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ESMO 2018: HOBOE-2: Zoledronic Acid in Premenopausal Hormone Receptor–Positive Early Breast Cancer

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Key Points

  • There were 32 disease-free survival events in patients treated with ZL, giving a 5-year disease-free survival probability of 0.93.
  • The risk of breast cancer recurrence or noncancer death was nearly halved in patients treated with ZL compared to those treated with T.
  • The improvement in DFS with ZL compared to tamoxifen was seen in all subgroups of patients apart from the small subgroup of women with tumors overexpressing HER2 who showed greater benefit with tamoxifen.

Adjuvant treatment with zoledronic acid, plus hormonal therapy with the aromatase inhibitor letrozole, significantly increases disease-free survival compared to tamoxifen in premenopausal women with hormone receptor–positive early breast cancer, according to results reported by Perrone et al at the European Society for Medical Oncology (ESMO) 2018 Congress (Abstract LBA14_PR).

HOBOE-2 is the first study to assess this specific combination in premenopausal breast cancer and adds to previous observations with zoledronic acid and anastrozole in premenopausal women receiving ovarian suppression reported by Gnant et al in The New England Journal of Medicine.

Previous Findings

Studies have shown reduced recurrence and breast cancer mortality with zoledronic acid plus hormonal therapy in HR-positive breast cancer in postmenopausal women, but the benefit in premenopausal women was previously less clear.

Zoledronic acid is a bisphosphonate that reduces the rate of bone turnover; it is licensed to treat osteopororosis and to reduce bone damage in advanced cancers involving bone and hypercalcaemia in cancer. Unlike tamoxifen, which blocks estradiol binding to the estrogen receptor, letrozole is an aromatase inhibitor that suppresses estradiol levels, but it has not previously been evaluated in premenopausal breast cancer.

HOBOE-2

The phase III HOBOE-2 (Hormonal BOne Effects-2) trial included 1,065 patients with estrogen/progesterone receptor–positive early breast cancer who had their last period within 1 year of randomization. They were treated with the gonadotrophin-releasing hormone agonist triptorelin (3.75 mg every 4 weeks) for 5 years up to the age of 55 to suppress ovarian function, and nearly two-thirds (63%) received chemotherapy before randomization.

The patients were randomly assigned to hormonal therapy with tamoxifen (20 mg/d) or letrozole (2.5 mg/d) or to combination therapy with zoledronic acid (4 mg intravenously every 6 months) plus letrozole (2.5 mg/d) for a planned treatment duration of 5 years. The study was stopped early in May 2018 after a median follow-up of 65 months, when the independent monitoring committee recommended sharing the data with the Early Breast Cancer Trialists’ Cooperative Group (EBCTCG) 2018 overview.

Key Results

Results reported at ESMO showed there were 32 disease-free survival events in patients treated with zoledronic acid/letrozole, giving a 5-year disease-free survival probability of 0.93. There were 58 events in patients treated with tamoxifen and 44 events in the letrozole group, giving 5-year disease-free survival event rates of 0.85 and 0.93, respectively (P = .008).

The risk of breast cancer recurrence or noncancer death was nearly halved in patients treated with zoledronic acid/letrozole compared to those treated with tamoxifen (hazard ratio [HR] = 0.52, 95% confidence interval [CI] = 0.34–0.80, P = .003).

The improvement in disease-free survival with zoledronic acid/letrozole compared to tamoxifen was seen in all subgroups of patients apart from the small subgroup of women with tumors overexpressing HER2 who showed greater benefit with tamoxifen (interaction P =.002).

There was no statistically significant difference in disease-free survival comparing letrozole with tamoxifen (HR = 0.72, 95% CI = 0.48–1.07, P = .06) or comparing zoledronic acid/letrozole with letrozole alone (HR = 0.70, 95% CI = 0.44–1.12, P = .22).

Adverse Events

As expected, side effects were more frequent in patients treated with zoledronic acid/letrozole, with 9% of patients experiencing grade 3 or 4 toxicity compared to 4% of those treated with tamoxifen and 7% of those treated with letrozole alone. Nearly 1 in 5 (17%) patients treated with zoledronic acid/letrozole stopped treatment before 5 years due to toxicity or refusal, compared to 7% of those on tamoxifen and 7% of those on letrozole alone. There were four cases of jaw osteonecrosis in the zoledronic acid/letrozole arm.

“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 study author Francesco Perrone, MD, PhD, Director of the Clinical Trials Unit at the Istituto Nazionale Tumori, Naples, in a statement.

Considering zoledronic acid, Dr. Perrone explained, “Our hypothesis is that the drug modifies the bone microenvironment that is the niche where breast cancer micrometastases remain in a state of dormancy, potentially for many years. 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.”

Reviewing the potential impact on clinical practice, Dr. Perrone suggested: “If the size of the benefit we saw is confirmed with longer follow-up, [zoledronic acid/letrozole] treatment might turn out to be a highly cost-effective treatment for premenopausal [hormone receptor]–positive breast cancer.”

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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