A Closer Look at HABITS Lars Holberg 2008 by Jeffrey Dach MD

In 2008, Dr. Lars Holmberg published the follow up data from the HABITS trial (2004). In this trial, 442 breast cancer survivors were recruited to study the safety of hormone replacement in this group compared to placebo.

In my previous newsletter, Adjuvant Endocrine Therapy for Breast Cancer Survivors, Dr Jekyll and Mr. Hyde, we discussed the disastrous 300% increased recurrence in the HABITS Trial by Lars Holmberg, 2004. This trial used estradiol combined with a synthetic progestin, norethisterone. 153 of the 442 women were also taking Tamoxifen.

Table 3 provides useful information about the incidence of cancer recurrence (see header image, courtesy of Lars Holmberg, 2008).

in 2008, Dr. Lars Holmberg writes:

The only notable difference between strata was for tamoxifen use, with a higher risk among women who were using tamoxifen at the start of the trial compared with women who were not on tamoxifen at the time of random assignment (HR = 4.7 [95% CI = 1.4 to 16.2] vs HR = 1.9 [95% CI = 1.0 to 3.6]).

Comparing Tamoxifen users to Tamoxifen nonusers

See the red rectangle in Table Three. Green ellipse shows hazard ratio for women on Tamoxifen and HRT (HR=4.7), compared to women Not on Tamoxifen and HRT (HR=1.9). The Breast Cancer Survivors on HRT plus Tamoxifen users had an almost 500 percent (HR=4.7) increase in recurrence compared to placebo, and a double the rate of recurrence compared to HRT users NOT taking Tamoxifen.

Correction: In 2022, Dr. Avrum Bluming wrote that all breast cancer recurrences in the HABITS Trial occurred in women taking Tamoxifen in addition to HRT. (3) This was actually 11 recurrences of 26 women in the Tamoxifen plus HRT group and 1 recurrence in 21 in the HRT alone group (nonsignificant). What Dr. Avrum Bluming’s meant to say is that the notable or significant increased recurrence was confined to the tamoxifen subgroup.

However, in the 2008 publication by Lars Holmberg, recurrences were no longer exclusively in the HRT plus Tamoxifen group. However,  the concurrent use of Tamoxifen and HRT doubled the recurrence rate from roughly HR=2.3 to HR=4.7. (Green Ellipse in Table Three)

When we see breast cancer recurrence while on the estrogen receptor blocking drug, Tamoxifen, by definition, this represents the third phase of anti-estrogen resistance described by Dr. Zsusana Suba. According to Dr. Suba’s three phases of antiestrogen administration, I speculate that these two drugs, the tamoxifen and the synthetic progestin, Norethisterone,  completely blocked estrogen signalling and exhausted the cancer cells’ ability to compensate, thus leading to the third phase, tamoxifen resistance and cancer progression. Obviously, this is a very bad thing.

Conclusion: Concurrent use of Tamoxifen with HRT doubled the breast cancer recurrence rate from HR= 2.3 to HR=4.7. This is counter-intuitive and supports Dr. Suba’s work on the pitfalls of anti-estrogen treatments, and cautions against the use of anti-estrogens for breast cancer prevention. Dr. Suba states that the use of anti-estrogens such as Tamoxifen is a medical mistake, and the 2008 follow-up of HABITS by Lars Holmberg of Sweden supports her conclusion.

Articles With Related Interest:

Hormone Replacement for Breast Cancer Survivors Part Two

Hormone Replacement for Breast Cancer Survivors Part One

Estrogen Metabolism, Iodine, 2MEO Part Three

Testosterone for Breast Cancer Prevention and Treatment

All Bioidentical Hormone Articles

References:

1) Holmberg, Lars, et al. “Increased risk of recurrence after hormone replacement therapy in breast cancer survivors.” Journal of the National Cancer Institute 100.7 (2008): 475-482.

(Extended follow-up to median ~4 years: 39 events in HRT arm vs. 17 in controls, HR=2.4, 95% CI 1.3-4.2. Subgroup analysis shows higher risk among tamoxifen users at baseline [higher HR in that stratum], but explicitly notes the “only notable difference between strata was for tamoxifen use, with a higher risk among women who were using tamoxifen at the start of the trial compared with those who were not.” This indicates elevated but not exclusive risk in the tamoxifen group—recurrences were not confined solely to tamoxifen users.)

2) Holmberg, Lars, and Harald Anderson. “HABITS (hormonal replacement therapy after breast cancer—is it safe?), a randomised comparison: trial stopped.” The Lancet 363.9407 (2004): 453-455.

This is the initial stopping paper; it reports 26 events in the HRT arm vs. 7 in controls after median 2.1 years, but does not break down all events by tamoxifen use in detail. It notes tamoxifen was allowed and stratified, with ~21% overall use.)

in the 2004 initial report (which led to the trial’s early termination), the overall relative risk of recurrence was elevated in the HRT arm (RR = 3.5, 95% CI 1.5–8.1). However, a test for heterogeneity showed a significantly higher relative risk in the subgroup of women using tamoxifen at randomization (RR = 11.0, 95% CI 1.4–85.2; 11 events in 26 HRT + tamoxifen users vs. 1 event in 21 non-HRT + tamoxifen users) compared to non-tamoxifen users (p = 0.02 for the difference between subgroups). This indicates the excess risk was disproportionately driven by the tamoxifen subgroup.

In the 2004 report (median follow-up 2.1 years, 33 breast cancer events total): Overall, HRT was associated with a significantly increased risk of recurrence: relative hazard (RH) = 3.5 (95% CI 1.5–8.1), with 26 events in 174 HRT-arm women vs. 7 in 171 controls.

Subgroup analysis by tamoxifen use at randomization (tamoxifen was used by ~21% overall) showed marked heterogeneity (p = 0.02 for difference between subgroups):Among women on tamoxifen: The relative risk was very high and statistically significant — RR = 11.0 (95% CI 1.4–85.2), based on 11 events in the HRT + tamoxifen subgroup vs. only 1 event in the control + tamoxifen subgroup.
Among women not on tamoxifen: The relative risk was lower and not statistically significant (specific RR not always quoted in secondary sources, but the wide CI in the tamoxifen group and the p=0.02 heterogeneity indicate the excess events driving the overall significance were disproportionately in the tamoxifen stratum).

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

In 2022, Dr. Avrum Bluming discusses the HABITS trial, writing:

The HABITS trial was prematurely terminated on December 17, 2003, after only 2 years of median follow-up and after only 434 women of the proposed 1300 had been enrolled. The reason for the sudden termination, according to the initial paper, was the disproportionate number of women randomized to HRT who developed another breast cancer (26 of 174 = 15%), compared with only 7 of the 171 (5%) randomized to no HRT. The increase was seen only as local recurrences or contralateral tumors. There was no increase in the development of distant metastases, nor was there an increase in the risk of death. Further, there was no increase among women randomized to estrogen alone; there was no increase when Premarin [CEE] (conjugated estrogens) was used as the source of estrogen; there was no increase among women who had been initially diagnosed with lymph node involvement, and the increase was noted only among women who were taking tamoxifen in conjunction with HRT.

Jeffrey Dach MD
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Published on January 12th, 2026 by Jeffrey Dach MD