nearly 233,000 new cases were estimated to be diagnosed in 2014 in the united states , representing 14% of all new cancer cases . although metastatic bc ( mbc ) is diagnosed in only 5% of cases , nearly 30% of bc patients with earlier stage tumors eventually develop metastases . this advanced disease is associated with worse prognosis than early stage bc , with 5-year survival rates around 25% . most bc samples overexpress hormone receptors ( hr ) , including estrogen receptor ( er ) and/or progesterone receptor ( pr ) [ 4 , 5 ] , whereas human epidermal growth factor receptor 2 ( her2 ) overexpression only occurs in 2030% of cases ; thus , the most common bc subtype is hr+/her2 . postmenopausal women , in particular , are more likely to have hr+/her2 tumors , as hr overexpression increases with age . the national comprehensive cancer network ( nccn )   treatment guidelines for hr+/her2 mbc recommend the use of endocrine therapy , particularly a nonsteroidal aromatase inhibitor ( ai ) , as first - line treatment in postmenopausal women . since most patients eventually develop resistance to these therapies , the nccn guidelines recommend another endocrine agent when the first therapy fails . after the failure of three sequential endocrine therapies , if symptomatic visceral disease is present or if the cancer is rapidly progressing or immediately life - threatening chemotherapy is recommended , either as monotherapy with an anthracycline , taxane , antimetabolite , or other microtubule inhibitors or as combination treatment . however , observed real - world treatment patterns are not consistent with nccn guidelines , showing that many hr+/her2 mbc patients only receive one line of endocrine therapy before switching to chemotherapy for second - line treatment [ 9 , 10 ] . chemotherapy is often accompanied by serious treatment side effects ( grade 3/4 ) , some of which have severe impact on the patients ' health - related quality - of - life ( qol ) [ 11 , 12 ] . therefore , there is an unmet need for efficacious but more tolerable alternatives for the treatment of hr+/her2 mbc . a novel targeted agent , everolimus , was approved in july 2012 to be used in combination with endocrine therapy exemestane for the treatment of mbc in patients who failed nonsteroidal ai . the efficacy of everolimus / exemestane combinational therapy was demonstrated in the phase iii , double - blind , randomized , bolero-2 trial with significantly improved progression - free survival ( pfs ) compared to exemestane monotherapy [ 1315 ] . the efficacy of other everolimus - based therapies , such as combinational therapy of everolimus and tamoxifen , has also been examined in other clinical studies . currently , there is limited evidence regarding the comparative effectiveness of everolimus - based therapy and chemotherapy , two common treatment options for hr+/her2 mbc after initial failure of nonsteroidal ai . several recent studies presented in oncology conferences have indicated that everolimus / exemestane combinational therapy was associated with significantly longer survival compared to chemotherapies [ 17 , 18 ] , but these studies were based on small samples of patients   or physician surveys . a network meta - analysis of previous mbc trials also found that everolimus / exemestane combinational therapy was associated with comparable or better pfs compared to some commonly - used chemotherapy ; however , findings in clinical trial settings may not represent the real - world comparative effectiveness . in addition , this analysis also had inherent limitations due to indirect comparisons of treatments from different studies with heterogeneous designs and patient populations . the present study aims to address this knowledge gap and to compare the real - world effectiveness of everolimus - based therapy versus chemotherapy in treating hr+/her2 mbc patients in community - based oncology practices in the us . the everolimus - based therapy group includes everolimus monotherapy and combination therapy of everolimus and either endocrine therapy or chemotherapy ; the chemotherapy group includes chemotherapy monotherapy , combinational therapy of chemotherapy agents , and combinational therapy of chemotherapy and endocrine therapy ( excluding combination of chemotherapy and everolimus ) . the clinical outcomes of interest include time on treatment ( tot ) , overall survival ( os ) , and pfs . community - based oncologists / hematologists who treated postmenopausal women with hr+/her2 stage iv mbc were invited from a nationwide online panel of over 9,500 oncologists / hematologists to participate in the chart review study . physicians were eligible for participation if they had treated one or more postmenopausal hr+/her2 mbc patients who met all the patient selection criteria described below . each physician was asked to provide data for up to 10 patients , selected at random from their list of eligible patients . stratified sampling was used to ensure sufficient sample size in each treatment group ( everolimus - based therapy or chemotherapy ) and by line of therapy ( first line , second line , third line , and above ) . a standardized electronic case report form ( ecrf ) the ecrf was extensively tested for logic and consistency and was pilot tested by three community based oncologists for clarity and understandability . the identity of physicians was blind to the authors and study sponsor , and vice versa . patient medical records were selected for abstraction if the patient was a postmenopausal woman who had bc recurrence or progression on or after a nonsteroidal ai in an adjuvant or metastatic setting and subsequently initiated an everolimus - based therapy or chemotherapy in any line of treatment for mbc between 07/01/2012 and 04/15/2013 ( the first treatment initiated during this time period that met the aforementioned criteria was defined as the index therapy ) . patients who received everolimus - based therapies before their index treatment were excluded from the current analysis for both treatment groups . furthermore , physicians were required to have access to their patients ' mbc - related medical records from the first mbc diagnosis to the last follow - up ( or death ) , while patients were required to not be enrolled in any clinical trials and to not have a history of primary malignancy of other nonbreast cancers ( with the exception of nonmelanoma skin cancer and carcinoma in situ of the uterine cervix ) within 3 years prior to the first mbc diagnosis date . tot was defined as the time from initiation of index therapy to either death or discontinuation of index therapy , whichever occurred first . patients without recorded death or discontinuation of the index therapy were censored at the last follow - up date . os was defined as the time from initiation of the index therapy to death from any cause . pfs was defined as time from initiation of index therapy to disease progression or death , whichever occurred first . progression was determined by the participating physicians with radiographic evidence or tests , physical exams , or assessment of symptoms or through the use of other methods . patients ' baseline characteristics at either the first mbc diagnosis or the initiation of index therapy were summarized . they included age , race , insurance type , disease status ( de novo , recurrent with adjuvant endocrine therapy , recurrent without adjuvant endocrine therapy ) , adjusted charlson comorbidity index ( cci ) ( excluding a score of 6 for metastatic cancer ) , eastern cooperative oncology group ( ecog ) performance status , number and sites of metastases , physician - classified tumor volume , prior chemotherapy in the mbc setting , and time from initiation of last adjuvant endocrine therapy to the first mbc diagnosis . patient baseline characteristics were compared between the everolimus - based therapy and chemotherapy groups using wilcoxon rank - sum tests for continuous variables and chi - square tests for categorical variables . patients treated with everolimus - based therapy and chemotherapy were compared for all study outcomes ( tot , os , and pfs ) using kaplan - meier ( k - m ) analyses and cox proportional hazards models . unadjusted comparisons between everolimus - based therapy and chemotherapy included ( 1 ) k - m curves generated for each study outcome and log - rank tests ; ( 2 ) median estimates obtained for patients who were not censored for tot and pfs ( e.g. , for tot , medians were assessed among those patients who had completed their index treatment ) ; ( 3 ) cox models used to compare each outcome using two approaches , one included treatment group assuming homogeneous comparative effectiveness across lines of therapy , and the other one included an interaction term between line of therapy and treatment group allowing heterogeneous comparative effectiveness across lines of therapy . adjusted comparisons between everolimus - based therapy and chemotherapy were conducted using multivariate cox models , controlling for patient baseline characteristics including age , race , insurance type , index therapy line , disease status , adjusted cci , sites of metastases , ecog performance status , prior chemotherapy in the mbc setting , and time from initiation of last adjuvant endocrine therapy to first mbc diagnosis . similar to the unadjusted cox regression analyses , one set of models adjusted for treatment group and the other adjusted for an interaction term between the line of therapy and treatment group . a total of 234 patients were included for the everolimus - based therapy group and 137 for the chemotherapy group . both groups had similar comorbidity burden , insurance coverage , ecog performance status , prior chemotherapy in the mbc setting , and time from initiation of last adjuvant endocrine therapy to first mbc diagnosis . patients treated with everolimus - based therapy were older ( 64 years versus 62 years , p = 0.050 ) and more likely to be caucasian than patients treated with chemotherapy ( 64.1% versus 50.4% , p = 0.009 ) . compared to the chemotherapy group , everolimus - based therapy group had a lower proportion of liver , lung , and visceral metastases , a smaller number of metastatic sites , and a lower proportion of high-/medium - volume tumors ( all p < 0.05 ) . overall , patients treated with everolimus - based therapy appeared to have less aggressive mbc than those treated with chemotherapy . everolimus - based therapy was associated with significantly longer tot than chemotherapy ( log - rank test p < 0.001 ; unadjusted hazard ratio ( hr ) = 0.36 , 95% confidence interval ( ci ) : 0.270.47 , p < 0.001 ; table 2 ) . median tot among patients who completed their index treatment was 8.6 months for everolimus - based therapy patients and 6.1 months for chemotherapy patients . multivariate - adjusted cox regression results showed that tot was significantly longer for everolimus - based therapy patients compared to chemotherapy patients ( adjusted hr = 0.34 , 95% ci : 0.250.45 , p < 0.001 ; table 2 ) . when further adjusted by the interaction between line of therapy and treatment group , tot was longer in patients who received everolimus - based therapy in all lines of therapy than patients who received chemotherapy in the same lines ( adjusted first - line hr = 0.30 , 95% ci : 0.200.46 , p < 0.001 ; adjusted second - line hr = 0.30 , 95% ci : 0.170.52 , p < 0.001 ; adjusted third - line and above hr = 0.45 , 95% ci : 0.260.78 , p = 0.004 ; table 3 ) . everolimus - based therapy was associated with significantly longer os than chemotherapy ( log - rank test p = 0.002 ; unadjusted hr = 0.49 , 95% ci : 0.300.78 , p = 0.003 ; table 2 ) . multivariate - adjusted cox model results showed that os was significantly longer for everolimus - based therapy patients compared to chemotherapy patients ( adjusted hr = 0.37 , 95% ci : 0.220.63 , p < 0.001 ; table 2 ) . when further adjusted by the interaction between line of therapy and treatment group , os was significantly longer in patients who received everolimus - based therapy in first - line or third - line and above than patients who received chemotherapy in the same lines ( adjusted first - line hr = 0.35 , 95% ci : 0.160.79 , p = 0.011 ; adjusted third - line and above hr = 0.29 , 95% ci : 0.120.75 , p = 0.010 ; table 3 ) . everolimus - based therapy was associated with numerically longer pfs than chemotherapy , although the difference was only marginally significant ( log - rank test p = 0.057 ; unadjusted hr = 0.74 , 95% ci : 0.551.01 , p = 0.058 ; table 2 ) . median pfs among patients who completed their index treatment was 8.5 months for everolimus - based therapy patients and 7.1 months for chemotherapy patients . multivariate - adjusted cox regression results showed that pfs was significantly longer for everolimus - based therapy patients compared to chemotherapy patients ( adjusted hr = 0.70 , 95% ci : 0.500.97 , p = 0.033 ; table 2 ) . when further adjusted by the interaction between line of therapy and treatment group , pfs was longer in patients who received everolimus - based therapy in third - line and above than patients who received chemotherapy in third - line and above , although the difference was marginally significant ( adjusted hr = 0.56 , 95% ci : 0.301.02 , p = 0.059 ; table 3 ) . for the treatment of hr+/her2 mbc , the nccn guidelines recommend three consecutive lines of endocrine therapy ( including everolimus / exemestane combinational therapy for patients who meet the eligibility criteria for the bolero-2 trial ) before chemotherapy . however , real - world studies report that many patients start chemotherapy earlier [ 9 , 10 ] , possibly due to concerns about endocrine resistance or visceral symptoms . as newer targeted therapies become available for hr+/her2 mbc , evidence of the comparative effectiveness of these treatments versus chemotherapy is important for the decision - making process of physicians and payers . the current retrospective chart review showed that in hr+/her2 postmenopausal women with mbc , patients receiving everolimus - based therapy tended to have less aggressive mbc , in particular visceral metastases , than patients receiving chemotherapy . everolimus - based therapy was associated with significantly longer os , pfs , and tot than chemotherapy after adjusting for the observed baseline characteristics ; and the findings were largely consistent across lines of therapy . the present comparative effectiveness findings are consistent with recent studies showing that hr+/her2 mbc patients treated with everolimus - based therapy tended to have better os [ 17 , 18 ] and pfs   than those treated with chemotherapy . for example , using a small sample of hr+/her2 mbc patients , pouget et al . showed that everolimus plus endocrine therapy resulted in significantly longer os than chemotherapy for patients pretreated with two or fewer lines of therapies for mbc [ 17 , 18 ] . ( 2013 ) conducted a network meta - analysis of available mbc clinical trials and concluded that despite differences in patient characteristics across studies , everolimus / exemestane combinational therapy was associated with the longer mean pfs until 20 months compared to commonly - used chemotherapies such as capecitabine , doxorubicin , paclitaxel , and vinorelbine . future head - to - head clinical trial evidence will help further assess the comparative efficacy of everolimus - based therapy compared to chemotherapy . a phase ii bolero-6 trial   is actively recruiting patients and aims to compare the efficacy of chemotherapy ( capecitabine monotherapy ) with everolimus - based therapy in er+ mbc patients after recurrence or progression on prior nonsteroidal ai . primary findings of the study are expected in early 2016 . while chemotherapy is recommended for more aggressive cancers , for the majority of hr+/her2 mbc patients  who present a more manageable course of disease endocrine therapy presents a more favorable risk - benefit profile , particularly due to the treatment 's similar efficacy but milder toxicity relative to chemotherapy . the current nccn guidelines recognize this and support subsequent treatment to prolong the benefits of endocrine therapies for as long as possible before initiating chemotherapy . together with recent studies [ 17 , 18 ] , the current findings suggest that everolimus - based therapy may be a more effective alternative to chemotherapy after initial failure of nonsteroidal ais . furthermore , previous studies have shown that while everolimus may result in some moderate toxicity [ 23 , 24 ] , the adverse events are generally manageable   and the patient 's health - related qol is similar to that of patients on endocrine therapy . this may make everolimus more preferable over chemotherapy , which is often accompanied by severe tolerability issues that result in worse health - related qol while on treatment [ 11 , 12 , 22 ] . the observed shorter tot among patients treated with chemotherapy may be due to oncologists ' preference of only prescribing a limited cycle of chemotherapy in order to avoid cumulative toxicity . future studies can compare real - world safety outcomes between the two treatments to better inform treatment decisions . first , inherent to observation studies , the findings may be subject to bias if important confounding factors are not identified and adjusted for in the study 's analyses [ 27 , 28 ] . in the current multivariable analyses , we adjusted for patient characteristics commonly recorded in medical charts and known to be prognostic for outcomes in mbc . these included characteristics such as age , race , insurance type , index therapy line , disease status , cci , sites of metastatic disease , ecog , prior chemotherapy in the mbc setting , and time from initiation of the last adjuvant endocrine therapy to the first stage iv mbc diagnosis . however , if patients treated with everolimus - based therapy are healthier based on unobserved measures of disease severity or have better coping skills , the results are likely to be biased in favor of everolimus . second , the frequency of patient follow - up could be different between the two treatment groups . the group with more frequent visits to oncologists was more likely to be identified to have an event ( such as discontinuation and progression ) . these limitations can only be addressed with a well - conducted randomized - controlled trial . nonetheless , observational studies constitute a valuable and rich source of data , as they allow researchers to examine treatment effectiveness across patient groups in a large sample set and are directly reflective of ( and applicable to ) real - world clinical practice . in this retrospective review of hr+/her2 mbc patients from community - based oncology practices in the us , patients treated with everolimus - based therapy tended to have less aggressive mbc than patients treated with chemotherapy . after controlling for the observed baseline characteristics , everolimus - based therapy was associated with significantly longer os , pfs , and tot than chemotherapy . as this is an observational study , unobserved patient characteristics may affect study findings .
objective . to compare the real - world effectiveness of everolimus - based therapy and chemotherapy in postmenopausal women with hormone - receptor - positive / human - epidermal - growth - factor - receptor-2-negative ( hr+/her2 ) metastatic breast cancer ( mbc ) 
 . methods . 
 this retrospective chart review examined a nationwide sample of postmenopausal hr+/her2 mbc women in community - based oncology practices . 
 patients received everolimus - based therapy or chemotherapy for mbc between 07/01/2012 and 04/15/2013 , after failure of a non - steroidal aromatase inhibitor . 
 overall survival ( os ) , progression - free survival ( pfs ) , and time on treatment ( tot ) were compared using kaplan - meier analysis and cox proportional hazards models adjusting for line of therapy and baseline characteristics . 
 results . 
 234 and 137 patients received everolimus - based therapy and chemotherapy . 
 patients treated with everolimus - based therapy tended to have less aggressive mbc than patients treated with chemotherapy . 
 multivariate - adjusted cox models showed that everolimus - based therapy was associated with significantly longer os [ hazard ratio ( hr ) = 0.37 , 95% confidence interval ( ci ) : 0.220.63 ] , pfs ( hr = 0.70 , 95% ci = 0.500.97 ) , and tot ( hr = 0.34 , 95% ci : 0.250.45 ) than chemotherapy . 
 adjusted comparative effectiveness results were generally consistent across lines of therapy . 
 conclusion . in this retrospective chart review of postmenopausal hr+/her2 
 mbc patients , treatment with everolimus - based therapy was associated with longer os , pfs , and tot than chemotherapy .