The Relationship Between HRT and Risk of Lobular Carcinoma

As a result ofthe observations described above, attention has been paid to potential risk factors that may be more strongly related to ILC risk than to IDC risk. In particular, there is a growing interest in the relationship between combined E and P HRT (CHRT) and ILC risk. Two main observations have driven this research. First, CHRT use in the USA increased over the same time period that ILC rates increased and IDC rates remained constant. From 1982-1992 the number E and P prescriptions increased 2.3-fold and 4.9-fold, respectively (24). Among controls from a recent USA multi-center case-control study of postmenopausal women spanning 1994-1998, 45% were current HRT users (25). Second, CHRT use has been shown to be associated with an elevated BC risk in numerous studies, and more recently in the Women's Health Initiative (WHI), a randomized controlled trial. The pooled analysis conducted by the Collaborative Group on Hormonal Factors in Breast Cancer of 51 observational studies found that current use of CHRT or P alone for 5 years or longer increased BC risk 53% (26). Consistent with this result, the WHI reported that CHRT is associated with a 26% increase in BC risk after 5.2 years of follow-up (27). Since ILCs are also more likely than IDCs to be hormone receptor positive, there is reason to suspect that ILCs may also be more responsive to hormonal exposures, like CHRT, than are IDCs.

Six case-control studies have now evaluated the relationship between CHRT use and risk of ILC compared to IDC (Table 1) (25, 28-32). Each of these studies were conducted using different USA populations. The number of lobular cases included in these studies ranged from 58 to 408. Three ofthe studies included a broad range of postmenopausal women (29-31), two focused on younger postmenopausal (<65 years of age) (25, 28), and the other on older postmenopausal women (65-79 years of age) (32). Each study evaluated ever and/or current use of ERT and CHRT separately. Three ofthese studies also evaluated different patterns of CHRT use (25, 29, 32). Two defined continuous CHRT (CCHRT) use as the use of the P component for 25+ days/month along with a daily dose of E, and sequential CHRT (SCHRT) use as the use ofthe P component for <25 days/month along with a daily dose of E (25, 32). The third study defined CCHRT use as the use of the same number of E and P pills in each prescription, and SCHRT use as that prescribed with different number of E and P pills in each prescription (29).

Ever Use of ERT and CHRT. Five of the six studies evaluated ever use of ERT and CHRT and risk of ILC and IDC (Table 2) (25, 28, 30-32). In general these studies were quite consistent. Ever use of ERT was associated with 1.1 - to 1.6-fold increases in risk of ILC (all of which were within the limits of chance) and 0.5- to 1.2-fold changes in risk of IDC in these studies. The two studies that evaluated duration of use were also consistent with each other, indicating that duration ofERT use was not associated with either ILC or IDC, including use for as long as 25 or more years according to one of these studies (25, 32).

Table 1. Studies of Use ofERT and CHRT and Risk of BC by Histologic Type.

Authors

Setting

Study

Age,

HRT Exposures

Design

Years

Reported

Li, et al.

Seattle

Population-based

50-64

Ever and current use

(28) (2000)

(King County)

case-control study

ofERT and CHRT

58 lobular cases

370 ductal cases

492 controls

Chen, et al.

Group Health

Nested case-control study

50-74

Current use and

(29) (2002)

Cooperative

91 lobular cases

durations of recent

ofPuget Sound

4 non-lobular cases

use ofERT and

92 controls

CHRT (including

SCHRT and CCHRT)

Neweomb,

Wisconsin,

Population-based

50-79

Ever use of

et al. (30)

Massachusetts,

case-control Study

ERT and CHRT

(2002)

and New

408 lobular eases

Hampshire

105 ductal cases

571 controls

Daling, et

Atlanta, Detroit,

Population-based

35-64

Ever use, current use,

al. (25)

Los Angeles,

case-control study

and durations of ever

(2002)

Philadelphia,

263 lobular cases

and current use of

and Seattle

1,386 ductal cases

ERT and CHRT

1,953 controls

(including SCHRT

and CCHRT)

Newcomer,

Wisconsin,

Population-based

<75

Ever use and

et al. (31)

Massachusetts,

case-control study

recent use of

(2003)

New Hampshire,

219 lobular cases

ERT and CHRT

and Maine

2,172 ductal cases

3,179 controls

Li, et al.

Seattie-Pugct

Population-based

65-79

Ever use, current use,

(32) (2003)

Sound Area

ease-control study

and durations of ever

(King, Pierce,

196 lobular cases

and current use of

and Snohomish

656 ductal cases

ERT and CHRT

counties)

1,007 controls

(including SCHRT

and CCHRT)

Table 2. Ever Use of ERT and CHRT and Risk of BC by Histologic Type.

Proportion of Controls Histology Type of Use/ Odds Ratio who were Duration of Use (95% CI)

Ever Users

Authors

Regimen

CHRT

Lobular Ductal Lobular Ductal

Ever use Ever use Ever use Ever use

1.2 (0.4-3.1) 0.5 (0.4-0.8) 2.0 (0.8-4.8) 0.7(0.5-1.1)

ERT Not reported CHRT Not reported

Lobular Ductal Lobular Ductal

Ever use

1,2(0.9-1.6)

Ever use

1.2(1.1-1.4)

Ever use

2.0(1.3-3.2)

Ever use

1.4(1.1-1.8)

CHRT

CHRT

Lobular

Ever use

1.1 (0.7-1.8)

6 mo-5 y

1.0 (0.6-1.7)

5+y

1.3 (0.8-2.2)

Ductal

Ever use

0.8 (0.6-1.0)

6 mo-5 y

0.8 (0.6-1.1)

5+y

0.7 (0.6-1.0)

Lobular

Ever use

1.8(1.2-2.6)

6 mo-5 y

1.6(1.0-2.4)

5+y

2.0(1.3-3.2)

Ductal

Ever use

1.0 (0.8-1.3)

6 mo-5 y

1.0 (0.8-1.3)

5+y

1.0 (0.8-1.3)

Lobular

Ever use

1.6(1.0-2.4)

Ductal

Ever use

1.1 (0.9-1.3)

Lobular

Ever use

3.0(1.6-5.7)

Ductal

Ever use

1.1 (0.8-1.5)

Table 2. Continued.

Proportion

Authors HRT

of Controls

Histology

Type of Use/

Odds Ratio

Regimen

who were Ever users

Duration of Use

(95% CI)

Li, et al. (32) ERT

39%

Lobular

Ever use

1.3 (0.8-2.0)

(2003)

6 mo-5 y 5-15 y 15-25 y 25+y

1.1 (0.6-2.0) 1.5 (0.8-2.9) 1.3 (0.6-2.6) 1.3 (0.7-2.4)

Ductal

Ever use 6 mo-5 y 5-15 y 15-25 y 25+y

1.0 (0.8-1.4) 0.9 (0.6-1.3) 1.2 (0.8-1.8) 1.4 (0.9-2.2) 0.9 (0.6-1.3)

CHRT

16%

Lobular

Ever use 6 mo-5 y 5-15 y 15+y

2.7(1.7-4.3) 1.8 (0.9-3.6) 3.7 (2.0-6.6) 2.6(1.3-5.3)

Ductal

Ever use 6 mo-5 y 5-15 y 15+y

1.5(1.1-2.0) 1.3 (0.9-2.1) 1.5(1.0-2.3) 1.6(1.0-2.6)

Ever use of CHRT was associated with 1.8- to 3.0-fold increased risks of ILC, but with 0.7- to 1.5-fold changes in risk of IDC. Further, CHRT appears to increase BC risk only when used for 5 years or longer (26). In the two studies evaluating the duration of CHRT, 5-year or longer users had higher risks of ILC than did users for less than 5 years in both studies (25, 32).

Together, these five studies indicate that ever use ofCHRT is associated with an elevation in ILC risk, and possibly, higher risk of IDC when used longer, but ever use of ERT was not associated with either ILC or IDC.

Current/Recent Use of ERT and CHRT. Five of the six studies also evaluated associations between current/recent use of HRT and risk of ILC and IDC (Table 3) (25, 28, 29, 31, 32). In three studies, current ERT use was not associated with ILC risk, with odds ratios (ORs) ranging from 0.9 to 1.3; while two found that current/recent use ofERT was associated with 1.8- to 2.0-fold increases in ILC risk (29, 31).

Table 3. Current Use of ERT and CHRT and Risk of BC by Histologic Type.

Authors

Regimen

% of Controls who were Current Users

Histology

Type of Use/ Duration of

Use

Odds Ratio (95% CI)

Li, et al. (28)

ERT

24%

Lobular

Current use

0.9 (0.3-3.0)

(2000)

Ductal

Current use

0.7 (0.4-1.1)

CHRT

14%

Lobular

Current use

2.1 (0.8-5.8)

Ductal

Current use

0.7 (0.4-1.1)

Chen, et al.

ERT

16%

Lobular

Current use

2.0(1.0-3.8)

(29) (2002)

Nonlobular

Current use

1.1 (0.8-1.5)

CHRT

11%

Lobular

Current use

3.9 (2.1-7.4)

Nonlobular

Current use

1.3 (0.9-1.8)

Daling, et al.

ERT

27%

Lobular

Current use

1.2 (0.7-2.J)

(25) (2002)

Ductal

Current use

0.8 (0.6-1.0)

CHRT

18%

Lobular

Current use

2.2(1.4-3.3)

Ductal

Current use

1.2 (0.9-1.5)

Newcomer,

ERT

7%

Lobular

Recent use

1.8(1.0-3.4)

et al. (31)

Ductal

Recent use

0.9 (0.7-1.2)

(2003)

CHRT

2%

Lobular

Recent use

3.6 (L8-7.6)

Ductal

Recent use

0.9 (0.6-1.3)

Li, etal. (32)

ERT

27%

Lobular

Current use

1.3 (0.8-2.2)

(2003)

6 mo-5 y

1.1 (0.4-2.9)

5-15 y

1.8 (0.8-3.9)

15+ y

1.4 (0.8-2.6)

Ductal

Current use

1.0 (0.7-1.3)

6 mo-5 y

0.5 (0.3-1.0)

5-15 y

1.3 (0.8-2.1)

15+y

1.1 (0.8-1,7)

Li, et al. (32)

CHRT

11%

Lobular

Current use

3.1 (1.9-5.2)

(2003)

6 mo-5 y

1.3 (0.5-3.6)

5-15 y

4.6 (2.5-8.5)

15+y

3.0(1.4-6.3)

Ductal

Current use

1.7(1.2-2.4)

6 mo-5 y

1.3 (0.8-2.3)

5-15 y

1.7(1.1-2.7)

15+y

2.0 (1.2-3.4)

However, the latter two studies included the smallest proportions of control women who were current users of ERT ofthe five studies (7% and 16% compared to 2427% in the other three studies), and thus had limited statistical power. None ofthe studies found an association between ERT use and risk of ductal, or in one study, "non-lobular" carcinoma (29).

With respect to CHRT, these five studies reported similar findings: current/recent CHRT use was associated with 2.1 - to 3.9-fold increases in ILC risk. Four of the five studies also found that current/recent use of CHRT was not associated with IDC risk (ORs ranging from 0.7 to 1.3) (25, 28, 29, 31). The one study that found an association between current CHRT use and IDC risk (OR = 1.7; 95% CI: 1.2-2.4) was the one that focused on older women with longer durations of CHRT use (32). In that study, CHRT use for five years or longer was associated with elevations in risk of both ILC and IDC, but use for less than five years was not (32). As a group, these studies suggest that current/recent CHRT use is associated with an elevated ILC risk, and that perhaps current/recent users of CHRT for more than five years may also have an elevated IDC risk.

Regimens of CHRT Use: Sequential vs. Continuous Use of Progestin. Three of the studies mentioned also evaluated associations between different regimens of CHRT use and BC risk by histologic type (25, 29, 32). Such evaluations are important because while the WHI study provided strong evidence that CCHRT is associated with an increased BC risk, limited data on the association between SCHRT and BC risk are available. The results oftwo ofthe studies summarized in Table 4 suggest that both SCHRT and CCHRT use are associated with an increased ILC risk, and with an increased risk of IDC/non-lobular carcinomas (29, 32). The other study, which was restricted to women younger than 65 years of age, observed that only CCHRT was associated with an increased ILC risk (25). Therefore, based on the limited evidence from these studies, SCHRT use appears to be associated with the same risk for ILC and IDC as is CCHRT use; however, further studies evaluating these associations are needed.

Summary. In the aggregate, the results of the studies described here suggest that neither ever use or current use ofERT is associated with changes in BC risk overall, IDC or ILC. This is inconsistent with the results of the meta-analysis by the Collaborative Group on Hormonal Factors in Breast Cancer, which found that current use ofERT for > 5 years was associated with a 1.34-fold increased risk of BC (26). This meta-analysis was limited because data on the type of HRT used were only available for 39% of the eligible women, and the analysis was not restricted to women who were exclusive ERT users. As a result, some of the associations observed may have been due to combined effects of ERT and CHRT use, since this study and others have found that CHRT use is a stronger BC risk factor than is ERT use (33, 34).

Table 4. Current Use of Sequential and Continuous CHRT and Risk of BC by Histologic Type.

Authors

CHRT Regimen

% of Controls Histology Type of Use/ who were Duration of Current Users Use

Odds Ratio (95% CI)

Chen, et al.

SCHRT

16%

Lobular

Recent use

(29) (2002)

<12 mo

1.2 (0.4-3.6)

13-35 mo

2.0 (0.8-5.4)

36+ mo

2.6(1.1-6.1)

Non lobular

Recent use

<12 mo

1.4 (0.9-2.3)

13-35 mo

0.9 (0.5-1.6)

36+ mo

1.5 (0.9-2.4)

CCHRT

5%

Lobular

Recent use

<11 mo

1.2 (0.3-6.0)

11+mo

6.1 (2.1-17.3)

Non lobular

Recent use

<11 mo

1.0 (0.5-2.0)

11+ mo

1.2 (0.6-2.4)

Daling, et al.

SCHRT

7%

Lobular

Current use

1.4 (0.8-2.5)

(25) (2002)

Ductal

Current use

0.9 (0.7-1.3)

CCHRT

10%

Lobular

Current use

2.4(1.5-3.8)

Ductal

Current use

1.3(1.0-1.7)

Li, et al. (32)

SCHRT

2%

Lobular

Current use

2.6(1.0-7.1)

(2003)

Ductal

Current use

1.8(1.0-3.6)

CCHRT

9%

Lobular

Current use

3.1 (1.8-5.3)

Ductal

Current use

1.6(1.1-2.3)

In a prior meta-analysis, use of ERT for > 10 years was associated with a 15%-49% increased BC risk (35). It is noteworthy that data from the Nurse's Health Study from 1976 to 1986, a time period prior to the widespread use of CHRT, are consistent with more recent studies, including those described above, indicating lack of association between ERT use and BC risk (36). Specifically, this report found that use of ERT for > 15 years was not associated with an increased

BC risk. This dataset was not included in the meta-analysis by Steinberg, et al. (35). They included data from the Nurse's Health Study that were published later (37), and included a larger proportion of ERT users who later also received CHRT. While recent data suggest that ERT use is not strongly associated with BC risk, completion ofthe ERT arm ofthe WHI randomized trial in the next few years will provide additional important information regarding this association. However, given the fact that the CHRT arm was terminated early, one could infer that any BC risk associated with ERT in the WHI study is likely to be smaller in magnitude than the BC risk found in the CHRT arm.

As previously indicated, there is convincing evidence from observational studies and the WHI randomized trial, that CHRT increase BC risk. Evidence is mounting regarding the adverse impact on BC risk by adding progestin to HRT. This adverse impact appears to manifest within several years of CHRT use, and is similar in magnitude irrespective of the type of CHRT (continuous or sequential use). Given the types of CHRT used most commonly by women in the latter part of the century, an increased incidence of BC must be tallied as a consequence.

Also, the six studies described above consistently indicate that CHRT use is more strongly associated with an increased risk for ILC than it is for IDC (25,2832). Thus, CHRT use may partially account for the increasing ILC rates observed in the USA and Europe (21-23). The biologic mechanisms underlying this association remain poorly understood, but one potential explanation may rest on the differences in ERa/PR expression between ILC and IDC, as 91 % of ILCs are ERa+ compared to 19% of IDCs, and 15% of ILCs are PR+ compared to 67% of IDCs (38).

P likely plays a key role in this association. We have observed that ERT use was not associated with BC risk of any particular ERa/PR tumor profile, but CHRT use was associated with an elevation in risk of ERa+/PR+ tumors. The magnitude ofthe risk increased with increased duration of CHRT use, but not for ERa+/PR~ or ERa/PR" tumors (32). These data suggest that CHRT may promote BC through the stimulation of both receptors, and not through ERa alone, since CHRT use was associated with an elevated risk for ERa+/PR+ tumors, but not for those ERa+/PR". While these findings require confirmation, they suggest that the P component ofCHRT may be particularly important with respect to altering BC risk.

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