Hormonal therapy might be a better choice as maintenance treatment than capecitabine after response to first-line capecitabine-based combination chemotherapy for patients with hormone receptor-positive and HER2-negative, metastatic breast cancer

The primary goals of metastatic breast cancer (MBC) treatment are to palliate symptoms, preserve quality of life, delay tumor progression, and extend overall survival (OS), not to cure the disease. For hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative patients with MBC, chemotherapy is needed as first-line treatment when hormonal therapy (HT) has been exhausted or symptomatic visceral metastasis is observed. When the disease is controlled by chemotherapy, several sequential strategies can be pursued: discontinuing chemotherapy and observing until progression; continuing the same therapy; maintaining with a single, mild agent that was used in the initial therapy; or switching to other drugs that are presumed to be effective. Several trials showed that maintenance combination chemotherapy extended the duration of remission [1–7], but modest OS benefits were seen in only two trials [3, 4], and the optimal duration of treatments was not determined. In addition, in most studies, incidence of toxicity was significantly increased. In a Korean phase III trial (KCSG-BRO7-02), patients in the paclitaxel/gemcitabine maintenance arm had much longer median progression-free survival (PFS) and OS than patients in the observation arm (PFS: 7.5 vs. 3.8 months, P = 0.026; OS: 32.3 vs. 23.5 months, P = 0.047) [4]. The results, however, were debatable because any treatment regarding to HR status was not allowed in the control group after completing six cycles of induced chemotherapy. At the same time, the rate of grade 3 or higher neutropenia for patients in the maintenance arm was as high as 61%, which inevitably resulted in more hospital visits [4]. In fact, many clinicians prefer to discontinue chemotherapy after 6–8 cycles when the disease enters non-progression status. However, it seems inappropriate to just wait for tumor progression. Switching to a more tolerable chemotherapy, such as monotherapy or antiangiogenic agents, might be a better treatment strategy.

Studies have suggested that maintenance monotherapy could be a low-toxicity intervention that significantly extends time to progression (TTP) and has potential OS benefits [8–11]. Since, for many years, anthracyclines or taxanes have been a mainstay of adjuvant therapy for breast cancer, the National Comprehensive Cancer Network has recommended capecitabine-based chemotherapies, such as capecitabine plus taxanes and capecitabine plus vinorelbine, as first-line chemotherapy for MBC patients after failure of taxanes and anthracycline-containing regimens and for patients who cannot receive further anthracycline therapy. In prospective, randomized phase II/III clinical trials, capecitabine monotherapy has shown substantial antitumor activity in the first-line treatment of patients with MBC. According to reports in the literature, patients who received first-line capecitabine monotherapy had a median TTP of 6.0–7.9 months [12]. Long-term administration of capecitabine is convenient and relatively economical and does not result in cumulative toxicity. It still works well in combination with target therapy [12–17]. Therefore, capecitabine is assumed to be a good option for maintenance monotherapy after first-line capecitabine-based combination chemotherapy (FCCT).

For patients with HR-positive and HER2-negative MBC, HT is also an attractive alternative, at least in patients with potentially endocrine-responsive diseases that have entered non-progression status after first-line chemotherapy. In several reported studies of HT with powerful endocrine agents [aromatase inhibitors (AIs) or tamoxifen], the median TTP of patients was 14.4–18.5 months after previous chemotherapy (first- or second-line) [18, 19]. There seemed to be a TTP disparity between the maintenance capecitabine monotherapy (MCT) and HT groups, but we must be cautious that the patient populations of the various studies might be completely different. Previous studies of HT enrolled patients with HR-positive MBC exclusively, whereas studies of MCT involved the whole population regardless of hormone status. Unquestionably, HR-positive patients have a better prognosis than HR-negative patients. Moreover, for patients who are recommended first-line chemotherapy, disease progression is more aggressive than for those who adopt first-line HT. This indicates that the population who are suggested FCCT may be more likely to benefit from chemotherapy. Until now, because no head-to-head comparisons or retrospective studies have been performed between maintenance chemotherapy and HT after disease control, no systematic assessment data exist on the efficacy of maintenance therapy. Therefore, in the present study, we examined HR-positive/HER2-negative patients with MBC after response to FCCT, divided them into HT and MCT treatment groups, compared the efficacy of distinct treatments, and sought to determine which treatment was superior.

In this study, we examined HR-positive and HER2-negative MBC patients after response to FCCT and found that the HT group had a much longer TTP than the MCT group. The efficacy was prominent regardless of age, interval of DFS, menopausal status, KPS score, number of metastases, visceral metastases, and response to first-line chemotherapy. We observed the same trend in OS, too. Moreover, HT also demonstrated a better safety profile. Therefore, we found that HT was a better treatment option for a subgroup of patients in this setting.

Unquestionably, HT plays an important role in the treatment of HR-positive breast cancer. Because HT has been shown to be remarkably efficacious in the adjuvant, neoadjuvant, and first-line palliative treatment of breast cancer, it is widely used in routine clinical practice during breaks in palliative chemotherapy for women with recurrent or metastatic disease characterized by HR-positive tumors [20, 21]. When HT is administered long term, therapeutic gains are expected due to its efficacy and good safety profile. However, we must be cautious in administering it to all HR-positive patients. Evidence-based data are lacking regarding its maintenance after disease control by previous chemotherapy. To date, only two small prospective trials have investigated the efficacy of maintenance HT after previous palliative chemotherapy. In one study, 90 patients with disease control after 6 cycles of anthracycline- and ifosfamide-containing regimens were randomized to receive maintenance medroxyprogesterone acetate (MPA) therapy or placebo. A longer median TTP was seen in the MPA arm compared with that in the placebo arm (4.9 vs. 3.7 months, P = 0.02) [22]. However, this study was conducted in 1990s, and currently MPA is rarely used as first-line endocrine therapy. In a letrozole-based single-arm phase II study, the median TTP from the initiation of letrozole after induced chemotherapy was as long as 18.5 months [18].

As with other orally administered drugs, capecitabine has been extensively evaluated in both pretreatment and first-line treatment for breast cancer patients. Adverse events are readily managed by dose modification. When using capecitabine as first-line treatment for MBC, the objective response rate was as high as 30%–36% for anthracycline- and/or taxane-resistant MBC [13–16]. Si et al. [23] reported that patients who received MCT after FCCT had a median TTP as long as 9.4 months, which is superior to the 4.5 months reported in the observation arm. Clinicians may prefer MCT in practice, expecting sustainability of its good response to FCCT regardless of HR status.

In our study, the survival results of each group were similar to those previously reported, which justified the option of HT for patients with HR-positive and HER2-negative MBC after response to FCCT. To our knowledge, ours is the first study to directly compare the efficacy of MCT with that of HT in this subgroup of patients. Our study did, however, have some limitations, mainly that it had a small sample size and was retrospective in nature, so it is not possible to conclusively say that HT contributed to extended TTP. Since most tumors develop resistance to endocrine therapies after two or three endocrine regimens, the effectiveness of these agents in later-line settings is limited. As reported in the literature, in most studies the median TTP of patients who underwent endocrine therapy as second-line or further treatment was 3–6 months [10], similar to that of whom underwent MCT in later lines [24]. Interestingly, in our study we observed a patient who maintained MCT for 41 months without progression after PR to FCCT. Therefore, we speculate that MCT may also be an appropriate option for a small subgroup of patients with HR-positive breast cancer and may be more effective in later settings. However, this warrants additional phase III clinical trials.

Currently, investigators trying to overcome endocrine resistance are studying many targeted agents, some of which have been found to be effective in the treatment of HR-positive MBC, including everolimus, cyclin-dependent kinase 4/6 inhibitors, and histone deacetylase inhibitors [25]. In a relatively short period of time, options for maintenance HT after previous chemotherapy will be more varied and powerful.

We conclude that maintenance HT may be considered prior to administration of capecitabine after response to FCCT for patients with HR-positive and HER2-negative MBC.