- Email: [email protected]
Characterization of Durable Responder for Capecitabine Monotherapy in Patients With Anthracycline- and Taxane-Pretreated Metastatic Breast Cancer
Original Study
Characterization of Durable Responder for Capecitabine Monotherapy in Patients With Anthracycline- and Taxane-Pretreated Metastatic Breast Cancer Jung Yong Hong,1,2 Yeon Hee Park,1 Moon Ki Choi,1,3 Hyun Ae Jung,1 Su Jin Lee,1 Jin Seok Ahn,1 Young-Hyuck Im1 Abstract The purpose of the study was to elucidate the clinical characteristics of durable responders to capecitabine monotherapy and to validate clinical factors that influence the efficacy of capecitabine monotherapy in anthracycline- and taxane-pretreated metastatic breast cancer (MBC) patients. In this analysis of 236 patients with MBC, durable responders to capecitabine monotherapy were the group who had estrogen receptor positivity, and absence of lymph node and single-organ metastasis. Background: The purpose of this study was to evaluate predictive factors and the clinical characteristics of durable responders to capecitabine monotherapy in heavily-treated patients with metastatic breast cancer (MBC). Patients and Methods: Between December 2000 and May 2012, a total of 236 evaluable patients with MBC who had been treated with second- or greater-line palliative capecitabine monotherapy after a previous treatment regimen with anthracycline and taxane were included. Capecitabine (1250 mg/m2 twice daily) was administered for 2 weeks followed by a 1-week rest period. Results: The response rate was 23.3% and median progression-free survival (PFS) was 4.7 months (95% confidence interval, 4.0-5.5). Among 236 patients, 33 patients (14.0%) showed durable response (>12 months) to capecitabine monotherapy. Patients with durable response showed significantly greater incidence of estrogen receptor (ER) positivity (81.8% vs. 59.1%; P ¼ .012), single-organ metastasis (51.5% vs. 32.0%; P ¼ .047), and absence of lymph node metastasis (75.8% vs. 54.2%; P ¼ .023), compared with patients without durable response. In multivariate analysis, ER positivity and single-organ metastasis retained a significant association with better PFS to capecitabine monotherapy (hazard ratio [HR], 0.51; P < .001 and HR, 0.62; P ¼ .004). Conclusion: Our data suggest that ER positivity and single-organ metastasis can be useful predictive markers for better PFS to second- or greater-line palliative capecitabine monotherapy in anthracycline- and taxane-pretreated MBC patients. Clinical Breast Cancer, Vol. 15, No. 5, e287-92 ª 2015 Elsevier Inc. All rights reserved. Keywords: Anthracycline- and taxane-pretreated, Capecitabine monotherapy, Durable responders, Durable response, ER
Introduction Capecitabine is an orally-administered fluoropyrimidine derivative that has shown high efficacy and low toxicity in metastatic breast cancer (MBC) and colorectal cancer patients. The US Food and Drug Administration has approved capecitabine to be used as Jung Yong Hong and Yeon Hee Park contributed equally to this work as first authors.
monotherapy or combination therapy with docetaxel, lapatinib, or ixabepilone in heavily treated MBC patients.1-4 In terms of quality of life, cancer patients prefer oral chemotherapy over intravenous chemotherapy, and capecitabine monotherapy can be administered orally with high efficacy and favorable toxicity profiles in the Submitted: Dec 25, 2014; Revised: Mar 31, 2015; Accepted: Apr 16, 2015; Epub: Apr 23, 2015
1
Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 2 Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Korea 3 Divisions of Hematology and Medical Oncology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Gyeonggi-do, Korea
1526-8209/$ - see frontmatter ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clbc.2015.04.004
Address for correspondence: Young-Hyuck Im, MD, PhD, Division of HematologyOncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 135-710, Korea Fax: þ82-2-3410-1756; e-mail contact: [email protected]
Clinical Breast Cancer October 2015
- e287
Clinical Characteristics of Durable Responders to Capecitabine Monotherapy in MBC outpatient clinic for anthracycline- and taxane-pretreated MBC patients.1,5-8 Few studies have evaluated predictive markers of capecitabine monotherapy in MBC patients. In one Japanese series Osako et al reported that capecitabine monotherapy is effective for patients with no liver metastasis, good performance status, longer disease-free interval, or hormone-receptor positivity.9 However, these results were derived from a small sample size and require further validation. Moreover, the clinical characteristics of durable responders to capecitabine monotherapy remain unclear. In this study, we sought to elucidate the clinical characteristics of durable responders to capecitabine monotherapy and aimed to validate clinical factors that influence the efficacy of capecitabine monotherapy in anthracycline- and taxane-pretreated MBC patients.
Patients and Methods Patients We retrospectively analyzed patients with MBC who were treated with second- or greater-line palliative capecitabine monotherapy after previous treatment with anthracycline- and taxanecontaining regimens at Samsung Medical Center between December 2000 and May 2012. Previous treatment with anthracycline- and taxane-containing regimens included the adjuvant/ neoadjuvant and palliative settings. We excluded patients who received first-line palliative capecitabine monotherapy before using anthracycline- or taxane-containing regimens. This study was approved by the institutional review board of Samsung Medical Center, and the confidentiality of all patients was protected.
Table 1 Characteristics of Patients According to the Duration of Response to Capecitabine
Median Age (Range), Years
Total (n [ 236)
Non-DR Group (n [ 203)
50 (30-76)
50 (30-76)
Age >40, n (%)
200 (84.7)
173 (85.2)
Median Duration of Response, (Range), Months
3.4 (0.0-42.0)
2.4 (0.0-11.6)
DR Group (n [ 33)
P
48 (36-74)
.458
27 (81.8)
.605
17.7 (12.4-42.0)
0-1
227 (96.2)
195 (96.1)
32 (97.0)
2
9 (3.8)
8 (3.9)
1 (3.0)
Subtype, n (%) HR
<.001 >.999
ECOG Performance Status
.054
þ
152 (64.4)
125 (61.6)
27 (81.8)
HER2þ
16 (6.8)
16 (7.9)
0 (0.0)
TN
68 (28.8)
62 (30.5)
6 (18.2)
147 (62.3)
120 (59.1)
27 (81.8)
.012
142 (60.2)
122 (60.1)
20 (60.6)
>.999
86 (36.4)
80 (39.4)
6 (18.2)
.019 >.999
ER Positivity, n (%) a
Perioperative CTx, n (%)
Anthracycline-containing regimen Taxane-containing regimen Palliative CTx, n (%) Anthracycline-containing regimen
111 (47.0)
96 (47.3)
15 (45.5)
Taxane-containing regimen
222 (94.1)
190 (93.6)
32 (97.0)
Second line
100 (42.4)
83 (40.9)
17 (51.5)
Third or more lines
136 (57.6)
120 (59.1)
16 (48.5)
124 (52.5)
104 (51.2)
20 (60.6)
.352
23 (9.7%)
22 (10.8)
1 (3.0)
.215
198 (83.9)
172 (84.7)
26 (78.8)
.442
Palliative Line of Capecitabine, n (%)
Previous Hormone Tx, n (%) Previous HER2-Targeted Tx, n (%) Previous Surgery, n (%)
.261
Metastatic Organs, n (%) Liver
77 (29.7)
62 (30.5)
8 (24.2)
.542
Lung
128 (54.2)
114 (56.2)
14 (42.4)
.187
Distant lymph node
101 (42.8)
93 (45.8)
8 (24.2)
.023
Brain
37 (15.7)
32 (15.8)
5 (15.2)
>.999
Bone
131 (55.5)
113 (55.7)
18 (54.5)
>.999
82 (34.7)
65 (32.0)
17 (51.5)
154 (65.3)
138 (68.0)
16 (48.5)
Involved organs, n (%) 1 2
.047
HRþ; ERþ, and/or PgR-positive irrespective of HER2 status, HER2þ; HRþ, and HER2þ patients, TN; ER-, PR-, and HER2- patients. Abbreviations: CTx ¼ chemotherapy; DR ¼ durable response; ECOG ¼ Eastern Cooperative Oncology Group; ER ¼ estrogen receptor; HR ¼ hormone receptor; PgR ¼ progesterone receptor; TN ¼ triple-negative; Tx ¼ treatment. a Includes neoadjuvant and adjuvant settings.
e288
-
Clinical Breast Cancer October 2015
Jung Yong Hong et al Treatment and Response Evaluation All patients received capecitabine monotherapy (1250 mg/m2 twice daily) for 2 weeks followed by a 1-week rest period. Treatment was repeated every 3 weeks until the occurrence of disease progression, unacceptable toxicity, or patient refusal. Treatment responses were evaluated at baseline and every 2 to 3 cycles of treatment using appropriate imaging studies, such as computed tomography, bone, and a magnetic resonance imaging scan if indicated. The responses were classified according to the Response Evaluation Criteria in Solid Tumors, version 1.0. The overall response rate (ORR) included complete response (CR) and partial response (PR). The disease control rate (DCR) included CR, PR, and stable disease.
Statistical Analysis Descriptive statistics are reported as proportions and medians. Intergroup comparisons were performed with Fisher exact test for categorical variables and the ManneWhitney test for age. Progression-free survival (PFS) was calculated from the first day of capecitabine monotherapy to the first day of disease progression, relapse, or death from any cause. Overall survival (OS) was calculated from the first day of capecitabine monotherapy to death. PFS and OS were censored on the last date of follow-up. Survival curves were estimated using the KaplaneMeier method, and survival distributions were compared using the log-rank test. Univariate and multivariate analysis were performed using Cox regression analysis. P values < .05 were considered statistically significant, and 2-sided tests were used. Statistical analyses were performed using the statistical software package IBM PASW version 18.0 (SPSS Inc, Chicago, IL).
Results
group and non-DR group. There were no significant differences in other baseline characteristics, including age, Eastern Cooperative Oncology Group (ECOG) performance status, HER2 status, triple negativity, or previous treatment history between the 2 groups.
Efficacy Outcomes Response and survival outcomes are summarized in Table 2. The ORR was 23.3%, and the DCR was 62.3%. The median PFS was 4.7 months (95% confidence interval [CI], 3.9-5.5) and the median OS was 20.0 months (95% CI, 16.1-23.9; Table 2). Significant differences in PFS were associated with ER status, single-organ metastasis, absence of LN metastasis, and triple negativity. The median PFS of patients with ER positivity versus negativity, single versus 2 metastases, absence versus presence of LN metastasis, and triple-negative versus other biomarker statuses were as follows: 6.9 versus 3.6 months (P < .001), 5.5 versus 4.3 months (P ¼ .005), 4.9 versus 4.3 months (P ¼ .018), and 6.2 versus 2.6 months (P < .001), respectively (Figure 1).
Prognostic Factor Analysis In univariate analysis, the clinical factors associated with better PFS were as follows: ER positivity (P < .001), single-organ metastasis (P ¼ .005), absence of LN metastasis (P ¼ .019), and biomarker status other than triple negativity (P < .001). In multivariate analysis, we included the following clinical factors: age > 40 years, ECOG performance status of 2 to 3, ER positivity, HER2 positivity, single-organ metastasis, and LN metastasis. Multivariate analysis indicated that ER positivity (hazard ratio [HR], 0.51; 95% CI, 0.38-0.69; P < .001) and single-organ metastasis (HR, 0.62; 95% CI, 0.44-0.86; P ¼ .004) retained a significant prognostic factor for better PFS (Table 3).
Patient Characteristics and Correlation of Duration of Response to Capecitabine With Clinical Features We identified a total of 236 patients who received second- or greater-line palliative capecitabine monotherapy after previous treatment with anthracycline- and taxane-containing regimens at Samsung Medical Center between December 2000 and May 2012. Baseline patient characteristics are shown in Table 1. According to the response duration of capecitabine monotherapy, we categorized the patients into durable responders (DR group; patients with response duration of 12 months) and nondurable responders (non-DR group; patients with no objective response or response duration < 12 months). The median age of all patients was 50 years (range, 20-76 years) and the median response duration of all patients treated with capecitabine monotherapy was 3.4 months (range, 0.0-42.0 months). Patients in the DR group were significantly associated with a higher proportion of estrogen receptor (ER) positivity (81.8% vs. 59.1%; P ¼ .012), single-organ metastasis (51.5% vs. 32.0%; P ¼ .047), and absence of lymph node (LN) metastasis (75.8% vs. 54.2%; P ¼ .023), compared with patients in the non-DR group. In terms of metastatic sites, there was no significant difference in the incidence of bone (54.5% vs. 55.7%; P > .999), lung (42.4% vs. 56.2%; P ¼ .187), liver (24.2% vs. 30.5%; P ¼ .542), and brain (15.2% vs. 15.8%; P > .999) metastasis between the DR
Table 2 Efficacy Outcomes to Capecitabine Monotherapy Outcome Variable
n (%)
Response CR
3 (1.3)
PR
52 (22.0)
SD
99 (41.9)
PD
80 (33.9)
Not Evaluable
2 (0.8)
OR (CR þ PR)
55 (23.3)
Disease Control (CR þ PR þ SD) Survival Median PFS (range)
154 (62.3) Months (95% CI) 4.7 (3.9-5.5)
6-Month PFS rate (%)
42.7
1-Year PFS rate (%)
20.9
2-Year PFS rate (%) Median OS (range)
9.3 20.0 (16.1-23.9)
6-Month OS Rate (%)
87.1
1-Year OS Rate (%)
69.9
2-Year OS Rate (%)
45.1
Abbreviations: OS ¼ overall survival; PFS ¼ progression-free survival.
Clinical Breast Cancer October 2015
- e289
Clinical Characteristics of Durable Responders to Capecitabine Monotherapy in MBC Figure 1 Progression-Free Survival (PFS) According to Clinicopathologic Parameters: (A) PFS According to Estrogen Receptor (ER) Status; (B) PFS According to Number of Metastatic Sites (Single vs. 2 or More); (C) PFS According to Lymph Node (LN) Metastasis; (D) PFS According to Triple Negativity (TN)
Discussion In this analysis of 236 patients with MBC, durable responders to capecitabine monotherapy ( 12 months) were the group who had ER positivity, and absence of LN and single-organ metastasis. Moreover, ER positivity and single-organ metastasis were useful independent predictive markers for better PFS in second- or greaterline palliative capecitabine monotherapy in anthracycline- and taxane-pretreated MBC patients. Intravenous cytotoxic chemotherapy, although highly efficacious, usually cannot be administered for a prolonged period because of cumulative toxicity, tolerability, and poor quality of life. However, in the clinical setting, we often encounter MBC patients with
e290
-
Clinical Breast Cancer October 2015
durable response to capecitabine monotherapy over 12 to 24 months. This reflects not only the efficacy, but also the good tolerability and convenience of oral capecitabine monotherapy in MBC. There even have been some reports showing durable response to capecitabine monotherapy in MBC patients with leptomeningeal seeding. One patient with such a response had relapsed anthracycline- and taxane-pretreated MBC with ER positivity, and the other patient had relapsed anthracycline-pretreated triple-negative MBC.10,11 The clinical characteristics of durable responders to capecitabine, however, have not been well defined. This study demonstrated that a substantial proportion of MBC patients treated with capecitabine monotherapy (14.0%) showed durable response
Jung Yong Hong et al Table 3 Univariate and Multivariate Cox Proportional Hazard Analysis for PFS Univariate Analysis
Multivariate Analysis
Variable
HR
(95% CI)
P
HR
(95% CI)
P
Age >40 Years ECOG PS 2-3 ERþ HER2þ Single-Organ Metastasis LN Metastasis
0.92 1.35 0.58 1.36 0.66 1.38
(0.71-1.47) (0.69-2.64) (0.44-0.76) (0.80-2.32) (0.50-0.88) (1.06-1.82)
.923 .376 <.001 .251 .005 .019
0.91 1.30 0.51 1.00 0.60 0.91
(0.62-1.32) (0.67-2.56) (0.37-0.69) (0.57-1.77) (0.43-0.84) (0.67-1.23)
.609 .441 <.001 .993 .003 .906
Abbreviations: ECOG PS ¼ Eastern Cooperative Oncology Group performance status; ER ¼ estrogen receptor; HR ¼ hazard ratio; LN ¼ lymph node; PFS ¼ progression-free survival.
for 12 months. We also identified ER positivity, LN metastasis, and single-organ metastasis as closely correlated with clinical characteristics of durable responders. In terms of predictive markers, Osako et al9 reported that capecitabine monotherapy is effective for patients with no liver metastasis, good performance status, longer-disease free interval, or hormone receptor positivity, and Lee et al5 also reported hormone receptor positivity, and a small number of metastatic organs (<3) predicted better survival in MBC patients treated with capecitabine monotherapy. However, these data are derived from small sample sizes and require further validation. In previous studies, ER-positive disease that demonstrated good response to hormonal treatment was associated with a poorer response to cytotoxic chemotherapy.12,13 However, in the case of capecitabine, ER positivity has been consistently associated with a better response and survival in previous studies and in the current study.5,9,14 There is no ready explanation for this observation. It is still uncertain whether a greater proportion of ER positivity in durable responders to capecitabine monotherapy reflects better prognosis of ER-positive disease or whether it can be explained by further biologic mechanisms between ER positivity and durable response to capecitabine. This should be investigated further with laboratory studies. In terms of other molecular predictors of response to capecitabine monotherapy, our group published a report that indicated that high thymidylate synthase and low thymidine phosphorylase levels along with hormonal subtypes are correlated with poor PFS with capecitabine monotherapy in patients who were pretreated with anthracyclines and taxanes.14 Regarding metastatic sites, a Japanese case series showed lack of liver metastasis to be significantly associated with better response and survival, but our series failed to reveal any significant association of specific metastatic organs (liver, lung, brain, LN) with PFS or OS at a multivariate level. In our study, bone-only metastasis showed better PFS in multivariate analysis adjusted by age > 40 years, ECOG performance status of 2 to 3, ER positivity, and HER2 positivity (HR, 0.61; 95% CI, 0.40-0.91; P ¼ .015). Our findings are based on a retrospective analysis and therefore need to be interpreted cautiously. Nevertheless, this study has several strengths. To our knowledge, this study shows the results of the largest data set to validate predictive factors for capecitabine monotherapy in anthracycline- and taxane-pretreated MBC patients, and revealed the clinical characteristics of patients who exhibited a durable response to capecitabine monotherapy for 12 months.
Conclusion The current study demonstrated the following distinct clinical features of durable responders to capecitabine monotherapy: ER positivity, absence of LN metastasis, and single-organ metastasis. In addition, this study reaffirmed ER positivity and single-organ metastasis as predictive markers to second- or greater-line palliative capecitabine monotherapy in large number of anthracyclineand taxane-pretreated MBC patients.
Clinical Practice Points The US Food and Drug Administration has approved capecita-
bine to be used as monotherapy or combination therapy with docetaxel, lapatinib, or ixabepilone in heavily treated MBC patients. In terms of quality of life, cancer patients prefer oral chemotherapy over intravenous chemotherapy, and capecitabine monotherapy can be administered orally with high efficacy and favorable toxicity profiles in the outpatient clinic for anthracycline- and taxane-pretreated MBC patients. The current study demonstrated the following distinct clinical features of durable responders to capecitabine monotherapy: ER positivity, absence of LN metastasis, and single-organ metastasis. In addition, this study validated ER positivity and single-organ metastasis as predictive markers for second- or greater-line palliative capecitabine monotherapy in anthracycline- and taxane-pretreated MBC patients.
Disclosure The authors have stated that they have no conflicts of interest.
References 1. Fumoleau P, Largillier R, Clippe C, et al. Multicentre, phase II study evaluating capecitabine monotherapy in patients with anthracycline- and taxane-pretreated metastatic breast cancer. Eur J Cancer 2004; 40:536-42. 2. Sparano JA, Vrdoljak E, Rixe O, et al. Randomized phase III trial of ixabepilone plus capecitabine versus capecitabine in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol 2010; 28: 3256-63. 3. Geyer CE, Forster J, Lindquist D, et al. Lapatinib plus capecitabine for HER2positive advanced breast cancer. N Engl J Med 2006; 355:2733-43. 4. O’Shaughnessy J, Miles D, Vukelja S, et al. Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: phase III trial results. J Clin Oncol 2002; 20:2812-23. 5. Lee SH, Lee J, Park J, et al. Capecitabine monotherapy in patients with anthracycline- and taxane-pretreated metastatic breast cancer. Med Oncol 2004; 21:223-31. 6. Wist EA, Sommer HH, Ostenstad B, et al. Oral capecitabine in anthracycline- and taxane-pretreated advanced/metastatic breast cancer. Acta Oncol 2004; 43:186-9.
Clinical Breast Cancer October 2015
- e291
Clinical Characteristics of Durable Responders to Capecitabine Monotherapy in MBC 7. Blum JL, Jones SE, Buzdar AU, et al. Multicenter phase II study of capecitabine in paclitaxel-refractory metastatic breast cancer. J Clin Oncol 1999; 17:485-93. 8. Blum JL, Dieras V, Lo Russo PM, et al. Multicenter, phase II study of capecitabine in taxane-pretreated metastatic breast carcinoma patients. Cancer 2001; 92:1759-68. 9. Osako T, Ito Y, Ushijima M, et al. Predictive factors for efficacy of capecitabine in heavily pretreated patients with metastatic breast cancer. Cancer Chemother Pharmacol 2009; 63:865-71. 10. Rogers LR, Remer SE, Tejwani S. Durable response of breast cancer leptomeningeal metastasis to capecitabine monotherapy. Neuro Oncol 2004; 6:63-4. 11. Tham YL, Hinckley L, Teh BS, et al. Long-term clinical response in leptomeningeal metastases from breast cancer treated with capecitabine monotherapy: a case report. Clin Breast Cancer 2006; 7:164-6.
e292
-
Clinical Breast Cancer October 2015
12. Bear HD, Anderson S, Brown A, et al. The effect on tumor response of adding sequential preoperative docetaxel to preoperative doxorubicin and cyclophosphamide: preliminary results from National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol 2003; 21: 4165-74. 13. Maehara Y, Emi Y, Sakaguchi Y, et al. Estrogen-receptor-negative breast cancer tissue is chemosensitive in vitro compared with estrogen-receptor-positive tissue. Eur Surg Res 1990; 22:50-5. 14. Lee SJ, Choi YL, Park YH, et al. Thymidylate synthase and thymidine phosphorylase as predictive markers of capecitabine monotherapy in patients with anthracycline- and taxane-pretreated metastatic breast cancer. Cancer Chemother Pharmacol 2011; 68:743-51.
Characterization of Durable Responder for Capecitabine Monotherapy in Patients With Anthracycline- and Taxane-Pretreated Metastatic Breast Cancer Jung Yong Hong,1,2 Yeon Hee Park,1 Moon Ki Choi,1,3 Hyun Ae Jung,1 Su Jin Lee,1 Jin Seok Ahn,1 Young-Hyuck Im1 Abstract The purpose of the study was to elucidate the clinical characteristics of durable responders to capecitabine monotherapy and to validate clinical factors that influence the efficacy of capecitabine monotherapy in anthracycline- and taxane-pretreated metastatic breast cancer (MBC) patients. In this analysis of 236 patients with MBC, durable responders to capecitabine monotherapy were the group who had estrogen receptor positivity, and absence of lymph node and single-organ metastasis. Background: The purpose of this study was to evaluate predictive factors and the clinical characteristics of durable responders to capecitabine monotherapy in heavily-treated patients with metastatic breast cancer (MBC). Patients and Methods: Between December 2000 and May 2012, a total of 236 evaluable patients with MBC who had been treated with second- or greater-line palliative capecitabine monotherapy after a previous treatment regimen with anthracycline and taxane were included. Capecitabine (1250 mg/m2 twice daily) was administered for 2 weeks followed by a 1-week rest period. Results: The response rate was 23.3% and median progression-free survival (PFS) was 4.7 months (95% confidence interval, 4.0-5.5). Among 236 patients, 33 patients (14.0%) showed durable response (>12 months) to capecitabine monotherapy. Patients with durable response showed significantly greater incidence of estrogen receptor (ER) positivity (81.8% vs. 59.1%; P ¼ .012), single-organ metastasis (51.5% vs. 32.0%; P ¼ .047), and absence of lymph node metastasis (75.8% vs. 54.2%; P ¼ .023), compared with patients without durable response. In multivariate analysis, ER positivity and single-organ metastasis retained a significant association with better PFS to capecitabine monotherapy (hazard ratio [HR], 0.51; P < .001 and HR, 0.62; P ¼ .004). Conclusion: Our data suggest that ER positivity and single-organ metastasis can be useful predictive markers for better PFS to second- or greater-line palliative capecitabine monotherapy in anthracycline- and taxane-pretreated MBC patients. Clinical Breast Cancer, Vol. 15, No. 5, e287-92 ª 2015 Elsevier Inc. All rights reserved. Keywords: Anthracycline- and taxane-pretreated, Capecitabine monotherapy, Durable responders, Durable response, ER
Introduction Capecitabine is an orally-administered fluoropyrimidine derivative that has shown high efficacy and low toxicity in metastatic breast cancer (MBC) and colorectal cancer patients. The US Food and Drug Administration has approved capecitabine to be used as Jung Yong Hong and Yeon Hee Park contributed equally to this work as first authors.
monotherapy or combination therapy with docetaxel, lapatinib, or ixabepilone in heavily treated MBC patients.1-4 In terms of quality of life, cancer patients prefer oral chemotherapy over intravenous chemotherapy, and capecitabine monotherapy can be administered orally with high efficacy and favorable toxicity profiles in the Submitted: Dec 25, 2014; Revised: Mar 31, 2015; Accepted: Apr 16, 2015; Epub: Apr 23, 2015
1
Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 2 Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Korea 3 Divisions of Hematology and Medical Oncology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Gyeonggi-do, Korea
1526-8209/$ - see frontmatter ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clbc.2015.04.004
Address for correspondence: Young-Hyuck Im, MD, PhD, Division of HematologyOncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 135-710, Korea Fax: þ82-2-3410-1756; e-mail contact: [email protected]
Clinical Breast Cancer October 2015
- e287
Clinical Characteristics of Durable Responders to Capecitabine Monotherapy in MBC outpatient clinic for anthracycline- and taxane-pretreated MBC patients.1,5-8 Few studies have evaluated predictive markers of capecitabine monotherapy in MBC patients. In one Japanese series Osako et al reported that capecitabine monotherapy is effective for patients with no liver metastasis, good performance status, longer disease-free interval, or hormone-receptor positivity.9 However, these results were derived from a small sample size and require further validation. Moreover, the clinical characteristics of durable responders to capecitabine monotherapy remain unclear. In this study, we sought to elucidate the clinical characteristics of durable responders to capecitabine monotherapy and aimed to validate clinical factors that influence the efficacy of capecitabine monotherapy in anthracycline- and taxane-pretreated MBC patients.
Patients and Methods Patients We retrospectively analyzed patients with MBC who were treated with second- or greater-line palliative capecitabine monotherapy after previous treatment with anthracycline- and taxanecontaining regimens at Samsung Medical Center between December 2000 and May 2012. Previous treatment with anthracycline- and taxane-containing regimens included the adjuvant/ neoadjuvant and palliative settings. We excluded patients who received first-line palliative capecitabine monotherapy before using anthracycline- or taxane-containing regimens. This study was approved by the institutional review board of Samsung Medical Center, and the confidentiality of all patients was protected.
Table 1 Characteristics of Patients According to the Duration of Response to Capecitabine
Median Age (Range), Years
Total (n [ 236)
Non-DR Group (n [ 203)
50 (30-76)
50 (30-76)
Age >40, n (%)
200 (84.7)
173 (85.2)
Median Duration of Response, (Range), Months
3.4 (0.0-42.0)
2.4 (0.0-11.6)
DR Group (n [ 33)
P
48 (36-74)
.458
27 (81.8)
.605
17.7 (12.4-42.0)
0-1
227 (96.2)
195 (96.1)
32 (97.0)
2
9 (3.8)
8 (3.9)
1 (3.0)
Subtype, n (%) HR
<.001 >.999
ECOG Performance Status
.054
þ
152 (64.4)
125 (61.6)
27 (81.8)
HER2þ
16 (6.8)
16 (7.9)
0 (0.0)
TN
68 (28.8)
62 (30.5)
6 (18.2)
147 (62.3)
120 (59.1)
27 (81.8)
.012
142 (60.2)
122 (60.1)
20 (60.6)
>.999
86 (36.4)
80 (39.4)
6 (18.2)
.019 >.999
ER Positivity, n (%) a
Perioperative CTx, n (%)
Anthracycline-containing regimen Taxane-containing regimen Palliative CTx, n (%) Anthracycline-containing regimen
111 (47.0)
96 (47.3)
15 (45.5)
Taxane-containing regimen
222 (94.1)
190 (93.6)
32 (97.0)
Second line
100 (42.4)
83 (40.9)
17 (51.5)
Third or more lines
136 (57.6)
120 (59.1)
16 (48.5)
124 (52.5)
104 (51.2)
20 (60.6)
.352
23 (9.7%)
22 (10.8)
1 (3.0)
.215
198 (83.9)
172 (84.7)
26 (78.8)
.442
Palliative Line of Capecitabine, n (%)
Previous Hormone Tx, n (%) Previous HER2-Targeted Tx, n (%) Previous Surgery, n (%)
.261
Metastatic Organs, n (%) Liver
77 (29.7)
62 (30.5)
8 (24.2)
.542
Lung
128 (54.2)
114 (56.2)
14 (42.4)
.187
Distant lymph node
101 (42.8)
93 (45.8)
8 (24.2)
.023
Brain
37 (15.7)
32 (15.8)
5 (15.2)
>.999
Bone
131 (55.5)
113 (55.7)
18 (54.5)
>.999
82 (34.7)
65 (32.0)
17 (51.5)
154 (65.3)
138 (68.0)
16 (48.5)
Involved organs, n (%) 1 2
.047
HRþ; ERþ, and/or PgR-positive irrespective of HER2 status, HER2þ; HRþ, and HER2þ patients, TN; ER-, PR-, and HER2- patients. Abbreviations: CTx ¼ chemotherapy; DR ¼ durable response; ECOG ¼ Eastern Cooperative Oncology Group; ER ¼ estrogen receptor; HR ¼ hormone receptor; PgR ¼ progesterone receptor; TN ¼ triple-negative; Tx ¼ treatment. a Includes neoadjuvant and adjuvant settings.
e288
-
Clinical Breast Cancer October 2015
Jung Yong Hong et al Treatment and Response Evaluation All patients received capecitabine monotherapy (1250 mg/m2 twice daily) for 2 weeks followed by a 1-week rest period. Treatment was repeated every 3 weeks until the occurrence of disease progression, unacceptable toxicity, or patient refusal. Treatment responses were evaluated at baseline and every 2 to 3 cycles of treatment using appropriate imaging studies, such as computed tomography, bone, and a magnetic resonance imaging scan if indicated. The responses were classified according to the Response Evaluation Criteria in Solid Tumors, version 1.0. The overall response rate (ORR) included complete response (CR) and partial response (PR). The disease control rate (DCR) included CR, PR, and stable disease.
Statistical Analysis Descriptive statistics are reported as proportions and medians. Intergroup comparisons were performed with Fisher exact test for categorical variables and the ManneWhitney test for age. Progression-free survival (PFS) was calculated from the first day of capecitabine monotherapy to the first day of disease progression, relapse, or death from any cause. Overall survival (OS) was calculated from the first day of capecitabine monotherapy to death. PFS and OS were censored on the last date of follow-up. Survival curves were estimated using the KaplaneMeier method, and survival distributions were compared using the log-rank test. Univariate and multivariate analysis were performed using Cox regression analysis. P values < .05 were considered statistically significant, and 2-sided tests were used. Statistical analyses were performed using the statistical software package IBM PASW version 18.0 (SPSS Inc, Chicago, IL).
Results
group and non-DR group. There were no significant differences in other baseline characteristics, including age, Eastern Cooperative Oncology Group (ECOG) performance status, HER2 status, triple negativity, or previous treatment history between the 2 groups.
Efficacy Outcomes Response and survival outcomes are summarized in Table 2. The ORR was 23.3%, and the DCR was 62.3%. The median PFS was 4.7 months (95% confidence interval [CI], 3.9-5.5) and the median OS was 20.0 months (95% CI, 16.1-23.9; Table 2). Significant differences in PFS were associated with ER status, single-organ metastasis, absence of LN metastasis, and triple negativity. The median PFS of patients with ER positivity versus negativity, single versus 2 metastases, absence versus presence of LN metastasis, and triple-negative versus other biomarker statuses were as follows: 6.9 versus 3.6 months (P < .001), 5.5 versus 4.3 months (P ¼ .005), 4.9 versus 4.3 months (P ¼ .018), and 6.2 versus 2.6 months (P < .001), respectively (Figure 1).
Prognostic Factor Analysis In univariate analysis, the clinical factors associated with better PFS were as follows: ER positivity (P < .001), single-organ metastasis (P ¼ .005), absence of LN metastasis (P ¼ .019), and biomarker status other than triple negativity (P < .001). In multivariate analysis, we included the following clinical factors: age > 40 years, ECOG performance status of 2 to 3, ER positivity, HER2 positivity, single-organ metastasis, and LN metastasis. Multivariate analysis indicated that ER positivity (hazard ratio [HR], 0.51; 95% CI, 0.38-0.69; P < .001) and single-organ metastasis (HR, 0.62; 95% CI, 0.44-0.86; P ¼ .004) retained a significant prognostic factor for better PFS (Table 3).
Patient Characteristics and Correlation of Duration of Response to Capecitabine With Clinical Features We identified a total of 236 patients who received second- or greater-line palliative capecitabine monotherapy after previous treatment with anthracycline- and taxane-containing regimens at Samsung Medical Center between December 2000 and May 2012. Baseline patient characteristics are shown in Table 1. According to the response duration of capecitabine monotherapy, we categorized the patients into durable responders (DR group; patients with response duration of 12 months) and nondurable responders (non-DR group; patients with no objective response or response duration < 12 months). The median age of all patients was 50 years (range, 20-76 years) and the median response duration of all patients treated with capecitabine monotherapy was 3.4 months (range, 0.0-42.0 months). Patients in the DR group were significantly associated with a higher proportion of estrogen receptor (ER) positivity (81.8% vs. 59.1%; P ¼ .012), single-organ metastasis (51.5% vs. 32.0%; P ¼ .047), and absence of lymph node (LN) metastasis (75.8% vs. 54.2%; P ¼ .023), compared with patients in the non-DR group. In terms of metastatic sites, there was no significant difference in the incidence of bone (54.5% vs. 55.7%; P > .999), lung (42.4% vs. 56.2%; P ¼ .187), liver (24.2% vs. 30.5%; P ¼ .542), and brain (15.2% vs. 15.8%; P > .999) metastasis between the DR
Table 2 Efficacy Outcomes to Capecitabine Monotherapy Outcome Variable
n (%)
Response CR
3 (1.3)
PR
52 (22.0)
SD
99 (41.9)
PD
80 (33.9)
Not Evaluable
2 (0.8)
OR (CR þ PR)
55 (23.3)
Disease Control (CR þ PR þ SD) Survival Median PFS (range)
154 (62.3) Months (95% CI) 4.7 (3.9-5.5)
6-Month PFS rate (%)
42.7
1-Year PFS rate (%)
20.9
2-Year PFS rate (%) Median OS (range)
9.3 20.0 (16.1-23.9)
6-Month OS Rate (%)
87.1
1-Year OS Rate (%)
69.9
2-Year OS Rate (%)
45.1
Abbreviations: OS ¼ overall survival; PFS ¼ progression-free survival.
Clinical Breast Cancer October 2015
- e289
Clinical Characteristics of Durable Responders to Capecitabine Monotherapy in MBC Figure 1 Progression-Free Survival (PFS) According to Clinicopathologic Parameters: (A) PFS According to Estrogen Receptor (ER) Status; (B) PFS According to Number of Metastatic Sites (Single vs. 2 or More); (C) PFS According to Lymph Node (LN) Metastasis; (D) PFS According to Triple Negativity (TN)
Discussion In this analysis of 236 patients with MBC, durable responders to capecitabine monotherapy ( 12 months) were the group who had ER positivity, and absence of LN and single-organ metastasis. Moreover, ER positivity and single-organ metastasis were useful independent predictive markers for better PFS in second- or greaterline palliative capecitabine monotherapy in anthracycline- and taxane-pretreated MBC patients. Intravenous cytotoxic chemotherapy, although highly efficacious, usually cannot be administered for a prolonged period because of cumulative toxicity, tolerability, and poor quality of life. However, in the clinical setting, we often encounter MBC patients with
e290
-
Clinical Breast Cancer October 2015
durable response to capecitabine monotherapy over 12 to 24 months. This reflects not only the efficacy, but also the good tolerability and convenience of oral capecitabine monotherapy in MBC. There even have been some reports showing durable response to capecitabine monotherapy in MBC patients with leptomeningeal seeding. One patient with such a response had relapsed anthracycline- and taxane-pretreated MBC with ER positivity, and the other patient had relapsed anthracycline-pretreated triple-negative MBC.10,11 The clinical characteristics of durable responders to capecitabine, however, have not been well defined. This study demonstrated that a substantial proportion of MBC patients treated with capecitabine monotherapy (14.0%) showed durable response
Jung Yong Hong et al Table 3 Univariate and Multivariate Cox Proportional Hazard Analysis for PFS Univariate Analysis
Multivariate Analysis
Variable
HR
(95% CI)
P
HR
(95% CI)
P
Age >40 Years ECOG PS 2-3 ERþ HER2þ Single-Organ Metastasis LN Metastasis
0.92 1.35 0.58 1.36 0.66 1.38
(0.71-1.47) (0.69-2.64) (0.44-0.76) (0.80-2.32) (0.50-0.88) (1.06-1.82)
.923 .376 <.001 .251 .005 .019
0.91 1.30 0.51 1.00 0.60 0.91
(0.62-1.32) (0.67-2.56) (0.37-0.69) (0.57-1.77) (0.43-0.84) (0.67-1.23)
.609 .441 <.001 .993 .003 .906
Abbreviations: ECOG PS ¼ Eastern Cooperative Oncology Group performance status; ER ¼ estrogen receptor; HR ¼ hazard ratio; LN ¼ lymph node; PFS ¼ progression-free survival.
for 12 months. We also identified ER positivity, LN metastasis, and single-organ metastasis as closely correlated with clinical characteristics of durable responders. In terms of predictive markers, Osako et al9 reported that capecitabine monotherapy is effective for patients with no liver metastasis, good performance status, longer-disease free interval, or hormone receptor positivity, and Lee et al5 also reported hormone receptor positivity, and a small number of metastatic organs (<3) predicted better survival in MBC patients treated with capecitabine monotherapy. However, these data are derived from small sample sizes and require further validation. In previous studies, ER-positive disease that demonstrated good response to hormonal treatment was associated with a poorer response to cytotoxic chemotherapy.12,13 However, in the case of capecitabine, ER positivity has been consistently associated with a better response and survival in previous studies and in the current study.5,9,14 There is no ready explanation for this observation. It is still uncertain whether a greater proportion of ER positivity in durable responders to capecitabine monotherapy reflects better prognosis of ER-positive disease or whether it can be explained by further biologic mechanisms between ER positivity and durable response to capecitabine. This should be investigated further with laboratory studies. In terms of other molecular predictors of response to capecitabine monotherapy, our group published a report that indicated that high thymidylate synthase and low thymidine phosphorylase levels along with hormonal subtypes are correlated with poor PFS with capecitabine monotherapy in patients who were pretreated with anthracyclines and taxanes.14 Regarding metastatic sites, a Japanese case series showed lack of liver metastasis to be significantly associated with better response and survival, but our series failed to reveal any significant association of specific metastatic organs (liver, lung, brain, LN) with PFS or OS at a multivariate level. In our study, bone-only metastasis showed better PFS in multivariate analysis adjusted by age > 40 years, ECOG performance status of 2 to 3, ER positivity, and HER2 positivity (HR, 0.61; 95% CI, 0.40-0.91; P ¼ .015). Our findings are based on a retrospective analysis and therefore need to be interpreted cautiously. Nevertheless, this study has several strengths. To our knowledge, this study shows the results of the largest data set to validate predictive factors for capecitabine monotherapy in anthracycline- and taxane-pretreated MBC patients, and revealed the clinical characteristics of patients who exhibited a durable response to capecitabine monotherapy for 12 months.
Conclusion The current study demonstrated the following distinct clinical features of durable responders to capecitabine monotherapy: ER positivity, absence of LN metastasis, and single-organ metastasis. In addition, this study reaffirmed ER positivity and single-organ metastasis as predictive markers to second- or greater-line palliative capecitabine monotherapy in large number of anthracyclineand taxane-pretreated MBC patients.
Clinical Practice Points The US Food and Drug Administration has approved capecita-
bine to be used as monotherapy or combination therapy with docetaxel, lapatinib, or ixabepilone in heavily treated MBC patients. In terms of quality of life, cancer patients prefer oral chemotherapy over intravenous chemotherapy, and capecitabine monotherapy can be administered orally with high efficacy and favorable toxicity profiles in the outpatient clinic for anthracycline- and taxane-pretreated MBC patients. The current study demonstrated the following distinct clinical features of durable responders to capecitabine monotherapy: ER positivity, absence of LN metastasis, and single-organ metastasis. In addition, this study validated ER positivity and single-organ metastasis as predictive markers for second- or greater-line palliative capecitabine monotherapy in anthracycline- and taxane-pretreated MBC patients.
Disclosure The authors have stated that they have no conflicts of interest.
References 1. Fumoleau P, Largillier R, Clippe C, et al. Multicentre, phase II study evaluating capecitabine monotherapy in patients with anthracycline- and taxane-pretreated metastatic breast cancer. Eur J Cancer 2004; 40:536-42. 2. Sparano JA, Vrdoljak E, Rixe O, et al. Randomized phase III trial of ixabepilone plus capecitabine versus capecitabine in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol 2010; 28: 3256-63. 3. Geyer CE, Forster J, Lindquist D, et al. Lapatinib plus capecitabine for HER2positive advanced breast cancer. N Engl J Med 2006; 355:2733-43. 4. O’Shaughnessy J, Miles D, Vukelja S, et al. Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: phase III trial results. J Clin Oncol 2002; 20:2812-23. 5. Lee SH, Lee J, Park J, et al. Capecitabine monotherapy in patients with anthracycline- and taxane-pretreated metastatic breast cancer. Med Oncol 2004; 21:223-31. 6. Wist EA, Sommer HH, Ostenstad B, et al. Oral capecitabine in anthracycline- and taxane-pretreated advanced/metastatic breast cancer. Acta Oncol 2004; 43:186-9.
Clinical Breast Cancer October 2015
- e291
Clinical Characteristics of Durable Responders to Capecitabine Monotherapy in MBC 7. Blum JL, Jones SE, Buzdar AU, et al. Multicenter phase II study of capecitabine in paclitaxel-refractory metastatic breast cancer. J Clin Oncol 1999; 17:485-93. 8. Blum JL, Dieras V, Lo Russo PM, et al. Multicenter, phase II study of capecitabine in taxane-pretreated metastatic breast carcinoma patients. Cancer 2001; 92:1759-68. 9. Osako T, Ito Y, Ushijima M, et al. Predictive factors for efficacy of capecitabine in heavily pretreated patients with metastatic breast cancer. Cancer Chemother Pharmacol 2009; 63:865-71. 10. Rogers LR, Remer SE, Tejwani S. Durable response of breast cancer leptomeningeal metastasis to capecitabine monotherapy. Neuro Oncol 2004; 6:63-4. 11. Tham YL, Hinckley L, Teh BS, et al. Long-term clinical response in leptomeningeal metastases from breast cancer treated with capecitabine monotherapy: a case report. Clin Breast Cancer 2006; 7:164-6.
e292
-
Clinical Breast Cancer October 2015
12. Bear HD, Anderson S, Brown A, et al. The effect on tumor response of adding sequential preoperative docetaxel to preoperative doxorubicin and cyclophosphamide: preliminary results from National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol 2003; 21: 4165-74. 13. Maehara Y, Emi Y, Sakaguchi Y, et al. Estrogen-receptor-negative breast cancer tissue is chemosensitive in vitro compared with estrogen-receptor-positive tissue. Eur Surg Res 1990; 22:50-5. 14. Lee SJ, Choi YL, Park YH, et al. Thymidylate synthase and thymidine phosphorylase as predictive markers of capecitabine monotherapy in patients with anthracycline- and taxane-pretreated metastatic breast cancer. Cancer Chemother Pharmacol 2011; 68:743-51.