Novel therapies based on cyclin-dependent kinase (CDK)4/6 and phosphatidylinositol 3-kinase (PI3K) / protein kinase B (AKT) / mammalian target of rapamycin (mTOR) inhibitors have significantly improved prognosis for patients, increasing progression-free survival rate, and, in some cases, overall survival.
Our results showed a PFS of 5.6 months in patients receiving the combination treatment of EVE and EXE, which is shorter than the PFS reported in the BOLERO-2 trial (7.8 months), primarily since the Oral Care-BC trial had many patients with visceral disease.
A meta-analysis of stomatitis in patients receiving EVE showed that stomatitis within 8 weeks was associated with longer PFS in several trials [16]. However, we demonstrated that mucositis within 2 and 8 weeks was not associated with longer PFS. The reason for the differences in results remains unknown, however, it could be due to differences in primary cancer sites or the interaction with combination therapies. The meta-analysis included patients with advanced carcinoid tumors, pancreatic neuroendocrine tumors, renal cell carcinomas, and tuberous sclerosis complex, but our trial included only breast cancer patients. Similarly, the meta-analysis included EXE, vinorelbine, trastuzumab, and long-acting repeatable octreotide as combination drugs for EVE, but our trial included only EXE. Furthermore, patients in our trial were obliged to receive severe prophylactic oral care, but those in the meta-analysis did not always receive oral care.
We observed that non-visceral metastasis was associated with a longer PFS than visceral metastasis. However, Jose et al. reported that the effects of EVE and EXE did not differ between visceral and non-visceral metastasis in the BOLERO-2 trial [3]. This could be attributed to the differences in clinical trial design.
It has been reported that women with a high BMI receiving aromatase inhibitors in an adjuvant setting experience more recurrences than women with a low BMI [17–23]. We also showed that low BMI patients were associated with longer PFS than those with a high BMI, although there were differences in EVE exposure and trial design (adjuvant vs. metastatic setting). Obesity is most strongly associated with postmenopausal hormone receptor‐positive breast cancer risk. Hormone replacement therapy (HRT) has been commonly used in Japan. A previous meta-analysis found that HRT recipients were at an increased risk of breast cancer, and since obesity is a side effect of HRT, it might influence our results.
Further, we discovered that non-bone-targeted therapy was a better prognostic factor of EVE and EXE. A recent meta-analysis reported that bone metastases (BMs) occur in 58% of patients with metastatic breast cancer [24]. BMs often cause severe bone pain and lead to bone fracture, known as skeletal-related events (SREs), including radiation or surgery to bone, fragile bone fracture, spinal cord compression, and hypercalcemia of bone metastasis [25]. SREs cause severe pain, impair mobility, reduce the quality of life (QoL), and increase mortality [26–29]. Patients receiving BMA had a poorer prognosis, including significant BM, prior to participating in our clinical trial.
The Safari study (UMIN000015168), a retrospective, multicenter cohort study, conducted in 1,072 patients in Japan taking fulvestrant (500 mg) for ER-positive metastatic breast cancer showed that early line fulvestrant (500 mg) (F500) administration was associated with significantly longer time to treatment failure (TTF) than late line use [30, 31], however, EVE and EXE did not show this trend in our trial. In other words, EVE and EXE may be a promising drug combination regardless of treatment line.
Although the results of this clinical study are important, there were several limitations. First, the primary endpoint of this trial was the comparison of incidence of grade 1 or worse oral mucositis over 8 weeks between the POC and C groups, and not PFS and OS. Secondly, a larger sample size could have provided more reliable results. However, the trial was well-powered for detecting a sufficiently strong association with PFS, e.g. a hazard ratio of >2.0, although in a post-hoc calculation, showed that BMI, use of BMA, and visceral involvement were important prognostic factors for progression and that the outcomes of the present trial are reliable. Lastly, a centralized data review of images and pathological examinations were not performed, as we felt that these were beyond the scope of this investigation. In future studies, a more extensive review of the literature could provide additional data to support our results.