Combo therapy with zoledronic acid improves DFS in premenopausal HR+ early BC
Adding the combination therapy of zoledronic acid + letrozole to triptorelin as adjuvant treatment for hormone receptor positive (HR+) early breast cancer in premenopausal women significantly improves disease-free survival (DFS) compared with the combination of tamoxifen and triptorelin, according to the HOBOE-2* study presented at ESMO 2018.
The clinical benefits of zoledronic acid + hormonal therapy have previously been demonstrated in postmenopausal women, but the effects in premenopausal women were less certain.
“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,” said lead author Prof Francesco Perrone, director of the Clinical Trials Unit at the Istituto Nazionale Tumori in Naples, Italy.
The multicentre phase III HOBOE-2 trial involved 1,065 premenopausal patients (median age 45 years; last period within 1 year) with oestrogen/progesterone receptor positive early breast cancer who had undergone surgery. They were randomized 1:1:1 to either tamoxifen 20 mg/day, letrozole 2.5 mg/day, or intravenous zoledronic acid 4mg every 6 months + letrozole 2.5 mg/day, all in addition to triptorelin 3.75 mg every 4 weeks for 5 years up to age 55. Sixty-three percent had received chemotherapy before randomization. [ESMO 2018, abstract LBA14_PR]
Over a median follow-up of 65 months, the zoledronic acid + letrozole arm had fewer DFS events than both the tamoxifen and letrozole arms (32, 58, and 44, respectively), with an absolute 5-year DFS advantage of 8 percent in the combination arm compared with the tamoxifen arm (DFS probability, 0.93 vs 0.85; p=0.008). DFS events include recurrence at locoregional or distant site, second breast or non-breast invasive cancer, and noncancer death.
The risk of DFS events was almost halved with zoledronic acid + letrozole vs tamoxifen (hazard ratio [HR] 0.52; p=0.003), and this benefit was seen across all subgroups tested except HER2-positive patients, who benefitted more with tamoxifen (interaction p=0.002).
No significant difference in DFS were observed when comparing zoledronic acid + letrozole vs letrozole alone (HR, 0.70; p=0.22) or letrozole vs tamoxifen (HR 0.72; p=0.06).
“If the size of the benefit we saw is confirmed with longer follow-up, zoledronic acid treatment might turn out to be a highly cost-effective treatment for premenopausal HR+ breast cancer,” Perrone continued, noting that both zoledronic acid and letrozole are very cheap drugs.
With regard to the possible mechanism driving the benefits seen, the researchers suggested that zoledronic acid may modify the bone microenvironment, making it lethal for micrometastases of breast cancer cells and thus reducing the likelihood of distant metastases.
“We had previously shown that, in combination with triptorelin, letrozole suppresses oestradiol levels much more than tamoxifen in premenopausal patients … [which] means cutting the fuel to endocrine-dependent breast cancer,” said Perrone. “The two mechanisms [of letrozole and zoledronic acid] are partially independent and, therefore, may sum up to give an additive benefit.”
Nonetheless, side effects were more common with zoledronic acid + letrozole, with grade 3–4 adverse events occurring in 9 percent of patients in the combination therapy group compared with 4 percent and 7 percent in the tamoxifen and letrozole groups, respectively. Four cases of jaw osteonecrosis were reported in the zoledronic acid + letrozole arm. Also, more patients in the combination therapy arm discontinued treatment before 5 years were up due to toxicity or refusal than those in receiving tamoxifen or letrozole (17 percent vs 7 percent and 7 percent).
“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 tumours,” said invited commentator Professor Robert Coleman from University of Sheffield, UK. “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.”