Hormone Replacement Therapy After Breast Cancer. Is It Safe? Part 2

Last week’s blog post, “Hormone Replacement Therapy After Breast Cancer. Is It Safe? Part 1,” began to address the controversial statement most believe to be true, “Hormone replacement therapy (HRT), especially estrogen, is dangerous and linked to cancer.”

The blog summarized the many health benefits of HRT, however:

• Is the risk too great for breast cancer survivors?
• Should breast cancer survivors be denied these benefits?
• What does the research show?

The following blog will look into the studies using HRT and estrogen replacement therapy (ERT)  in breast cancer survivors as discussed in “Hormone Replacement Therapy After Breast Cancer: It Is Time” by oncologist Avrum Bluming, MD.

HRT refers to hormone replacement using Prempro, Premarin plus a progestin.  ERT refers to estrogen replacement using Premarin only.  Both were used in the Women’s Health Initiative study, one of the largest women’s health studies. These are NOT bioidentical hormones.

WHI Shut Down ERT Clinical Trials in Breast Cancer Survivors

As a result of the early shut down of the Women’s Health Initiative (WHI) claiming HRT increased the incidence of breast cancer, clots and stroke, the clinical trials among breast cancer survivors were largely shut down.

Between 1980 and 2013, only 25 studies have been published on this topic.  Their results are summarized below:

• 5 studies reported fewer breast cancer events among survivors receiving HRT
• 4 studies reported reduced mortality from breast cancer
• 4 of 5 studies prospectively randomized trials reported no increase in breast cancer among survivors receiving HRT
• Stockholm trial reported no significant overall increase in breast cancer events, distant metastases or mortality at 10-year follow-up
• 1 of 25 studies (HABITS) reported an increased risk of breast cancer events following HRT

HABITS TRIAL: HABITS was the only study reporting an increased risk.  It received all the attention, with many falsely stating as fact “HRT increases cancer.”  After only 2 years of median follow-up, and only 434 women left out of 1300 enrolled in the trial, the trial was prematurely terminated in 2003.

According to the initial paper, the trial was terminated due to the disproportionate number of women randomized to HRT who developed breast cancer: 26 in the HRT group versus 7 in the no HRT group. There was no difference in incidence of metastatic disease nor risk of death between the two groups during that time period.

The increase in breast cancer was only noted in women who were taking tamoxifen (blocking conversion of estrogen in the body) with HRT.  This contradicted current research on tamoxifen and prevention of cancer recurrence.

Recurrence in the trial was defined as contralateral tumors and local recurrences without distant metastases nor increase in death.

Women with positive lymph-node involvement which is associated with an increased risk of recurrence, had no new breast cancers. There was noted to be no increase in cancer among women receiving “estrogen” alone (Premarin – synthetic conjugated estrogen).

In 2004, the principal investigator of the trial wrote a letter stating though the study was terminated early, the results should be interpreted cautiously and not be the “final word” on HRT use in breast cancer patients. 

Mortality was an important endpoint to follow. In 2008, mortality was not increased although 39 of 221 (18%) randomized to HRT experienced a new breast cancer event versus 17 of 221 (8%) randomized to no HRT. 

“It is primarily on the basis of this difference between 39 of 17 (a total of 22 patients) that HRT is being denied to millions of breast cancer survivors around the world. Interestingly, the HABITS article amended the explanation for prematurely stopping the study, this time stating the reason was due to reports from the WHI and the Million Women Study that hormone therapy increases the risk of breast cancer among healthy women.”

Over the course of nearly three decades, the HABITS study was the only one out of 25 other reported individual studies and 20 review articles to cite an increased risk of cancer recurrence with HRT use, but only in women also taking tamoxifen.

“…You have to ask: What was wrong with all of the preceding studies, or why did this anomaly turn out as it did?”

Experts have criticized the many flaws of the HABITS trial:

• Baseline breast imaging was not required prior to entry: women did not know at start of trial if they were cancer free.
• Over 20% of women in the trial were not included in the analysis as they did not have at least one follow-up visit.
• The individual HRT regimen was determined by the treating provider at different institutions so there was no uniformity in hormones prescribed.
• Breast cancer staging and lymph node status was not provided when women were randomized for treatment and are important factors in determining risk of recurrence, therefore risk factors for both groups are unknown

Curiously and to add to the confusion, the Stockholm trial, being conducted around the same time, had a larger percentage of women taking tamoxifen with HRT and reported no increase in breast cancer events. There was no difference in mortality and this remained true at ten-year follow-up.

Misinterpretation of Data

A paradigm is demonstrated in review articles. Between 1994 and 2021, twenty review articles have been published on the topic with a striking theme in which some of the authors misinterpret their own data on the preconceived assumption HRT is harmful. One such review references a sharp increase in breast cancer in a referenced study but the actual author of the study concluded lower risks of both mortality and recurrence were demonstrated in women using HRT and no adverse impact was demonstrated with use of HRT after breast cancer.

As previously mentioned, the investigators of the HABITS trial later admitted the trial was prematurely stopped due to the flawed reports from the WHI. The author of a 2020 review concluded the Stockholm trial revealed an increased risk of recurrence despite the study concluding there was no difference in new breast cancer events. This paradigm continues in many of the reviews.

Definitive Answers At Large 

Definitive answers regarding HRT for breast cancer survivors cannot be deemed from the original 25 studies due to short duration of HRT and follow-up range though “Neither estrogen alone nor estrogen and progestogen provide a sufficient condition to cause breast cancer…”

Pregnancy after breast cancer, even among women with BRCA mutations and ER+ cancer did not affect prognosis. Breast cancer survivors in a clinical trial (SOFT) receiving tamoxifen alone or tamoxifen plus suppression of ovarian estrogen production did not experience a significant difference in cancer recurrence. If estrogen is the cause of cancer recurrence, blocking it should have led to a significant decrease in recurrence.

All evidence available leads to questioning the objection of giving ERT to breast cancer survivors.

“It is probable no study in the future will provide the definitive answer we would all find convincing. But the fact only 1 of the 25 studies found an increased risk of recurrence (local only)—without an increased risk of systemic recurrence or mortality—could help us formulate a current, albeit tentative, assessment of risk and provide guidelines for how best to manage this question at our present state of knowledge.”

Conclusion:  Empowering Patients to Make an Informed Decision concerning HRT

Approximately 2.3 million women are diagnosed with breast cancer globally per year with 330,840 among US women. The high cure rate of 90% results in approximately 300,000 breast cancer survivors per year, many of whom are afflicted by abrupt debilitating menopausal symptoms. It is regrettable many randomized trials assessing HRT in breast cancer survivors were prematurely halted as a result of the misleading WHI.

Just one of twenty-five HRT studies revealed an increased risk of local breast cancer recurrence, though the results are not straightforward and flawed. More clinical research is needed on the topic of HRT after breast cancer.

HRT or ERT in breast cancer survivors as well as healthy women should not be withheld from patients – instead, patients should be empowered with available information and weigh personal risk and benefit to make an informed decision.

In healthy women, clinical trials show bioidentical testosterone and estrogen pellet hormone replacement therapy decreases the risk of breast cancer by 56%.

Have an awesome day!   Dr D