Zometa Plus Femara Seems Better Than Tamoxifen for Premenopausal Women With Hormone-Receptor-Positive Breast Cancer, but Causes More Side Effects

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After surgery, women diagnosed with hormone-receptor-positive breast cancer usually take hormonal therapy medicine to reduce the risk of the cancer coming back (recurrence). Hormonal therapy medicines work in two ways:

  • by lowering the amount of estrogen in the body
  • by blocking the action of estrogen on breast cancer cells

A study suggests that the combination of the bisphosphonate Zometa (chemical name: zoledronic acid) and the aromatase inhibitor Femara (chemical name: letrozole) after surgery offers better disease-free survival than tamoxifen for premenopausal women diagnosed with early-stage, hormone-receptor-positive breast cancer. Still, adding Zometa to Femara caused more side effects.

The research was presented on Oct. 20, 2018, at the European Society for Medical Oncology 2018 Congress. Read the abstract of “The HOBOE-2 multicenter randomized phase 3 trial in premenopausal patients with hormone-receptor positive early breast cancer comparing triptorelin plus either tamoxifen or letrozole or letrozole + zoledronic acid.”

About Zometa and Femara

Zometa limits the activity of certain bone cells, called osteoclasts, which help cause the bone weakening and destruction that can happen when breast cancer spreads to the bone. Zometa is typically used to reduce bone complications and bone pain caused by advanced-stage breast cancer that has spread to the bone.

Earlier research has suggested Zometa also might help stop breast cancer from spreading to the bones by making it harder for breast cancer cells to grow in bones and might help reduce the risk of the cancer coming back (recurrence) in women diagnosed with early-stage breast cancer.

There are several types of hormonal therapy medicines. Tamoxifen, a selective estrogen receptor modulator (SERM), is one of the most well-known. Tamoxifen can be used to treat both premenopausal and postmenopausal women.

In the early 2000s, the aromatase inhibitors:

  • Femara
  • Arimidex (chemical name: anastrozole)
  • Aromasin (chemical name: exemestane)

were shown to be more effective at reducing recurrence risk in postmenopausal women, and they are now used more often than tamoxifen to treat women who’ve gone through menopause. Aromatase inhibitors aren’t commonly used to reduce recurrence risk in premenopausal women, but they are used in some cases if the women also take medicine to shut down ovarian function.

Most women take hormonal therapy for 5 to 10 years after breast cancer surgery.

The HOBOE-2 trial

This study, called the HOBOE-2 (Hormonal BOne Effects-2) trial, included 1,065 premenopausal women diagnosed with early-stage, hormone-receptor-positive breast cancer between March 2004 and August 2015. The women were randomly assigned to one of three treatment groups for 5 years after breast cancer surgery:

  • tamoxifen plus Trelstar (chemical name: triptorelin) to suppress ovarian function (354 women)
  • Femara plus Trelstar (356 women)
  • Zometa plus Femara plus Trelstar (355 women)

About 63% of the women also had been treated with chemotherapy.

Median follow-up time was 65 months. This means that half the women were followed for a longer time and half the women were followed for a shorter time.

During follow-up, the number of women in each group who had a breast cancer recurrence or a diagnosis of a new breast cancer was:

  • 32 in the Zometa-Femara-Trelstar group
  • 44 in the Femara-Trelstar group
  • 58 in the tamoxifen-Trelstar group

Disease-free survival rates were:

  • 93% in the Zometa-Femara-Trelstar group
  • 93% in the Femara-Trelstar group
  • 85% in the tamoxifen-Trelstar group

Disease-free survival is how long the women lived with no cancer recurrence. The difference in disease-free survival between the Zometa-Femara-Trelstar group and the tamoxifen-Trelstar group was statistically significant, which means that it was likely due to the difference in treatment and not just because of chance.

Zometa caused more side effects

Like almost all cancer medicines, Zometa, Femara, and tamoxifen can cause side effects, some of them severe.

Zometa and other bisphosphonates can increase the risk of atypical femur fractures when taken for 5 years or longer. The femur is the large leg bone that runs from your hip to your knee. An atypical fracture means that the bone is broken in an unusual spot. Still, atypical femur fractures are rare — only about 0.22% of women taking a bisphosphonate for more than 5 years will have an atypical femur fracture.

Bisphosphonates also can sometimes cause another rare but serious side effect, osteonecrosis of the jaw, a condition in which the cells in the jawbone start to die. Researchers think that osteonecrosis of the jaw may develop because bisphosphonates stop the body from repairing microscopic damage to the jawbone that can happen during routine dental procedures or from everyday wear and tear. But it's still not clear why this happens in some people and not in others.

Tamoxifen may cause hot flashes and increase the risk of blood clots and stroke. Aromatase inhibitors may cause muscle and joint aches and pains. Less common but more severe side effects of aromatase inhibitors are heart problems, osteoporosis, and broken bones.

In the HOBOE-2 study, 9% of women treated with Zometa, Femara, and Trelstar had moderate or severe side effects compared to 7% of women treated with Femara and Trelstar, and 4% of women treated with tamoxifen and Trelstar.

About 17% of women in the Zometa-Femara-Trelstar group stopped treatment before 5 years because of side effects, compared to 7% of women in the tamoxifen-Trelstar group and 7% of women in the Femara-Trelstar group.

Four women treated with Zometa developed osteonecrosis of the jaw.

Zometa plus Femara may be best for women at high risk of recurrence

"HOBOE-2 strongly supports the hypothesis that combination treatment with an aromatase inhibitor and bisphosphonate plus triptorelin may improve prognosis in premenopausal patients with [hormone-receptor]-positive breast cancer," said lead author Francesco Perrone, director of the Clinical Trials Unit at the Istituto Nazionale Tumori in Naples, Italy, in a statement. "We had previously shown that, in combination with triptorelin, letrozole suppresses estradiol levels much more than tamoxifen in premenopausal patients. And we know that suppressing estradiol levels means cutting the fuel to endocrine-dependent breast cancer.

"Our hypothesis is that the drug modifies the bone microenvironment that is the niche where breast cancer micro metastases remain in a state of dormancy, potentially for many years,” he continued. “Microenvironment modifications may be lethal for isolated cancer cells, reducing the risk of distant metastases over time. The two mechanisms are partially independent and, therefore, may sum up to give an additive benefit."

Robert Coleman, emeritus professor of medical oncology at the University of Sheffield, UK, said the combination of Zometa, Femara, and Trelstar may be best for premenopausal women diagnosed with hormone-receptor-positive disease with a high risk of recurrence.

“The findings add to existing information to support the use of more intensive treatment with an aromatase inhibitor and bisphosphonate in women at high risk for recurrence, either by virtue of node involvement or high-grade or large tumors,” he said. “Both treatments add toxicity over and above tamoxifen and so are best limited to women at intermediate to high risk where the risk-benefits are likely to be acceptable. This study is not definitive but adds to the information on these two treatment approaches.”

While the results of this study are encouraging, more research is needed before Zometa is routinely used with Femara to reduce the risk of recurrence of early-stage, hormone-receptor-positive breast cancer in premenopausal women.

Stay tuned to Breastcancer.org Research News for the latest information on hormonal therapy, targeted therapy, and other breast cancer treatments.


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