advanced breast cancer (metastatic)

     

Select            
Trial Studied trt Control trt patientstagsROB Trial resultdeath (overall survival) progression or death (progression free survival PFS)

selective estrogen receptor modulator (SERM)  

tamoxifen  
Viladiu, 1985      -
Kuss, 1997     tamoxifen -
De Lena, 1990     tamoxifen -
Takatsuka, 1989     tamoxifen 20 mg/day40 mg/day -
Ingle, 1986     tamoxifenbilateral oophorectomy -
Perry, 1985     tamoxifen + CATCAT -
Mouridsen, 1985     tamoxifen + CMFCMF -
Spooner, 1991     loading dose regimen of tamoxifenconventional dosing -
Gockerman, 1986     tamoxifendiethylstilbestrol -
Beex, 2006         intermittent tamoxifenIntermittent tamoxifen -
Muss, 1994       tamoxifenmedroxyprogesterone -
Castiglione-Gertsch, 1993     tamoxifenmedroxyprogesterone acetate -
van, 1986     tamoxifenmedroxyprogesterone acetate -
Stuart, 1996     tamoxifenmegestrol acetate -
Gill, 1993     tamoxifenmegestrol acetate -
Ettinger, 1986     tamoxifenmegestrol acetate -
Kellokumpu-Lehtinen, 1987     tamoxifennandrolone decanoate -
Beelen, 2014     tamoxifenno systemic treatment -
Sawka, 1997     tamoxifenovarian ablation -
Willsher, 1996     tamoxifenradiotherapy -
Mauriac, 1986     alternatingsuccessive -
Buchanan, 1986     tamoxifensurgical oophorectomy -
toremifene  
Nomura, 1993   toremifenetamoxifenLow risk of bias negative
Gershanovich, 1997   toremifenetamoxifennegative
Milla-Santos, 2001   toremifenetamoxifenLow risk of bias negative
Hayes, 1995   toremifenetamoxifennegative
Stenbygaard, 1993   toremifenetamoxifennegative
Pyrhonen, 1997   toremifenetamoxifensuggesting

angiogenesis inhibitors  

not classified  
LEA     bevacizumab + endocrine therapyendocrine therapy -
De Jong     enzastaurin + fulvestrantFulvestrant -
Dickler (CALGB 40503°, 2015       Letrozole plus bevacizumabletrozole -
bevacizumab  
RIBBON-I (Robert) on top capecitabine, 2009     bevacizumab + capecitabinecapecitabine 1st line Low risk of bias suggesting -15%-32%
AVF2119g (Miller) cape, 2005   bevacizumab + capecitabinecapecitabine 2nd line Risk of bias suggesting7%-2%
RIBBON-2 (Brufsky), 2009     bevacizumav + CTCT alone 2nd line suggesting-10%-22%
AVADO (Miles) 15mg , 2009     bevacizumab + docetaxeldocetaxel 1st line HER-2 negative suggesting-8%-31%
AVADO (Miles) 7.5mg, 2010   bevacizumab + docetaxeldocetaxel 1st line HER-2 negative Low risk of bias negative5%-14%
Burstein, 2005   bevacizumab + methotrexatemethotrexatenegative
Martin bevacizumab, 2011     bevacizumab + paclitaxelpaclitaxel 1st line HER-2 negative Risk of bias negative-21%
E2100 (Miller), 2007      NCTbevacizumab + taxanestaxanes 1st line Risk of bias suggesting-14%-44%
RIBBON-I (Robert) on top Tax or anthra, 2009     bevacizumab + taxanestaxanes 1st line suggesting 3%-23%
ceritinib  
Hyams      NCTcediranib + fulvestrantfulvestrant -
motesanib  
Martin (motesanib), 2011      NCTmotesanib + paclitaxelpaclitaxel 1st line HER-2 negative Low risk of bias -
sorafenib  
Schwartzberg, 2013      NCTsorafenib + gemcitabine or capecitabinegemcitabine or capecitabine alone 2nd line HER-2 negative Exploratory suggesting1%-36%
Gradishar, 2013     sorafenib + paclitaxelpaclitaxel alone 1st line HER-2 negative Low risk of bias negative2%-21%

Anthracyclines based regimen  

not classified  
Stewart, 1997     CNFCAF -
Smalley, 1983   CAFCMFVP -
ANZBC, 1986     sequentiallycombination -
Namer, 2001     MVFAC/FEC -
French Epirubicin Study , 1988     FACFEC -
Italian Study, 1988     FACFEC -
Ejlertsen   FEC x 24 + tamoxifenFEC x 8 + tamoxifen -

aromatase inhibitors  

not classified  
Goss, 1999   vorozolemegestrol acetatesuggesting 10%27%
Rose, 1986   aminoglutethimide + tamoxifentamoxifennegative-9%
aminoglutethimide  
Mercer, 1993   aminoglutethimidehydrocortisonenegative
Canney, 1988   aminoglutethimidemedroxyprogesterone acetatesuggesting
Garcia-Giralt, 1992   aminoglutethimidemedroxyprogesterone acetatenegative
Samonis, 1994   aminoglutethimidemedroxyprogesterone acetatenegative
Lundgren, 1989   aminoglutethimidemegestrol acetatenegative
Russell, 1997   aminoglutethimidemegestrol acetatenegative -11%25%
Alonso-Munoz, 1988   aminoglutethimidetamoxifennegative
Gale, 1994   aminoglutethimidetamoxifennegative 12%-16%
Ingle, 1986   aminoglutethimide + tamoxifentamoxifennegative -21%-15%
Powles, 1984   combination of hormone therapiestamoxifennegative
anastrozole  
Mauriac, 2003   anastrozolefulvestrantnegative34%
Buzdar a, 1996   anastrozolemegestrol acetatenegative -22%
TARGET (Bonneterre), 2001   anastrozoletamoxifensuggesting-3%-18%
Milla-Santos, 2003   anastrozoletamoxifennegative -8%
exemestane  
Chia, 2008   exemestanefulvestrantnegative4%
Kaufmann, 2000   exemestanemegestrol acetatenegative -15%-18%
Paridaens, 2003   exemestanetamoxifennegative
fadrozole  
Bezwoda, 1998   fadrozolemegestrol acetatenegative35%
Buzdar b, 1996   fadrozolemegestrol acetatenegative
Buzdar c, 1996   fadrozolemegestrol acetatenegative
Thuerlimann, 1996   fadrozoletamoxifennegative-9%
Falkson, 1996   fadrozoletamoxifennegative
formestane  
Kleeberg, 1997   formestaneanastrozolenegative
Thuerlimann, 1997   formestanemegestrol acetatenegative-7%
Freue, 2000   formestanemegestrol acetatesuggesting6%
Perez Carrion, 1994   formestanetamoxifennegative
letrozole  
Gershanovich, 1998   letrozoleaminoglutethimidenegative-28%
Rose, 2003   letrozoleanastrozolenegative
Goss, 2007   letrozoleatamestane + toremifenenegative0%
Tominaga, 2003   letrozolefadrozolenegative
Buzdar, 2001   letrozolemegestrol acetatesuggesting-8%-1%
Dombernowsky, 1998   letrozolemegestrol acetatenegative-18%-2%
Mourisden, 2001   letrozoletamoxifennegative -30%

Capecitabine containing-regimen  

capecitabine  
Oshaughnessy, 2001     capecitabineCMF -
Joensuu, 2009      NCTcapecitabinecontrolRisk of bias -
Stockler, 2011     capecitabinecyclophosphamide, methotrexate, and 5-fluorouracil -
GeparQuattro, 2010      NCTcapecitabine docetaxeldocetaxel -
Mavroudis, 2010     capecitabinedocetaxel + epirubicin -
Verma, 2005     capecitabine + docetaxeldocetaxel alone -
Miles, 2004     capecitabine + docetaxeldocetaxel alone -
O'Shaughnessy, 2002     capecitabine + docetaxeldocetaxel alone -
Lee, 2008     capecitabine + docetaxeldoxorubicin + cyclophosphamide -
Hori     capecitabine MPAIV CT -
Talbot, 2002     capecitabinepaclitaxel -
Moiseenko, 2000     capecitabinepaclitaxel -
Jäger, 2010   capecitabinepegylated liposomal doxorubicin -
EORTC 10001 (Pajk), 2008     capecitabinevinorelbine -

CDK (cyclin-dependent kinase) inhibitor  

abemaciclib  
MONARCH 3, 2017        NCTAbemaciclib +nsAInsAI 1st line HER-2 negative HR positive postmenopausal Low risk of bias conclusive-46%
palbociclib  
PALOMA 3, 2015            NCTpalbociclib + fulvestrantfulvestrant alone2nd line 2nd line HER-2 negative HR positive Low risk of bias conclusive-58%
PALOMA-2, 2016      NCTpalbociclib + letrozoleletrozole alonefirst line 1st line HER-2 negative HR positive postmenopausal Low risk of bias conclusive-42%
PALOMA 1/TRIO-18, 2015      NCTpalbociclib + letrozoleletrozole alone 1st line HER-2 negative HR positive postmenopausal Exploratory suggesting-51%
ribociclib  
MONALEESA-2, 2016        NCTribociclib (LEE011) + letrozoleletrozole alonefirst line 1st line HER-2 negative HR positive postmenopausal Low risk of bias conclusive-44%

combination chemotherapy with platinum salts  

cisplatin  
Costanza, 1999   carboplatin followed by CAFCAFsuggesting
Creagan ET, 1984   CAPCFPsuggesting
Cocconi, 1991   cisplatin + etoposideCMFsuggesting
Cocconi, 1999   CMF, cisplatin, etoposide, and doxorubicinCMFsuggesting
Cocconi G, 1996   MPEPIV or MPEMiCMFsuggesting
Kolaric, 1985   CAPCMFVPsuggesting
Eisen, 1998     EcisFECycloFnegative
Nielsen, 2000   EPI + CISEPIsuggesting
Kolaric, 1989   CAPFACsuggesting
Berruti A, 2002   cisplatin + epirubicinlonidamine + epirubicinnegative
Berruti B, 2002   cisplatin + epirubicinlonidamine + epirubicinsuggesting
Icli, 2002   VP-16+Ppaclitaxelsuggesting
Fountzilas, 2002       PCbPEnegative

Gemcitabine containg regimen  

gemcitabine  
Seidman, 2011     gemcitabine + docetaxel capecitabine + docetaxel -
Chan, 2009     gemcitabine + docetaxelcapecitabine plus docetaxel -
Nielsen, 2011     gemcitabine + docetaxeldocetaxel -
Feher, 2005     gemcitabineepirubicin -
Brufsky, 2011     gemcitabine + paclitaxel + bevacizumabpaclitaxel + bevacizumab -
Albain, 2008     gemcitabine + paclitaxelpaclitaxel monotherapy -
Martín, 2007     gemcitabine + vinorelbinevinorelbine monotherapy -
Papadimitriou, 2009       gemcitabine + weekly docetaxelweekly docetaxel -

HER2 inhibitors  

pertuzumab  
CLEOPATRA, 2012          NCTpertuzumab + trastuzumab +docetaxeltrastuzumab + docetaxel 1st line HER-2 positive Low risk of bias suggesting-32%-38%
neoSphere (Group B), 2012      NCTpertuzumab + trastuzumab +docetaxeltrastuzumab + docetaxel HER-2 positive Exploratory -
trastuzumab  
TAnDEM (Kaufman), 2009   trastuzumab + anastrozoleanastrozole alone HER-2 positive HR positive -
von Minckwitz, 2009   trastuzumab + capecitabinecapecitabine alone HER-2 positive previously treated by HER-2 antibody trastuzumab failure -
Marty, 2005   trastuzumab + docetaxeldocetaxel alone 1st line HER-2 positive -
Blackwell, 2010   trastuzumab + lapatiniblapatinib alone ErbB2 positive previously treated by HER-2 antibody trastuzumab failure -
Huober, 2012   trastuzumab + letrozoleletrozole alone HER-2 positive HR positive -
Gasparini, 2006   trastuzumab + paclitaxelpaclitaxel alone HER-2 positive -
Slamon, 2001   trastuzumab + standard chemotherapystandard chemotherapy alone HER-2 positive -
trastuzumab emtansine  
EMILIA, 2012      NCTtrastuzumab emtansinelapatinib plus capecitabine 2nd line HER-2 positive previously treated by HER-2 antibody previously treated by taxanes suggesting-32%-35%
TH3RESA, 2014    NCTtrastuzumab emtansineusual care 2nd+ line HER-2 positive previously treated by HER-2 antibody Risk of bias suggesting-47%

high dose chemotherapy  

not classified  
ECOG, 200   high-dose chemotherapyconventional-dose chemotherapynegative
IBDIS, 2003   high-dose chemotherapyconventional-dose chemotherapynegative
NCIC, 2001   high-dose chemotherapyconventional-dose chemotherapynegative
PEGASE 03, 2002   high-dose chemotherapyconventional-dose chemotherapynegative
PEGASE 04, 1999   high-dose chemotherapyconventional-dose chemotherapynegative
Schmid, 2005   high-dose chemotherapyconventional-dose chemotherapynegative

histone deacetylase (HDAC) inhibitors  

entinostat  
ENCORE 301, 2013      NCTEntinostat + exemestaneexemestane -

immune checkpoint inhibition  

not classified  
IMpassion130, 2018   atezolizumab + Nab-Paclitaxel Nab-Paclitaxel -

ixabepilone based chemotherapy  

ixabepilone  
Sparano, 2010       ixabepilone (on top capecitabine)no ixabepiloneRisk of bias negative-10%
Thomas, 2007     ixabepilone (on top capecitabine)no ixabepiloneRisk of bias suggesting-10%-25%

locoregional treatment of the primary tumor  

not classified  
Badwe, 2015     locoregional treatmentno treatment of the primary tumour -

maintenance chemotherapy  

not classified  
Mayordomo, 2009   negative-6%
Harris, 1990     maintenancecontrolnegative6%
Muss, 1991     maintenancecontrolnegative11%
Gregory, 1997     maintenancecontrolnegative-19%
Falkson, 1998     maintenancecontrolnegative-6%
Nooij, 2003     maintenancecontrolnegative3%
Gennari, 2006     maintenancecontrolnegative12%
Alba, 2010     maintenancecontrolnegative-14%
Coates, 1987     continuousintermittentnegative-21%
Ejlertsen, 1993   longshortsuggesting-22%
French Epirubicin Study Group, 2000     longshortnegative-4%

mTOR inhibitor  

everolimus  
BOLERO-2, 2011        NCTeverolimus + exemestaneexemestane alone HER-2 negative HR positive nsNAI failure previously treated with endocrine therapy Low risk of bias conclusive-11%-57%
TAMRAD , 2012      NCTeverolimus + tamoxifentamoxifen alone 1st line HER-2 negative HR positive postmenopausal previously treated with endocrine therapy Risk of bias suggesting-55%
BOLERO-3, 2014      NCTeverolimus + trastuzumab + vinorelbinetrastuzumab + vinorelbine alone HER-2 positive previously treated by taxanes trastuzumab failure Low risk of bias conclusive-22%
temsirolimus  
HORIZON, 2013      NCTtemsirolimus + letrozoleletrozole alone 1st line HR positive postmenopausal Low risk of bias negative-11%-10%

multi target TKI  

not classified  
Geyer, 2006        NCTlapatinib + capecitabinecapecitabine alone 2nd line HER-2 positive previously treated by HER-2 antibody previously treated by taxanes Risk of bias suggesting-22%-45%
lapatinib  
Johnston (EGF30008) , 2009      NCTlapatinib + letrozoleletrozole alone HR positive Low risk of bias conclusive -22%-29%
Di Leo, 2008        NCTlapatinib + paclitaxelpaclitaxel alone 1st line Low risk of bias negative -14%-10%
sorafenib  
Baselga, 2012     sorafenib + capecitabinecapecitabine alone HER-2 negative Low risk of bias suggesting-14%-42%
Schwartzberg, 2013      NCTsorafenib + gemcitabine or capecitabinegemcitabine or capecitabine alone 2nd line HER-2 negative Exploratory suggesting1%-36%
Gradishar, 2013     sorafenib + paclitaxelpaclitaxel alone 1st line HER-2 negative Low risk of bias negative2%-21%

nontaxane microtubule dynamics inhibitor  

eribulin  
Trial 301 (Kaufman), 2015        NCTeribulincapecitabineRisk of bias negative-12%8%
Vahdat, 2013      NCTeribulinixabepiloneExploratory -
EMBRACE (Cortes), 2011        NCTeribulintreatment of physicianRisk of bias conclusive-19%-13%

Phosphoinositide 3-kinase inhibitor  

taselisib  
SANDPIPER, 2018    NCTtaselisib + fulvestrantfulvestrant alone2L ER PIK3CA-MUTLow risk of bias -

poly ADP-ribose polymerase (PARP) inhibitor  

olaparib  
OlympiAD, 2017      NCTolaparibPhysician s choice chemotherapy BRCA-mutated HER-2 negative Risk of bias conclusive-10%-42%

Selective estrogen receptor downregulators (SERDs)  

fulvestrant  
GEICAM/2006-10    NCTfulvestrant + anastrozoleanastrozole HER-2 negative HR positive postmenopausal Risk of bias -
FACT (Bergh), 2012      NCTfulvestrant + anastrozoleanastrozole first line of endocrine therapy HR positive postmenopausal negative0%-1%
Mehta(SWOG-S0226), 2012      NCTfulvestrant + anastrozoleanastrozole HR positive suggesting-19%-20%
Xu et al., 2011      NCTfulvestrant 250mganastrozole HR positive postmenopausal Low risk of bias -
0021 (Osborne), 2002      NCTfulvestrant 250mganastrozole postmenopausal Low risk of bias negative
0020 (Howell), 2002     fulvestrant 250mganastrozoleRisk of bias negative
FIRST (Robertson), 2010    NCTfulvestrant 500mganastrozole first line of endocrine therapy postmenopausal suggesting
9238UK/0005 (fluvestrant alone)    NCTfluvestrant 250mgexemestane postmenopausal previously treated with endocrine therapy Low risk of bias -
SoFEa (Johnston) fluvestrant alone, 2012      NCTfluvestrant 250mgexemestane postmenopausal previously treated with endocrine therapy -
9238UK/0005 (combination)    NCTfulvestrant + anastrozoleexemestane postmenopausal previously treated with endocrine therapy Low risk of bias -
SoFEa (Johnston) combination, 2012      NCTfulvestrant + anastrozoleexemestane HR positive postmenopausal previously treated with endocrine therapy negative-5%
EFECT (Chia)    NCTfulvestrant 250mgexemestane HR positive postmenopausal Low risk of bias negative
D6997L00021    NCTfulvestrant 500mgfulvestrant 250mg HR positive previously treated with endocrine therapy Low risk of bias -
CONFIRM (Di Leo), 2010      NCTfulvestrant 500mgfulvestrant 250mg HR positive previously treated with endocrine therapy Low risk of bias -
FINDER 1 (Ohno), 2010     fulvestrant 500mgfulvestrant 250mg postmenopausal -
FINDER 2, 2010      NCTfulvestrant 500mgfulvestrant 250mg postmenopausal previously treated with endocrine therapy Exploratory -
9238IL/0025    NCTfulvestrant 250mgtamoxifen first line of endocrine therapy Low risk of bias -
0025 (Howell), 2004     fulvestrant 250mgtamoxifen previously treated with endocrine therapy Low risk of bias negative

Taxanes  

not classified  
Nabholtz   Exploratory suggesting
Yardley, 2009   Exploratory negative
AGO, 1998   Exploratory negative
Lyman   Exploratory suggesting
TRAVIOTA   Exploratory negative
EU-1, 2004   Exploratory suggesting
306 Study Group, 2003   docetaxel + doxorubicindoxorobicin + cyclophosphamide 1st line Risk of bias suggesting
EORTC 10961, 2002   paclitaxel + doxorubicindoxorobicin + cyclophosphamide 1st line Exploratory negative
303 Study Group, 1999   docetaxeldoxorubicin 2nd+ line Risk of bias suggesting
Meier, 2008   docetaxelvinorelbine 2nd+ line previous anthracycline Exploratory negative
docetaxel  
JCOG, 2005   docetaxeldoxorubicin + cyclophosphamide 1st line Exploratory negative
Blohmer, 2010   docetaxel + epirubicinepirubicin, cyclophosphamide 1st line Risk of bias negative
Rivera , 2008   Weekly DocetaxelEvery three weeks Docetaxel -
Tabernero , 2004   Weekly DocetaxelEvery three weeks Docetaxel -
Sedky , 2002   Weekly DocetaxelEvery three weeks Docetaxel -
Willemse , 2007   Weekly DocetaxelEvery three weeks Docetaxel -
Bontenbal, 2005   docetaxel + doxorubicinfluorouracil, doxorubicin, cyclophosphamide 1st line Risk of bias suggesting
Bonneterre, 2004   docetaxel + epirubicinfluorouracil, epirubicin, cyclophosphamideRisk of bias suggesting
TXT Group, 2002   docetaxelfluorouracil, vinorelbine 2nd line previous anthracycline Exploratory suggesting
304 Study Group, 1999   docetaxelmitomycin, vinblastine 2nd+ line previous anthracycline Risk of bias suggesting
Sjostrom, 1999   docetaxelsequential methotrexate and 5-fluorouracil 2nd+ line previous anthracycline Exploratory suggesting
HERNATA, 2011   docetaxel + trastuzumabvinorelbine, trastuzumab 1st line HER-2 positive Exploratory suggesting
nab-paclitaxel  
Gradishar, 2009              NCTnab-paclitaxeldocetaxel 1st line Exploratory -
Roy, 2008        NCTnab-paclitaxel +gencotabinegencitabine 1st line -
paclitaxel  
Talbot, 2002   pacclitaxelcapecitabineExploratory negative
TOG, 2005   paclitaxelcisplatin, etoposideExploratory negative
ANZ TITG, 1999   paclitaxelCMFP 1st line Risk of bias suggesting
ECOG E1193 (B), 2003   paclitaxeldoxorubicinExploratory negative
EORTC 10923, 2000   paclitaxeldoxorubicin 1st line Exploratory negative
UKCCCR AB01, 1997   paclitaxel + epirubicinepirubicin, cyclophosphamide 1st line Exploratory suggesting
Gradishar , 2009   Weekly PaclitaxelEvery three weeks DocetaxelExploratory negative
Fountzilas , 2008   Weekly PaclitaxelEvery three weeks Docetaxelnegative
Khoo , 2006   split doseEvery three weeks Paclitaxel not previously treated by anthracycline negative
CLGB 9840 (Seidman), 2008   Weekly PaclitaxelEvery three weeks Paclitaxelsuggesting
Frasci , 2006   Weekly PaclitaxelEvery three weeks Paclitaxelnegative
Frasci , 2005   Weekly PaclitaxelEvery three weeks Paclitaxelnegative
Sikov , 2002   Weekly PaclitaxelEvery three weeks Paclitaxelnegative
Jassem, 2001   paclitaxel + doxorubicinfluorouracil, doxorubicin, cyclophosphamide 1st line Exploratory suggesting
CECOG BM1, 2005   gemcitabine, epirubicin, paclitaxelfluorouracil, epirubicin, cyclophosphamide 1st line Exploratory suggesting
Dieras, 1995   paclitaxelmitomycinExploratory negative

Vinorelbine containing regimen  

vinorelbine  
Meier, 2008      -
Martin, 2007      -
Kim, 2006      -
Norris, 2000      -
Ejlertsen, 2004      -
Pajk, 2007      -
Venturino, 2000   -
Frasci, 2000      -
Verma, 2007   -