Bangladesh Journal of Pharmacology Meta-Analysis Effect of capecitabine on breast cancer patients with different estrogen re- ceptor status BJP Introduction The incidence of breast cancer increases with age, which has become the second leading cause of cancer death in women (Tang et al., 2016). Breast cancer molecular typing has gained international attention for therapy purpose. The concept of molecular portraits of breast cancer was classified into two subtypes: estrogen receptor positive and estrogen receptor negative breast cancer (Perou et al., 2000). In the 12th St. Gallen Interna- tional Breast Cancer Conference, a new approach to the classification of breast cancer patients according to intrinsic biological subtypes has been adopted by an expert panel. Capecitabine is used for treating progressive and metastatic breast cancer, which is concerted to 5-fluoro- uracil selectively in tumors via a cascade of three enzy- mes (Miwa et al., 1998). In addition, high expression profile of thymidine phosphorylase in breast cancer cells accounts for the superior efficacy of capecitabine treatment in breast cancer. The previous foreign studies indicated that the effective rate of capecitabine monotherapy or combination therapy with other drugs ranged from 28 to 75% (O'Shaughnessy et al., 2010; Tan et al., 2012). Another study found that cytotoxic drugs such as texol and texotere simultaneously increased the thymidine phosphorylase activity, which might result in improving the efficacy of capecitabine (Sawada et al., 1998). Researches have shown that either capecitabine Abstract This meta-analysis is to compare the efficacy of capecitabine versus non- capecitabine chemotherapy on breast cancer patients with different estrogen receptor status. We searched relevant literature from the EMBASE, PubMed and OVID library to analyze the pathologic complete response (PCR) rate, overall survival (OS), disease-free survival (DFS), progression-free survival (PFS), and time to disease progression (TTP). Eleven different studies were enrolled, which revealed that estrogen receptor positive breast cancer patients who received treatment regimen containing capecitabine can effectively improve PFS, PCR, TTP. However, the difference between capecitabine- containing and non-capecitabine groups had no significant effect for DFS and OS. Estrogen receptor negative breast cancer patients who received treatment regimen containing capecitabine could improve DFS and TTP. However, there was no significant effect for PFS, PCR and OS. The results indicated that capecitabine in combination with other chemotherapy drugs for breast cancer is effective, which can delay the progression time in patients to some extent. Article Info Received: 12 October 2019 Accepted: 3 March 2020 Available Online: 20 April 2020 DOI: 10.3329/bjp.v15i2.43522 Cite this article: Xu G, Lu K, Shen M, Zhang Q, Pan W. Effect of capecitabine on breast cancer patients with different estrogen recep- tor status. Bangladesh J Pharmacol. 2020; 15: 47-57. Effect of capecitabine on breast cancer patients with different estrogen receptor status Gang Xu1, Xin Lv2, Ke Lu3, Ming Hai Shen3, Qing Hua Zhang3 and Wan Neng Pan3 1Department of General Surgery, Zhejiang Hospital, City of Hangzhou, Zhejiang Province 310013, China; 2Fourth Wards of General Surgery, Shengzhou People’s Hospital (The First Affiliated Hospital of Zhejiang University Shengzhou Branch), City of Shengzhou, Zhejiang Province 312400, China; 3The First Surgical Department, The Affiliated Hangzhou Xixi Hospital of Zhejiang Chinese Medical University, City of Hangzhou, Zhejiang Province, 310023, China. This work is licensed under a Creative Commons Attribution 4.0 License. You are free to copy, distribute and perform the work. You must attribute the work in the manner specified by the author or licensor. A Journal of the Bangladesh Pharmacological Society (BDPS) Bangladesh J Pharmacol 2020; 15: 47-57 Journal homepage: www.banglajol.info Abstracted/indexed in Academic Search Complete, Agroforestry Abstracts, Asia Journals Online, Bangladesh Journals Online, Biological Abstracts, BIOSIS Previews, CAB Abstracts, Current Abstracts, Directory of Open Access Journals, EMBASE/Excerpta Medica, Global Health, Google Scholar, HINARI (WHO), International Pharmaceutical Abstracts, Open J-gate, Science Citation Index Expanded, SCOPUS and Social Sciences Citation Index ISSN: 1991-0088 M et a- an al ys is monotherapy or combined with cytotoxic drug or targeted drugs presented different clinical benefit rates and efficiency (Lee et al., 2008; von Minckwitz et al., 2010; Bear et al., 2012). The efficacy of capecitabine therapy for heavily pretreated metastatic breast cancer patients had an association with estrogen receptor status (Osako et al., 2009). Advanced breast cancer patient with estrogen receptor positive status responses better to capecitabine therapy (Siva et al., 2008). In this study, we classified the research object according to estrogen receptor status to determine whether there were differences in the efficacy under capecitabine treatment. Information obtained from this paper can help to suggest patients selecting capecitabine-contain- ing chemotherapy drugs based on the status of the estrogen receptor. Materials and Methods Inclusion criteria Inclusion criteria for this meta-analysis were as follows: a) hormone receptor status had been evaluated in pathologically confirmed breast cancer patients; b) com- parison of capecitabine-containing therapy with non- capecitabine therapy; c) sufficient information provided to analyze pathologic complete response (PCR) rate, overall survival (OS), disease-free survival (DFS), progression-free survival (PFS), and time to disease progression (TTP); d) retrospective or prospective studies. Exclusion criteria Studies meeting the following one criterion were exclu- ded: a) study objects without clear diagnosis or inclu- sion and exclusion criteria; b) study objects without hormone receptor status; and c) studies had no suffi- cient data. Search strategy We conducted a systematic search in the Pubmed, EMBASE, and OVID databases, using the MeSH terms and free keywords “breast cancer” combined with “capecitabine”, from their dates of inception to Novem- ber 1, 2016, and identified all potentially relevant articles, language restrictions were not employed. We also searched the reference lists of the full-text papers and reviewed studies from all of the relevant publica- tions to identify any omitted studies. Data extraction and statistical analysis A self-designed data extraction form was used to extract information including first author, year of publication, characteristics of the study population, study design, outcome measures. The literature screen- ing, quality assessment and data extraction were carried out by two reviewers. In case of disagreement, a third investigator would help to resolve the discrepancies Stata 13.1 software was used for statistical analysis. Relative risk (RR) and 95% CI were used to assess the binary data value in this meta-analysis. The statistical heterogeneity among the various studies was assessed by the Chi-squared study and its associated I2 value. The fixed-effects model was applied to merge the inclu- ded studies for further analysis if no significant hetero- geneity was detected (p>0.1, I2≤50%), whereas the trials were sub-grouped according to the medicine used to analyze the sources of clinical heterogeneity if the heterogeneity was significant (p≤0.1, I2>50%). Egger's test was used for estimating a possible publication bias. Results Literature search results A total of 2,197 literature were retrieved. After dedup- lication, preliminary screening and intensive reading, eleven literature were finally included after intensive reading of the text (Figure 1). Quality assessment and publish bias A summary of quality evaluation results for included studies is presented in Figure 2 and Figure 3. Because of the nature of the interventions, most studies have high- risk of blinding of participants and intervention provi- ders. There are 4 studies reference to randomization used computer-generated random sequence and a block -design randomization procedure, while other studies no description of how to carry out randomization. 3 trials allocated patients treatment were not masked and 5 trials had comparable baselines. Blinded data analysis independent of the trial in all studies. Most of the trial reports were not complete and not selective. Overall, the studies enrolled in this meta-analysis had moderate quality. Egger's test obtained p=0.245, indicated there was no obvious publication bias. Basic information of the included literature The basic information of all the included studies is shown in Table I, which mainly included first author, year of publication, follow-up time, median follow-up period, basic characteristics of the study object, chemo- therapy program, study group and control group population, and outcome measures. Analysis of capecitabine treatment for ER+ breast cancer vs. ER- breast cancer Eleven literature were included (Lee et al., 2008; O'Sha- ughnessy et al., 2010; Joensuu et al., 2012; Zambetti et al., 2012; Glück et al., 2013; Gligorov et al., 2014; Twelves et al., 2014; Martin et al., 2015; Shankar et al., 2015; Twelves et al., 2016; Zielinski et al., 2016). Inter- ventions in the study group consisted of capecitabine treatment, while interventions in the control group that 48 Bangladesh J Pharmacol 2020; 15: 47-57 did not contain capecitabine. In ER+ breast cancer trials, there were five outcome measures which included PFS, PCR, DFS, OS, and TTP. PFS [RR= 0.93, 95% CI (0.88- 0.97)] (Figure 4A), PCR [RR= 0.24, 95% CI (0.09-0.63)] (Figure 4B), and TTP [RR= 0.62, 95% CI (0.46-0.84)] were reported in four (Gligorov et al., 2014; Twelves et al., 2014; Shankar et al., 2015; Twelves et al., 2016), two (Lee et al., 2008; Zambetti et al., 2012), and one (Zam- betti et al., 2012) studies respectively that presented significantly difference between the study group and control group. When the outcome measures were, three studies have reported the results of DFS [RR= 0.89, 95% CI (0.71-1.12)] (O'Shaughnessy et al., 2010; Joensuu et al., 2012; Martin et al., 2015) and OS [RR= 0.89, 95% CI (0.74-1.07)] (Glück et al., 2013; Gligorov et al., 2014; Zielinski et al., 2016) that revealed that the difference Figure 1: Preliminary screening and intensive reading of literatures finally included Figure 2: Quality evaluation results for included studies Bangladesh J Pharmacol 2020; 15: 47-57 49 T a b le I B a si c in fo rm a ti o n o f in cl u d e d s tu d ie s R ef er en ce s Fo llo w -u p d u ra ti on M ed ia n fo llo w -u p d u ra ti on (m on th s) Pa tie nt s’ C ha ra ct er s T re at m en t r eg im en s N u m be r of p at ie nt s in e ac h gr ou p O u tc om es E R + E R + E R - E R - St u d y gr ou p C on tr ol g ro u p St u d y gr ou p C on - tr ol g ro u p M ar tí n et al ., 20 15 79 .2 W om en a ge 1 8 to 7 0 ye ar s w it h a hi st o- lo gi c d ia gn os is of in va si ve hu m an ep id er m al gr ow th fa ct or re ce p to r 2 (H E R 2) –p os it iv e br ea st ca nc er w it h ax ill ar y in vo lv em en t ( T 1- 3/ N 1- 3) . E p ir u bi ci n p lu s cy cl op ho sp ha m id e (E C ; 90 a nd 6 00 m g/ m 2 , re sp ec ti ve ly , fo u r cy cl es ), fo llo w ed by d oc et ax el (1 00 m g/ m 2 ; fo u r cy cl es ; E C -T ) as co nt ro l gr ou p ; ep ir u bi ci n p lu s d oc et - ax el ( E T ; 9 0 an d 7 5 m g/ m 2 , re sp ec ti ve - ly , fo u r cy cl es ), fo llo w ed b y ca p ec it a- bi ne ( 1, 25 0 m g/ m 2 t w ic e a d ay o n d ay s 1 to 1 4, f ou r cy cl es ; E T -X ) as t re at m en t gr ou p ; a ll re gi m en s w er e gi ve n ev er y 3 w ee ks 39 50 26 27 D FS Z ie lin sk i et a l., 2 01 6 20 08 -2 01 4 54 .3 P at ie nt s ag ed 1 8 ye ar s or o ld er w ho ha d a n E as te rn C oo p er at iv e O nc ol og y G ro u p p er fo rm an ce st at u s 0– 2 an d m ea su ra bl e or n on -m ea su ra bl e H E R 2- ne ga ti ve l oc al ly r ec u rr en t or m et as ta ti c br ea st ca nc er w ho ha d re ce iv ed no p re vi ou s ch em ot he ra p y fo r lo ca ll y re cu rr en t o r m et as ta ti c br ea st c an ce r. B e v a ci z u m a b p lu s p a cl it a x e l (b ev ac iz u m ab 1 0 m g/ kg o n d ay s 1 an d 15 p lu s p ac lit ax el 9 0 m g/ m ² on d ay s 1, 8, a nd 1 5 ev er y 4 w ee ks ) as c on tr ol gr ou p ; be va ci zu m ab p lu s ca p ec it ab in e (b ev ac iz u m ab 1 5 m g/ kg o n d ay 1 p lu s ca p ec it ab in e 10 00 m g/ m ² tw ic e d ai ly on d ay s 1– 14 e ve ry 3 w ee ks ) as t re at - m en t g ro u p . 20 1 20 5 64 60 O S T w el ve s et al ., 20 16 * * W om en a ge d 1 8 ye ar s or o ld er w ho ha d lo ca lly ad va nc ed or m et as ta ti c br ea st ca nc er , 3 p ri or ch em ot he ra p y re gi m en s (i nc lu d in g 2 fo r ad va nc ed an d / or m et as ta ti c d is ea se ), in cl u d in g an a nt hr ac yc lin e an d a t ax an e. H E R 2- ta rg et ed t he ra p y w as n ot a llo w ed d u r- in g st u d y tr ea tm en t. In tr av en ou s er ib u lin m es yl at e 1. 4 m g/ m 2 on d ay s 1 an d 8 a s co nt ro l gr ou p ; tw ic e- d ai ly o ra l c ap ec it ab in e 12 50 m g/ m 2 on d ay s 1– 14 (2 1- d ay cy cl es ) as tr ea tm en t g ro u p . 27 8 25 9 21 6 23 3 P FS T w el ve s et al ., 20 14 * * W om en w it h lo ca ll y re cu rr en t or m et a- st at ic b re as t ca nc er h ad r ec ei ve d b e- tw ee n tw o an d f iv e p re vi ou s ch em o- th er ap y re gi m en s (i nc lu d in g an an - th ra cy cl in e an d a t ax an e) , t w o or m or e of w hi ch w er e fo r lo ca lly r ec u rr en t or m et as ta ti c d is ea se . In tr av en ou s er ib u lin m es yl at e 1. 4 m g/ m 2 on d ay s 1 an d 8 a s co nt ro l gr ou p ; tw ic e- d ai ly o ra l c ap ec it ab in e 12 50 m g/ m 2 on d ay s 1– 14 (2 1- d ay cy cl es ) as tr ea tm en t g ro u p . 44 9 59 5 28 8 37 6 P FS 50 Bangladesh J Pharmacol 2020; 15: 47-57 T a b le I ( C o n t. ) B a si c in fo rm a ti o n o f in cl u d e d s tu d ie s R ef er en ce s Fo llo w -u p d u ra ti on M ed ia n fo llo w -u p d u ra ti on (m on th s) Pa tie nt s’ C ha ra ct er s T re at m en t r eg im en s N u m be r of p at ie nt s in e ac h gr ou p O u tc om es E R + E R + E R - E R - St u d y gr ou p C on tr ol g ro u p St u d y gr ou p C on tr ol g ro u p Sh an ka r et al ., 20 15 20 05 -2 01 0 38 P at ie nt s ag ed r an ge f ro m 4 0- 72 y ea rs w it h ho rm on e re ce p to r p os it iv e m et a- st at ic b re as t c an ce r. C om bi na ti on o f an a ro m at as e in hi bi to r (A I) an d ca p ec it ab in e as tr ea tm en t gr ou p ; ar om at as e in hi bi to r (A I) as co nt ro l gr ou p . C ap ec it ab in e 65 0 m g/ m 2 o n d ay s 1– 14 (2 1- d ay c yc le s) 31 22 P FS Jo en su u e t al ., 20 12 20 04 -2 01 0 59 W om en a ge 1 8 to 6 5 ye ar s ha d h is to - lo gi ca lly co nf ir m ed in va si ve br ea st ca nc er w it h re gi on al ly m p h no d es co nt ai ni ng ca nc er or no d e- ne ga ti ve ca nc er w it h p ri m ar y tu m or d ia m et er gr ea te r th an 2 0 m m a nd n eg at iv e p ro - ge st er on e re ce p to r ex p re ss io n in im - m u no hi st oc he m is tr y D o ce ta x e l p lu s ca p e ci ta b in e + cy cl op ho sp ha m id e ep ir u bi ci n an d ca p ec it ab in e as tr ea tm en t gr ou p ; d oc et ax el + cy cl op ho sp ha m id e, ep ir u - bi ci n an d fl u or ou ra ci l a s co nt ro l g ro u p . C ap ec it ab in e 90 0 m g/ m ² tw ic e a d ay , d ay s 1– 15 , e ve ry 3 w ee ks 58 0 56 2 17 1 18 3 D FS G li go ro v et a l., 2 01 4 20 09 -2 01 1 11 .9 W om en a ge d 1 8 ye ar s or o ld er w it h H E R 2- ne ga ti ve m et as ta ti c br ea st c an ce r w it h at le as t on e m ea su ra bl e le si on ac co rd in g to R es p on se E va lu at io n C ri - te ri a in S ol id T u m or s; h av in g an E as t- er n C oo p er at iv e O n co lo gy G ro u p (E C O G ) p er fo rm an ce s ta tu s of 1 o r 0; a li fe e xp ec ta nc y of a t l ea st 1 2 w ee ks . B ev ac iz u m ab an d ca p ec it ab in e as tr ea tm en t gr ou p ; B ev ac iz u m ab o nl y as co nt ro l gr ou p . C ap ec it ab in e 10 00 m g/ m ² tw ic e p er d ay o n d ay s 1– 14 , e ve ry 3 w ee ks . 64 69 27 25 P FS O S L ee e t a l., 20 08 * 37 P at ie nt s ha d t o be a ge d 1 8 ye ar s or ol d er w it h an E as te rn C o- op er at iv e O nc ol og y G ro u p ( E C O G ) p er fo rm an ce st at us ≤1 an d ha ve bi op sy -p ro ve n, ne w ly d ia gn os ed st ag e II / II I br ea st ca nc er w it h ax ill ar y ly m p h no d e in - vo lv em en t. D oc et ax el an d ca p ec it ab in e as tr ea t- m en t gr ou p ; d ox or u bi ci n an d cy cl o- p ho sp ha m id e as c on tr ol g ro u p . C ap e- ci ta bi ne 1, 00 0 m g/ m 2 or al ly tw ic e d ai ly o n d ay s 1– 14 e ve ry 3 w ee ks f or fo u r cy cl es . 64 62 39 39 P C R G lü ck e t al ., 20 13 * E R + (C + D ) 48 .4 E R + (D ) 43 .6 E R - ( C + D ) 23 .9 E R - ( D ) 21 .5 P at ie nt s w er e ag ed 1 8 ye ar s w it h hi st o- lo gi ca ll y or cy to lo gi ca ll y co n fi rm ed u nr es ec ta bl e m et as ta ti c br ea st ca nc er th at h ad r ec u rr ed f ol lo w in g an th ra cy - cl in e tr ea tm en t in th e (n eo )a d ju va nt se tt in g. P at ie nt s w er e re qu ir ed t o ha ve a K ar no fs ky p er fo rm an ce sc or e 70 % an d li fe e xp ec ta nc y 3 m on th s. C ap ec it ab in e an d d oc et ax el (C + D ) as tr ea tm en t gr ou p ; d oc et ax el (D ) as c on - tr ol g ro u p . C ap ec it ab in e 12 50 m g/ m 2 tw ic e d ai ly , d ay s 1- 14 , 2 1- d ay c yc le s. 90 95 88 83 O S T T P Bangladesh J Pharmacol 2020; 15: 47-57 51 between the study group and control group was not statistically significant, as shown in Figure 4C and Figure 5A. In the ER- breast cancer, there were also five outcome measures: PFS, PCR, DFS, OS, and TTP. When the outcomes were PFS [RR= 0.96, 95% CI (0.91-1.02)], PCR [RR= 1.09, 95% CI (0.73-1.63)], and OS [RR= 0.94, 95% CI (0.72- 1.22)], three (Gligorov et al., 2014; Twelves et al., 2014; Twelves et al., 2016), two (Lee et al., 2008; Zambetti et al., 2012), and three (Glück et al., 2013; Gligorov et al., 2014; Zielinski et al., 2016) studies were included respectively. Results showed that the difference between study group and control group was not statistically significant, as shown in Figure 5B, Figure 6A and Figure 6B. Whereas, the obvious difference between study group and control group of DFS [RR= 0.74, 95% CI (0.58-0.95)] (Figure 5C) and TTP [RR= 0.73, 95% CI (0.53- 0.98)] had been confirmed using meta-analysis of three (Joensuu et al., 2012; Glück et al., 2013; Martin et al., 2015) and one (Glück et al., 2013) included studies respectively. The summary of the results of all outcome measures is shown in Table II. Discussion Breast cancer is a common malignant tumor that has a strong heterogeneity of clinical presentation, histological and molecular typing in the female worldwide. Diagnosis by estro- gen-receptor status subtype added significant prognostic and predictive information for breast cancer (Parker et al., 2009). Capecitabine monotherapy for locally advanced or metas- tatic breast cancer had different overall res- ponse rate and progression-free survival in patients with different hormone-receptor status (Osako et al., 2009). The results of this study indicated that ER+ breast cancer patients receiving capecitabine containing treatment regimens could significantly improve PFS, PCR and TTP. Whereas the difference in DFS and OS between study and control groups was not significant. ER- breast cancer patients recei- ving capecitabine contain-ing treatment regimens could improve DFS and TTP, while the comparison of PFS, PCR and OS had no statistical difference. In contrast to patients with ER- disease, those with ER+ tumors seem- ed to benefit from the capecitabine treatment regimens, suggesting capecitabine-containing chemotherapy regimens have different treat- ment effects by ER status. T a b le I ( C o n t. ) B a si c in fo rm a ti o n o f in cl u d e d s tu d ie s R ef er en ce s Fo llo w -u p d u ra ti on M ed ia n fo llo w -u p d u ra ti on (m on th s) Pa tie nt s’ C ha ra ct er s T re at m en t r eg im en s N u m be r of p at ie nt s in e ac h gr ou p O u tc om es E R + E R + E R - E R - St u d y gr ou p C on tr ol g ro u p St u d y gr ou p C on tr ol g ro u p Z am be tt i et a l., 2 01 2 20 04 -2 00 9 * Pa tie nt s ha d to b e fe m al es ≥ 18 y ea rs ol d , p re se nt in g fo r th e fi rs t ti m e w it h u ni la te ra l, op er ab le , in va si ve br ea st ca nc er ＞ 2. 0 cm i n d ia m et er , w it h no p re vi ou s tr ea tm en t fo r in va si ve m al ig - na nc y, an d an E as te rn C oo p er at iv e O nc ol og y G ro u p ( E C O G ) p er fo rm an ce st at us ≤ 1. S uf fic ie nt t is su e fo r re ce pt or st at u s an d tr an sl at io na l st u d ie s w as m an d at or y. D ox or u bi ci n an d p ac lit ax el + C yc lo - p ho sp ha m id , m et ho tr ex at e an d c ap e- ci ta bi ne a s tr ea tm en t gr ou p ; d ox or u bi - ci n an d p ac lit ax el + C yc lo ph os p ha m id , m et ho tr ex at e an d fl u or ou ra ci l as co nt ro l gr ou p . 18 50 m g/ m 2 or al c ap e- ci ta bi ne d iv id ed i nt o tw o d ai ly d os es fr om d ay 1 to 1 4) a t 4 -w ee k in te rv al s 61 60 42 43 P C R O 'S ha u gh - ne ss y et al ., 20 10 * 60 P at ie nt s ag ed 1 8- 70 y ea rs , w it h br ea st ca nc er a s ≥1 p os iti ve ly m ph n od e, T 1- 3, an d M 0; o r no d e ne ga ti ve w it h tu m or s > 2 cm a nd M 0; o r no d e ne ga ti ve w it h tu m or s > 1 cm . D ox or u bi ci n pl u s cy cl op ho sp ha m id e fo llo w ed b y d oc et ax el w it h ca pe ci ta - bi ne a s tr ea tm en t gr ou p ; d ox or u bi ci n p lu s cy cl op ho sp ha m id e fo llo w ed by d oc et ax el w it ho u t ca p ec it ab in e as co nt ro l g ro u p . * * * * D FS 52 Bangladesh J Pharmacol 2020; 15: 47-57 The reasons for the different results obtained in ER+ or ER- studies may relate to the patient populations enrolled, the patients in the meta-analysis included node-positive early breast cancer and advan-ced or metastatic breast cancer. The National Compre-hensive Cancer Network (NCCN) guideline for early breast cancer patients recommends treatment with anthracycline and/or taxane chemotherapy which contained no capecitabine. And the capecitabine dosing regimen recommended by NCCN is 1000–1250 mg/m2 twice daily, but several studies included in our meta- analysis reduced this by 10 to 35%. Finally, capecitabine -based chemotherapy resulted in increasing in adverse effects, which may have led to reduced compliance with therapy. The main limitation of this study is that the included original studies were very few. And the number of studies for each outcome measure was less than four, which resulting in a big bias to influence the authen- ticity of effect. Further randomized controlled trials of capecitabine therapy on targeted populations with the adjuvant and neoadjuvant setting. Conclusion Capecitabine in combination with other chemotherapy drugs for breast cancer is effective, which can delay the progression time in patients to some extent. Compared with ER-breast cancer, the curative effect of capecita- bine-containing chemotherapy regimen is more obvious in ER+ breast cancer patients. Whether there is an additional capecitabine treatment benefit in ER positive and ER negative breast cancer requires further evalua- tion because of potential bias. Table II Summary of outcome measures in the included studies Outcome measures Number of studies Included studies ER+ RR and 95%RR ER- RR and 95%RR PFS 4 (ER+) Twelves et al., 2016 0.93 (0.88-0.97) 0.96 (0.91-1.02) 3 (ER-) Twelves et al., 2014 PFS 4 (ER+) Shankar et al., 2015 0.93 (0.88-0.97) 0.96 (0.91-1.02) 3 (ER-) Gligorov et al., 2014 PCR 2 Lee et al., 2008 0.24 (0.09-0.63) 1.09 (0.73-1.63) PCR 2 Zambetti et al., 2012 0.24 (0.09-0.63) 1.09 (0.73-1.63) DFS 3 Martín et al., 2015 0.89 (0.71-1.12) 0.74 (0.58-0.95) Joensuu et al., 2012 O'Shaughnessy et al., 2010 OS 3 Zielinski et al., 2016 0.89 (0.74-1.07) 0.94 (0.72-1.22) Gligorov et al., 2014 Glück et al., 2013 TTP 1 Glück et al., 2013 0.62 (0.46-0.84) 0.73 (0.53-0.98) Figure 3: Risk of bias summary Shankar et al., 2015 Zielinsk et al., 2016 Twelves et al., 2014 Twelves at al., 2016 Joensuu et al., 2012 Gligorov et al., 2014 Lee et al., 2008 Martín et al., 2015 Zambetti et al., 2012 O’Shaughnessy et al., 2010 Glück et al., 2013 Bangladesh J Pharmacol 2020; 15: 47-57 53 Figure 4: ER+ breast cancer PFS analysis of different comparison groups (A); ER+ breast cancer PCR analysis of different compari- son groups (B); ER+ breast cancer DFS analysis of different comparison groups (C) C B A Shankar et al., 2015 Gligorov et al., 2014 Twelves et al., 2016 Twelves et al., 2014 Lee et al., 2008 Joensuu et al., 2012 Zambetti et al., 2012 USO, 2010 Martín et al., 2015 54 Bangladesh J Pharmacol 2020; 15: 47-57 Financial Support Self-funded Conflict of Interest Authors declare no conflict of interest. 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