fulvestrant ( faslodex ; astrazeneca ) is a novel steroidal estrogen receptor ( er ) antagonist lacking agonist effects . by covalent binding to the er , receptors are rapidly downregulated , resulting in a decrease of cellular er levels and complete abrogation of estrogen - sensitive gene transcription .
the efficacy of fulvestrant in patients with tamoxifen - resistant disease [ 2 , 3 ] and in patients progressing on aromatase inhibitors   has been confirmed , thus giving the opportunity to extend the overall period during which hormonal agents may be used in women with endocrine - responsive advanced breast cancer .
two recent clinical trials are focusing on fulvestrant high - dose regimens ( 500 mg monthly ) to optimize fulvestrant treatment .
the neoadjuvant newest trial   showed significantly greater biological activity benefit with high - dose fulvestrant compared to the approved dose . the randomized , double - blind confirm ( comparison of faslodex in recurrent or metastatic breast cancer ) trial presented recently  
has shown a small but statistically significant increase in time to progression for fulvestrant 500 mg compared with fulvestrant 250 mg , without increase of toxicity .
we report a case achieving long - term complete remission under fulvestrant introduced after no or poor response to prior endocrine therapies , in whom the most efficacious dosing regimen was below the approved dose .
in january 1993 , a 47-year - old , premenopausal woman was diagnosed with a left breast cancer ( pt1c(m)pn0m0 ) after bilateral subcutaneous mastectomy for relapsing fibroadenomas .
the tumor was er - positive ( 90% ) , pgr - positive ( 70% ) as evaluated by immunohistochemistry and had a low - level her2-gene amplification ratio of 2.22 ( positive > 2.20 ) as assessed in 2007 .
axillary dissection was carried out followed by radiotherapy ( 50 gy total dose ) , but no adjuvant endocrine therapy was given . in january 1998 , distant recurrence was diagnosed in soft tissue ( er - negative , pgr - positive by histological assessment ) , in bone , pleura and lung ( lymphangiosis carcinomatosa ) .
anastrozole was started as 1st - line endocrine treatment in a clinical trial , but discontinued after 3 months due to progression in pleura / lung and in the contralateral breast .
1 ) . six cycles of chemotherapy with paclitaxel ( 175 mg / m ) and doxorubicin ( 60 mg / m ) , every 21 days ( eortc 10961 ) , were given , followed by monthly pamidronate for 8 months .
partial remission for 10 months was achieved with normalized chest x - ray and ca 15 - 3 . in june 1999
she received 9 months of tamoxifen as 2nd - line endocrine treatment , which resulted in stable disease for 6 months prior to progression ( ca 15 - 3 re - rising ) .
exemestane was started as 3rd - line endocrine treatment , but discontinued 14 days later due to severe allergic exanthema . in march 2001 ,
cytological assessment of a further progression in the contralateral breast revealed an er - positive , pgr - negative tumor and fulvestrant ( 250 mg intramuscular , monthly ) was initiated as 4th - line endocrine treatment .
as the drug had not yet been licensed in switzerland at that time , fulvestrant was initially provided free of charge through a named patient program ( supported by astrazeneca ) .
twelve months later complete remission was achieved ( normal cervical / thoracic / abdominal computed tomography scan , disappearance of previous tracer uptake in bone scan ) . however , the patient experienced painful oral and vaginal dryness with loss of libido , ulcerative stomato - pharyngitis and an extensive thrombophlebitis of the left arm requiring temporary treatment interruptions .
symptomatic treatment was given in different combinations , but mucosal dryness and inflammation became an ongoing problem diminishing her quality of life .
therefore , in february 2004 , we decided to continue fulvestrant at half dose ( 125 mg monthly ) .
mucosal symptoms improved ; however , when fulvestrant was once administered in full dose by error , painful oral and vaginal mucositis reoccurred . in june 2006 , complete remission was reconfirmed and fulvestrant was tentatively stopped 63 months after the 1st injection .
however , complete remission was lost shortly thereafter ( ca 15 - 3 re - rising , small suspicious pleura effusion ) , but re - achieved 10 months after renewal of fulvestrant ( 125 mg monthly ) ( fig .
, we finally decided to determine the patient 's fulvestrant plasma concentrations under the 125-mg dose by the high - performance liquid chromatography ( hplc ) method in the standard lab for fulvestrant plasma sample analyses .
the maximum concentration detected was even below the predicted level ( table 1 ) . at follow - up in september 2008
thereafter , ca 15 - 3 ranged between upper normal limit ( unl ) and 1.3  unl , but so far progression of disease has not been confirmed on restaging . at the last follow - up in march 2010 , the patient was doing well .
as observed in several clinical trials and case studies , some patients experience prolonged duration of response with fulvestrant treatment for endocrine - responsive advanced breast cancer [ 3 , 8 , 9 ] . to our knowledge
, a 9-years response to 4th - line endocrine treatment with fulvestrant has not been reported in the literature so far .
this case is remarkable in several aspects : first , achievement of long - lasting complete remission ( last reconfirmed 90 months after treatment start ) is very rare , especially after no or poor response to prior anastrozole / tamoxifen , obviously both not predictive for the efficacy of fulvestrant in this patient .
second , reducing the dose of fulvestrant due to unanticipated intensity of mucosal toxicity maintained complete remission in this case .
we think it is important to alert oncologists to the fact that the prior response to an aromatase inhibitor does not appear to be predictive for the benefit of fulvestrant , an observation also made in a phase ii trial investigating fulvestrant in patients with primary or acquired aromatase inhibitor - resistance .
abram et al . presented a case with endocrine - responsive advanced breast cancer , which also appeared to respond better to fulvestrant than to prior endocrine therapies .
they assumed that the intramuscular administration by a health care professional may have resulted in improved compliance .
a belgian study found a greater activity of fulvestrant in tumors expressing both er and pgr .
other investigators found fulvestrant activity not being reduced in pgr - negative tumors . in our case ,
hormone receptor status was er - positive / pgr - negative when repeated prior to start of fulvestrant treatment , though the primary tumor was er - and pgr - positive .
pgr expression within the tumor is known to be patchy and a sampling error might have led to the er - positive , pgr - negative result in the immunocytochemical analysis of the fine needle aspiration material .
tumors for which fulvestrant therapy might be particularly appropriate are those er - positive tumors with her2 overexpression assuming ligand - independent er activation seems to be a key feature
. however , available data are conflicting . in our case , her2 amplification with a ratio of 2.22 was low and unlikely to contribute to the superiority of fulvestrant compared to anastrozole and tamoxifen by the above - mentioned mechanism .
several large trials have shown that fulvestrant is well tolerated [ 2 , 3 , 4 , 14 ] .
our patient experienced unusually severe mucosal toxicity together with complete remission under the approved 250-mg dose , but clearly less toxicity while maintaining complete remission under a 125-mg dose .
the pharmacokinetic profile excluded faster absorption or a variation in drug metabolism which theoretically could have contributed to the observed toxicity and efficacy ( table 1 ) .
her fulvestrant plasma concentrations were below the observed mean for a 250-mg dose   and , importantly , even below the predicted mean for a 125-mg dose .
we therefore hypothesize an extraordinary sensitivity , but not a metabolic phenomenon as a key factor in the observations made in this case .
this observation is of particular interest in the ongoing fulvestrant dosing debate : our case might serve as a basis for future strategies investigating individual dosing as a promising approach for optimizing fulvestrant treatment .
 we report a case of long - term ( 9 years ) response to 4th - line endocrine treatment with fulvestrant given for advanced breast cancer after no or poor response to prior endocrine therapies . 
 complete remission was achieved with full dose and maintained even after dose reduction due to unanticipated intensity of mucosal toxicity . 
 complete remission was temporarily lost after fulvestrant was tentatively withdrawn ( 63 months after treatment start ) , but was re - achieved after renewal of half - dose treatment and last reconfirmed 90 months after treatment start . 
 the pharmacokinetic profile provides evidence to hypothesize a unique sensitivity to fulvestrant in this patient which might explain both : toxicity and extraordinary efficacy . 