6) Jordan, V. Craig. “The new biology of estrogen-induced apoptosis applied to treat and prevent breast cancer.” Endocrine-related cancer 22.1 (2015): R1.

Alexander Haddow (2) reported that high doses of synthetic estrogens were able to produce a 30% response rate in women with metastatic breast cancer. High dose estrogen therapy was to remain the standard of care until the introduction of tamoxifen a non-steroidal anti-estrogen, for the treatment of breast cancer in the 1970s (18). But here was a paradox. All the laboratory and clinical evidence suggested that breast cancer was dependent on estrogen for growth but Haddow taught us that estrogen causes tumor regression!
The first clinical trial published in 1944(2), is summarized in Table 1. Responses were consistent at about 30% but for less than a year. These preliminary data showed that both breast and prostate cancer were responsive but no other tumor types responded.
The results were clear; a period of 5 years post menopause was necessary for optimal antitumor action with high dose estrogen for breast cancer treatment. All clinical results were, therefore, consistent – a period of time after the menopause was necessary to expose the effectiveness of high dose estrogen as an anticancer agent for metastatic breast cancer.

Early clinical trials of the treatment of metastatic breast cancer in postmenopausal women showed similar response rates and durations of responsiveness as DES, but with fewer side effects than high doses of estrogen (3, 40). However, it was noted that reanalysis of a randomized trial of DES vs. tamoxifen (3) demonstrated that patients treated with DES had a more prolonged survival when compared to those treated with tamoxifen (41).

The successful use of high dose synthetic estrogens to treat post-menopausal metastatic breast cancer, is the first effective “chemical therapy” proven in clinical trial to treat any cancer. This review documents the clinical use of estrogen for breast cancer treatment or estrogen replacement therapy (ERT) for postmenopausal hysterectomized women which can either result in breast cancer cell growth or breast cancer regression. This has remained a paradox since the 1950s until the discovery of the new biology of estrogen induced apoptosis at the end of the 20^th century. The key to triggering apoptosis with estrogen is the selection of breast cancer cell populations that are resistant to long term estrogen deprivation.

7) Ingle, James N., et al. “Randomized clinical trial of diethylstilbestrol versus tamoxifen in postmenopausal women with advanced breast cancer.” New England Journal of Medicine 304.1 (1981): 16-21.
Before the introduction of tamoxifen, diethylstilbestrol (DES) was widely considered to be the hormonal treatment of choice in postmenopausal women with advanced breast cancer. We performed a randomized clinical trial of these two agents to determine their relative efficacy and toxicity. The trial involved 143 evaluable patients, of whom 99 had received no prior systemic therapy and 44 had received previous chemotherapy. The regression rates (complete plus partial) were higher in patients receiving DES (41 per cent) than in those receiving tamoxifen (33 per cent), but not significantly so (P = 0.37). (note P value of .05 is needed)  In patients who had had no prior systemic therapy, the rates were 44 per cent and 38 per cent, respectively (P = 0.55), and in those who had had previous chemotherapy, 32 per cent vs. 23 per cent (P = 0.50). Analysis of the time until treatment failure for the two treatment groups showed no significant difference (medians: DES, 142 days; tamoxifen, 171 days). Toxicity was greater in patients receiving DES; nine of 74 patients (12 per cent) discontinued therapy solely because of adverse reactions. Since there was no statistically significant difference in efficacy and since tamoxifen was less toxic, tamoxifen appears to be the preferred agent.

143 pts. RCT w/ progressive metastatic breast cancer RX DES vs. TAM

Survival was significantly better for women on DES than for women on TAM (adjusted p = 0.039).

Duration of response and progression-free survival were not found to be significantly different between DES and TAM (p = 0.32 and 0.65, respectively).

8) Peethambaram, Prema P., et al. “Randomized trial of diethylstilbestrol vs. tamoxifen in postmenopausal women with metastatic breast cancer. An updated analysis.” Breast Cancer Research and Treatment 54 (1999): 117-122.

One hundred fifty-one postmenopausal women with progressive metastatic breast cancer and no prior hormonal therapy were treated with either diethylstilbestrol (DES) or tamoxifen (TAM). One hundred forty-three eligible patients were followed until death or for a minimum of 14.1 years on the DES arm or 16.7 years on the TAM arm. The overall objective response was 42% for DES and 33% for TAM (p = 0.31) and the median duration of response was 11.8 months for DES and 9.9 months for TAM (p = 0.38). Duration of response and progression-free survival were not found to be significantly different between DES and TAM (p = 0.32 and 0.65, respectively). The median survival was 3.0 years for DES vs. 2.4 years for TAM. The 5-year survival was 35% for the DES arm and 16% for the TAM arm. Survival was significantly better for women on DES than for women on TAM (adjusted p = 0.039).

Review of records did not show any difference in pattern of treatment failure or subsequent treatments in the DES and TAM arms. Treatment with DES was more commonly associated with toxicity such as nausea, edema, vaginal bleeding, and cardiac problems, whereas hot flashes were commonly seen with TAM therapy. The initial treatment with DES is associated with increased survival. The basis of this survival advantage is not known. TAM still is the preferred agent in the treatment of metastatic breast cancer, but this trial underscores the fact that estrogens have activity and remain in the armamentarium for treatment of selected patients with metastatic breast cancer.

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26 Studies of HRT in Breast Cancer Survivors
======================================

Premarin CEE Only 39 pts.
LTED 40 months

Recurrence rate for HRT half  that of non-user  controls.

9) Vassilopoulou-Sellin, Rena, et al. “Estrogen replacement therapy after localized breast cancer: clinical outcome of 319 women followed prospectively.” Journal of clinical oncology 17.5 (1999): 1482-1482.

Median DFI at entry was 114 months (range, 24 to 234 months), and median observation duration was 40 months (range, 24 to 99 months).

Therefore, a total of 39 women were administered ERT (ERT group), consisting of conjugated estrogens (0.625 mg on days 1 to 25 of each month) without progesterone. The other 280 women (control group) did not take hormones.

1/39 (2.6%) recurrence Premarin-alone
14/280 (5.0%) recurrence NO HRT COntrols.

observed prospectively for at least 2 years whether they enrolled onto the randomized trial or not.

Therefore, a total of 39 women were administered ERT (ERT group), consisting of conjugated estrogens (0.625 mg on days 1 to 25 of each month) without progesterone. The other 280 women (control group) did not take hormones.

In the present study, there were no excess events among the women taking ERT. One patient (2.6%) in the ERT group developed a new breast cancer whereas 14 patients (5.0%) in the control group developed new or recurrent breast cancer. Given the small number of patients (n 5 319) and the small number of all events in both groups (n 5 20 in the control group and n 5 1 in the ERT group),

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50 reduction in Breast Cancer Recurrence and Total Mortality Reduced in HRT Users

62.5 % Reduction in Mortality from breast cancer for HRT users.

Five HRT users (3%) and 59 nonusers (8%) died of breast cancer during followup

175 HRT users who appeared to be free of breast cancer disease. half 51% had hysterectomy. 68% had used HRT before Dx of breast cancer.
695 non-users

79% unopposed estrogen-alone (62% oral, 38% vaginal) x 15 months
(50% Premarin CEE 50% estradiol)
21 % progestogen added

Women were followed for a median of 3.7 years for recurrence and 4.6 years for mortality.

The median duration of oral HRT use during follow-up was 15 months.

LTED :Time from diagnosis to reference, years
years    users    nonusers
<1       47 (27)   188 (27)
1–2     46 (26) 184 (26)
3–7     44 (25) 175 (25)

8         37 (21) 148 (21)
About half under 2 years, half over 2 years

Breast cancer recurrence was diagnosed in 16 HRT users (9%) and in 101 nonusers (15%) (Table 4). 40% Less recurrence in users.
The rate of recurrence was 17 per 1000 person-years in users (95% CI
11 to 29) and 30 per
1000 person-years in nonusers (95% CI
25 to 37). (43% less for users)

10) O’Meara, Ellen S., et al. “Hormone replacement therapy after a diagnosis of breast cancer in relation to recurrence and mortality.” Journal of the National Cancer Institute 93.10 (2001): 754-761. Fred Hutchinson Cancer Research Center and Department of Epidemiology, University of Washington, Seattle;

Retrospective records study. excluded: in-situ cancer and metastatic cancer. Recurrence was defined as invasive disease confined to the ipsilateral breast (22% of diagnosed recurrences) or metastasis. New primary contralateral breast cancers were not included
in this definition.

The cohort comprised 2755 women who met these criteria.

This record-based study 174 users and 695 nonusers of hormone replacement therapy (HRT) after a diagnosis of breast cancer

The median duration of oral HRT use during follow-up was 15 months. Estrogens were unopposed by progestogens for 79% of the users; the rest combined a progestogen with estrogen for at least one monthly cycle.

The rate of breast cancer recurrence was 17 per 1000 person-years in women who used HRT after diagnosis and 30 per 1000 person-years in nonusers (adjusted relative risk for users compared with nonusers = 0.50; 95% confidence interval [CI] = 0.30 to 0.85).

Comparison of rates yielded an unadjusted relative risk associated with ever use of HRT after breast cancer of 0.58 (95% CI
0.34 to 0.98). Adjusting for bilateral oophorectomy, hysterectomy, mastectomy, tamoxifen, and the matching variables in a Cox model resulted in a relative risk of 0.50 (95% CI
0.30 to 0.85). Further adjustments did not appreciably
change the results. The relative risk was similar when restricting to users of unopposed estrogens only.

Breast cancer mortality rates were five per 1000 person-years in HRT users and 15 per 1000 person-years in nonusers (adjusted relative risk = 0.34; 95% CI = 0.13 to 0.91).

Total mortality rates were 16 per 1000 person-years in HRT users and 30 per 1000 person-years in nonusers (adjusted relative risk = 0.48; 95% CI = 0.29 to 0.78).

Route of HRT administration Estrogen type No. of prescriptions* (% of total)
Oral 1182 (   62)
    Conjugated 562
Esterified 543 Estratab and Menest
Ethinyl estradiol 77
Vaginal 728 (38)
    Conjugated 442
Dienestrol 286
Topical Estradiol 3 (<1)

Total 1913 (100)

Estrogens can stimulate the growth of breast cancer cells in tissue culture at low doses
but can inhibit growth at high doses (23).
Breast tumors can regulate and maintain internal levels of estradiol independent of levels outside the tumor (24), so exogenous estrogens may have relatively little effect on tumor growth (10).

============

Why did not Dr Bluming mark this one along with HABITS as increased recurrence?

BAD OUTCOME (estrdiol p[lus progestin) I would assume the progestin was highly carcinogenic (norethisterone, like the HABITS)

Abstract only
ALL 21 PATIENTS USED ESTRADIOL. plus progestin (was it norethisterone?)..
LTED OF 5 YEARS
ALMOST DOUBLE (1.7X) RELAPSE RATE for HRT GROUP at 28 months

11) Uršič-Vrščaj, Marjetka, and Sonja Bebar. “A case-control study of hormone replacement therapy after primary surgical breast cancer treatment.” European Journal of Surgical Oncology (EJSO) 25.2 (1999): 146-151.
Department of Gynecological Oncology, Institute of Oncology, Ljubljana, Slovenia

HRT was started on average 62 months (range 1-180 months) after diagnosis, and lasted an average of 28 months (range 3-72 months).

All 21 patients used estradiol as HRT, i.e. a non-conjugated estrogen. Combined hormonal therapy (estrogens + progestagens) was given to 95% of patients with median age of 47 years (range 41-59 years) at the beginning of HRT.

Relapse was observed in four patients (19%) of the HRT group; of these, one had a carcinoma of the contralateral breast. In the control group, relapse was observed in five patients (11%); one of these five patients had a carcinoma of the contralateral breast. In the HRT group, there were no deaths among the patients with confirmed relapse, while one patient died in the control group.

The estimated risk (OR= 1.74, 95%S CI 0.34-8.88) of relapse of breast cancer was calculated by comparing data from HRT users, who had received HRT for 28 months (range 3-72 months) on average, with data from the control group.

The estimated risk of breast cancer relapse in HRT users who had been receiving HRT for less than 24 months was 0.65 (OR = 0.65, 95% CI 0.02-7.85).

All 21 patients used estradiol as HRT, i.e. a non-conjugated oestrogen. Combined hormonal therapy (estrogens + progestagens) was given to 95% of patients with median age of 47 years (range 41–59 years) at the beginning of HRT.

Relapse was observed in four patients (19%) of the HRT group; of these, one had a carcinoma of the contralateral breast.

In the control group, relapse was observed in five patients (11%); one of these five patients had a carcinoma of the contralateral breast. In the HRT group, there were no deaths among the patients with confirmed relapse, while one patient died in the control group. The estimated risk (OR=1.74, 95% CI 0.34–8.88) of relapse of breast cancer was calculated by comparing data from HRT users, who had received HRT for 28 months (range 3–72 months) on average, with data from the control group. The estimated risk of breast cancer relapse in HRT users who had been receiving HRT for less than 24 months was 0.65 (OR=0.65, 95% CI 0.02–

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Poor Outcome OR=1.7 for recurrence for HRT USERS (Premarin+Medroxyprogesterone)
LTED?
Prior Pregnancy?

Very Careful In Person Interview to determine type of HRT used.

CEE with medroxyprogesterone – OR=1.7 for recurrence in HRT Users!!!!

Cee alone- 30% reduction in Recurrence of advanced disease stage, later stage disease ? only the tumors of patients who used ERT retained a substantive reduced relative odds of advanced disease stage [OR  0.7 (95% CI, 0.6–0.9)].

12) Daling, Janet R., et al. “Association of regimens of hormone replacement therapy to prognostic factors among women diagnosed with breast cancer aged 50–64 years.” Cancer Epidemiology Biomarkers & Prevention 12.11 (2003): 1175-1181.
Fred Hutchinson Cancer Research Center, Division of Public Health Sciences,
Seattle, Washington; 2

Women’s CARE Study: multicenter population-based case-control study of invasive breast cancer was conducted. five geographic areas: Atlanta; Detroit; Los Angeles; Philadelphia; and Seattle.

In-person interviewscollected adetailed history of all episodes of hormone use.

2346 women with diagnosed with invasive breast cancer.

In this study, 84.0% of estrogen use was conjugated estrogen, and 94.0% of progestin use was medroxyprogesterone acetate

The tumors of cases who used each regimen of HRT were smaller and of earlier stage than those of non-HRT users.

and only cases who used estrogen alone(estrogen replacement therapy) had reduced odds of being diagnosed with later-stage disease (regional or distant) than cases who never used HRT (OR, 0.7; 95% CI, 0.6–0.9).

Accumulating evidence indicates a more favorable tumor biology
among women who develop breast cancer who are either current or past users of HRT.11

11.Chen, C-L., Weiss, N. S., Newcomb, P., Barlow, W., and White, E. Hormone
replacement therapy in relation to breast cancer. J. Am. Med. Assoc., 287:
734–747, 2002.

70 % Greater Recurrence Using C-CHRT

Among women with breast cancer who had used C-CHRT [Continuous Combined HRT],
20.5% developed a tumor of either lobular or mixed lobular/ductal histology compared with 12.1% of women who had never used any HRT (OR, 1.7; 95% CI, 1.2–2.4; Tables 1 and
2).

ERT users were at 30% reduced odds of being diagnosed with their cancer at later stage (regional or distant) relative to nonusers. Ross et al. (19), whose study included in situ cancers, found that ERT was inversely related to the risk of developing these late-stage
tumors but found no effect of the regimen of CHRT on stage of disease. Magnusson et al. (5) found CHRT was related to reduced risk of developing larger and later stage tumors; however, they made no adjustment for screening practices.

The pooled analysis of 51 epidemiological studies (1) and a number of recent studies indicate CHRT is related to an increased risk of developing breast cancer (9, 11, 12, 15, 17–21).

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TESTOSTERONE ADDED !!! Much Better Results

Mortality of estrogen (estradiol) HRT users was (3 of 50) 6% (81% reduction in Mortality)
One died of MI.

Mortality of Non-users of HRT (6 of18) women 33%

76 pts, 50 on HRT, of the 50, 40 (80%) were also given testosterone, 50% pellets

LTED of the 6 deaths in HRT :
1 pt = 2 years
2 pts 5 years

Prior Pregnancy or Prior Hormone USe ? There were 3 nulliparous women (6%) in this group (on HRT after Breast Cancer), and the mean parity was 2.2 ± 1.17.
Non-Hormone Users: There were 3 nulliparous women (16.7%) in this group,
and the mean parity was 1.7 ± 1.02.

In the 50 hormone users, 45 were also given progestogens, mostly megestrol acetate.
Willemse, P. H., et al. “A randomized comparison of megestrol acetate (MA) and medroxyprogesterone acetate (MPA) in patients with advanced breast cancer.” European journal of cancer (Oxford, England: 1990) 26.3 (1990): 337-343.

13) Natrajan, Puthgraman K., Kostas Soumakis, and R. Don Gambrell Jr. “Estrogen replacement therapy in women with previous breast cancer.” American journal of obstetrics and gynecology 181.2 (1999): 288-295.
Augusta, Georgia

The study group consisted of 76 patients with breast cancer, including 50 using estrogen
replacement for up to 32 years, 8 using nonestrogenic hormone replacement for up to 6 years and followed for up to 11 years, and 18 using no hormones for up to 10 years. In addition to estrogen use, 40 of the 50 hormone users were treated with androgens, usually in the form of implantation of testosterone pellets. Forty-five subjects were also given progestogens, usually megestrol acetate 20 to 40 mg for 10 to 25 days each month. The 8 nonestrogen hormone users were treated with various combinations of testosterone pellets, tamoxifen, and progestogens.

Therapy No. of patients Range Mean ± SEM (y)
Testosterone 150 mg, estradiol 25 mg, progestogen 19 6 mo–24 y 5.7 ± 2.36
Testosterone 150 mg, estradiol 50 mg, progestogen 8 2.5-7 y 3.7 ± 1.16
Oral estradiol, progestogen 4 6 mo–2 y 1.0 ± 0.78
Testosterone 75 mg, estradiol 25 mg, progestogen 3 1.5-9 y 4.5 ± 1.80
Oral estrogen, testosterone, progestogen 3 1.5-3.5 y 2.3 ± 0.92
Testosterone 225 mg, estradiol 50 mg, progestogen 2 3-4.5 y 3.5 ± 0.71
Transdermal estrogen, progestogen 4 2-5 y 3.2 ± 1.14
Testosterone 75 mg, estradiol 50 mg 2 16-17 y 16.5 ± 0.71
Testosterone 75 mg, estradiol 25 mg 1 32 y —
Testosterone 150 mg, estradiol 50 mg 1 21.5 y —
Estradiol 75 mg, progestogen 1 2 y —
Testosterone 225 mg, estradiol 75 mg, progestogen 1 1.5 y —
Oral estradiol 1 5 y —

TOTAL 50 6 mo–32 y 5.5 ± 2.53

The mortality rate among the estrogen users was 6%. Of the 3 deaths, 2 patients died of breast cancer. mean duration of follow-up of 83.3 ± 8.81 months.

Of the nonestrogenic HRT group, 1 patient died of breast cancer,for a mortality of 12.5%.

In the group not receiving hormonal replacement, 33% have died. Five of the 6 died of breast cancer

Testosterone and estradiol pellets were implanted every 4.5 to 6 months in 38 of the 50 women (76%), and 45 of the 50 women (90%) were given oral progestogen. The
most frequently used progestogen was megestrol acetate 20 to 40 mg given from 10 to 25 days each month to 29 of the 45 progestogen users (64%). Medroxyprogesterone
acetate 10 mg from 10 to 13 days was given to 8 patients, and norethindrone acetate 2.5 to 5 mg was given to the other 8 patients along with the estrogen.

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abstract only
HRT: Premarin/MPA same as WHI 2002 first arm.
No Control Group for Comparison

LTED: 41 months…41 percent started HRT within 3 year of diagnosis of Br CA
HRT: premarin/MPA , 9 percent recurrence rate.

14) Brewster, Wendy R., et al. “An experience with estrogen replacement therapy in breast cancer survivors.” International journal of fertility and women’s medicine 44.4 (1999): 186-192.  University of California Irvine Medical Center, Orange 92868,

Breast cancer survivors who elected ERT received the preferred regimen of conjugated estrogen 0.625 mg/day with medroxyprogesterone acetate 2.5 mg/day.

145 patients received ERT for at least 3 months. Thirteen recurrences (9%) were identified; 10 are alive with disease, 3 are dead of disease. The median interval between diagnosis and commencement of ERT was 41 months. Forty-one percent of the study group initiated ERT within 3 years of their breast cancer diagnosis. The median duration of follow-up on ERT was 30 months.

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abstract only

277 pts on HRT.
LTED 3.6 years,
recurrence rate same for HRT vs non-HRT
HRT Mortality half that of control group.

HRT formula? not mentioned

There was no significant difference between the ERT and control groups in ipsilateral primary/recurrence (5/155 v 5/143; P = 0.85), contralateral breast cancers (10/258 v 9/260; P = 0.99), or systemic metastasis (8/277 v 15/277; P = 0.13). Noncause-specific deaths in the control group numbered 15 (of 277), and in the ERT group, 7 (of 277) (P = 0.03). Overall survival favored the ERT group (P = 0.02).

Type of estrogen ? US study- probably premarin ???
Department of Medicine, William Beaumont Hospital, Royal Oak-Troy, MI

15) Decker, David A., et al. “Estrogen replacement therapy in breast cancer survivors: a matched-controlled series.” Menopause 10.4 (2003): 277-285.

Design: Two hundred seventy-seven disease-free survivors received ERT. Controls were matched for exact stage, a recurrence-free period similar to the period to ERT initiation in the ERT group, approximate age, and duration of follow-up. The mean time from breast cancer diagnosis to initiation of ERT was 3.61 (+/- 0.25) years, with a median of 1.88 years. The mean duration of ERT was 3.7 (+/- 3.01) years, with a median of 3.05 years.

Results: Hot flashes were relieved in 206 of 223 women (92%), dyspareunia/vaginal dryness in 149 of 167 women (89%), and reactive depression/anxiety/mood change in 111 of 126 women (88%). Univariate analysis demonstrated no statistical differences between the groups for age, stage, pathology at diagnosis, progesterone receptor status, local therapy, breast at risk, prior chemotherapy, and duration of follow-up. The ERT group was more likely to be estrogen receptor negative (P = 0.01), to have received prior ERT (P < 0.001), and to have received no adjuvant tamoxifen (P < 0.001).

There was no significant difference between the ERT and control groups in ipsilateral primary/recurrence (5/155 v 5/143; P = 0.85), contralateral breast cancers (10/258 v 9/260; P = 0.99), or systemic metastasis (8/277 v 15/277; P = 0.13). Noncause-specific deaths in the control group numbered 15 (of 277), and in the ERT group, 7 (of 277) (P = 0.03). Overall survival favored the ERT group (P = 0.02).

Conclusions: In these selected patients, ERT relieved estrogen deficiency symptoms and did not increase the rate or time to an ipsilateral recurrence/new primary, contralateral new primary, local-regional recurrence, or systemic metastases.

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Mostly CEE (44/56 patients)
Excellent Results: 2 local recurences after 13.5 and 9.6 years, no deaths.

One local recurrence and one contralateral breast cancer occurred during the follow-up period (13.5 and 9.6 years, respectively), with no regional or distant recurrences, for a 15-year actuarial disease-free survival rate of 92.5%. There were no breast cancer deaths.

16) Peters, George N., et al. “Estrogen replacement therapy after breast cancer: a 12-year follow-up.” Annals of surgical oncology 8 (2001): 828-832.

From The Center for Breast Care, The University of Texas Southwestern Medical Center at Dallas (GNP, TF, DE), and Baylor University Medical Center, Dallas, Texas (JS, SJ).

LTED: DFI (DISEASE FREE INTERVAL) at entry (initiation of ERT) 3.9 years ,,,….median
disease-free interval before initiation of ERT was 46.7 months (range, 0–448 months).

607 breast cancer survivors, 64 on HRT

The median follow- up from diagnosis was 12.8 years (range, 4.7–38.9
years), and the median number of years on ERT since breast cancer diagnosis was 6.4 years (range, 1.0–20.9 years) (Table 2).

The remaining 56 received ERT as conjugated estrogens, an estradiol patch, estropipate, or birth control pills.

After initial identification of breast cancer patients using ERT, their clinical outcome was prospectively observed for a minimum of 60 months.

44/56 on HRT
24 RECEIVED CEE ALONE
20 CEE + MPA
10 Estradiol

LTED: 38% of the patients initiated ERT within 2 years of diagnosis.
52% after 2 years.

Half received adjuvant or chemo.

Conjugated estrogens 24
Conjugated estrogen and medroxyprogesterone acetate 20
Estradiol 10
Estropipate 1
Birth control pills 1

Methods: From February to August 1995, 607 breast cancer survivors were interviewed concerning ERT usage.

Sixty-four patients indicated they received some form of ERT after their breast
cancer diagnosis. Medical records for these patients were analyzed for disease stage, surgical treatment, adjuvant treatment, estrogen and progesterone receptor status, date of initiation of ERT, type of ERT, recurrence, and final outcome. Patients receiving ERT were followed prospectively.

Results: Eight patients were excluded because they had used only vaginal cream ERT.

The remaining 56 received ERT as conjugated estrogens, an estradiol patch, estropipate, or birth control pills. The median follow-up from diagnosis was 12.8 years (range, 4.7–38.9 years). The median time on ERT since diagnosis was 6.4 years (range, 1.0 –20.9 years); 38% of the patients initiated ERT within 2 years of diagnosis. Estrogen receptors were positive in 28 (74%) of the 38 cases with available information. Pathological disease stage at time of diagnosis and treatment was 0 in 15 cases (27%), I in 27 (48%), and II in 14 (25%).
Twenty-six patients (47%) received adjuvant chemotherapy or hormonal therapy.

One local recurrence 13.7 years after initial diagnosis of her breast cancer. She had been on  ERT for 3.8 years at the time of local recurrence. She is now disease-free at 3 years after treatment of her local recurrence and not on ERT.

and one contralateral breast cancer (DCIS) occurred during the follow-up period (13.5 and 9.6 years, respectively), with no regional or distant recurrences, for a 15-year actuarial disease-free survival rate of 92.5%. There were no breast cancer deaths.

Only two patients (4%) developed either recurrent or new disease. To date, our study provides the longest follow-up of breast cancer survivors on ERT with the longest duration of ERT usage.

Comparison Group

Twelve-year follow-up data of the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-06 protocol provides the only comparable results for our ERT
group. The estimate of overall survival at 12 years is 63%; disease-free survival is 50%; and local recurrence for the group treated by lumpectomy and breast irradiation
is 10%.32

For comparison, disease-free survival was calculated for a cohort of 74 stage 0-II breast cancer patients from our practice who were diagnosed and treated in 1996.
These women ranged in age from 36 to 82 years (mean, 61 years). There were 9 stage 0 (12%), 40 stage I (54%), and 25 stage II (34%) patients. After a median follow-up
of 37 months, disease-free survival was 67% for the 1996 cohort as compared to 100% for the ERT cohort (P  .029, Fig. 1). Because half of the patients in our group
started ERT nearly 4 years after diagnosis, our ERT patients are likely to be self-selected for good-prognosis tumors, because patients with poor-prognosis tumors  would have died of breast cancer earlier, in the first few years after diagnosis.

USE of Vaginal Creams

Of the eight patients who have used only vaginal cream ERT, median follow-up from diagnosis was 11.4 years, and median time on ERT since diagnosis was 4.0
years. There have been no contralateral breast cancers; no local, regional, or distant recurrences; and no cancer deaths in this group.

Conclusions: Use of ERT in a cohort of breast cancer survivors with tumors of generally good prognosis was not associated with increased breast cancer events compared with non-ERT users, even over a long follow-up period.

Two centuries ago, less than 30% of women lived long enough to
reach menopause, but today 90% of women reach theclimacteric. In the United States, more than 30 million women have an average postmenopausal life expectancy
of 28 years.1 Marchant DJ. Estrogen-replacement therapy after breast cancer.
Risks versus benefits. Cancer 1993;71(6 Suppl):2169–76.

With an average age at diagnosis of 60 years, coupled with a 25-year expected
survival, it is estimated that the number of breast cancer survivors in the United States is nearly 2.5 million women. The short-term effects of estrogen deficiency (e.g., vasomotor instability and urogenital atrophy) and long-term consequences (e.g., osteoporosis and cardiovascular disease) are important quality-of-life and health issues for breast cancer survivors.10

However, prior studies have documented that up to 10% of breast cancer survivors use ERT for relief of menopausal symptoms.11

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abstract only
230 pts prospective study- many of these patients had a premature, artificial, chemo-induced menopause.
LTED at least 2 years
(estradiol + a progestin compound) given either continuously or with a 5-d interruption each month. The mean duration of treatment was 2.5 years.

17 (7 percent) of cases recurrence (relapse) (seven local, six in the contro-lateral breast and four metastases (7%)).

17) Gorins A, Espié M, Bedairia N, et al. Hormone replacement therapy in breast cancer patients: a study of 230 patients, with a case-control study. Gynecol Obstet Fertil. 2003;31:614–619.
Center of Breast Diseases in Saint-Louis hospital in Paris France.

Objectives: After recalling the classical contra-indication of hormone replacement therapy (HRT) concerning patients with a personal history of breast cancer (BC), and arguments that may be opposed, the authors report the present results of a prospective study undertaken in the Center of Breast Diseases in Saint-Louis hospital in Paris since February 1992.

Patients and methods: By April 2001, 230 patients had been included. A free interval of 2 years at least since the treatment of the primary BC has been observed. The reasons for prescribing HRT were vasomotor troubles (flushes, nightly sweats) or a dyspareunia, which were severe and not controlled by non-hormonal treatments. There was also an indication of a major osteoporotic or cardiovascular danger. In fact, many of these patients had a premature, artificial, chemo-induced menopause. The HRT most often used was an estro-progestin association (estradiol + a progestin compound) given either continuously or with a 5-d interruption each month. The mean duration of treatment was 2.5 years.

Results: Results, concerning the improvement of menopause troubles, were remarkable in the great majority of troubles. HRT had to be stopped in 39 cases, reading as follows: 17 cases for relapses (seven local, six in the contro-lateral breast and four metastases (7%)). Also, 22 patients (9%) interrupted their HRT for serious side-effects. A case-control study did not show any significant difference between with and without HRT patients concerning the overall survival without relapse.

Discussion and conclusions: Quality of life of patients was often substantially improved, and a deleterious effect on the cancer disease was not found. Our results are in agreement with the literature from other countries. However, one must be cautious. In such circumstances, HRT must be prescribed with the informed consent of the patients and delivered in appropriate hospital and university centers. It is wished that large randomised prospective studies may be undertaken.

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Abstract only

33 percent reduction in recurrence in HRT users.
15% reduction in progestin -alone users

continuous combined estrogen/progestogen hormonal therapy

167 subjects had used an oral or transdermal estrogen

hazard ratio for the estrogen-progestin users was 0.67 (95% confidence interval (CI) 0.38-1.16) and for the progestin alone users was 0.85(95% CI 0.44-1.65).

152 (91%) had also used a progestin

18) Dew, J., et al. “A cohort study of hormone replacement therapy given to women previously treated for breast cancer.” Climacteric: the journal of the International Menopause Society 1.2 (1998): 137-142.

Women’s Health Institute, Royal Hospital for Women, Barker Street, Randwick, NSW 2031, Australia.

Women who have been previously treated for breast cancer are usually advised to avoid hormone therapy for fear of increasing their risk of tumor recurrence. However, for some women, menopausal symptoms are so severe that their quality of life is poor. Because ethic committees are reticent to permit a double-blind randomized trial, we performed a cohort study of hormone therapy after breast cancer.

Methods: The study group comprised 1472 women with breast cancer. A total of 167 subjects had used an oral or transdermal estrogen after their treatment for breast cancer. Amongst these estrogen users, 152 (91%) had also used a progestin. In total, 106 other women had used a progestin alone as a treatment for menopausal flushes and not as a treatment for breast cancer. Cox regression analysis was performed using estrogen as a time-dependent covariate with disease-free interval as the outcome.

Results: The uncorrected hazard ratio for the estrogen-progestin users was 0.67(95% confidence interval (CI) 0.38-1.16) and for the progestin alone users was 0.85 (95% CI 0.44-1.65).

Conclusions: This study was unable to demonstrate a significant increase in risk of breast cancer recurrence for women who used HRT and suggests that the time is now appropriate for a randomized prospective trial of hormone therapy after breast cancer.

=================================================
abstract only : Same study as Eden (20)
LTED ?
Exact HRT formula ?
Length of follow up?

Most were using combined continuous estrogen-progestin therapy, usually an oral estrogen with a moderate dosage progestin

120 patients, 90 estrogen users

Among the 90 estrogen users, there were no deaths and only 7% developed a recurrence, compared to 17% of the nonusers (using two matched controls);
RR = 0.40 (95% CI 0.17–0.93).

19) Espie, M., A. Gorins, and F. Perret. “Hormone replacement therapy (HRT) in patients treated for breast cancer: analysis of a cohort of 120 patients.” Proc Am Soc Clin Oncol. Vol. 18. 1999.

Ninety had taken estrogen for relief of severe menopausal symptoms after their diagnosis and treatment of breast cancer. Most were using combined continuous estrogen-progestin therapy, usually an oral estrogen with a moderate dosage progestin. Controls were matched subjects from the same database who had not taken sex steroids after their diagnosis of cancer. The main outcome measures were all-cause mortality and recurrence of breast cancer (or new contralateral breast cancer). Relative risks (RR) were then calculated comparing sex-hormone users with matched controls.

Among the 90 estrogen users, there were no deaths and only 7% developed a recurrence, compared to 17% of the nonusers (using two matched controls); RR = 0.40 (95% CI 0.17–0.93).

These results suggest that short-term usage of combined continuous hormone replacement therapy (HRT) by women with a personal history of breast cancer may be safe and might even reduce the risk of recurrence. A formal prospective double-blind controlled study is needed to confirm these results.

==========================

Abstract only / SAME as 19) Espie?

Premarin/MPA (Assumed because of the good results) 90 women
LTED ???? not disclosed in abstract

20) Eden, John A., et al. “A case-control study of combined continuous estrogen—progestin replacement therapy among women with a personal history of breast cancer.” Menopause 2.2 (1995): 67-72. New South Wales, Australia;

combined continuous estrogen-progestin therapy, usually an oral estrogen with a moderate dosage progestin.

continuous estrogen-progestin therapy given to symptomatic menopausal women with a personal history of breast cancer.

901 women with surgically confirmed breast cancer attending one of three teaching hospitals in south-eastern Sydney, Australia. Ninety had taken estrogen for relief of severe menopausal symptoms after their diagnosis and treatment of breast cancer. Most were using combined continuous estrogen-progestin therapy, usually an oral estrogen with a moderate dosage progestin.

Among the 90 estrogen users, there were no deaths and only 7% developed a recurrence, compared to 17% of the nonusers (using two matched controls); RR = 0.40 (95% CI 0.17–0.93).

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FULL PDF

This Durna study is continuation of study group data from Eden.

retrospective observational study of breast cancer recurrence and mortality among postmenopausal women with histopathologically confirmed breast cancer

Only study so far to include vaginal estriol cream. !!!!
Parity the same for HRT and NON-HRT (N=2.2)
HRT use before diagnosis
Prior Use of HRT:
Number of women NO HRT = 683 127 (19%)
HRT = 240 161 (67%) <0.001

those who used vaginal estrogen alone [32 patients] had a significantly lower risk of recurrence or new breast cancer (adjusted RR, 0.18; 95% CI, 0.04–0.75)

Of the 1122 women in the study, 286 used HRT after breast cancer diagnosis to treat menopausal symptoms.

A total of 1122 women met the entry criteria and were followed up for a median of 6.08 years (range, 0 to 36 /years).

half used Premarin plus Progestin
LTED = one year. Years from diagnosis to HRT start
(median, range) n=258 1.0 years (0–23)

20) Durna, Eva M., et al. “Hormone replacement therapy after a diagnosis of breast cancer: Cancer recurrence and mortality.” Medical Journal of Australia 177.7 (2002): 347-351.

Sydney, New South Wales Australia

retrospective observational study of breast cancer recurrence and mortality among postmenopausal women with histopathologically confirmed breast cancer.

three surgeons and two gynaecologists at three tertiary hospitals in Sydney, New South Wales

286 used HRT
Types of HRT used after breast cancer diagnosis were
continuous combined oestrogen plus progestin (138; 48%),
oral progestin alone (78; 27%),
vaginal oestrogen alone (32; 11%),
vaginal oestrogen plus oral progestin (21; 7%), and
oral or transdermal oestrogen alone (17; 6%).

Tumour size was significant to all outcomes, with larger tumours associated
with higher risk of recurrence and death.

Those who used HRT after diagnosis were significantly younger when diagnosed with breast cancer than nonusers (P <0.001). They were also significantly more likely to have used HRT before diagnosis (P <0.001), had smaller tumours (P <0.001) and fewer positive axillar y lymph nodes (P =0.006) and were followed up for longer (P <0.001). There were no significant differences between the two groups in ages at menarche and menopause, parity and gravidity. Oestrogen receptor status of the tumour was known in only 282 patients and was not included in the analysis. Most women in both groups took tamoxifen (58% and 60%, respectively).

Results: 1122 women were followed up for 0–36 years (median, 6.08 years); 154 were lost to follow-up. 286 women used HRT for menopausal symptoms for up to 26 years (median, 1.75 years).Compared with non-users,

HRT users had reduced risk of cancer recurrence (adjusted relative risk [RR], 0.62; 95% CI,0.43–0.87), all-cause mortality (RR, 0.34; 95% CI, 0.19–0.59) and death from primary tumour (RR, 0.40; 95% CI, 0.22–0.72).

Continuous combined HRT was associated with a reduced risk of death from primary tumour (RR, 0.32; 95% CI, 0.12–0.88) and all-cause mortality (RR, 0.27; 95% CI, 0.10–0.73).

Median daily dose of oestrogen used by women taking continuous combined HRT was 0.625 mg conjugated equine oestrogen (range, 0.3–0.625 mg) or equivalent (1.25 mg oestrone sulfate, 2 mg oestradiol valerate or 50 g transdermal oestradiol). Median daily dose of progestin in combined HRT was 50 mg medroxyprogesterone acetate
(range, 10–500 mg) or 5 mg norethisterone (range, 1–5 mg). Similar doses of oestrogen and progestin, respectively, were used by women who took oestrogen or progestin alone. Vaginal oestrogens included estriol cream (0.5 g) and estradiol vaginal tablets (25 g) used twice weekly, either alone or combined with oral progestins in similar doses to those in combined HRT.

the group that used HRT after diagnosis had a significantly lower risk of recurrence or new breast cancer compared with the no-HRT group (adjusted relative risk [RR], 0.62;95% CI, 0.43–0.87).
The HRT group also had significantly lower risks of death from all causes (adjusted RR, 0.34; 95% CI, 0.19–0.59) and from the primary tumour (adjusted RR, 0.40; 95% CI, 0.22–0.72).

Women who used HRT also had significantly lower risks of death from all
causes (RR, 0.34) and from the primary tumour (RR, 0.40).

3: Rates of recurrence and death and adjusted relative risks in women who used hormone replacement therapy (HRT) after diagnosis versus non-users

Recurrence or new breast cancer Death from all causes Death from primary tumour

Type of HRT Number of events Rate per 1000 person-years Adjusted relative risk (95% CI) Number of events

Rate per 1000 person-years Adjusted relative risk (95% CI) Number of events Rate per 1000 person-years
Adjusted relative risk (95% CI)

No HRT (n=836) 247 58.2 1 (referent) 199 29.4 1 (referent) 122 18.0 1 (referent)
HRT (all types) (n=286) 44 24.0 0.62 (0.43–0.87) 16 8.3 0.34 (0.19–0.59) 13 6.7 0.40 (0.22–0.72)
Combined HRT* (n=138) 23 23.6 0.81 (0.52–1.27) 5 4.9 0.27 (0.10–0.73) 4 3.9 0.32 (0.12–0.88)
Progestin alone (n=78) 12 32.5 0.59 (0.32–1.09) 4 9.6 0.34 (0.12–0.93) 4 9.6 0.33 (0.12–0.91)
Vaginal oestrogen (n=32) 4 14.9 0.18 (0.04–0.75) 4 14.3 0.30 (0.07–1.30) 2 7.1 0.35 (0.07–1.68)
Vaginal oestrogen plus progestin (n=21)
1 8.6 0.00 (0.00–) 0 0.0 0.00 (0.00–) 0 0.0 0.00 (0.00–)
Oestrogen alone (n=17) 4 39.2 0.81 (0.30–2.21) 3 28.8 0.85 (0.26–2.75) 3 28.8 1.11 (0.35–3.60)
*Combined=continuous combined oestrogen plus progestin.

All HRT regimens were associated with smaller risks of recurrence and death than no HRT use, with the exception of unopposed oestrogen for risk of death from primary tumour. ?????????

A possible explanation of the results is that women with oestrogen deficiency tend to have better outcomes after breast cancer. (LTED effect)

A 1997 meta-analysis of 51 studies from 21 countries reported a per annum increased risk of breast cancer of 1.7% with use of oestrogen alone, 1.8% with oestrogen plus continuous progestins, and 7.6% with oestrogen plus cyclic progestins.17

17. see imediately below this

Other recent observational studies also suggest that the use of sequential or cyclic progestins in HRT may increase the risk of breast cancer.18-20

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2019 Version of study

21) Collaborative Group on Hormonal Factors in Breast Cancer. “Type and timing of menopausal hormone therapy and breast cancer risk: individual participant meta-analysis of the worldwide epidemiological evidence.” The Lancet 394.10204 (2019): 1159-1168.

Every MHT type, except vaginal oestrogens, was associated with excess breast cancer risks, which increased steadily with duration of use and were greater for oestrogen-progestagen than oestrogen-only preparations.

If these associations are largely causal, then for women of average weight in developed countries, 5 years of MHT, starting at age 50 years, would increase breast cancer incidence at ages 50–69 years by about
one in every 50 users of oestrogen plus daily progestagen preparations;
one in every 70 users of oestrogen plus intermittent progestagen preparations; and
one in every 200 users of oestrogen-only preparations.
The corresponding excesses from 10 years of MHT would be about twice as great.

Older Version of study:

(See above 17.)
Collaborative Group on Hormonal Factors in Breast Cancer. “Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52 705 women with breast cancer and 108 411 women without breast cancer.” The Lancet 350.9084 (1997): 1047-1059.

In North America and Europe the cumulative incidence of breast cancer between the ages of 50 and 70 in never-users of HRT is about 45 per 1000 women. The cumulative excess numbers of breast cancers diagnosed between these ages per 1000 women who began use of HRT at age 50 and used it for 5, 10, and 15 years, respectively, are estimated to be 2 (95% CI 1–3), 6 (3–9), and 12 (5–20). Whether HRT affects mortality from breast cancer is not known.

==================================
abstract only

185 BC patients, 64 with and 121 without HRT
?LTED probably
? premarin ? Germany, probably not.
Progestin? probably
5 year follow up
Dramatic benefits for bone density in HRT group.

22) Beckmann, Matthias W., et al. “Hormone replacement therapy after treatment of breast cancer: effects on postmenopausal symptoms, bone mineral density and recurrence rates.” Oncology 60.3 (2001): 199-206.
Department of Obstetrics and Gynecology, Friedrich Alexander University, Erlangen, Germany.

In a retrospective study (total n = 185 BC patients, 64 with and 121 without HRT), the effect of HRT during or after adjuvant therapy [chemotherapy and/ or (anti-) hormonotherapy] has been investigated. The surveillance period was up to 60 months. Evaluated were HRT effects on (1) PMS measured by a comprehensive life quality questionnaire, (2) bone mineral density (BMD) measured by osteodensitometry and (3) morbidity as well as mortality rates. Results: Both groups did not differ with regard to tumor stage, lymph node involvement, metastasis, grading, and steroid hormone receptor status. A reduction in PMS was significant in women taking HRT (p < 0.001), especially in the subgroup of women ≤50 years (p < 0.0001).

For both age groups, the median reduction in BMD (z-score) was less in women receiving HRT (≤50 years: without HRT –1.99 vs. with HRT –0.95, p < 0.05; >50 years: without HRT –2.29 vs. with HRT –1.19, p < 0.01).

There were no statistically significant differences regarding morbidity and mortality (p = 0.29). Conclusion: In this study of BC patients, the use of HRT shows positive effects on PMS and BMD. There was no significant influence on morbidity or mortality. However, a reevaluation of HRT in the routine management of BC patients should await the results of prospective randomized trials

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FULL PDF !!!!

LTED 4.2 years
88 pts
54 pts estradiol and 10 days of MPA
34 pts hyx oral E2 only ESTRADIOL (Helsinki Finland)
43 pts controls

With HRT  Without HRT
Nulliparous 14 (16%) 10 (23%) NS
Parous        74 (84%) 33 (77%) NS

Recurrence Rate
7/216 woman-years (3% per year). HRT group.
5/112 woman-years, (4% per year). Non-HRT Group

23) Marttunen, Merja B., et al. “A prospective study on women with a history of breast cancer and with or without estrogen replacement therapy.” Maturitas 39.3 (2001): 217-225.

Department of Obstetrics and Gynaecology, Helsinki University Central Hospital, PO Box 140, FIN-00029 HUS, Helsinki, Finland.

We recruited 131 patients who had been treated for breast cancer for a mean of 4.2 years (range 1 month to 20 years) before. Eighty-eight decided to use ERT, whereas 43 refused or had no need for ERT. At recruitment, the patients were carefully examined for breast and gynaecologic findings. Non-hysterectomized patients wishing to receive ERT (n=54) then started using estradiol as oral tablets (2 mg/day) (n=44) or as transdermal gel (1.5 mg/day) (n=10) in combination with 10-day courses of oral medroxyprogesterone acetate at 4-week intervals, whereas hysterectomized patients (n=34) used only estradiol, orally (2 mg/day) (n=31) or transdermally (1.5 mg/day) (n=3).

The patients using ERT were carefully examined 6 and 12 months later, and then annually at a specific outpatient department, and the mean follow-up time is now 2.5 years (range from 1 month to 5.2 years, 216 woman-years). The 43 patients not wishing to receive ERT were followed annually at the oncologic department for a mean of 2.6 years (range from 1 month to 4.7 years), and served as a control group.

Results: ERT significantly reduced climacteric symptoms, and the Kupperman score fell by 63%, from 26.9+/-8.6 to 9.9+/-6.7 (mean+/-SD). In non-hysterectomized women, medroxyprogesterone acetate triggered withdrawal bleeding in all except seven women. Seven patients (13%) experienced spotting during ERT. In 27 women, endometrial thickness exceeded 10 mm, and two of the total of 54 patients (3.7%) had simple hyperplasia. This vanished spontaneously in 3-6 months. Ten patients terminated the use of ERT within the first 12 to 39 months due to the lack of severe vasomotor symptoms (n=4) or due to the recurrence of breast cancer or to cancer of the contralateral breast (n=6).

Eighty-one of the 88 patients (92%) using ERT showed no evidence of recurrence, whereas five patients (5.7%) had recurrence in 12-36 months and two patients (2.3%) developed a cancer of the contralateral breast in 14-24 months; another one of those wanted to continue with ERT. Thus the combined risk of recurrence or a new cancer of the contralateral breast in ERT users was 7/216 woman-years (3% per year).

In the control group, 38 of 43 patients (88.4%) showed no evidence of recurrence or contralateral cancer, whereas four patients had recurrence and one developed a contralateral breast cancer (5/112 woman-years, 4% per year).

Large prospective, preferably placebo-controlled trials would be necessary to assess the final safety of ERT in healthy women, not to mention patients with a history of breast cancer. In practice such a study would be difficult to perform, and perhaps even unethical, because one cannot offer a placebo for a symptomatic climacteric patient wishing to receive ERT. Moreover, due to the good present prognosis of breast cancer patients [1–3], thousands of such patients would be needed if the end point of the trial were to be a recurrence of the cancer.

The role of progestin on the development of breast cancer is still unclear. The data from Sweden and United States have shown that adding progestin to estrogen replacement increases the risk of breast cancer by 14–40% in healthy women [27–29], whereas a progestin addition does not affect the risk of cancer recurrence in women with a history of breast cancer who are using estrogen replacement [21,23,25].
Why should this be the case ?

27.Persson I, Weiderpass E, Bergstro¨m R, Schairer C. Risks
of breast and endometrial cancer after estrogen and estrogen-
progestin replacement therapy. Cancer Causes Control
1999;10:253–60.
[28] Schairer C, Lubin J, Troisi R, Sturgeon S, Brinton L,
Hoover R. Menopausal estrogen and estrogen-progestin
replacement therapy and beast cancer risk. JAMA
2000;283:485–91.
[29] Ross RK, Paganini-Hill A, Wan PC, Pike MC. Effect of
hormone replacement therapy on breast cancer risk: estrogen
versus estrogen-progestin. J Natl Cancer Inst
2000;92:328–32.

[21] Eden JA, Bush T, Nand S, Wren BG. A case-control
study of combined continuous oestrogen-progestin replacement
therapy among women with a personal history
of breast cancer. Menopause 1995;2:67–72.

[23] Natrajan PK, Soumakis K, Gambrell RD. Estrogen replacement
therapy in women with previous breast cancer.
Am J Obstet Gynecol 1999;181:288–95.

[25] Dew J, Eden J, Beller E, Magarey C, Schwartz P, Crea P,
Wren B. A cohort study of hormone replacement therapy
given to women previously treated for breast cancer.
Climactric 1998;1:137–42.

Conclusions: Symptomatic climacteric patients with a history of breast cancer benefited from ERT without increasing their risk of recurrence, but the short follow-up and the small number of patients limit any definitive recommendations.

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abstract only
41 pts
no info as to HRT type

24) DiSaia, PhilipJ, et al. “Hormone replacement therapy in breast cancer.” The Lancet 342.8881 (1993): 1232.

25) DiSaia PJ, Grosen EA, Kurasaki T, Gildea M, Cowen B, Anton-Culver H. Hormone replacement therapy in breast cancer survivors:a cohort study. Am J Obstet Gynecol 1996;174:1494-8.

Objective: Our purpose was to measure any adverse effect (if one exists) of hormone replacement therapy administered to breast cancer survivors.

Study design: Forty-one patients from a group of 77 patients who received hormone replacement therapy after therapy for breast cancer were matched with 82 comparison patients not receiving hormone replacement therapy. Both groups were taken from the same population on the basis of cancer registry of the Cancer Surveillance Program of Orange County and were compared with regard to survival results.

Results: An analysis of survival time and disease-free time revealed no statistically significant difference between the two groups.

Conclusions: No obvious adverse effect of hormone replacement therapy could be shown in this pilot study. A case is made for a prospective randomized trial.

LTED 46 months
The risk of death was lower among the HRT survivors; odds ratio 0.28

26) Disaia PJ, Brewster WR, Ziogas A, et al. Breast cancer survival and hormone
replacement therapy. A cohort analysis. Am J Clin Oncol. 2000;23:541–545.

Controversy exists regarding the safety of hormone replacement therapy (HRT) after a diagnosis of breast cancer. The objective of this study is to perform a matched cohort analysis to evaluate the impact of HRT on mortality in breast cancer survivors. Patients with breast cancer who received HRT after diagnosis of breast cancer were identified. Control subjects were identified from the regional cancer registry. Matching criteria included age at diagnosis, stage of breast cancer, and year of diagnosis. Controls were selected only if they were alive at the time of initiation of HRT of the matched case. Only subjects not included in a previously reported matched analysis were selected.

One hundred twenty-five cases were matched with 362 controls.

Ninety-eight percent (123/125) of the cases received systemic estrogen; 90/125 (72%) also received a progestational agent.

The median interval between diagnosis of breast cancer and initiation of HRT was 46 months (range 0-401 months). The median duration of HRT was 22 months (range 1-357 months).

The risk of death was lower among the HRT survivors; odds ratio 0.28 (95% confidence interval 0.11-0.71). This analysis does not suggest that HRT after the treatment of breast cancer is associated with an adverse outcome.

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NICE STUDY Showing value of LTED > 2 years (no recurrence), less than 2 years LTED recurrence in 3/25.

Abstract only

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

25 pts

LTED group I <24 months (7.9 months average)
LTED group II >24 months (64.5 mo. average)

Three of 25 patients have had a recurrence, all in group I.

We report our experience with 25 women previously treated for breast cancer who subsequently received hormone replacement therapy (HRT) for the relief of menopausal symptoms and the prevention of postmenopausal cardiovascular disease and osteoporosis. Two patients had in situ disease, 13 had stage I disease, 7 had stage II disease, 1 had stage III disease, and 2 had invasive cancer of undetermined stage.

Seventeen patients (group I) began HRT less than 24 months after primary breast cancer therapy, and 8 patients (group II) began HRT more than 24 months after breast cancer therapy.

The HRT-free interval for group I patients averaged 7.9 months and for group II patients averaged 64.5 months.

The average period of observation while receiving HRT for the entire group was 35.2 months (range: 24 to 82 months).

Three of 25 patients have had a recurrence, all in group I.

One patient developed local recurrence after breast conservation treatment, and her condition was salvaged by further wide excision.

Two patients developed recurrence after mastectomy, and one patient ultimately died of systemic disease. The overall survival rate for the entire group was 96%.

Overall survival of high-risk group I patients, with a mean follow-up of 30.4 months, was 94%. We recognize that this report of HRT in a small group of patients does not have the power to demonstrate an adverse effect of HRT on breast cancer. However, the lack of an obvious adverse effect of HRT in this group of breast cancer patients and the known beneficial effect of HRT on postmenopausal cardiovascular disease and osteoporosis warrant formal prospective trials of HRT in such patients.

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Full pdf

28) Guidozzi F. Estrogen replacement therapy in breast cancer survivors. Int J
Gynecol Obstet. 1999;64:59–63.

Department of Obstetrics and Gynaecology, Johannesburg Hospital, University of the Witwatersrand Medical School, South Africa.

20 premarin and medroxyprogesterone and four tibolone.
no recurrences to date after 24-44 months

Results: Twenty-four patients who had previously been treated for breast cancer 8-91 months prior to their initiating ERT have been observed for 24-44 months. There were 15 patients with stage 1, eight with stage 2 and one with stage 4 breast cancer. The mean age of the patients at commencement of ERT was 48 years (range 42-61). Two patients had a biopsy of a suspicious breast nodule: both of which were benign. There have not been any recurrences to date.

Conclusion: Breast cancer survivors did not have their outcome adversely affected by ERT during an observation period of 24-44 months.

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full pdf
Randominzed Controlled Trial
LTED 37 months
Duration of study ONLY 6 months
estradiol valerate 2 mg/day plus levonorgestrel if intact uterus
100 patients randomized to HRT vs no HRT
some used TAM.

Full text
29) Marsden J, Whitehead M, A’Hern R, et al. Are randomized trials of hormone replacement therapy in symptomatic women with breast cancer feasible? Fertil Steril. 2000;73:292–299.

Postmenopausal women (i.e., >1 year since their last menstrual period), with a previous diagnosis of in situ disease or stage I/II breast carcinoma were identified from preliminary inspection of medical records before their attendance at breast cancer follow-up clinics at The Royal Marsden and St. George’s Hospital NHS Trusts, London.

Women were randomized (1:1) to HRT or no HRT for the 6-month duration of the study (Fig. 1).

The HRT used in this study was either estradiol valerate 2 mg/d (Progynova; Schering Health Care Ltd., Burgess Hill, West Sussex, UK) in hysterectomized women or the same estrogen plus levonorgestrel 75 μg/d for 12 of 28 days (Nuvelle; Schering Health Care Ltd.) in those with an intact uterus.

A total of 100 women were randomized so that continuance with HRT and no HRT could be estimated in 50 patients

Half were on tamoxifen

TAM − ve (n = 51) TAM + ve (n = 49)

Of the 100 women recruited, 51 were not currently taking tamoxifen (TAM − ve), whereas 49 did take the drug (TAM + ve).

To date, three women have developed recurrent breast cancer, two of which were taking HRT. One was randomized to receive opposed HRT 38 months after diagnosis and developed recurrence after taking HRT for 2 years. The second patient received unopposed HRT 9 years after diagnosis and developed recurrent disease after only 6 weeks of treatment. The third patient, who never took HRT, developed recurrent disease 6 months after her initial diagnosis.
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HABITS
Estradiol plus Progestin, norethisterone

LTED ??? However, for 80% of the women in both arms, the time between first diagnosis and random assignment was between 7 months and approximately 8 years.

HABITS was a randomized, non-placebo-controlled noninferiority trial that aimed to be at a power of 80% to detect a 36% increase in the hazard ratio (HR) for a new breast cancer event following HT.
continuous combined or sequential estradiol hemihydrate and norethisterone.
39 of the 221 women in the HT arm and
17 of the 221 women in the control arm
experienced a new breast cancer event (HR = 2.4, 95% CI = 1.3 to 4.2).

30) Holmberg L, Anderson H. HABITS (hormonal replacement therapy after
breast cancer—is it safe?), a randomised comparison: trial stopped. Lancet. 2004;363:453–455. Full pdf Holmberg HABITS Lancet 2004
Regional Oncologic Centre, University Hospital, SE-751 85 Uppsala, Sweden.

Abstract
In the 1990s, two randomised clinical trials started in Scandinavia addressing whether hormone replacement therapy (HRT) is safe for women with previous breast cancer. We report the findings of the safety analysis in HABITS (hormonal replacement therapy after breast cancer–is it safe?), an open randomised clinical trial with allocation to either HRT or best treatment without hormones. The main endpoint was any new breast cancer event. All analyses were done according to intention-to-treat.

Until September, 2003, 434 women were randomised; 345 had at least one follow-up report.

After a median follow-up of 2.1 years, 26 women in the HRT group and seven in the non-HRT group had a new breast-cancer event. All women with an event in the HRT group and two of those in the non-HRT group were exposed to HRT and most women had their event when on treatment. We decided that these findings indicated an unacceptable risk for women exposed to HRT in the HABITS trial, and the trial was terminated on Dec 17, 2003.

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HABITS 2008 Holmberg full pdf

continuous combined or sequential estradiol hemihydrate and norethisterone

HR = 2.4

continuous combined or sequential estradiol hemihydrate and norethisterone.testosterone-like progestagen, NETA, either continuously or for at least 10 days of a 28-day cycle
There are also indications that NETA is associated with a higher risk of
breast cancer than MPA, especially if continuous combined regimens are used ( 21 , 22 ).

Nice review of different estrogens and progestins and cancer risk
full text
21. Stahlberg C , Tonnes PedersenA , LyngeE , OttesenB . Hormone replacement therapy and risk of breast cancer: the role of progestins . Acta Obstet Gynecol Scand . 2003 ; 82 ( 7 ) : 335 – 344

In the USA the predominant compounds are conjugated estrogens and medroxyprogesterone-acetate, whereas oestradiol combined with testosterone-like progestins is commonly used in Europe. The progestin preferred in the USA is medroxyprogesterone-acetate (MPA), which resembles natural progesterone and is administered either cyclically or continuously. In Europe the predominant regimen prescribed is 17-b-oestradiaol opposed by testosterone-derived progestins, mainly norethistosteroneacetate (NETA) or levonorgestrel (LNG); while the less androgenic progestin MPA is used to a lesser extent.

Magnusson et al. found a 5-fold increased breast cancer risk with the continuous treatment
with NETA/LNG after more than 10 years of use as compared with never-users. This was not found for the continuous treatment with MPA in the study by Ross et al.

full text
22. Magnusson C , Baron JA , CorreiaN , Bergström R , Adami HO , Persson I .Breast cancer risk following long-term oestrogen- and oestrogenprogestin-replacement therapy . Int J Cancer . 1999 ; 81 ( 3 ) : 339 – 344 .1Department of Medical Epidemiology, Karolinska Institutet, Stockholm, Sweden

Exclusive use of oestrogen with progesterone-derived progestins did not appear to confer an excess breast-cancer risk (OR per year of use 0.95, 95% CI 0.80–1.14) (Table IV), an analysis based, however, on few exposed women (32 cases and 34 controls). In contrast, use of oestrogen with testosterone-derived progestins increased the risk of breast cancer by 8% per year of use (OR 1.08,95% CI 1.07–1.13), and use for more than 10 years conferred an OR of 3.41 (95% CI 1.91–6.08), as compared with never-use

While use of hormone-replacement therapy (HRT) effectively alleviates menopausal symptoms and prevents osteoporosis and possibly cardiovascular disease, there is concern of a detrimental impact on breast-cancer risk. There is a particular lack of data regarding the effect of long-term use of oestrogen-progestin combinations on breast-cancer risk. We conducted a large epidemiological study in Sweden, where combined oestrogen-progestin treatment has been predominant, to examine the influence of different regimens of menopausal hormone therapy on breast-cancer risk. In this population-based case-control study, 3,345 women aged 50 to 74 years with invasive breast cancer (84% of all eligible) and 3,454 controls of similar age (82% of all selected) were included. Mailed questionnaires and telephone interviews were used to collect detailed information on use of hormone replacement and on potential confounding factors. Odds ratios (OR) and 95% confidence intervals (CI) were estimated through multiple logistic regression. There was a trend of increasing breast-cancer risk with duration of oestrogen/oestrogen-progestin use (OR for women treated at least 10 years, 2.43; 95% CI, 1.79-3.30, as compared to never-users), with statistically significant estimates only for women with BMI<27 kg/m2.

Excess risks were observed to current use and use that ceased more than 10 years ago (OR for women treated at least 5 years, OR was 2.68, 95% CI, 2.09-3.42, and OR 2.57, 95% CI, 1.28-5.15, as compared with never-users, respectively). A positive association which was noted for use of oestrogen combined with testosterone-derived progestins appeared especially pronounced with continuously combined regimens. Long-term use of replacement oestrogens with or without progestins may substantially increase the incidence of post-menopausal breast cancer, particularly among non-obese women.

LTED ??? Time in years between primary treatment and randomization, median (range) 2.1 years (0.1 – 23.2) 2.2 (0.1 – 26.5)
33.5% were taking tamoxifen at the time of random assignment

A total of 442 women could be followed for a median of 4 years.
Women in the HT arm experienced new breast cancer events more than twice as often as women in the control arm (39 out of 221 vs 17 out of 221; hazard ratio = 2.4, 95% confidence interval = 1.3 to 4.2).
The cumulative incidence of a new breast cancer event at 5 years was estimated at 22.2% for the HT arm and at 8.0% for the control arm.

Continuation of Holmberg………………………..2008

Holmberg L, Iversen OE, Rudenstam CM, et al. Increased risk of recurrence after hormone replacement therapy in breast cancer survivors.J Natl Cancer Inst. 2008;100:475–482.
Regional Oncologic Centre, University Hospital, SE-751 85 Uppsala, Sweden.

Background: Hormone replacement therapy (HT) is known to increase the risk of breast cancer in healthy women, but its effect on breast cancer risk in breast cancer survivors is less clear. The randomized HABITS study, which compared HT for menopausal symptoms with best management without hormones among women with previously treated breast cancer, was stopped early due to suspicions of an increased risk of new breast cancer events following HT. We present results after extended follow-up.

Methods: HABITS was a randomized, non-placebo-controlled noninferiority trial that aimed to be at a power of 80% to detect a 36% increase in the hazard ratio (HR) for a new breast cancer event following HT. Cox models were used to estimate relative risks of a breast cancer event, the maximum likelihood method was used to calculate 95% confidence intervals (CIs), and chi(2) tests were used to assess statistical significance, with all P values based on two-sided tests. The absolute risk of a new breast cancer event was estimated with the cumulative incidence function. Most patients who received HT were prescribed continuous combined or sequential estradiol hemihydrate and norethisterone.

Results: Of the 447 women randomly assigned, 442 could be followed for a median of 4 years. Thirty-nine of the 221 women in the HT arm and 17 of the 221 women in the control arm experienced a new breast cancer event (HR = 2.4, 95% CI = 1.3 to 4.2). Cumulative incidences at 5 years were 22.2% in the HT arm and 8.0% in the control arm.

By the end of follow-up, six women in the HT arm had died of breast cancer and six were alive with distant metastases. In the control arm, five women had died of breast cancer and four had metastatic breast cancer (P = .51, log-rank test).

Conclusion: After extended follow-up, there was a clinically and statistically significant increased risk of a new breast cancer event in survivors who took HT.

When preliminary results based on a median follow-up of 2 years were reported ( 4 ), 33 breast cancer events had occurred and the hazard ratio had reached 3.5 (95% CI = 1.5 to 7.4). Here, we report results from a median follow-up of 4 years and a total of 56 breast cancer events.

We recommended that the patients receive mammograms every 12 – 24 months or participate in routine mammographic screening with target intervals of 18 – 24 months.

HT was given for 2 years in the HT arm. The majority of centers prescribed a sequential or continuously com-bined regimen of estradiol hemihydrate (E2) and norethisterone acetate (NETA) for women with an intact uterus or estradiol for women who had undergone hysterectomy.

For the 54 women exposed to estrogen only (47 from the HT arm and seven from the control arm), 20 women took 1 – 2 mg E2 (Estrofem) daily and 10 took 0.625 or 1.25 mg conjugated estrogens (Compremin) daily.

Exposure to estrogen alone yielded a HR of 1.4 (95% CI = 0.55 to 3.3) as compared with exposure to a continuously combined regimen. (1.4 x 1.6=2.24)

All women in the HT arm who developed a breast cancer event had been exposed to HT. Five of the women with a breast cancer event in the non-HT arm had also taken HT after random assign-ment. Nineteen women in the HT arm had a new breast cancer event after the 2-year follow-up period (when the treatment should have stopped according to protocol). Nine of these women had con-tinued to use HT until the time of the event, and one had exposure until 4 months before the event.

By the end of follow-up, six women from the HT group had died of breast cancer and six were alive with distant metastases. For the non-HT group, five women had died of breast cancer and four were alive with distant metastases. The difference in distant metastasis –free survival was not statistically significant ( P = .51, log-rank test). Three women in the HT arm died of causes other than breast cancer, compared with none in the non-HT arm.

Because it was open label and not placebo-controlled, there was a risk for a bias related to possibly more vigorous follow-up and diagnosis of events in the HT arm.

All women with breast cancer events assigned to the HT arm were exposed to HT, and fi ve of the 17 women in the non-HT arm with a new breast cancer event were also exposed to HT.

It is not surprising that the results from this randomized trial deviate from those in the observational series ( 2 ). The majority of the observational studies were not formal studies that could con-trol suffi ciently for bias and confounding. Even in the carefully designed observational study from Seattle ( 12 ) that studied the risk of breast cancer recurrence following HT among breast cancer survivors and found decreased risk for HT users compared with nonusers (HR = 0.50, 95% CI = 0.30 to 0.85), it was diffi cult to completely exclude selection bias. An important methodological problem in observational studies is to adjust for the effects of any pretreatment screening for metastases and restaging of those exposed to HT. Furthermore, reliable data on patterns of HT exposure are seldom available in the observational setting. In several of the case series ( 13 – 18 ), one or more of the investigators were also the patients’ physicians, which increases the risk that patients do not report back bad outcomes

First, there was a higher proportion of women with node-positive breast cancer in the HABITS trial than in the Stockholm trial.

Second, a higher proportion of the women in the Stockholm study were being treated with tamoxifen, which would theoretically confer protection from breast cancer recurrence.

A third possible reason for the different results between the HABITS trial and the Stockholm study is that in the HABITS trial the most commonly used HT regimens included a potent testosterone-like progestagen, NETA, either continuously or for at least 10 days of a 28-day cycle. By contrast, the Stockholm study was specifi cally designed to keep doses of progestagen as low as possible and to use a naturally occurring progesterone, [error-this is not anaturally ocurring progesterone] medroxyprogesterone acetate (MPA), instead of NETA.

The addition of progestagens in HT has been found to increase the risk of breast cancer ( 6 , 7 , 19 – 21 ). There are also indications that NETA is associated with a higher risk of breast cancer than MPA, especially if continuous combined regimens are used (21, 22).

21. Stahlberg C , Tonnes Pedersen A , Lynge E , Ottesen B . Hormone replace-ment therapy and risk of breast cancer: the role of progestins . Acta Obstet Gynecol Scand . 2003 ; 82 ( 7 ) : 335 – 344 .

22. Magnusson C , Baron JA , Correia N , Bergström R , Adami HO , Persson I . Breast cancer risk following long-term oestrogen- and oestrogen-progestin-replacement therapy . Int J Cancer . 1999 ; 81 ( 3 ) : 339 – 344 .

In the HABITS trial, the new breast cancer events in the HT arm were mainly local events, and there was no convincing evi-dence for a higher breast cancer mortality associated with HT exposure.

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Stockholm trial full pdf

32) von Schoultz Eva, Rutqvist LE, Stockholm Breast Cancer Study Group. Menopausal hormone therapy after breast cancer: the Stockholm randomized trial. J Natl Cancer Inst. 2005;97:533–535.

Among the 188 patients who had been randomly assigned to receive menopausal
hormone therapy, 42 (22%) started cyclic estradiol and medroxyprogesterone
acetate, 94 (50%) started spacing out estradiol and medroxyprogesterone acetate,
and 43 (23%) started estradiol valerate alone.

At a median follow-up of 4.1 years (end date for follow-up = January 2004)
in the Stockholm trial, there was a total of 24 breast cancer recurrences: 11 in the
menopausal hormone therapy group and 13 in the control no-treatment group
( Table 2 ). The total number of deaths in the menopausal hormone therapy group
was four (two from breast cancer) and in the control group nine (four from breast
cancer).

In 1997 two independent randomized clinical trials, Hormonal Replacement Therapy After Breast Cancer–Is It Safe? (HABITS; 434 patients) and the Stockholm trial (378 patients), were initiated in Sweden to compare menopausal hormone therapy with no menopausal hormone therapy after diagnosis of early-stage breast cancer. Much of the design of both studies was similar; however, a goal of the Stockholm protocol, not shared with the HABITS trial, was to minimize the use of progestogen combined with estrogen. The HABITS trial was prematurely stopped in December 2003, because, at a median follow-up of 2.1 years, the risk for recurrence of breast cancer among patients receiving menopausal hormone therapy was statistically significantly higher (relative hazard [RH] = 3.3, 95% confidence interval [CI] = 1.5 to 7.4) than among those receiving no treatment. In the Stockholm trial, however, at a median follow-up of 4.1 years, the risk of breast cancer recurrence was not associated with menopausal hormone therapy (RH = 0.82, 95% CI = 0.35 to 1.9). Statistically significant heterogeneity in the rate of recurrence was observed (P = .02; two-sided likelihood-ratio test) between the two studies, indicating that chance may not be the only explanation. Doses of estrogen and progestogen and treatment regimens for menopausal hormone therapy may be associated with the recurrence of breast cancer.

Patients who had had a hysterectomy in the menopausal hormone therapy group
were given continuous treatment with 2 mg of estradiol valerate daily.

Patients in the group receiving no menopausal hormone therapy were asked
to refrain from use of all types of menopausal hormone therapy. Local vaginal
treatment with low-dose estrogen gels or vagitories was allowed.

For example, the proportion of lymph node – positive patients was higher in the
HABITS trial than in the Stockholm trial (26% versus 16%, respectively), and
fewer patients received concomitant adjuvant tamoxifen therapy in the HABITS
trial than in the Stockholm trial (21% versus 52%, respectively). In addition, the
Stockholm protocol attempted to minimize the use of progestogen in combination
with estrogen. In contrast to the HABITS trial, the Stockholm trial recommended
that patients avoid continuous combined treatment with estrogen and progestogen
and use regimens that incorporated 1 week of no treatment every 1 (cyclic regimen)
or 3 (spacing out regimen) months

These treatment recommendations were based on the following results, available when the trial was initiated, that indicated differential effects on the breast when treatment with estrogen alone was compared with combined treatment with estrogen and progestogen
( 2 – 4 ) . First, breast cell proliferation is increased only during the luteal phase of
the menstrual cycle when levels of both estrogen and progesterone are high ( 2 ) .
Second, using a relevant prospective monkey model for menopausal hormone
therapy, we reported statistically significantly higher proliferation in the breast
during continuous combined estrogen and progestogen treatment than during
estrogen-only treatment ( 3 ) . Finally, cyclic discontinuation of hormonal treatment
was hypothesized to decrease the expression of local growth factors in
breast tissue and to initiate and stimulate apoptosis ( 4 ) .

In the Stockholm trial, 73% of the women were first assigned to menopausal
hormone therapy containing either estrogen alone or the spacing out
regimen, in which progestogen was given for only 14 days at 3-month intervals.
This protocol could provide one explanation for the lack of difference in
breast cancer recurrence between the menopausal hormone therapy group and
the no treatment group in the Stockholm trial.

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full text
Stockholm randomized trial 10 year follow up

33) Fahlén M, Fornander T, Johansson H, et al. Hormone replacement therapy after breast cancer: 10 year follow-up of the Stockholm randomized trial. Eur J Cancer. 2013;49:52–59.

Background: The management of hormonal deficiency symptoms in breast cancer survivors is an unsolved problem. While hormone replacement therapy (HRT) may increase the risk of breast cancer in healthy women, its effects on recurrence is unclear. Observational studies have suggested decreased recurrence rates from HRT. The few clinical trials in this field have all been closed preterm.

Methods: The Stockholm trial was started in 1997 and designed to minimise the dose of progestogen in the HRT arm. Disease-free women with a history of breast cancer were randomised to HRT (n=188) or no HRT (n=190). The trial was stopped in 2003 when another Swedish study (HABITS, the Hormonal Replacement After Breast Cancer – Is it Safe?) reported increased recurrence. However the Stockholm material showed no excess risk after 4 years of follow-up. A long term follow-up has now been performed.

Findings: After 10.8 years of follow-up, there was no difference in new breast cancer events: 60 in the HRT group versus 48 among controls (hazard ratio (HR)=1.3; 95% confidence interval (CI)=0.9-1.9). Among women on HRT, 11 had local recurrence and 12 distant metastases versus 15 and 12 for the controls. There were 14 contra-lateral breast cancers in the HRT group and four in the control group (HR=3.6; 95% CI=1.2-10.9; p=0.013). No differences in mortality or new primary malignancies were found.

Interpretation: The number of new events did not differ significantly between groups, in contrast to previous reports. The increased recurrence in HABITS has been attributed to higher progestogen exposure. As both trials were prematurely closed, data do not allow firm conclusions. Both studies found no increased mortality from breast cancer or other causes from HRT. Current guidelines typically consider HRT contraindicated in breast cancer survivors. Findings suggest that, in some women symptom relief may outweigh the potential risks of HRT.

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No abstract available

34) Bluming AZ. Hormone replacement therapy (HRT) in women with previously treated primary breast cancer: update XIV. Proc ASCO. J Clin Oncol.2008;15 s:20693.
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OCP’s

35) Figueiredo JC, Bernstein L, Capanu M, et al. Oral contraceptives, postmenopausal hormones, and risk of asynchronous bilateral breast cancer: the WECARE study group. J Clin Oncol. 2008;26:1411–1418

Abstract/ Purpose: To investigate whether oral contraceptive (OC) use and postmenopausal hormones (PMH) are associated with an increased risk of developing asynchronous bilateral breast cancer among women diagnosed with breast cancer younger than 55 years.

Patients and methods: The WECARE (Women’s Environment, Cancer, and Radiation Epidemiology) study is a population-based, multicenter, case-control study of 708 women with asynchronous bilateral breast cancer and 1,395 women with unilateral breast cancer. Risk factor information collected during a telephone interview focused on exposures before and after the first breast cancer diagnosis. Treatment and tumor characteristics were abstracted from medical records. Multivariable conditional logistic regression was used to estimate rate ratios (RR) and 95% CIs.

Results: OC use before the first breast cancer diagnosis was not associated with risk of asynchronous bilateral breast cancer (RR = 0.88; 95% CI, 0.67 to 1.16). OC use after breast cancer diagnosis was also not significantly associated with risk (RR = 1.56; 95% CI, 0.71 to 3.45). Risk did not increase with longer duration of use or among women who had begun using OCs at a younger age. No evidence of an increased risk of asynchronous bilateral breast cancer was observed with PMH use before (RR = 1.21; 95% CI, 0.90 to 1.61) or after breast cancer diagnosis (RR = 1.10; 95% CI, 0.67 to 1.77). Neither duration nor type of PMH were associated with risk. Age at and time since first breast cancer diagnosis did not substantially affect these results.

Conclusion: This study provides no strong evidence that OC or PMH use increases the risk of a second cancer in the contralateral breast.

===================================================
LTED from Marttunen,2001
===================================================

Mean interval between surgery and start of ERT / follow-up months

Wile 1992      26

Powles 1993  31

DiSaia 1993   24

Eden 1995     60

V-Sellin 1995 84

Narrajan 1999 17

U-Vrscaj 1999 62

===================================

duplicate: See (1)

36) Bluming, Avrum Zvi. “Hormone replacement therapy after breast cancer: it is time.” The Cancer Journal 28.3 (2022): 183-190.

1a. Palshof et al. 1980 Prospective randomized 37/95 2 3 Reduced recurrence* 61
1b. Palshof et al. 1985 Updates of the original study 51/103 2 6.5 Reduced recurrence
Reduced mortality
62
2. Stoll and Parbhoo 1988 Prospective single-arm 14/ 0.25–0.5 2 No recurrence 63
3. Powles et al. 1993 Retrospective observational 35/ 1.2/0.1–3.7 3.6 2 of 35 developed recurrence No breast cancer deaths 64
4. Eden et al. 1995 Retrospective case-control 90/811 1.5/0.25–12 3 Reduced recurrence 65
5. Vassilopoulou-Sellin et al. (feasibility study) 1997 Prospective single-arm 43/ 2.6/2–12 12
1 of 43 developed recurrence No breast cancer deaths 66
6. Dew et al. 1998 Retrospective cohort 167/1305 1.6/0.25–22 4 No difference† 67
7. Espie et al. 1999 Retrospective cohort 120/240 2.4/1–10.6 2.4 No difference 68
8. Guidozzi 1999 Prospective single-arm 20/ 2.7/2–3.7 5.7 No recurrence 69
9. Natrajan et al. 1999 Retrospective cohort 50/26 5.5/0.5–32 7 No difference 70
10. Uršič-Vrščaj and Bebar 1999 Prospective cohort 21/42 2.3/0.25–6 2.3 No difference 71
11. Vassilopoulou-Sellin et al. 1999 Prospective cohort 39/280 4/2–6 3.8 No difference 72
12. Disaia et al. 2000 Retrospective cohort 125/362 1.8/0.1–30 Reduced mortality 73
13. Marsden et al. 2000 Prospective randomized 51/49 0.5 No difference 74
14. Peters et al. 2001 Prospective cohort 56/551 6.4/1–20.9 12.8 No difference 75
15. Marttunen et al. 2001 Prospective cohort 88/43 2.6 2.6 No difference 76
16. Beckmann et al. 2001 Retrospective cohort 64/121 3.5/3 5 No difference 77
17. O’Meara et al. 2001 Retrospective case-control 174/695 1.25 4.6 Reduced recurrence
Reduced mortality 78
18. Vassilopoulou-Sellin et al. 2002 Prospective randomized 56/243 5 6 No difference 79
19. Durna et al. 2002 Retrospective observational 286/836 1.75/0.17–34 6 Reduced recurrence Reduced mortality 80
20. Decker et al. 2003 Prospective cohort 277/554 3.7 No difference 81
21. Gorins et al. 2003 Prospective cohort 230/ 2.5 No difference 82
22a. Holmberg and Anderson (HABITS) 2004 Prospective randomized 174/171 2 2.1 Increased risk of local or contralateral tumors only No increased risk of metastases or death 83
22b. Holmberg et al. (HABITS) 2008 Updates of the original study 221/221 2 5 No increased mortality 84
23a. von Schoultz and Rutqvist (Stockholm) 2005 Prospective randomized 175/184 4.1/0.2–7 4.1 No difference 85
23b. Fahlén et al. (Stockholm) 2013 Updates of the original study 188/190 2.6 10.8 No difference 86
24. Bluming 2008 Prospective cohort 117/63 7.5/1–15 7.5 Reduced recurrence 87
25. Figueiredo et al. 2008 Retrospective case-control 708/1399 No difference 88

Boldface is employed to identify the prospective randomized trials and to identify significant positive or negative findings.
*Reduced recurrence = breast cancer survivors given HRT had fewer recurrences of breast cancer, or lower risk of death, than control group not on HRT.
†

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No abstract available
37) Hayes, Theresa M., et al. “Hormone replacement therapy after a diagnosis of breast cancer: cancer recurrence and mortality.” The Medical Journal of Australia 178.8 (2003): 412-413.

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Testosterone Pellets

Full pdf

38) Glaser, Rebecca L., Anne E. York, and Constantine Dimitrakakis. “Incidence of invasive breast cancer in women treated with testosterone implants: a prospective 10-year cohort study.” BMC cancer 19.1 (2019): 1271.

39) Glaser, R. L., A. E. York, and C. Dimitrakakis. “Abstract P6-13-02: Reduced incidence of breast cancer with testosterone implant therapy: A 10-year cohort study.” Cancer Research 79.4_Supplement (2019): P6-13.

Testosterone implants have been used for over eighty years to treat symptoms of hormone deficiency in pre and postmenopausal women. Evidence supports that androgens are breast protective. However, there is a lack of data on the long-term effect of testosterone therapy on the incidence of invasive breast cancer (IBC). This study was specifically designed to investigate the incidence of IBC in pre and postmenopausal women (presenting with symptoms of androgen deficiency) treated with subcutaneous testosterone implants or testosterone implants combined with anastrozole.
Methods

The 10-year prospective cohort study was approved in March 2008 at which time recruitment was initiated. Recruitment was closed March 2013. Pre and postmenopausal women receiving at least two pellet insertions were eligible for analysis (N = 1267). Breast cancer incidence rates were reported as an unadjusted, un-weighted value of newly diagnosed cases divided by the sum of ‘person-time of observation’ for the at-risk population. Incidence rates on testosterone therapy were compared to age-specific Surveillance Epidemiology and End Results (SEER) incidence rates and historical controls. Bootstrap sampling distributions were constructed to verify comparisons and tests of significance that existed between our results and SEER data.
Results

As of March 2018, a total of 11 (versus 18 expected) cases of IBC were diagnosed in patients within 240-days following their last testosterone insertion equating to an incidence rate of 165/100000 p-y, which is significantly less than the age-matched SEER expected incidence rate of 271/100000 p-y (p < 0.001) and historical controls.
Conclusion
Long term therapy with subcutaneous testosterone, or testosterone combined with anastrozole, did not increase the incidence of IBC. Testosterone should be further investigated for hormone therapy and breast cancer prevention.

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40) Donovitz, Gary, and Mandy Cotten. “Breast cancer incidence reduction in women treated with subcutaneous testosterone: testosterone therapy and breast cancer incidence study.” European journal of breast health 17.2 (2021): 150.

Testosterone (T) therapy has been shown to be breast protective in both pre- and post-menopausal patients. Additionally, estradiol (E) does not cause breast cancer (BC) in the majority of the world’s literatures. This study aimed to investigate the incidence of invasive BC (IBC) in pre- and postmenopausal women treated with T therapy and T in combination with E (T/E).

Materials and Methods:
Since January 2010, a total of 2,377 pre- and post-menopausal women were treated with T or T/E implants. IBC rates were reported based on newly diagnosed IBC cases in the total study. Total cases divided by the total sample size and years in study was expressed as an incidence per 100,000 person-years (P-Ys). The BC incidence was compared with age-specific Surveillance Epidemiology and End Results (SEER) incidence rates.

Results:
As of October 2020, 14 cases diagnosed with IBC have been found in 9,746 P-Y of follow up for an incidence of 144 cases per 100,000 P-Y, substantially less than the age-specific SEER incidence rates (223/100,000), placebo arm of Women’s Health Initiative Study (330/100,000), and never users of hormone therapy from the Million Women Study (312/100,000).

Conclusion:
T and/or T/E pellet implants significantly reduced the incidence of BC in pre- and post-menopausal women. The addition of E did not increase the incidence over using T alone. This is the second multi-year long-term study demonstrating the benefits of T therapy in reducing the incidence of IBC.
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41) Cline, J. M., et al. “Effects of hormone replacement therapy on the mammary gland of surgically postmenopausal cynomolgus macaques.” American journal of obstetrics and gynecology 174.1 Pt 1 (1996): 93-100.

OBJECTIVE: Our purpose was to define the proliferative response and receptor status in the mammary glands of surgically postmenopausal macaques given hormone replacement therapy, equivalent for monkeys to that given women.
STUDY DESIGN: Surgically postmenopausal adult female cynomolgus macaques (Macaca fascicularis) were given either no treatment (n = 26), conjugated equine estrogens (n = 22), or combined therapy with conjugated equine estrogens and medroxyprogesterone acetate (n = 21). Drugs were administered in the diet, at doses equivalent on a caloric basis to 0.625 mg per woman per day for conjugated equine estrogens and 2.5 mg per woman per day for medroxyprogesterone acetate, for 30 months. Mammary gland proliferation was assessed
subjectively and by morphometric and stereologic means. Estrogen receptor and progesterone receptor content and proliferation were studied by immunohistochemistry.
RESULTS:In this model combined therapy with conjugated equine estrogens and medroxyprogesterone acetate induced greater proliferation than did conjugated equine estrogens alone. The percentage of estrogen receptor – positive cells was decreased in the conjugated equine estrogens plus medroxyprogesterone acetate group. The percentage of progesterone receptor -positive cells was increased by treatment with conjugated equine estrogens alone.
CONCLUSION: These results indicate a proliferative response of mammary gland epithelium to therapy with conjugated equine estrogens plus medroxyprogesterone acetate in postmenopausal macaques. The clinical implication of this finding may be a greater risk for development of breast neoplasms in women receiving combined hormone replacement therapy.

42) Reid SE, Murthy MS, Kaufman M, Scanlon EF. Endocrine and paracrine hormones in the promotion, progression and recurrence of breast cancer. Br J Surg 1996 ; 83 : 1037 – 46.

43) Santen RJ, Pinkerton J, McCartney C, Petroni GR. Risk of breast cancer with progestins
in combination with estrogen as hormone replacement therapy. J Clin Endocrinol
Metab 2001 ; 86 : 16 – 23.

44) Weiss LK, Burkman RT, Cushing-Haugen KL, Voigt LF, Simon MS, Daling JR, et al. Hormone replacement therapy regimens and breast cancer risk. Obstet Gynecol 2002; 100 : 1148 – 58.

45) Olsson HL, Ingvar C, Bladström A. Hormone replacement therapy containing progestins and given continuously increases breast carcinoma risk in Sweden. Cancer 2003 ; 97 : 1387 – 92.

46) Chlebowski RT, Hendrix SL, Langer RD, Stefanick ML, Gass M, Lane D, et al. Influence
of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal
women: the Women’s Health Initiative Randomized Trial. JAMA 2003; 289: 3243 – 53.

47) Bluming, Avrum Z. “Progesterone and breast cancer pathogenesis.” Journal of molecular endocrinology 66.1 (2021): C1-C2.

48) Bluming, Avrum Z, Estrogen Matters, Little, Brown Spark; 1st edition (September 4, 2018)

49) Fournier, Agnès, et al. “Postmenopausal hormone therapy initiation before and after the Women’s Health Initiative in two French cohorts.” Menopause (New York, NY) 18.2 (2011): 219-223.

50) Fournier, Agnes, et al. “Breast cancer risk in relation to different types of hormone replacement therapy in the E3N‐EPIC cohort.” International journal of cancer 114.3 (2005): 448-454.

51) Fournier, Agnès, Franco Berrino, and Françoise Clavel-Chapelon. “Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study.” Breast cancer research and treatment 107 (2008): 103-111.

52) Fournier, Agnès, et al. “Use of different postmenopausal hormone therapies and risk of histology-and hormone receptor–defined invasive breast cancer.” Journal of Clinical Oncology 26.8 (2008): 1260-1268.

53) Fournier, Agnès, et al. “Estrogen-progestagen menopausal hormone therapy and breast cancer: does delay from menopause onset to treatment initiation influence risks?.” Journal of Clinical Oncology 27.31 (2009): 5138-5143.

54) Fournier, Agnès, et al. “Risk of breast cancer after stopping menopausal hormone therapy in the E3N cohort.” Breast cancer research and treatment 145 (2014): 535-543.

55) Berkson, Devaki Lindsey. “Estrogen Vindication, Part 1: Estrogen and the WHI.” Townsend Letter 445-446 (2020): 36-40.

56) Berkson, Devaki Lindsey. “Estrogen Vindication, Part 2: Estrogen, Cancer Stem Cells, and Studies.” Townsend Letter 447 (2020): 60-66. Berkson Devaki Lindsey Estrogen Vindication Part 1 and 2 Townsend Letter 445-446 2020 36-40

57) Lippman, Marc, Gall Bolan, and Karen Huff. “The effects of estrogens and antiestrogens on hormone-responsive human breast cancer in long-term tissue culture.” Cancer research 36.12 (1976): 4595-4601.

58) Ellis, Matthew J., et al. “Lower-dose vs high-dose oral estradiol therapy of hormone receptor–positive, aromatase inhibitor–resistant advanced breast cancer: A phase 2 randomized study.” Jama 302.7 (2009): 774-780.

59) Bennink, Herjan JT Coelingh, et al. “The use of high-dose estrogens for the treatment of breast cancer.” Maturitas 95 (2017): 11-23.

60) Lønning, Per E., et al. “High-dose estrogen treatment in postmenopausal breast cancer patients heavily exposed to endocrine therapy.” Breast cancer research and treatment 67 (2001): 111-116.

61) Haddow, Alexander, et al. “Influence of synthetic oestrogens on advanced malignant disease.” British medical journal 2.4368 (1944): 393.

62) Giulianelli, Sebastián, et al. “Estrogen receptor alpha mediates progestin-induced mammary tumor growth by interacting with progesterone receptors at the cyclin D1/MYC promoters.” Cancer research 72.9 (2012): 2416-2427.

63) O’Malley, Bert W., and Sohaib Khan. “Elwood V. Jensen (1920–2012): father of the nuclear receptors.” Proceedings of the National Academy of Sciences 110.10 (2013): 3707-3708.

64) Gustafsson, Jan-Åke. “Estrogen Receptor β—A Multifaceted Player.” Women’s Health and Menopause: New Strategies—Improved Quality of Life. Boston, MA: Springer US, 2002. 1-5.

65) Koehler, Konrad F., et al. “Reflections on the discovery and significance of estrogen receptor β.” Endocrine reviews 26.3 (2005): 465-478.

66) Mohammed, Hisham, et al. “Progesterone receptor modulates ERα action in breast cancer.” Nature 523.7560 (2015): 313-317.

67) Maximov, Philipp Y., et al. “Estrogen receptor complex to trigger or delay estrogen-induced apoptosis in long-term estrogen deprived breast cancer.” Frontiers in Endocrinology 13 (2022): 869562.

68) Feigman, Mary J., et al. “Pregnancy reprograms the epigenome of mammary epithelial cells and blocks the development of premalignant lesions.” Nature communications 11.1 (2020): 2649.

69) Subramani, Ramadevi, et al. “Pregnancy Inhibits Mammary Carcinogenesis by Persistently Altering the Hypothalamic–Pituitary Axis.” Cancers 13.13 (2021): 3207.

70) Barton, Maria, Julia Santucci-Pereira, and Jose Russo. “Molecular pathways involved in pregnancy-induced prevention against breast cancer.” Frontiers in endocrinology 5 (2014): 213.