This Combo Improves Outcomes Over Tamoxifen in Early Breast Cancer

Combining zoledronic acid and letrozole offers improved disease-free survival compared with tamoxifen in premenopausal patients with hormone receptor (HR)-positive early breast cancer, according to a randomized trial.

Previous work has shown that letrozole, in combination with triptorelin, suppresses estradiol levels more than tamoxifen does in premenopausal patients; suppressing those levels essentially means the fuel source for endocrine-dependent breast cancer is cut off. “Our hypothesis is that [zoledronic acid] modifies the bone microenvironment that is the niche where breast cancer micrometastases remain in a state of dormancy, potentially for many years,” said Francesco Perrone, MD, of the Istituto Nazionale Tumori in Naples, Italy, according to a press release.

“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.”

The HOBOE-2 trial was a multicenter study including 1,065 patients, randomized 1:1:1 to receive triptorelin along with either tamoxifen (354 patients), letrozole (356 patients), or zoledronic acid plus letrozole (ZL; 355 patients), for 5 years. The median age in the trial was 45 years, and 63% had received chemotherapy before entering the study; patients were followed for a median of 65 months. Perrone presented the results at the European Society for Medical Oncology (ESMO) 2018 Congress, held in Munich.

In the ZL group, there were 32 breast cancer recurrences or second breast or non-breast cancers or deaths, for a 5-year disease-free survival (DFS) probability of 0.93. In the tamoxifen group, there were 58 such events, for a 5-year DFS probability of 0.85, and in the letrozole group there were 44 events for a probability of 0.93 (P = .008).

When compared with tamoxifen, ZL resulted in a risk of breast cancer recurrence or non-cancer death that was nearly halved, with a hazard ratio of 0.52 (95% CI, 0.34–0.80; P = .003). This improvement was seen across all patient subgroups, except for a small subgroup of women with tumors that overexpressed HER2; this group showed better results with tamoxifen. There was no significant difference when comparing letrozole and tamoxifen, or comparing the ZL combination with letrozole alone.

In the ZL group, 9% of patients experienced a grade 3/4 adverse event, compared with 4% in the tamoxifen group and 7% in the letrozole group. Seventeen percent of the ZL group stopped the therapy before 5 years because of toxicity or refusal; this rate was 7% in both of the other groups. There were four cases of jaw osteonecrosis in the ZL group.

“HOBOE-2 strongly supports the hypothesis that combination treatment with an aromatase inhibitor and bisphosphonate plus triptorelin may improve prognosis in premenopausal patients with HR-positive breast cancer,” Perrone said, adding that the combination therapy could be a cost-effective option given the low price of both drugs.

Robert Coleman, MBBS, MD, of the University of Sheffield in the United Kingdom, commented on the study for ESMO, and he noted that the increased toxicity suggests that the therapy should be limited to women at intermediate to high risk where that toxicity may be more acceptable. He also pointed out that the study was underpowered. “This study is not definitive but adds to the information on these two treatment approaches,” he said.