2002 / Volume 95 / Number 12 TABLE 3 Relation of Hormone Replacement Therapy to Risk of Histologic Types of Breast Cancer by Regimen and Duration among Women with Known Age at Menopause Control group (n 1210) Ductal (n 841) Type of breast carcinoma Lobular (n 145) a HRT regimen No. % No. % OR b 95%CI No. % OR b 95%CI Never used HRT c Ref Ref Unopposed estrogen pill/patch Duration 6 months Only used ( 6 months) d Ever used ( 6 months) months to 5 yrs yrs Estrogen and progestin pill/patch Duration 6 months Only used ( 6 months) d Ever used ( 6 months) months to 5 yrs yrs Sequential estrogen and progestin pill/patch e Duration 6 months Only used ( 6 months) d Ever used ( 6 months) months to 5 yrs yrs Continuous combined estrogen and progestin pill/patch f Duration 6 months Only used ( 6 months) d Ever used ( 6 months) months to 5 yrs yrs HRT: hormone replacement therapy OR: odds ratio; 95%CI: 95% confidence interval; Ref. reference. a Lobular includes lobular carcinoma and mixed lobular and ductal carcinoma. b The OR was adjusted for age, race, study site, type of menopause, and known age at menopause. c Never used any HRT. d Exclusively used this specified regimen. e Progestin was added 25 days per month. f Progestin was added 25 days per month. ciated with CHRT separately. O Connor et al. 12 found that the risk of invasive lobular carcinoma was slightly more common in HRT users, similar to the findings of Bonnier et al. 13 and of Manjer et al. 14 in a populationbased cohort study in Sweden, who found that women who developed breast carcinoma while on HRT were 4 times as likely to develop a lobular carcinoma (95%CI, ) compared with women who were not HRT users. Gapstur et al. 6 grouped tumors of ductal and lobular histologies together and compared the risk associated with HRT in this grouping with the risk of a group of tumors believed to have a favorable prognosis (i.e., papillary, tubular, mucinous, and medullary). Those authors found that the relative risk of tumors with favorable histology was elevated among current users of HRT, whereas the risk associated with current HRT use among the ductal-lobular histologic group was more modest. We attempted to replicate their findings but did not find a similar association between this histologic group and current use of ERT; however, the risk associated with CHRT was elevated (OR, 1.9; 95%CI, ). Differences in durations and regimens of use may account for these disparate results, because the age range of study participants and the years of diagnosis were not the same in the two studies. Most of the previous studies that have assessed the risk of breast carcinoma with CHRT have not distinguished between sequential and continuous use of progestin. Ross et al. 15 found a 24% increase in the risk of breast carcinoma (all histologic types combined) for every 5 years of use associated with CHRT. In their study, women who used progestin sequentially had a 38% increase in risk for every 5 years of use, whereas women who used the progestin continuously had a 9%

9 Combined HRT Use and Breast Carcinoma/Daling et al TABLE 4 Relation of Hormone Replacement Therapy to Risk of Histologic Type of Breast Carcinoma by Regimen and Time since Last Use Control group (n 2029) Type of breast carcinoma Ductal (n 1424) Lobular (n 271) Other (n 105) a HRT regimen No. % No. % OR b 95%CI No. % OR b 95%CI No. % OR b 95%CI Never used HRT c Ref Ref Ref. Unopposed estrogen pill/patch d Former 5 years ago Former ( 6 months to 5 yrs ago) Current (within 6 months) Estrogen and progestin pill/patch d Former 5 years ago Former ( 6 months to 5 yrs ago) Current (within 6 months) e Sequential estrogen and progestin pill/patch d,f Former 5 years ago Former ( 6 months to 5 yrs ago) Current (within 6 months) Continuous combined estrogen and progestin pill/patch d,g Former 5 years ago Former ( 6 months to 5 yrs ago) Current (within 6 months) HRT: hormone replacement therapy OR: odds ratio; 95%CI: 95% confidence interval; Ref. reference. a Lobular includes lobular carcinoma and mixed lobular and ductal carcinoma; other includes papillary, tubular, mucinous, and medullary carcinoma. b The OR was adjusted for age, race, study site, and type of menopause. c Never used any HRT. d Excludes women who used the regimen for 6 months. e 95%CI does not include 1.0. f Progestin was added 25 days per month. g Progestin was added 25 days per month. increase in risk. In contrast, Magnusson et al., 16,17 in a study from Sweden, found that the women who used continuous CHRT were at highest risk of breast carcinoma (all histologic types combined), with an increase 2-fold per 5 years of use (OR, 2.2; 95%CI, ). There is reason to suspect that the use of CHRT may have different effects on the risk of different histologic types of breast carcinoma. Breast carcinomas originate from the cells that line the small terminal ductolobular or alveolar units. These alveloli, or lobules, mature during pregnancy in response to progesterone stimulation, which promotes cell differentiation. 18 The lobules have been classified further in four groups that vary in development and differentiation. 19 The proportion of the various types of lobules changes with parity and with age. 20 The postmenopausal breast is comprised predominantly of Type 1 lobules. Ductal carcinomas develop from Type 1 lobules, which are undifferentiated, and lobular carcinomas develop in the somewhat more differentiated Type 2 lobules. In the absence of hormonal stimulation, the proportion of Type 2 lobules decreases as women proceed through menopause. The use of CHRT may push the differentiation of Type 1 lobules to Type 2 lobules, leading to an increased risk in carcinomas with lobular histology. The hypothesis that continuous regimens of progestin may confer a higher risk of lobular breast carcinoma compared with sequential use of progestin also has some biologic foundation. Apoptosis (i.e., programmed cell death) is a major mechanism whereby DNA-damaged cells are removed from the breast. It has been shown that progestins are proapoptotic in normal as well as hormone dependent breast carcinoma cells. 21 The removal of progestins for a short period triggers the maximum apoptotic mechanisms, whereas continued progestin administration causes suppression of cyclins, with resulting fixation of mammary cells in G1-phase. 22,23 Druckmann 24 proposes that progestin supplementation should be given sequentially, thus providing interruption to achieve a sufficient inhibition of proliferation and, secondarily, a maximum apoptotic rate. Evidence is mounting with regard to the adverse effects of adding progestin to HRT in relation to the risk of breast carcinoma. Studies that have included women who were diagnosed during the 1990s and, hence, that had adequate numbers of women with long-term exposure have shown an increased risk for breast carcinoma among women using combined therapy. 15,16,25,26 The results of the current study, in agreement with three

10 2464 CANCER December 15, 2002 / Volume 95 / Number 12 other reports, 3 5 indicate that the adverse effect of HRT may be confined to the risk of lobular or mixed lobular breast carcinoma, histologies that are less common and are more likely to be estrogen receptor positive and to indicate a more favorable prognosis compared with ductal carcinoma. 27,28 Also in agreement with those studies, we did not find an increase in the risk of ductal breast carcinoma associated with the use of unopposed estrogen. However, we included only women who were diagnosed with breast carcinoma at age 65 years; thus, the influence of ERT on ductal breast carcinoma in women diagnosed at older ages could not be evaluated. Further studies are needed that address the risk of breast carcinoma associated with CHRT according to both histologic type and the number of days of progestin administration. Because the use of continuous progestin therapy is relatively recent, studies in older women who have used CHRT for long durations will be important. REFERENCES 1. Li CL, Anderson BO, Porter P, Holt SK, Daling JR, Moe RE. Changing incidence rate of invasive lobular breast carcinoma among older women. Cancer. 2000;88: Surveillance, Epidemiology, and End Results (SEER) Program. Public-use data ( ) released April 2001 [based on the August 2000 submission]. Bethesda: National Cancer Institute, DCCPS, Surveillance Research Program, Cancer Statistics Branch, Newcomer LM, Newcomb PA, Daling JR, Yasui Y, Potter JD. Post-menopausal hormone use and risk of breast cancer by histologic type. Presented at the Society of Epidemiologic Research 1999 SER Meeting, Baltimore, MD June 10 12, Li CL, Weiss NS, Stanford JL, Daling JR. Hormone replacement therapy in relation to risk of lobular and ductal breast carcinoma in middle-aged women. 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