Postmenopausal Women who Progress on Fulvestrant ('Faslodex') Remain Sensitive to Further Endocrine Therapy Comparison of fulvestrant versus tamoxifen for the treatment of advanced breast cancer in postmenopausal women previously untreated with endocrine therapy: a multinational, double-blind, randomized trial. Equivalent single-dose pharmacokinetics of two different dosing methods of prolonged-release fulvestrant ('Faslodex') in postmenopausal women with advanced breast cancer Results of the CONFIRM phase III trial comparing fulvestrant 250 mg with fulvestrant 500 mg in postmenopausal women with estrogen receptor-positive advanced breast cancer. Double-blind, randomized placebo controlled trial of fulvestrant compared with exemestane after prior nonsteroidal aromatase inhibitor therapy in postmenopausal women with hormone receptor-positive, advanced breast cancer: results from EFECT. Three dose regimens of fulvestrant in postmenopausal Japanese women with advanced breast cancer: results from a double-blind, phase II comparative study (FINDER1). Final Overall Survival: Fulvestrant 500mg vs 250mg in the Randomized CONFIRM Trial Fulvestrant 500 mg versus anastrozole 1 mg for the first-line treatment of advanced breast cancer: follow-up analysis from the randomized ‘FIRST’ study Fulvestrant 500 mg Versus Anastrozole 1 mg for the First-Line Treatment of Advanced Breast Cancer: Overall Survival Analysis From the Phase II FIRST Study Sentinel lymph node biopsy for patients with early-stage breast cancer: American Society of Clinical Oncology clinical practice guideline update. Sensitivity to further endocrine therapy is retained following progression on first-line fulvestrant Results of a phase II study comparing three dosing regimens of fulvestrant in postmenopausal women with advanced breast cancer (FINDER2) Locally Advanced, Unresectable Pancreatic Cancer: American Society of Clinical Oncology Clinical Practice Guideline. Sentinel Lymph Node Biopsy for Patients With Early-Stage Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update. Chemotherapy and targeted therapy for women with human epidermal growth factor receptor 2-negative (or unknown) advanced breast cancer: American Society of Clinical Oncology Clinical Practice Guideline. Fulvestrant in women with advanced breast cancer after progression on prior aromatase inhibitor therapy: North Central Cancer Treatment Group Trial N0032. Fulvestrant, formerly ICI 182,780, is as effective as anastrozole in postmenopausal women with advanced breast cancer progressing after prior endocrine treatment. Ganitumab with either exemestane or fulvestrant for postmenopausal women with advanced, hormone-receptor-positive breast cancer: a randomised, controlled, double-blind, phase 2 trial. Oral metronomic cyclophosphamide and methotrexate plus fulvestrant in advanced breast cancer patients: a mono-institutional case-cohort report. Endocrine therapy with or without inhibition of epidermal growth factor receptor and human epidermal growth factor receptor 2: a randomized, double-blind, placebo-controlled phase III trial of fulvestrant with or without lapatinib for postmenopausal women with hormone receptor-positive advanced brea Fulvestrant 250 mg versus anastrozole for Chinese patients with advanced breast cancer: results of a multicentre, double-blind, randomised phase III trial Double-blind, randomized trial comparing the efficacy and tolerability of fulvestrant versus anastrozole in postmenopausal women with advanced breast cancer progressing on prior endocrine therapy: results of a North American trial. A retrospective analysis of the proportion of patients responding for > 1 year in two phase III studies of fulvestrant vs. anastrozole.
Abstract Purpose . This retrospective evaluation of data from two r and omized , multicenter trials examined whether tumor responses to further endocrine therapy were seen in postmenopausal women with advanced breast cancer who had progressed on both initial endocrine therapy , usually tamoxifen , and on the estrogen receptor ( ER ) antagonist fulvestrant ( ' Faslodex ' ) . Patients and methods . A combined total of 423 patients received fulvestrant 250 mg as a monthly intramuscular injection . After progression on fulvestrant , some patients received another endocrine therapy . Responses to subsequent endocrine therapy were assessed using a question naire sent to the trial investigators . Best responses were classified as a complete or partial response ( CR or PR ) , stable disease ( SD ) lasting ≥24 weeks , or disease progression . Results . Follow-up data were available for 54 patients who derived clinical benefit ( CB , defined as CR , PR or SD ) from fulvestrant and who received subsequent endocrine therapy  , result ing in a PR in 4 patients , SD in 21 patients , and disease progression in 29 patients . Data were available for 51 patients who derived no CB from fulvestrant and who received further endocrine therapy , result ing in a PR in 1 patient , SD in 17 patients , and disease progression in 33 patients . Aromatase inhibitors were used as subsequent endocrine therapy in > 80 % of patients . Conclusions . After progression on fulvestrant , patients may retain sensitivity to other endocrine agents . Fulvestrant provides an additional option to existing endocrine therapies for the treatment of advanced or metastatic breast cancer in postmenopausal women , and may provide the opportunity to extend the sequence of endocrine regimens before cytotoxic chemotherapy is required PURPOSE To evaluate the efficacy and tolerability of fulvestrant ( Faslodex ; AstraZeneca Pharmaceuticals LP , Wilmington , DE ) , a new estrogen receptor ( ER ) antagonist that downregulates ER and has no agonist effects , versus tamoxifen , an antiestrogen with agonist and antagonist effects , for the treatment of advanced breast cancer in postmenopausal women . PATIENTS AND METHODS In this multicenter , double-blind , r and omized trial , patients with metastatic/locally advanced breast cancer previously untreated for advanced disease were r and omly assigned to receive either fulvestrant ( 250 mg , via intramuscular injection , once monthly ; n = 313 ) or tamoxifen ( 20 mg , orally , once daily ; n = 274 ) . Patients ' tumors were positive for ER ( ER+ ) and /or progesterone receptor ( PgR+ ) , or had an unknown receptor status . RESULTS At a median follow-up of 14.5 months , there was no significant difference between fulvestrant and tamoxifen for the primary end point of time to progression ( TTP ; median TTP , 6.8 months and 8.3 months , respectively ; hazard ratio , 1.18 ; 95 % CI , 0.98 to 1.44 ; P = .088 ) . In a prospect ively planned subset analysis of patients with known ER+ and /or PgR+ tumors ( approximately 78 % ) , median TTP was 8.2 months for fulvestrant and 8.3 months for tamoxifen ( hazard ratio , 1.10 ; 95 % CI , 0.89 to 1.36 ; P = .39 ) . The objective response rate for the overall population was 31.6 % with fulvestrant and 33.9 % with tamoxifen , and 33.2 % and 31.1 % , respectively , in the known hormone receptor-positive subgroup . Both treatments were well tolerated . CONCLUSION In the overall population , between-group differences in efficacy end points favored tamoxifen , and statistical noninferiority of fulvestrant could not be demonstrated . However , in patients with hormone receptor-positive tumors , fulvestrant had similar efficacy to tamoxifen and was well tolerated Purpose To compare the pharmacokinetics of two different dosing methods of fulvestrant ( ' Faslodex ' ) , an estrogen receptor antagonist with no known agonist activity , for the treatment of advanced breast cancer . Methods Postmenopausal women with advanced breast cancer were r and omly assigned to receive a single 5-ml intramuscular injection of 250 mg fulvestrant , or two 2.5-ml intramuscular injections with a total of 250 mg fulvestrant .  Blood sample s were taken for pharmacokinetic analysis up to 28 days after injection . Results Plasma concentrations of fulvestrant were measurable up to 28 days after both dosing methods . The concentration-time profiles were relatively shallow , spanning an approximate threefold range from 3 h after dosing to Cmin measured on day 28 . Peak plasma concentrations ( Cmax ) of fulvestrant occurred between 1 and 11 days after dosing , with mean Cmax values of 6.0 and 6.2 ng/ml following one 5-ml injection and two 2.5-ml injections , respectively . The plasma concentration-time profiles were very similar in terms of duration and concentration , and overall exposure to fulvestrant was similar in both dosing groups ( the ratio of the AUC0–28 of the single-injection group to that of the double-injection group was 1.01 ; 95 % confidence interval 0.68–1.51 ) . Conclusion This study found no evidence of any pharmacokinetic difference between one 5-ml injection and two 2.5-ml injections . The two methods can be used interchangeably , depending on which is more convenient in any particular clinical setting PURPOSE We compared fulvestrant 500 mg regimen with the approved dose of fulvestrant 250 mg per month for treatment of postmenopausal women with estrogen receptor-positive advanced breast cancer who experienced progression after prior endocrine therapy . PATIENTS AND METHODS Comparison of Faslodex in Recurrent or Metastatic Breast Cancer ( CONFIRM ) is a double-blind , parallel-group , multicenter , phase III study . Patients were r and omly assigned to fulvestrant 500 mg ( 500 mg intramuscularly [ IM ] on day 0 , then 500 mg IM on days 14 and 28 and every 28 days thereafter ) or 250 mg every 28 days . Primary end point was progression-free survival ( PFS ) . Secondary end points included objective response rate , clinical benefit rate ( CBR ) , duration of clinical benefit ( DoCB ) , overall survival ( OS ) , and quality of life ( QOL ) . RESULTS PFS was significantly longer for fulvestrant 500 mg ( n = 362 ) than 250 mg ( n = 374 ) ( hazard ratio [ HR ] = 0.80 ; 95 % CI , 0.68 to 0.94 ; P = .006 ) , corresponding to a 20 % reduction in risk of progression . Objective response rate was similar for fulvestrant 500 mg and 250 mg ( 9.1 % v 10.2 % , respectively ) . CBR was 45.6 % for fulvestrant 500 mg and 39.6 % for fulvestrant 250 mg . DoCB and OS were 16.6 and 25.1 months , respectively , for the 500-mg group , whereas DoCB and OS were 13.9 and 22.8 months , respectively , in the 250-mg group . Fulvestrant 500 mg was well tolerated with no dose-dependent adverse events . QOL was similar for both arms . CONCLUSION Fulvestrant 500 mg was associated with a statistically significant increase in PFS and not associated with increased toxicity , corresponding to a clinical ly meaningful improvement in benefit versus risk compared with fulvestrant 250 mg PURPOSE The third-generation nonsteroidal aromatase inhibitors ( AIs ) are increasingly used as adjuvant and first-line advanced therapy for postmenopausal , hormone receptor-positive ( HR+ ) breast cancer . Because many patients subsequently experience progression or relapse , it is important to identify agents with efficacy after AI failure . MATERIAL S AND METHODS Evaluation of Faslodex versus Exemestane Clinical Trial ( EFECT ) is a r and omized , double-blind , placebo controlled , multicenter phase III trial of fulvestrant versus exemestane in postmenopausal women with HR+ advanced breast cancer ( ABC ) progressing or recurring after nonsteroidal AI . The primary end point was time to progression ( TTP ) . A fulvestrant loading-dose ( LD ) regimen was used : 500 mg intramuscularly on day 0 , 250 mg on days 14 , 28 , and 250 mg every 28 days thereafter . Exemestane 25 mg orally was administered once daily . RESULTS A total of 693 women were r and omly assigned to fulvestrant ( n = 351 ) or exemestane ( n = 342 ) . Approximately 60 % of patients had received at least two prior endocrine therapies .  Median TTP was 3.7 months in both groups ( hazard ratio = 0.963 ; 95 % CI , 0.819 to 1.133 ; P = .6531 ) . The overall response rate ( 7.4 % v 6.7 % ; P = .736 ) and clinical benefit rate ( 32.2 % v 31.5 % ; P = .853 ) were similar between fulvestrant and exemestane respectively . Median duration of clinical benefit was 9.3 and 8.3 months , respectively . Both treatments were well tolerated , with no significant differences in the incidence of adverse events or quality of life . Pharmacokinetic data confirm that steady-state was reached within 1 month with the LD schedule of fulvestrant . CONCLUSION Fulvestrant LD and exemestane are equally active and well-tolerated in a meaningful proportion of postmenopausal women with ABC who have experienced progression or recurrence during treatment with a nonsteroidal AI BACKGROUND FINDER1 compared efficacy , tolerability and pharmacokinetics ( PK ) of three fulvestrant dose regimens in postmenopausal Japanese women with estrogen receptor (ER)-positive locally advanced/metastatic breast cancer recurring or progressing after prior endocrine therapy . PATIENTS AND METHODS The primary end point of this r and omised , multicentre , phase II study was objective response rate ( ORR ) and the secondary end points included time to progression ( TTP ) , clinical benefit rate ( CBR ) , PK profiles and tolerability .  Postmenopausal women with ER-positive advanced breast cancer were r and omised to 28-day cycles of fulvestrant approved dose ( AD ) , loading dose ( LD ) or high dose ( HD ) until disease progression . RESULTS Hundred and forty-three patients ( median age 61 years ) received fulvestrant AD ( n = 45 ) , LD ( n = 51 ) or HD ( n = 47 ) . ORR was similar across dose regimens : 11.1 % , 17.6 % and 10.6 % for AD , LD and HD , respectively , with overlapping confidence intervals . TTP and CBR were also similar between groups ( median TTP : 6.0 , 7.5 and 6.0 months , respectively ; CBR : 42.2 % , 54.9 % and 46.8 % for AD , LD and HD , respectively ) . C(max ) and area under the plasma concentration-time curve were dose proportional and PK steady state was reached earlier with LD and HD than with AD . All three doses were well tolerated , with a similar adverse-event profile and no emerging safety concerns . CONCLUSION Fulvestrant AD , LD and HD had similar efficacy and tolerability profiles in postmenopausal Japanese women with ER-positive advanced breast cancer Background At the time of the initial analysis of overall survival ( OS ) for the Comparison of Faslodex in Recurrent or Metastatic Breast Cancer ( CONFIRM ) r and omized , double-blind , phase III trial , approximately 50 % of patients had died . A final analysis of OS was subsequently planned for when 75 % of patients had died . Methods Patients were r and omly assigned 1:1 to fulvestrant 500 mg administered as two 5-mL intramuscular injections on days 0 , 14 , and 28 and every 28 ( ±3 ) days thereafter or fulvestrant 250 mg administered as two 5-mL intramuscular injections ( one fulvestrant and one placebo [ identical in appearance to study drug ] ) on days 0 , 14 ( two placebo injections only ) , and 28 and every 28 ( ±3 ) days thereafter . OS was analyzed using an unadjusted log-rank test . No adjustments were made for multiplicity . Serious adverse events ( SAEs ) and best response to subsequent therapy were also reported . All statistical tests were two-sided . Results In total , 736 women ( median age = 61.0 years ) were r and omly assigned to fulvestrant 500 mg ( n = 362 ) or 250 mg ( n = 374 ) . At the final survival analysis , 554 of 736 ( 75.3 % ) patients had died . Median OS was 26.4 months for fulvestrant 500 mg and 22.3 months for 250 mg ( hazard ratio = 0.81 ; 95 % confidence interval = 0.69–0.96 ; nominal P = .02 ) . There were no clinical ly important differences in SAE profiles between the treatment groups ; no clustering of SAEs could be detected in either treatment group . Type of first subsequent therapy and objective responses to first subsequent therapy were well balanced between the two treatment groups . Conclusions In patients with locally advanced or metastatic estrogen receptor – positive breast cancer , fulvestrant 500 mg is associated with a 19 % reduction in risk of death and a 4.1-month difference in median OS compared with fulvestrant 250 mg . Fulvestrant 500 mg was well tolerated , and no new safety concerns were identified Fulvestrant fIRst-line Study comparing endocrine Treatments is a phase II , r and omized , open-label study comparing fulvestrant 500 mg with anastrozole 1 mg as first-line endocrine therapy for postmenopausal women with hormone receptor-positive ( HR+ ) advanced breast cancer . At data cut-off , only 36 % of patients had progressed and the median time to progression ( TTP ) had not been reached for fulvestrant . Here , we report follow-up data for TTP for fulvestrant 500 mg versus anastrozole 1 mg . Key inclusion criteria were postmenopausal women with estrogen receptor-positive and /or progesterone receptor-positive locally advanced or metastatic breast cancer and no prior endocrine therapy . Key exclusion criteria were presence of life-threatening metastases and prior treatment with a non-approved drug .  Fulvestrant was administered 500 mg/month plus 500 mg on day 14 of month 1 ; anastrozole was administered 1 mg/day . TTP was defined by modified Response Evaluation Criteria in Solid Tumors v1.0 before data cut-off for the primary analysis , and investigator opinion after data cut-off . Best overall response to subsequent therapy and serious adverse events are also reported . In total , 205 patients received fulvestrant 500 mg ( n = 102 ) or anastrozole ( n = 103 ) . Follow-up analysis was performed when 79.5 % of patients had discontinued study treatment . Median TTP was 23.4 months for fulvestrant versus 13.1 months for anastrozole ; a 34 % reduction in risk of progression ( hazard ratio 0.66 ; 95 % confidence interval : 0.47 , 0.92 ; P = 0.01 ) . Best overall response to subsequent therapy and clinical benefit rate for subsequent endocrine therapy was similar between the treatment groups . No new safety concerns for fulvestrant 500 mg were documented . These longer-term , follow-up results confirm efficacy benefit for fulvestrant 500 mg versus anastrozole as first-line endocrine therapy for HR+ advanced breast cancer in terms of TTP , and , importantly , show similar best overall response rates to subsequent endocrine therapy Purpose To compare overall survival ( OS ) for fulvestrant 500 mg versus anastrozole as first-line endocrine therapy for advanced breast cancer . Patients and Methods The Fulvestrant First-Line Study Comparing Endocrine Treatments ( FIRST ) was a phase II , r and omized , open-label , multicenter trial . Postmenopausal women with estrogen receptor – positive , locally advanced/metastatic breast cancer who had no previous therapy for advanced disease received either fulvestrant 500 mg ( days 0 , 14 , 28 , and every 28 days thereafter ) or anastrozole 1 mg ( daily ) . The primary end point ( clinical benefit rate [ 72.5 % and 67.0 % ] ) and a follow-up analysis ( median time to progression [ 23.4 months and 13.1 months ] ) have been reported previously for fulvestrant 500 mg and anastrozole , respectively . Subsequently , the protocol was amended to assess OS by unadjusted log-rank test after approximately 65 % of patients had died . Treatment effect on OS across several subgroups was examined . Tolerability was evaluated by adverse event monitoring . Results In total , 205 patients were r and omly assigned ( fulvestrant 500 mg , n = 102 ; anastrozole , n = 103 ) . At data cutoff , 61.8 % ( fulvestrant 500 mg , n = 63 ) and 71.8 % ( anastrozole , n = 74 ) had died . The hazard ratio ( 95 % CI ) for OS with fulvestrant 500 mg versus anastrozole was 0.70 ( 0.50 to 0.98 ; P = .04 ; median OS , 54.1 months v 48.4 months ) . Treatment effects seemed generally consistent across the subgroups analyzed . No new safety issues were observed . Conclusion There are several limitations of this OS analysis , including that it was not planned in the original protocol but instead was added after time-to-progression results were analyzed , and that not all patients participated in additional OS follow-up . However , the present results suggest fulvestrant 500 mg extends OS versus anastrozole . This finding now awaits prospect i ve confirmation in the larger phase III FALCON ( Fulvestrant and Anastrozole Compared in Hormonal Therapy Naïve Advanced Breast Cancer ) trial ( Clinical Trials.gov identifier : NCT01602380 ) PURPOSE To provide evidence -based recommendations to practicing oncologists , surgeons , and radiation therapy clinicians to up date the 2005 clinical practice guideline on the use of sentinel node biopsy ( SNB ) for patients with early-stage breast cancer . METHODS The American Society of Clinical Oncology convened an Up date Committee of experts in medical oncology , pathology , radiation oncology , surgical oncology , guideline implementation , and advocacy . A systematic review of the literature was conducted from February 2004 to January 2013 in Medline . Guideline recommendations were based on the review of the evidence by Up date Committee . RESULTS This guideline up date reflects changes in practice since the 2005 guideline . Nine r and omized clinical trials ( RCTs ) met systematic review criteria for clinical questions 1 and 2 ; 13 cohort studies informed clinical question 3 . RECOMMENDATIONS Women without sentinel lymph node ( SLN ) metastases should not receive axillary lymph node dissection ( ALND ) .  Women with one to two metastatic SLNs planning to undergo breast-conserving surgery with whole-breast radiotherapy should not undergo ALND ( in most cases ) . Women with SLN metastases who will undergo mastectomy should be offered ALND . These three recommendation are based on RCTs . Women with operable breast cancer and multicentric tumors , with ductal carcinoma in situ ( DCIS ) who will undergo mastectomy , who previously underwent breast and /or axillary surgery , or who received preoperative/neoadjuvant systemic therapy may be offered SNB . Women who have large or locally advanced invasive breast cancer ( tumor size T3/T4 ) , inflammatory breast cancer , or DCIS ( when breast-conserving surgery is planned ) or are pregnant should not undergo SNB . These recommendations are based on cohort studies and /or informal consensus . In some cases , up date d evidence was insufficient to up date previous recommendations Summary There is a need for new endocrine agents that lack cross-resistance with currently available treatments to extend the endocrine treatment window and delay the need for cytotoxic chemotherapy . This retrospective analysis evaluated the response of postmenopausal patients with previously untreated metastatic/locally advanced breast cancer to further endocrine treatment following progression on first-line fulvestrant or tamoxifen .  Patients received fulvestrant 250 mg ( intramuscular injection every 28 days ) plus matching tamoxifen placebo ( once daily ) , or tamoxifen 20 mg ( orally once daily ) plus matching fulvestrant placebo ( every 28 days ) in a double-blind , r and omized , phase III trial . Treatment continued until disease progression or withdrawal , when further endocrine therapy was initiated ( at the treating physician ’s discretion ) . Information regarding subsequent therapies and responses was obtained by follow-up question naire . Two-hundred- and -forty-five question naires were returned ( from 587 patients ) , 149 of which yielded follow-up data on patients receiving second-line endocrine therapy following fulvestrant ( n=83 ) and tamoxifen ( n=66 ) . Second-line therapy produced objective responses ( OR ) in 6/44 ( 13.6 % ) and clinical benefit ( CB ) in 25/44 ( 56.8 % ) patients who had CB with fulvestrant and produced OR in 5/41 ( 12.2 % ) patients and CB in 27/41 ( 65.8 % ) patients who had CB with first-line tamoxifen . For patients deriving no CB from trial therapy , second-line therapy produced OR in 3/39 ( 7.7 % ) and CB in 15/39 ( 38.5 % ) patients in the fulvestrant group and OR in 4/25 ( 16.0 % ) and CB in 12/25 ( 48.0 % ) patients in the tamoxifen group . Results from this question naire-based study suggest that postmenopausal women with advanced breast cancer who respond to first-line fulvestrant or tamoxifen retain sensitivity to subsequent endocrine therapy The Faslodex Investigation of Dose evaluation in Estrogen Receptor-positive advanced breast cancer (FINDER)2 study evaluated the efficacy , safety , and pharmacokinetics ( PK ) of three fulvestrant dosing regimens . FINDER2 enrolled Western postmenopausal women recurring or progressing after prior endocrine therapy . Primary endpoint : objective response rate ( ORR ) ; secondary endpoints : time to progression ( TTP ) , clinical benefit rate ( CBR ) , tolerability , and PK parameters .  Patients were r and omized to receive fulvestrant : 250 mg/month ( approved dose [ AD ] ) ; 250 mg plus loading dose ( loading dose [ LD ] ; 500 mg on day 0 , 250 mg on days 14 , 28 , and monthly thereafter ) ; or 500 mg ( high dose [ HD ] ; 500 mg/month plus 500 mg on day 14 of Month 1 ) . Treatment continued until disease progression or discontinuation . 144 patients were r and omized : fulvestrant AD ( n = 47 ) ; LD ( n = 51 ) ; HD ( n = 46 ) . ORRs were : 8.5 % ( 95 % confidence interval [ CI ] : 2.4 , 20.4 % ) , 5.9 % ( 1.2 , 16.2 % ) , and 15.2 % ( 6.3 , 28.9 % ) in the AD , LD , and HD arms , respectively . CBRs were : 31.9 % ( 95 % CI : 19.1 , 47.1 % ) , 47.1 % ( 32.9 , 61.5 % ) , and 47.8 % ( 32.9 , 63.1 % ) for the AD , LD , and HD arms , respectively . Median TTP ( months ) was numerically longer for HD ( 6.0 ) and LD ( 6.1 ) versus AD ( 3.1 ) . Tolerability was similar across dosing regimens . Steady-state plasma fulvestrant concentrations were predictable and achieved earlier with LD and HD . While there appeared to be a trend toward improved efficacy with HD and LD versus AD , no significant differences could be shown . A parallel study ( FINDER1 ) has reported similar findings in Japanese patients PURPOSE To provide evidence -based recommendations to oncologists and others for treatment of patients with locally advanced , unresectable pancreatic cancer . METHODS American Society of Clinical Oncology convened an Expert Panel of medical oncology , radiation oncology , surgical oncology , gastroenterology , palliative care , and advocacy experts and conducted a systematic review of the literature from January 2002 to June 2015 . Outcomes included overall survival , disease-free survival , progression-free survival , and adverse events . RESULTS Twenty-six r and omized controlled trials met the systematic review criteria . RECOMMENDATIONS A multiphase computed tomography scan of the chest , abdomen , and pelvis should be performed . Baseline performance status and comorbidity profile should be evaluated . The goals of care , patient preferences , psychological status , support systems , and symptoms should guide decisions for treatments . A palliative care referral should occur at first visit . Initial systemic chemotherapy ( 6 months ) with a combination regimen is recommended for most patients ( for some patients radiation therapy may be offered up front ) with Eastern Cooperative Oncology Group performance status 0 or 1 and a favorable comorbidity profile . There is no clear evidence to support one regimen over another . The gemcitabine-based combinations and treatments recommended in the metastatic setting ( eg , fluorouracil , leucovorin , irinotecan , and oxaliplatin and gemcitabine plus nanoparticle albumin-bound paclitaxel ) have not been evaluated in r and omized controlled trials involving locally advanced , unresectable pancreatic cancer . If there is local disease progression after induction chemotherapy , without metastasis , then radiation therapy or stereotactic body radiotherapy may be offered also with an Eastern Cooperative Oncology Group performance status ≤ 2 and an adequate comorbidity profile . If there is stable disease after 6 months of induction chemotherapy but unacceptable toxicities , radiation therapy may be offered as an alternative . Patients with disease progression should be offered treatment per the ASCO Metastatic Pancreatic Cancer Treatment Guideline . Follow-up visits every 3 to 4 months are recommended . Additional information is available at www.asco.org/ guidelines /LAPC and www.asco.org/ guidelines /MetPC and www.asco.org/ guidelines wiki Purpose To provide current recommendations on the use of sentinel node biopsy ( SNB ) for patients with early-stage breast cancer . Methods PubMed and the Cochrane Library were search ed for r and omized controlled trials , systematic review s , meta-analyses , and clinical practice guidelines from 2012 through July 2016 . An Up date Panel review ed the identified abstract s. Results Of the eight publications identified and review ed , none prompted a change in the 2014 recommendations , which are reaffirmed by the up date d literature review . Conclusion Women without sentinel lymph node ( SLN ) metastases should not receive axillary lymph node dissection ( ALND ) . Women with one to two metastatic SLNs who are planning to undergo breast-conserving surgery with whole-breast radiotherapy should not undergo ALND ( in most cases ) . Women with SLN metastases who will undergo mastectomy should be offered ALND . These three recommendations are based on r and omized controlled trials . Women with operable breast cancer and multicentric tumors , with ductal carcinoma in situ , who will undergo mastectomy , who previously underwent breast and /or axillary surgery , or who received preoperative/neoadjuvant systemic therapy may be offered SNB .  Women who have large or locally advanced invasive breast cancer ( tumor size T3/T4 ) , inflammatory breast cancer , or ductal carcinoma in situ ( when breast-conserving surgery is planned ) or are pregnant should not undergo SNB PURPOSE To identify optimal chemo- and targeted therapy for women with human epidermal growth factor 2 (HER2)- negative ( or unknown ) advanced breast cancer . METHODS A systematic review of r and omized evidence ( including systematic review s and meta-analyses ) from 1993 through to current was completed . Outcomes of interest included survival , progression-free survival , response , quality of life , and adverse effects . Guideline recommendations were evidence based and were agreed on by the Expert Panel via consensus . RESULTS Seventy-nine studies met the inclusion criteria , comprising 20 systematic review s and /or meta-analyses , 30 trials on first-line treatment , and 29 trials on second-line and subsequent treatment . These trials form the evidence base for the guideline recommendations . RECOMMENDATIONS Endocrine therapy is preferable to chemotherapy as first-line treatment for patients with estrogen receptor-positive metastatic breast cancer unless improvement is medically necessary ( eg , immediately life-threatening disease ) . Single agent is preferable to combination chemotherapy , and longer planned duration improves outcome but must be balanced against toxicity . There is no single optimal first-line or subsequent line chemotherapy , and choice of treatment will be determined by multiple factors including prior therapy , toxicity , performance status , comorbid conditions , and patient preference . The role of bevacizumab remains controversial . Other targeted therapies have not so far been shown to enhance chemotherapy outcome in HER2-negative breast cancer PURPOSE Fulvestrant is an antiestrogen that leads to estrogen receptor degradation and has demonstrated efficacy in breast cancer patients who have had disease recurrence or progression after tamoxifen . This study was design ed to examine the efficacy and toxicity of fulvestrant in patients with disease progression on a third-generation aromatase inhibitor ( AI ) .  PATIENTS AND METHODS A one-stage phase II trial was conducted in postmenopausal women with measurable disease by Response Evaluation Criteria in Solid Tumors criteria who experienced disease progression after treatment with a third-generation AI and , at most , one additional hormonal agent .  Tumors must have been estrogen receptor and /or progesterone receptor positive . The primary end point was objective response rate , and secondary end points were time to disease progression , survival , duration of response , and toxicity . RESULTS Eighty patients were enrolled , and three were ineligible . Characteristics of the 77 eligible patients included median age of 68 years , performance score of 0 or 1 in 91 % of patients , visceral dominant disease in 88 % of patients , two prior hormonal treatments in 73 % of patients , and prior chemotherapy for metastatic disease in 32 % of patients . Eleven patients ( 14.3 % ) achieved a partial response , and 16 patients ( 20.8 % ) had stable disease for at least 6 months , for a clinical benefit rate of 35 % . Antitumor activity seemed to be higher in women with prior treatment with AI alone compared with women whose prior treatment also included tamoxifen . Median time to progression was 3 months , and median survival time was 20.2 months . Fulvestrant was well tolerated . CONCLUSION Fulvestrant is a well-tolerated treatment and has efficacy against breast cancers that have progressed after therapy with a third-generation AI PURPOSE To compare the efficacy and tolerability of fulvestrant ( formerly ICI 182,780 ) and anastrozole in postmenopausal women with advanced breast cancer progressing after prior endocrine treatment . PATIENTS AND METHODS Patients ( n = 451 ) with advanced breast cancer were r and omized to receive fulvestrant 250 mg as a once-monthly ( one x 5 mL ) intramuscular injection or an oral dose of anastrozole 1 mg in this open , parallel-group , multicenter trial . The primary end point was time to progression ( TTP ) . Secondary end points included objective response ( OR ) rates , defined as complete response ( CR ) or partial response ( PR ) , duration of response ( DOR ) , and tolerability . RESULTS Patients were followed for a median period of 14.4 months . In terms of TTP , fulvestrant was as effective as anastrozole ( hazard ratio , 0.98 ; confidence interval [ CI ] , 0.80 to 1.21 ; P = .84 ) . Median TTP was 5.5 months for fulvestrant and 5.1 months for anastrozole . OR rates showed a numerical advantage for fulvestrant ( 20.7 % ) over anastrozole ( 15.7 % ) ( odds ratio , 1.38 ; CI , 0.84 to 2.29 ; P = .20 ) . Clinical benefit rates ( CR + PR + stable disease > or = 24 weeks ) were 44.6 % for fulvestrant and 45.0 % for anastrozole . Median DOR was 14.3 months for fulvestrant and 14.0 months for anastrozole . Both treatments were well tolerated , with 3.2 % and 1.3 % of fulvestrant- and anastrozole-treated patients , respectively , withdrawn from treatment because of an adverse event . CONCLUSION Fulvestrant was as effective as anastrozole . These data confirm that fulvestrant is an additional , effective , and well-tolerated treatment for advanced breast cancer in postmenopausal women whose disease progressed on prior endocrine therapy BACKGROUND Insulin-like growth factors ( IGF-1 and IGF-2 ) bind to the IGF-1 receptor ( IGF-1R ) , increasing cell proliferation and survival .  Ganitumab is a monoclonal IgG1 antibody that blocks IGF-1R . We tested the efficacy and safety of adding ganitumab to endocrine treatment for patients with hormone-receptor-positive breast cancer . METHODS We did this phase 2 trial in outpatient clinics and hospitals . We enrolled postmenopausal women with hormone-receptor-positive , locally advanced or metastatic breast cancer previously treated with endocrine treatment . They were r and omly assigned ( 2:1 ) with a central r and omisation schedule to receive intravenous ganitumab 12 mg per kg bodyweight or placebo in combination with open-label intramuscular fulvestrant ( 500 mg on day 1 , then 250 mg on days 15 , 29 , and every 28 days ) or oral exemestane ( 25 mg once daily ) on a 28-day cycle . Patients , investigators , study monitors , and the sponsor staff were masked to treatment allocation . Response was assessed every 8 weeks . The primary endpoint was median progression-free survival in the intention-to-treat population . We analysed overall survival as one of our secondary endpoints . The study is registered at Clinical Trials.gov , number NCT00626106 . FINDINGS We screened 189 patients and enrolled 156 ( 106 in the ganitumab group and 50 in the placebo group ) . Median progression-free survival did not differ significantly between the ganitumab and placebo groups ( 3·9 months , 80 % CI 3·6 - 5·3 vs 5·7 months , 4·4 - 7·4 ; hazard ratio [ HR ] 1·17 , 80 % CI 0·91 - 1·50 ; p=0·44 ) . However , overall survival was worse in the the ganitumab group than in the placebo group ( HR 1·78 , 80 % CI 1·27 - 2·50 ; p=0·025 ) . With the exception of hyperglycaemia , adverse events were generally similar between groups . The most common grade 3 or higher adverse event was neutropenia-reported by six of 106 ( 6 % ) patients in the ganitumab group and one of 49 ( 2 % ) in the placebo group . Hyperglycaemia was reported by 12 of 106 ( 11 % ) patients in the ganitumab group ( with six patients having grade 3 or 4 hyperglycaemia ) and none of 49 in the placebo group . Serious adverse events were reported by 27 of 106 ( 25 % ) patients in the ganitumab group and nine of 49 ( 18 % ) patients in the placebo group . INTERPRETATION Addition of ganitumab to endocrine treatment in women with previously treated hormone-receptor-positive locally advanced or metastatic breast cancer  did not improve outcomes . Our results do not support further study of ganitumab in this subgroup of patients . FUNDING Amgen Fulvestrant is effective in postmenopausal women with estrogen receptor-positive advanced breast cancer ( ABC ) . So far , no published data exist on fulvestrant combined with chemotherapy . We retrospectively assessed the role of combining oral metronomic cyclophosphamide and methotrexate ( CM ) to fulvestrant in two cohorts ( A and B ) of heavily pre-treated estrogen receptor-positive advanced ABC patients . From October 2006 to September 2009 , 33 postmenopausal patients received  fulvestrant 250 mg via i.m . injection q28 days . In A , 20 patients added metronomic cyclophosphamide ( 50 mg p.o . daily ) and methotrexate ( 2.5 mg p.o . twice daily on day 1 and day 4 weekly ) after disease progression , continuing fulvestrant at the same dose . In B , 13 patients started fulvestrant plus metronomic CM upfront . Thirty-two patients were evaluable for response . Clinical benefit ( partial response + stable disease > 24 months ) for A + B was 56 % ( 95 % CI 38 - 74 % ) . The addition of metronomic CM did not determine relevant toxicities . Treatment with  fulvestrant plus metronomic CM  was effective in advanced ABC and was minimally toxic providing long-term disease control in a high proportion of patients . The prolonged clinical benefit , often desirable in such patients , supports this regimen as an additional and useful therapeutic tool PURPOSE CALGB 40302 sought to determine whether lapatinib would improve progression-free survival ( PFS ) among women with hormone receptor-positive metastatic breast cancer treated with fulvestrant . PATIENTS AND METHODS Eligible women had estrogen receptor-positive and /or progesterone receptor-positive tumors , regardless of human epidermal growth factor receptor 2 ( HER2 ) status , and prior aromatase inhibitor treatment . Patients received fulvestrant 500 mg intramuscularly on day 1 , followed by 250 mg on days 15 and 28 and every 4 weeks thereafter , and either lapatinib 1,500 mg or placebo daily . The study planned to accrue 324 patients and was powered for a 50 % improvement in PFS with lapatinib from 5 to 7.5 months . RESULTS At the third planned interim analysis , the futility boundary was crossed , and the data and safety monitoring board recommend study closure , having accrued 295 patients . At the final analysis , there was no difference in PFS ( hazard ratio [ HR ] of placebo to lapatinib , 1.04 ; 95 % CI , 0.82 to 1.33 ; P = .37 ) ; median PFS was 4.7 months for fulvestrant plus lapatinib versus 3.8 months for fulvestrant plus placebo . There was no difference in overall survival ( OS ) ( HR , 0.91 ; 95 % CI , 0.68 to 1.21 ; P = .25 ) . For HER2-normal tumors , median PFS did not differ by treatment arm ( 4.1 v 3.8 months ) . For HER2-positive tumors , lapatinib was associated with longer median PFS ( 5.9 v 3.3 months ) , but the differential treatment effect by HER2 status was not significant ( P = .53 ) . The most frequent toxicities were diarrhea , fatigue , and rash associated with lapatinib . CONCLUSION Adding lapatinib to fulvestrant does not improve PFS or OS in advanced ER-positive breast cancer and is more toxic Background and purpose Fulvestrant , an oestrogen receptor ( ER ) antagonist with no known agonist effects , has shown activity in postmenopausal patients with ER-positive advanced breast cancer recurring or progressing following prior endocrine therapy . This double-blind , double-dummy , r and omised phase III study ( NCT00327769 ) was design ed to compare the efficacy and safety of fulvestrant versus anastrozole in advanced breast cancer of Chinese postmenopausal women whose disease has progressed following prior endocrine treatment . Material s and methods A total of 234 patients were r and omised to  fulvestrant 250 mg/month ( n = 121 ) or 1 mg/day anastrozole ( n = 113 ) , together with matching placebo . The primary endpoint was time to progression ( TTP ) . Secondary endpoints included objective response rate ( ORR ) , duration of response ( DoR ) , clinical benefit rate ( CBR ) and time to treatment failure ( TTF ) . Results Baseline characteristics were similar , with the possible exception that a higher number of fulvestrant patients had received two prior chemotherapy regimens . Median TTP was 110 days in the fulvestrant group versus 159 days in the anastrozole group ( hazard ratio [ HR ] , 1.314 ; 95 % confidence intervals [ CI ] , 0.948 , 1.822 ; P = 0.101 ) . ORR was 10 % in the fulvestrant group and 14 % in the anastrozole group . Median DoR from r and omisation to progression was 436 days versus 432 days for the fulvestrant and anastrozole groups , respectively . CBR for fulvestrant ( 36.1 % ) versus anastrozole ( 48.2 % ) was not statistically different between the groups . TTF ( 110 days versus 147 days for the fulvestrant and anastrozole groups , respectively ) was not statistically different between the treatments ( HR , 1.307 ; 95 % CI , 0.961 , 1.778 ; P = 0.088 ) . Both treatments were well tolerated , with only two patients treated with fulvestrant and four patients treated with anastrozole withdrawn from study treatment due to adverse events . Conclusions These data demonstrate that fulvestrant 250 mg and anastrozole were similarly effective and well tolerated in the treatment of postmenopausal Chinese women with advanced breast cancer whose disease had progressed or recurred on prior endocrine treatment PURPOSE To compare the efficacy and tolerability of fulvestrant ( formerly ICI 182,780 ) with anastrozole in the treatment of advanced breast cancer in patients whose disease progresses on prior endocrine treatment . PATIENTS AND METHODS In this double-blind , double-dummy , parallel-group study , postmenopausal patients were r and omized to receive either an intramuscular injection of fulvestrant 250 mg once monthly or a daily oral dose of anastrozole 1 mg . The primary end point was time to progression ( TTP ) . Secondary end points included objective response ( OR ) rate , duration of response ( DOR ) , and tolerability . RESULTS Patients ( n = 400 ) were followed for a median period of 16.8 months . Fulvestrant was as effective as anastrozole in terms of TTP ( hazard ratio , 0.92 ; 95.14 % confidence interval [ CI ] , 0.74 to 1.14 ; P = .43 ) ; median TTP was 5.4 months with fulvestrant and 3.4 months with anastrozole . OR rates were 17.5 % with both treatments . Clinical benefit rates ( complete response + partial response + stable disease > or = 24 weeks ) were 42.2 % for fulvestrant and 36.1 % for anastrozole ( 95 % CI , -4.00 % to 16.41 % ; P = .26 ) . In responding patients , median DOR ( from r and omization to progression ) was 19.0 months for fulvestrant and 10.8 months for anastrozole . Using all patients , DOR was significantly greater for fulvestrant compared with anastrozole ; the ratio of average response duration s was 1.35 ( 95 % CI , 1.10 to 1.67 ; P < 0.01 ) . Both treatments were well tolerated . CONCLUSION Fulvestrant was at least as effective as anastrozole , with efficacy end points slightly favoring fulvestrant . Fulvestrant represents an additional treatment option for postmenopausal women with advanced breast cancer whose disease progresses on tamoxifen therapy 737 Background : Fulvestrant ( Faslodex ) is an estrogen receptor antagonist with no agonist effects . Two phase III trials have compared the efficacy of fulvestrant 250 mg ( once-monthly , intramuscular injection ) and anastrozole ( 1 mg/daily , p.o . ) in patients with advanced breast cancer progressing on prior endocrine therapy .  Fulvestrant was at least as effective as anastrozole for the primary endpoint of time to progression and the secondary endpoint of objective response ( OR ) . Here , we report a retrospective analysis of duration of response ( DOR ) by categorical time period ( ≥1 year ) in patients experiencing an OR ( complete [ CR ] or partial response [ PR ] ) or clinical benefit ( CB ; CR + PR + stable disease [ SD ] ≥24 weeks ) in these two trials . METHODS Duration of OR and CB was calculated from r and omization until disease progression and percentages were calculated using the total number of patients per treatment group as the denominator ( fulvestrant n=428 ; anastrozole n=423 ) . RESULTS Median follow-up was 22.1 months . A total of 186 patients receiving fulvestrant had CB ( CR : n=20 ; PR : n=62 ; SD ≥24 weeks : n=104 ) compared with 173 patients receiving anastrozole ( CR : n=11 ; PR : n=59 ; SD ≥24 weeks : n=103 ) . A numerically greater proportion of patients receiving fulvestrant achieved OR and CB for ≥1 year than those receiving anastrozole . CONCLUSION Fulvestrant has benefits in terms of the numbers of patients with prolonged duration of response . These data support the initial DOR findings in these trials . [ Figure : see text ] [ Table : see text ]
Fulvestrant can therefore be considered as alternative therapy to anastrozole or exemestane in postmenopausal women with locally advanced or metastatic breast cancer that has recurred on prior adjuvant endocrine therapy or progressed on prior endocrine therapy for advanced disease .
A systematic review was undertaken to examine all available evidence to develop and support clinical recommendations regarding the use of fulvestrant ( Faslodex ® ) as systemic therapy of locally advanced or metastatic breast cancer in postmenopausal women .