Abstract
Background: Capecitabine is a widely accepted option in pre-treated metastatic breast cancer (MBC) patients. However, little is known about specific activity in molecularly defined subgroups of patients. Here, response, survival and prognostic factors were examined in a prospectively characterized cohort of human epidermal growth factor receptor 2 (HER2) negative MBC patients receiving capecitabine following anthracycline and taxane failure. Patients and Methods: Medical records from 75 HER2-negative MBC pre-treated with anthracycline and/or taxane and receiving capecitabine monotherapy at the Institut Paoli-Calmettes between 2002 and 2009 were reviewed. Univariate and multivariate analysis according the Cox regression model were employed to identify factors predictive for response, progression-free survival (PFS) and overall survival (OS). Results: Overall, the objective response rate (ORR) was 29.3% (95% CI: 20-40). The ORR in HER2-negative/hormonal receptor (HRe) positive and HER2-negative/HRe-negative patients were 37% (95% CI: 26-50) and 0% (95% CI: 0-19), respectively, (p=0.003, Fisher's test). With a median follow-up of 35.2 months after capecitabine initiation, median PFS was 6.6 months (95% CI: 4.7-10.4) and median OS was 18.4 months (95% CI:14.1-24.9). In univariate analysis, HRe-negative status was the strongest prognostic factor for PFS (hazard ratio (HR)=2.09; p-value=0.015, log-rank test). In multivariate analysis, only three variables (HRe-negative status, initial disease-free interval <24 months and extra-regional lymph node involvement) were considered independently associated with poor PFS, while five variables (grade 2/3, initial disease-free interval <24 months, central nervous system metastases, interval between diagnosis of metastases and capecitabine initiation <24 months, and number of metastatic sites on capecitabine initiation) were associated with poor OS. Conclusion: The median OS of pretreated patients with HER2-negative MBC receiving capecitabine is approximately 18 months, but HER2-negative/HRe-negative patients have a low probablility of response/disease control to capecitabine and require innovative therapies.
Breast cancer (BC) is among the most common malignancies in Western countries and is the leading cause of death in women aged between 40 and 54 years (1). Around 5% of patients with newly diagnosed disease have synchronous metastases, while 20 to 40% of patients with localized disease will eventually progress to metastatic breast cancer (MBC), all being presumed to ultimately die from their disease. MBC is heterogeneous disease, the management of which is based on sequential or concomitant combinations of cytotoxics, endocrine manipulations and targeted molecular therapies (such as anti-HER2 agents trastuzumab and lapatinib, and anti-VEGF mAb bevacizumab), the choice between these strategies being selected according to molecular parameters (including estrogen receptor (ER) and HER2 status), the patient's characteristics and preferences, and previously administered therapies (2-4). Anthracyclines and taxanes are the most active cytotoxic agents, but treatment failure occurs in a substantial number of patients and median survival for MBC remains 2 to 3 years (5, 6). In addition, anthracyclines and taxanes are increasingly incorporated in the adjuvant treatments of early breast cancer. Hence, the optimal therapy for patients with anthracycline and taxane-refractory MBC presents an ever-growing challenge to the oncologist.
Capecitabine, a tumor-activated fluoropyrimidine, is commonly used as single-agent in MBC patients after anthracyclines and taxane exposure. Capecitabine was approved in this setting following numerous phase II clinical trials showing significant activity and a good tolerance profile in this population (7-12). Capecitabine in association with docetaxel in anthracyline-pretreated MBC patients was also shown to increase overall survival (OS) compared to docetaxel alone, leading to registration of this combination (13). Most recently, capecitabine has been combined with the novel microtubule-binding agent ixabepilone in taxane-resistant MBC and was shown to significantly increase progression-free survival (PFS) compared to capecitabine alone (14), the combination gaining U.S. Food and Drug Administration (FDA) approval. However, no improvement in OS was noted and a debatable benefit/toxicity ratio resulted in the same association not being registered by European Medicines Agency (EMEA).
Although a large body of data is available on capecitabine activity in MBC, most of these results come from general and molecularly unselected populations. However, the clinical outcome, as well as current management, of MBC is not uniform, but rather based on molecular typing, including at least ER/progesterone receptor (PgR) and HER2 status. Specifically, all HER2-positive MBC patients are now supposed to receive first-line trastuzumab-based therapies (15, 16), which have probably significantly impacted the natural outcome in this subset (17). In addition, even taxane/anthracycline-resistant patients now benefit from second or further lines of anti-HER2-based treatments (18-20). Consequently, response and efficacy data for various cytotoxics that had already been reported in the pre-trastuzumab era, including capecitabine, are likely to be derived from patients with mixed HER2-status and may not reflect the reality of modern management of MBC.
Here, a retrospective study to assess the outcome of MBC patients with prospectively determined HER2-negative status receiving capecitabine as single-agent after anthracycline and taxane exposure and to identify factors predictive for response and survival is reported.
Patients and Methods
Patient selection. Between 1997 and 2009, 363 histologically proven MBC patients treated at the Institut Paoli-Calmettes were prospectively tested for HER2 expression, mainly from 2002 onwards. The HER2-negativity was determined at diagnosis in the primary tumor and defined as immunohistochemistry (IHC; HercepTest™, Dako, Glostrup, Denmark) 0 or 1+ or as IHC 2+ and fluorescence in situ hybridization (FISH) negativity. A total of 237 patients (65% of the tested cases) had HER2-negative MBC. Among them, 162 patients were pre-treated with anthracyclines and taxanes-based chemotherapy in adjuvant or first-line chemotherapy, including 75 cases treated with capecitabine as a single agent in the routine setting. None of them had received bevacizumab. This study was approved by the Review Board of the Institut Paoli-Calmettes.
Assessment. Metastatic lesions were detected by routine follow-up including clinical examination, serum CA15-3 level, and standard imaging methods (chest radiographs, abdominal ultrasound, thoracic and abdominal computed tomography scan, bone scan), which were performed every 12 weeks (except bone scan) until progression. The best overall tumor response achieved was reported for each patient according to WHO criteria (21). A complete response (CR) required a complete disappearance of all lesions, and a partial response (PR) required at least 50% decrease of the sum of the longest diameters of the target lesions. Stable disease (SD) was defined as neither sufficient shrinkage to qualify for PR, nor sufficient increase to qualify for progressive disease (PD). PD was defined as at least a 25% increase in the sum of the longest diameters of the target lesions and/or the appearance of new lesions. Clinical benefit was defined as an objective response or SD for at least 6 months.
Data collected at baseline were number of metastatic chemotherapy lines, response at last chemotherapy regimen, number and nature of metastatic sites before capecitabine initiation, tumor response with capecitabine, date of tumor progression or death, date of the last follow-up from capecitabine initiation and patient's status. All these characteristics were collected by local doctors. The breast cancer Institutional Review Board approved and validated all the information entered in the database.
Statistical methods. Data analysis was descriptive and performed using R software, version 2.7.1. (http://CRAN.R-project.org) and SAS software, version 9.1 (SAS Institute Inc., Cary, NC, USA). The quantitative data were described by the median value and ranges and categorical data by the numbers in each category and corresponding percentages.
Survival estimations were calculated using the Kaplan–Meier method. OS and PFS were defined by the time between the start of capecitabine treatment and death (OS) or disease progression, treatment discontinuation before progression or death, whichever occurred first (PFS). The data were censored at the last follow-up in the absence of event. Univariate correlations with baseline parameters were calculated for PFS and OS using the log-rank test for categorical variables or Wald's test for continuous variables. All variables with a p-value <0.15 in the univariate analysis were entered in a Cox proportional hazard model, using a stepwise backward procedure. Only variables with a p-value <0.05 in this multivariate analysis were considered as independent prognostic factors.
Results
Patient characteristics. The characteristics of the 75 HER2-negative MBC patients, pre-treated with anthracyclines and taxanes and subsequently treated with capecitabine as a single agent are summarized in Table I. All the patients were women. The histological type of the primary disease was predominantly ductal carcinoma (75%) with high-grade histology II (33%) or III (48%). The hormonal receptor (HRe) status was positive in 79% of the patients and negative in 21%.
Characteristics of the 75 patients.
The median disease-free-interval between diagnosis of primary BC and that of metastatic disease was 25 months, and 71% of the patients had received initial adjuvant chemotherapy. The median number of chemotherapy lines administered for metastatic disease was 1. Examining the best response status achieved with the last regimen administered before capecitabine, an objective response was observed in 47% of cases, whereas PD was observed in 28 patients (37%).
Response to capecitabine.
The median age before starting capecitabine was 53 years. The median time between metastasis diagnosis and capecitabine initiation was 16 months. On capecitabine initiation, 64% of the patients had visceral metastases and a median number of two metastatic sites (range 1-6), the most frequent localizations were bone (59%) and liver (47%).
Treatment response. The overall tumor response over the entire treatment period is presented in Table II. Twenty-two patients had an objective response (29.3% [95% CI: 20.2-40.4]), including 3 CR and 19 PR. The median duration of response was 9 months (range 4-20). In addition, 21 patients (28%) had SD for a median duration of 9.5 months (range 4-47). Forty-one patients (54.6% [95% CI: 43-65]) obtained a clinical benefit (objective response, or SD for at least 6 months). Thirty-one patients (42%) experienced PD within the first 6 weeks of capecitabine therapy.
The features investigated in association with the tumor response to capecitabine are shown in Table III. No objective response was observed in the 15 HRe-negative (i.e. triple-negative patients, 95% CI: 0-19) compared to 22 out of 59 HRe-positive patients (95% CI: 26-50), p=0.003, Fischer's test). No significant association was found between objective response and histology, initial grade, time between diagnosis of primary BC and metastasis diagnosis, time between metastasis diagnosis and capecitabine initiation, reponse to the last regimen before capecitabine initiation, visceral metastasis on capecitabine initiation, or the number of previous cytotoxic lines.
Survival. With a median follow-up of 35.2 months after capecitabine initiation, the median PFS was 6.6 months (95% CI: 4.7-10.4; Figure 1A) and the median OS was 18.4 months (95% CI: 14.1-24.9; Figure 1B). In univariate analysis, the HRe status was one of the strongest prognostic factors for PFS (HR=2.09, 95% CI: 1.13-3.87; Table IV). The median PFS in the HRe-positive patients was 8.1 months (95% CI: 5.3-12.3), significantly higher than that observed in the HRe-negative patients (3.6 months, 95% CI: 2.8-5.2; p=0.015, log-rank test; Figure 2). Other parameters significantly associated with shorter PFS included grade II and III, time between diagnosis of primary BC and metastasis diagnosis <24 months, and the presence of non-regional lymph node metastasis. All these parameters, except grade, remained associated with PFS in multivariate analysis (Table IV).
A: Progression free survival (PFS), events: 60; censored: 15, 1-year PFS: 31.8% (95% CI: 22.3-45.4), 2-year PFS: 17.3% (95% CI: 9.9-30.4). B: Overall survival (OS), events: 51; censored: 24, 1-year survival: 66% (95% CI: 56-77.8), 2-year survival: 38.1% (95% CI: 28-51.8).
Progression-free survival in HER2-negative/HRe-positive and HER2-negative/HRe-negative MBC patients.
Response to capecitabine according to patient characteristics.
The following factors were significantly associated with shorter OS in univariate analysis: time between diagnosis of primary BC and metastasis diagnosis <24 months, time between metastasis diagnosis and capecitabine initiation <24 months, central nervous system (CNS) metastasis, non-regional lymph node metastasis and the number of metastatic sites on capecitabine initiation (Table V). Of note, a non-significant trend was observed for HRe-negativity (p=0.058). Building a multivariate model including all these parameters, as well as grade (which tended to be associated with OS in univariate analysis, p=0.14), revealed that grade, time between diagnosis of primary BC and metastasis relapse <24 months, time between metastasis diagnosis and capecitabine initiation <24 months, CNS metastasis and number of metastatic sites on capecitabine initiation were significantly and independently associated with shorter OS (Table V).
Factors predictive of progression-free survival: univariate and multivariate analyses.
Discussion
Capecitabine has been extensively evaluated as a single agent in pre-treated MBC with an overall response rate of around 20% of patients and additionally SD in approximately 40% of patients, a median time to progression (TTP) around three months and a median OS of approximately 12 months (7-12). Although consistent with these data, the results reported in the present study were better, in terms of response rate (29%), PFS (6.6 months) and OS (18 months). Even though such differences may have been due to the retrospective and uncontrolled nature of the study, an alternative explanation may be that the previous capecitabine monotherapy studies included MBC patients regardless of HER2 tumor status. Since HER2-positive MBC patients are now clearly known to display a poor outcome when treated without HER2-directed therapy (15-19), the prospective selection performed in the present study of HER2-negative MBC patients may have contributed to the better outcome reported.
Factors predictive of overall survival: univariate and multivariate analyses
Within the context of the HER2 heterogeneity, Pierga et al. (22) identified performance status (which was not examined in the present study due to the number of missing data) as the only factor independently associated with TTP. In a more recent study, Osako et al. found, as in the present study, that short initial disease-free interval and HRe-negativity were independently associated with time to treatment failure (23). In both these studies, as the present study, classical indicators of disease aggressiveness such as high grade, number of metastatic sites, time between metastasis diagnosis and capecitabine initiation, and also visceral or liver involvement impacted OS. Interestingly, in the current study, neither liver nor visceral metastasis correlated clearly with survival, suggesting that this classical poor-prognosis feature may not have a major impact in HER2-negative MBC patients in the present treatment setting.
One of the most striking findings of the present study was the drastic negative impact of HRe-negative status on the probability of tumor response or disease control after capecitabine. No HRe-negative patient displayed an objective response, and the median PFS in this subset of patients was estimated at 3.6 months, with a median OS of 10.8 months. This appeared surprising, since a large number of previous preclinical and clinical studies had identified ER positivity as a powerful marker of chemoresistance to 5-FU and other anticancer drugs (24-27). However, recent exploratory data from comparative clinical trials have suggested that the benefits of capecitabine may be minor in or absent from ER-negative patients. Thus, a retrospective analysis of a randomized trial of docetaxel-capecitabine versus docetaxel alone found that the combination was superior only in patients with ER-positive tumors (28). Similarly, in a randomized study evaluating capecitabine versus conventional adjuvant chemotherapy (CMF or AC) in elderly women with early breast cancer, capecitabine was associated with a higher risk of relapse in patients with ER-negative tumors, but not in patients with ER-positive tumors (29).
One important point to note was that HRe-negativity in the present cohort of HER2-negative MBC patients was synonymous with a TPN phenotype. In this subset of patients, clinical outcome at metastatic stage has now clearly been demonstrated to be largely unfavourable with conventional cytotoxic approaches (30). TPN phenotype was the strongest independent predictor of poor PFS and OS in our recently examination of docetaxel-based therapy (31). Similarly, PFS was only 4.6 months in patients with TPN tumors in the E2100 paclitaxel trial (paclitaxel-alone control arm) (32). Altogether, these data and the results of the present study suggest that conventional cytotoxics, including taxanes and capecitabine, do not drastically alter the poor natural history of TPN MBC patients. Since these patients are also most commonly pre-treated with anthracyclines in the adjuvant setting, alternative therapies are urgently needed. These may include anti-angiogenic strategies, other cytotoxics such as the novel microtubule-binding agent.ixabepilone or platinium compounds, and most promisingly, the addition of PARP-1 inhibitor to chemotherapy combination (33, 34).
In conclusion, capecitabine provides an acceptable palliative approach in HER2-negative MBC patients treated after anthracycline and taxane exposure but essentially restricted to those with HRe-positive tumors, since little or no benefit is observed in patients with HRe-negative tumors (i.e. TPN tumors), which urgently require alternative strategies.
Acknowledgements
We are grateful to Dominique Maraninchi, MD, for helpful discussions.
This study was supported by Inserm, Institut Paoli-Calmettes, and grants from Institut National du Cancer (Cancéropôle PACA) and the French Ministry of Health (PHRC 2004).
Footnotes
-
↵* This work was presented at the poster session of American Society of Clinical Oncology 2010, Chicago, IL, USA. Abstract 1105.
- Received December 2, 2010.
- Revision received February 2, 2011.
- Accepted February 4, 2011.
- Copyright© 2011 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
