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542 Background: The TAILORx trial demonstrated that adjuvant endocrine and chemoendocrine therapies had similar efficacy in patients with hormone receptor-positive, HER2-negative, node-negative breast cancer with an Oncotype DX recurrence score (RS) of 11-25. However, a predictive strategy is needed to identify patients with intermediate RS who may benefit from adjuvant chemoendocrine therapy. Curebest 95GC Breast (95GC) is a 95-gene signature that can stratify patients into two groups with high (95GC-H) and low (95GC-L) groups to predict the risk of recurrence. Our primary objective was to show that 95GC can classify patients with intermediate RS into binary recurrence risk groups. Methods: Patients with ER-positive, HER2-negative, node-negative invasive breast cancer and RS 11-30 who underwent definitive surgery and adjuvant endocrine therapy were included. RNA was derived from archived formalin-fixed, paraffin-embedded samples, and 95GC was calculated as reported previously. The Fisher exact and Brunner-Munzel tests were used to compare variables between 95GC groups. A Kaplan-Meier estimate with a log-rank test was used for recurrence-free survival (RFS) analysis. Results: The analysis included 178 patients from five institutions. The 5-year RFS rate in patients with RS 18-30 was higher in the 95GC-L group (n = 129, 96.3%) than in the 95GC-H group (n = 49, 90.9%; p = 0.002), which was consistent with results in an independent Japanese population (n = 224; p < 0.001). RFS rates significantly differed between the groups among patients with RS 11-25 as well (95GC-L, 97.4%; 95GC-H, 87.1%; p = 0.001). RFS rates did not differ between patients with RS 18-25 (94.8%) and those with RS 26-30 (93.8%; p = 0.33). Conclusions: 95GC can predict recurrence risk in patients with ER-positive, HER2-negative, node-negative invasive breast cancer and intermediate RS. Further prospective retrospective studies in the TAILORx population are warranted to confirm that 95GC can identify patients who may benefit from adjuvant chemoendocrine therapy.

Purpose To evaluate the efficacy and tolerability of dofequidar plus cyclophosphamide, doxorubicin, and fluorouracil (CAF) therapy in comparison with CAF alone, in patients with advanced or recurrent breast cancer. Dofequidar is a novel, orally active quinoline derivative that reverses multidrug resistance. Patients and Methods In this randomized, double-blind, placebo-controlled trial, patients were treated with six cycles of CAF therapy: 28 days/cycle, with doxorubicin (25 mg/m2) and fluorouracil (500 mg/m2) administered on days 1 and 8 and cyclophosphamide (100 mg orally [PO]) administered on day 1 through 14. Patients received dofequidar (900 mg PO) 30 minutes before each dose of doxorubicin. Primary end point was overall response rate (ORR; partial or complete response). In total, 221 patients were assessable. Results ORR was 42.6% for CAF compared with 53.1% for dofequidar + CAF, a 24.6% relative improvement and 10.5% absolute increase (P = .077). There was a trend for prolonged progression-free survival (PFS; median 241 days for CAF v 366 days for dofequidar + CAF; P = .145). In retrospectively defined subgroups, significant improvement in PFS in favor of dofequidar was observed in patients who were premenopausal, had no prior therapy, and were stage IV at diagnosis with an intact primary tumor. Except for neutropenia and leukopenia, there was no statistically significant excess of grade 3/4 adverse events compared with CAF. Treatment with dofequidar did not affect the plasma concentration of doxorubicin. Conclusion Dofequidar + CAF was well tolerated and is suggested to have efficacy in patients who had not received prior therapy.

1048 Background: The Phase 3 randomized FALCON trial (NCT01602380) demonstrated improved progression-free survival with fulvestrant 500 mg (F) vs anastrozole 1 mg (A) in postmenopausal women with hormone receptor-positive (HR+) locally advanced or metastatic breast cancer (BC) without prior endocrine therapy (hazard ratio [HR] 0.797, 95% confidence interval [CI] 0.637-0.999; p = 0.0486; Robertson et al. Lancet 2016). Overall health-related quality of life (HRQoL) was maintained and similar for F and A. There was no evidence of a detriment with F vs A in time to deterioration for both Trial Outcome Index (TOI; HR 0.90, 95% CI 0.70-1.15; p = 0.4008) and Functional Assessment of Cancer Therapy for Breast Cancer (FACT-B) total score (HR 0.84, 95% CI 0.66-1.07; p = 0.1594). We present additional analyses of patient (pt)-reported HRQoL outcomes from FALCON. Methods: Women with HR+ BC were randomized 1:1 to F (Days 0, 14, 28, then every 28 days) or A (daily) until disease progression or discontinuation. HRQoL was assessed by FACT-B questionnaire (TOI [summary of physical and functional well-being and breast cancer subscale scores] and FACT-B total score) at randomization and every 12 weeks during treatment. HRQoL data post-treatment (with or without progression) were also collected. Results: 462 pts were randomized (F, n = 230; A, n = 232). Compliance to FACT-B during treatment ranged from 84.6-100.0%. Mean change from baseline in TOI (scale range 0-92) and FACT-B total score (scale range 0-144) remained broadly stable (approximately ±3 points to Week 132) and similar between arms during treatment. HRQoL was also maintained in FACT-B subscales. Approximately one third of pts had improved TOI (≥ +6 points) and FACT-B (≥ +8 points) total scores from baseline up to Week 144 of treatment with F (ranges 26.4-45.0%, and 20.0-35.8%, respectively) and A (ranges 18.6-32.9%, and 22.7-37.9%, respectively). Conclusions: Compliance to the FACT-B questionnaire on treatment with F and A for HR+ BC in the FALCON trial was good; mean change from baseline in TOI and FACT-B total score was maintained, and similar proportions of pts had improved TOI and FACT-B total score in both arms. Clinical trial information: NCT01602380.

516 Background: PIK3CA mutations (mt) are frequently observed in BC but their clinical relevance is unclear. We performed an individual pt data pooled-analysis to evaluate the prognostic impact of ...

152 Background: In BOLERO-2 (NCT00863655), everolimus plus exemestane (EVE + EXE) more than doubled median progression-free survival (PFS) vs placebo (PBO) + EXE (by local assessment: 7.8 vs 3.2 mo; hazard ratio [HR], 0.45; P < 0.0001; by central assessment: 11.0 vs 4.1 mo; HR, 0.38; P < 0.0001) in patients (pts) with hormone-receptor–positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer (ABC). This exploratory analysis assessed the efficacy and safety of EVE + EXE in a subset of pts with baseline invasive lobular carcinoma (ILC) (elderly pts with predominantly peritoneal, gastrointestinal, and ovarian metastases [mets]). Methods: Pts with HR+, HER2– ABC recurring or progressing on/after prior nonsteroidal aromatase inhibitor therapy were randomized 2:1 to receive EVE 10 mg/day + EXE 25 mg/day or PBO + EXE. Primary efficacy end point was PFS (by local assessment). Results: Of 724 pts, 77% (n = 556) had ductal carcinoma and 14% (n = 104; EVE + EXE, n = 64; PBO + EXE, n = 40) had ILC. In ILC subset, median age was 63 years, 47.1% had measurable disease, and majority of baseline characteristics were similar to overall study population with exception of main mets sites. In pts with ILC, 36% reported visceral mets (lung, liver, pleural, pleural effusions, peritoneum, and ascites), 10% lung mets, and 23% liver mets when compared with 59% visceral mets, 31% lung mets, and 33% liver mets in overall study population. Median PFS was higher with EVE + EXE vs PBO + EXE (6.9 vs 4.2 mo; HR, 0.59; 95% CI, 0.37-0.95). Objective response rates were 14.1% (EVE + EXE arm) and 0% (PBO + EXE arm) vs 12.6% and 1.7%, respectively, among overall study population. Clinical benefit rates were 45.3% (EVE + EXE arm) and 30.0% (PBO + EXE arm); 51.3% vs 26.4% in overall study population. The safety profile of EVE + EXE in pts with ILC was similar to overall study population. Most common adverse events (all grades) in EVE-treated pts with ILC were stomatitis (50%), diarrhea (41%), nausea (36%), fatigue (34%), and rash (33%). Conclusions: EVE + EXE prolonged PFS in pts with ILC who had different patterns of mets. Other outcomes were similar to those in overall study population. Clinical trial information: NCT00863655.

553 Background: The phase 3 BOLERO-2 study at 18 months’ median follow-up showed that everolimus (EVE) + exemestane (EXE) significantly improved progression-free survival (PFS) vs EXE alone in 724 hormone-receptor–positive (HR+) advanced breast cancer (ABC) patients with recurrence/progression during/after nonsteroidal aromatase inhibitor (NSAI) therapy. A higher rate of grade 3/4 adverse events was noted with EVE + EXE, but was not associated with deterioration in quality of life (QOL) based on the EORTC QLQ-C30 Global Health Status scale. Additional patient-reported post hoc analyses of QOL are reported herein. Methods: During BOLERO-2, QOL (EORTC QLQ-C30 and QLQ-BR23) was assessed at baseline and q 6 wk thereafter until progression or discontinuation. Physical, emotional, and social functioning subscales of QLQ-C30 were analyzed. Time to definitive deterioration (TTD) was defined based on either a 5% (protocol specified) or 10-point (more stringent) decrease from baseline for each subscale and analyzed by Kaplan-Meier methods. The difference between treatments was assessed by a log-rank test stratified by randomization factors. Results: QLQ-C30 compliance was > 80% at week 48. Among the 3 protocol-specified QLQ-C30 subscales, analyses based on a 5% decrease in QOL showed a longer TTD for both physical and emotional functioning in the EVE + EXE group vs EXE alone (log-rank P = .0120 and P = .0277, respectively). The TTD for social functioning was similar in both treatment arms (log-rank P = .3374). Analyses based on a 10-point decrease indicated a longer TTD for physical functioning in the EVE + EXE group (15.2 mo) vs EXE alone (9.7 mo; log-rank P = .0211). The TTDs for emotional and social functioning were similar between EVE + EXE and EXE alone: 13.9 vs 13.8, respectively (log-rank P = .4023), and 11.5 vs 9.5, respectively (log-rank P = .2507). Conclusions: The treatment goal for ABC is to maximize clinical benefit with minimal negative effects on QOL. These additional BOLERO-2 QOL analyses confirmed that the more than doubling of PFS with EVE + EXE was accompanied by maintained physical, emotional, and social functioning compared with EXE alone in patients with HR+ ABC progressing after NSAI. Clinical trial information: NCT00863655.

142 Background: Everolimus (EVE) plus exemestane (EXE) more than doubled progression-free survival (PFS) while maintaining quality of life vs EXE alone in postmenopausal women with hormone receptor–positive (HR+), HER2-negative (HER2–) advanced breast cancer (BOLERO-2 phase III; NCT00863655). PFS benefit was seen in all clinically defined subgroups. We evaluated genetic variations of a broad panel of cancer-related genes and explored their correlations with EVE benefit. Methods: Exon sequence and gene copy number variations were analyzed in 182 cancer-related genes by next-generation sequencing (NGS). Correlations with PFS were evaluated using univariate and multivariate Cox models. Results: NGS data (>250x coverage) were successfully generated from archival tumor specimens from 227 patients (NGS population, 157 in EVE + EXE arm and 70 in EXE arm) whose baseline characteristics and clinical outcome were comparable to the trial population (PFS HR = 0.40 and 0.45, respectively). The treatment benefit of EVE + EXE over EXE was maintained in the subgroups defined by each of the 9 genes with a mutation rate >10% (e.g., PIK3CA, FGFR1, CCND1) or when less frequently mutated genes (e.g., PTEN, AKT1) were included in their respective pathways. Patients with 0 or 1 genetic alteration in PI3K or FGFR pathways or CCND1 had a greater treatment effect from EVE (HR = 0.27, 95% CI 0.18-0.41, adjusted by covariates, in 76% of the NGS population), indicating the value of these pathways for predicting sensitivity to EVE in this setting. Conclusions: This is the first global registration trial in which efficacy-predictive biomarkers were explored by correlating broad genetic variations with clinical efficacy. The preliminary results suggest that a large subgroup of patients (76%), defined by minimal genetic variations in the PI3K or FGFR pathways or CCND1, derives the most benefit from EVE therapy (HR = 0.27 vs 0.40 for the full NGS population). These exploratory results and their implication in understanding the interplay of multiple pathways in tumor cells and testing new hypotheses for targeted combination therapies in HR+/HER2– BC will be further investigated. Clinical trial information: NCT00863655.

LBA509 Background: Everolimus (EVE) plus exemestane (EXE) more than doubled progression-free survival (PFS) while maintaining quality of life vs EXE alone in postmenopausal women with hormone-receptor positive (HR+), HER2-negative (HER2-) advanced breast cancer (BOLERO-2 phase III; NCT00863655). PFS benefit was seen in all clinically defined subgroups. We evaluated genetic variations of a broad panel of cancer-related genes and explored their correlations with EVE benefit. Methods: Exon sequence and gene copy number variations were analyzed in 182 cancer-related genes by next-generation sequencing (NGS). Correlations with PFS were evaluated using both univariate and multivariate Cox models. Results: NGS data (>250x coverage) were successfully generated from archival tumor specimens from 227 patients (NGS population, 157 and 70 in EVE+EXE and EXE arms, respectively) whose baseline characteristics and clinical outcome were comparable with the trial population (PFS HR = 0.40 and 0.45, respectively). The treatment benefit of EVE+EXE over EXE is maintained in the subgroups defined by each of the nine genes with a mutation rate >10% (eg, PIK3CA, FGFR1, and CCND1), or when less frequently mutated genes (eg, PTEN, AKT1) were included in their respective pathways. Patients with no or only 1 genetic alteration in PI3K or FGFR pathways, or CCND1, had a greater treatment effect from EVE (HR = 0.27, 95% CI 0.18-0.41, adjusted by covariates, in 76% of the NGS population), indicating the value of these pathways for predicting sensitivity/resistance to EVE in this setting. Conclusions: This is the first global registration trial in which efficacy-predictive biomarkers were explored by correlating broad genetic variations with clinical efficacy. It demonstrated the feasibility of applying large-scale NGS and subsequent correlative analysis to such trials. The observations suggest that a large subgroup of patients (76%), defined by minimal genetic variations in the PI3K or FGFR pathways, or CCND1, derives the most benefit from EVE therapy (HR = 0.27 vs 0.40 for the full NGS population). These exploratory results and their implication in understanding the interplay of multiple pathways in tumor cells and testing new hypotheses for targeted combination therapies in HR+/HER2- BC will be further investigated. Clinical trial information: NCT00863655.

558 Background: In BOLERO-2, adding everolimus (EVE) to exemestane (EXE) more than doubled progression-free survival without affecting quality of life vs EXE alone in postmenopausal women with hormone-receptor–positive advanced breast cancer who had recurrence or progression on/after nonsteroidal aromatase inhibitor therapy. Although mTOR inhibitors are generally well tolerated, stomatitis is one of their most clinically relevant and potentially dose-limiting toxicities (Sonis Cancer2010). The incidence, grade, and clinical course of stomatitis among patients (pts) participating in the BOLERO-2 study are described. Methods: Pts were randomized 2:1 to receive EVE+EXE or placebo (PBO)+EXE. Stomatitis incidence, severity, consequent dose interruptions/adjustments, study drug discontinuations, and time to resolution were recorded. Results: The median duration of EVE+EXE treatment exposure was 30 wk (range, 1-123 wk). Stomatitis (any grade) occurred more frequently with EVE+EXE than with PBO+EXE (59% vs 12%, respectively). Grade 3 stomatitis occurred in 8% vs 1% of pts receiving EVE+EXE vs PBO+EXE, respectively; no grade 4 was reported. Onset of grade ≥2 stomatitis after treatment initiation was earlier in the EVE+EXE arm vs the PBO+EXE arm: median time was 15d vs 24d, respectively. In the EVE+EXE arm, 97% of pts with grade 3 stomatitis (n=38) improved to ≤1 after a median of 13 d. Complete resolution was observed in 82% of these pts after a median of 38 d. In the PBO+EXE arm, all pts with grade 3 stomatitis (n=2) improved to ≤1 after a median of 18 d. Complete resolution was observed after a median of 29 d. Overall, 24% of pts in the EVE+EXE arm required dose interruptions/adjustments vs 1% of pts in the PBO+EXE arm, and 3% of pts (n=13) discontinued EVE+EXE vs

557 Background: In patients with hormone-receptor–positive (HR+) breast cancer, endocrine therapy is the standard of care both in the adjuvant setting and as first-line treatment for ABC. For selected HR+ patients with ABC, chemotherapy (CT) may be utilized if disease burden is high and rapid symptom control is required (Barrios CH. GAMO.2010). In the phase 3 BOLERO-2 study (NCT00863655), 1 line of prior CT in the ABC setting was allowed. This subset analysis examined disease characteristics and the efficacy of everolimus (EVE) plus exemestane (EXE) in patients who received CT for ABC prior to BOLERO-2 study entry. Methods: In BOLERO-2, 724 patients with HR+, human epidermal growth factor receptor-2–negative (HER2–) ABC whose disease recurred or progressed during/after a nonsteroidal aromatase inhibitor were randomized 2:1 to EVE (10 mg/d) + EXE (25 mg/d) or placebo (PBO) + EXE. The primary endpoint was progression-free survival (PFS) by local investigator review and confirmed by blinded independent central review. Results: A subset of 186 patients (26%) received prior CT for ABC: 125 in the EVE + EXE group and 61 in PBO + EXE. In this subset, 54% (67 of 186) of patients received prior CT only in the advanced setting and 46% (58 of 186) of patients received prior CT in both the neoadjuvant/adjuvant and advanced settings. Incidences of visceral metastases (67% vs 56%), multiple metastases (79% vs 66%), and ≥ 4 metastatic sites (18.3% vs 15%) were higher in ABC patients with prior CT for ABC at study entry versus those with no prior CT for ABC. Disease recurrence < 6 months from initial diagnosis was recorded in 32.2% (n = 60) of prior CT patients versus 17.3% (n = 93) of patients with no prior CT. Median PFS (by local assessment) in patients who received prior CT for ABC was substantially longer with EVE + EXE versus PBO + EXE (6.1 vs 2.7 mo; HR = 0.38; 95% CI, 0.27-0.53). PFS by central review showed similar results (7.1 vs 2.8 mo, respectively; HR = 0.42; 95% CI, 0.27-0.65). Conclusions: These results demonstrate that patients with HR+, HER2– ABC who received previous CT in the advanced setting had a higher tumor burden and derived clinically significant benefit from combination treatment with EVE + EXE. Clinical trial information: NCT00863655.

e20510 Background: We reported 12-month results of upfront zoledronic acid (ZOL) therapy, which prevented bone loss in postmenopausal Japanese women who were receiving adjuvant letrozole, confirming the Z-FAST and ZO-FAST studies results. But the examination in the long term of aromatase inhibitor-associated bone loss has not been proved in the Japanese or Asia women. Methods: Postmenopausal women with hormone receptor positive early breast cancer (BC) patients receiving adjuvant letrozole were randomly assigned to receive either upfront or delayed-start ZOL (4mg intravenously every 6 months) for 5 years. The delayed group received ZOL when lumbar spine (L2-L4) BMD decreased to less than young adult mean (YAM) – 2.0 S.D or when a nontraumatic fractured occurred. The primary endpoint of this study was to compare the changes in L1-L4 BMD at month 12 between the groups. Secondary endpoints, measured at other predetermined timepoints, included comparing changes in L1-L4, L2-L4and total hip (TH) BMD and markers of bone turnover, fracture incidence, and time to disease recurrence. We report the results of 36-month interim analysis. Results: At 36 months, mean change in L1-L4 BMD was 10.7% higher in the upfront group than in the delayed group ( 95% CI, 9.2% to 12.1%; p< 0.001 ), L2-L4BMD was 10.9% higher ( 95% CI, 9.3% to 12.5%; p< 0.001 ), and TH BMD was 6.7% higher ( 95% CI, 5.3% to 8.1%; p< 0.001 ). The incidence of fracture was not significantly different between each group (upfront, 1(1.0%) vs. delayed, 4(4.1%)). Disease recurrence was reported in 3 upfront (3.1%) and 1 delayed (1.0%) patients. By month 36, 11 patients (11.3%) in the delayed group initiated ZOL therapy. There was no significant difference of adverse events other than fever with ZOL at the first treatment between the two groups. Conclusions: Upfront ZOL seems to be the preferred treatment strategy versus delayed administration, as it significantly and progressively increases BMD in postmenopausal Japanese women with early BC who were receiving adjuvant letrozole for 36 months. Clinical trial information: UMIN000001104.

142 Background: Everolimus (EVE) plus exemestane (EXE) more than doubled progression-free survival (PFS) while maintaining quality of life vs EXE alone in postmenopausal women with hormone receptor–positive (HR+), HER2-negative (HER2–) advanced breast cancer (BOLERO-2 phase III; NCT00863655). PFS benefit was seen in all clinically defined subgroups. We evaluated genetic variations of a broad panel of cancer-related genes and explored their correlations with EVE benefit. Methods: Exon sequence and gene copy number variations were analyzed in 182 cancer-related genes by next-generation sequencing (NGS). Correlations with PFS were evaluated using univariate and multivariate Cox models. Results: NGS data (>250x coverage) were successfully generated from archival tumor specimens from 227 patients (NGS population, 157 in EVE + EXE arm and 70 in EXE arm) whose baseline characteristics and clinical outcome were comparable to the trial population (PFS HR = 0.40 and 0.45, respectively). The treatment benefit of EVE...

561 Background: The BOLERO-2 trial showed that adding everolimus (EVE) to exemestane (EXE) more than doubled progression-free survival (PFS) without reducing quality of life versus placebo (PBO) + EXE alone in postmenopausal women with hormone-receptor–positive (HR+), HER2-negative (HER2–) advanced breast cancer (ABC) progressing on/after nonsteroidal aromatase inhibitor (NSAI) therapy. Although generally well tolerated, mTOR inhibitors such as EVE have been associated with noninfectious pneumonitis (NIP). Methods: Patients (pts) were randomized 2:1 to receive EVE+EXE or PBO+EXE. Incidence and severity of NIP, consequent dose interruptions/adjustments, study drug discontinuations, and time to resolution were recorded. Results: Median duration of exposure to EVE was 24 weeks with median dose intensity of 8.6 mg/d. Pulmonary adverse events (AEs) of any grade (NIP, interstitial lung disease, lung infiltration, pneumonia, or pulmonary fibrosis) were recorded in 97 of 482 pts (20%) in the EVE+EXE arm versus 1 of 238 pts (+, HER2– ABC progressing on/after NSAI. The incidence of NIP in this study was generally consistent with reports from other oncology settings, was of mild to moderate severity, and was generally reversible with appropriate interventions and temporary dose modifications. Patient and healthcare provider education for early diagnosis and management of NIP are highly recommended. Clinical trial information: NCT00863655.

104 Background: Postmenopausal women with estrogen-receptor–positive (ER+) BC who relapse/progress on a nonsteroidal aromatase inhibitor (NSAI) are usually treated with the steroidal AI exemestane (EXE), but there is no currently approved treatment for this indication. The BOLERO-2 trial showed that adding everolimus (EVE), an oral inhibitor of mammalian target of rapamycin (mTOR), to EXE significantly improved clinical benefit beyond that of EXE alone (Hortobagyi et al, SABCS 2011, Abstract S3-7). As many women with advanced BC are elderly, the tolerability profile of EVE + EXE in this population is of interest. Methods: BOLERO-2 is a phase III, randomized trial comparing EVE (10 mg once daily) vs placebo (PBO), both plus EXE (25 mg once daily), in postmenopausal women with advanced ER+ BC progressing or recurring after NSAIs. Safety data with a focus on elderly patients are reported at 12.5 months’ median follow-up. Results: Baseline disease characteristics, age, and prior cancer therapy were well balanced between treatment arms (N = 724). At 12.5 months’ median follow-up, the addition of EVE to EXE significantly improved progression-free survival in patients

125 Background: BOLERO-2, a phase III study, randomized 724 patients with hormone-receptor–positive metastatic breast cancer, who had recurrence or progression on/after prior nonsteroidal aromatase inhibitor therapy, to everolimus (EVE) + exemestane (EXE) or EXE + placebo. A preplanned 12-mo median time interim analysis demonstrated that EVE + EXE significantly improved progression-free survival (PFS) vs EXE + placebo, but EVE + EXE resulted in a higher rate of grade 3-4 toxicity. Per-protocol patients reported HRQoL data are limited; here we report on additional post hoc analyses of these outcomes. Methods: Using the EORTC QLQ-C30 questionnaire, HRQoL was assessed at baseline and every 6 weeks thereafter until progression. QLQ-C30 consists of 30 items combined into 15 subscales, including a Global Health Status (GHS), where higher scores (range, 0-100) indicate better HRQoL. Analysis included a protocol-specified time to definitive deterioration (TTD) analysis at a 5% decrease in QoL relative to baseline, with no subsequent increase above this threshold. We report additional sensitivity analyses using 10-point minimally important difference (MID) decreases in QLQ-C30 score relative to baseline. Treatment arms were compared using a stratified log-rank test and a Cox proportional hazards model adjusted for trial stratum (visceral metastases and previous hormone sensitivity), age, sex, race, baseline score, ECOG performance status, prognostic risk factors, and treatment history. Results: Baseline QLQ-C30 GHS scores were not statistically significantly different across treatment groups (64.7 vs 65.3; difference –0.7 [95% CI, –4.3-3.0]). Median TTD in HRQoL was 7.0 mo (95% CI, 5.6-8.3) for EVE + EXE vs 5.6 (95% CI, 4.2-7.0) for EXE (p = .0792). Adjusted HR (0.80) approached significance (95% CI, 0.63-1.02). At the 10-point MID, median TTD for EVE + EXE was 9.7 mo (95% CI, 8.3-11.2) vs 8.4 mo (95% CI, 6.3-12.5) for EXE. Adjusted HR was 0.90 (95% CI, 0.69-1.18). Conclusions: These additional analyses from the BOLERO-2 study demonstrate that in addition to significantly improving PFS, EVE + EXE does not compromise HRQoL.

99 Background: Current treatment options for postmenopausal patients with estrogen-receptor–positive breast cancer (BC) who relapse or progress on a nonsteroidal aromatase inhibitor (NSAI) are limited. The BOLERO-2 trial supports the activity of everolimus (EVE; an oral mammalian target of rapamycin [mTOR] inhibitor) added to the steroidal aromatase inhibitor exemestane (EXE) to prolong progression-free survival (PFS) in this patient population. Long-term PFS and survival data are awaited. Methods: BOLERO-2 is a phase 3, double-blind, randomized, international trial comparing EVE (10 mg once daily) + EXE (25 mg once daily) vs. placebo (PBO) + EXE in postmenopausal women with advanced estrogen-receptor–positive BC progressing or recurring after NSAIs (letrozole or anastrozole). Patients were randomized (2:1) to EVE + EXE or PBO + EXE. The primary endpoint was PFS by local investigator assessment. Main secondary endpoints included centrally assessed PFS, overall survival (OS), safety, bone turnover, and overall response rate. Results: Baseline disease characteristics including tumor burden and prior cancer therapy were well balanced between treatment arms (N = 724). Median PFS was doubled and response rates were consistently improved with EVE + EXE (n = 485) vs PBO + EXE (n = 239) in interim analyses. Median PFS by local assessment was ~3 mo with PBO + EXE vs 6.9 mo (hazard ratio [HR], 0.43; P < .0001) and 7.4 mo (HR, 0.44; P < .0001) with EVE + EXE at 7.5 mo and 12.5 mo follow-up, respectively. Fewer deaths were reported with EVE + EXE (17.2%) vs PBO + EXE (22.7%) at 12.5 mo follow-up. Safety profiles were consistent with previous reports for mTOR inhibitors. PFS data including 528 events (protocol-specified final analysis), and updated OS and safety data will be presented. Conclusions: Adding EVE to EXE markedly prolonged PFS in patients with NSAI-refractory advanced estrogen-receptor–positive BC. There were fewer deaths among patients receiving EVE, and further follow-up will evaluate the effect of EVE on OS.

551 Background: Postmenopausal women with estrogen-receptor–positive (ER+) BC who relapse/progress on a nonsteroidal aromatase inhibitor (NSAI) are usually treated with the steroidal AI exemestane (EXE); but there is no currently approved treatment for this indication. The BOLERO-2 trial showed that adding everolimus (EVE), an oral inhibitor of mammalian target of rapamycin (mTOR), to EXE significantly improved clinical benefit beyond that of EXE alone (Hortobagyi et al, SABCS 2011, Abstract S3-7). As many women with advanced BC are elderly, the tolerability profile of EVE + EXE in this population is of interest. Methods: BOLERO-2 is a phase III, randomized, trial comparing EVE (10 mg once daily) vs placebo (PBO), both plus EXE (25 mg once daily) in postmenopausal women with advanced ER+ BC progressing or recurring after NSAIs. Safety data with a focus on elderly patients are reported at 12.5 mo median follow-up. Results: Baseline disease characteristics, age, and prior cancer therapy were well balanced between treatment arms (N = 724). At 12.5 months’ median follow-up, the addition of EVE to EXE significantly improved progression-free survival in patients

539 Background: BOLERO-2, a phase III study, randomized 724 patients with hormone-receptor–positive metastatic breast cancer, who had recurrence or progression on/after prior nonsteroidal aromatase inhibitor therapy, to everolimus (EVE) plus exemestane (EXE) or EXE and placebo. A preplanned 12-month median time interim analysis demonstrated that EVE+EXE significantly improved progression-free survival (PFS) vs EXE+placebo but that EVE+EXE resulted in a higher rate of grade 3/4 toxicity. Per-protocol patient reported health-related quality-of-life (HRQoL) data are limited; here we report on additional post-hoc analyses of these outcomes. Methods: Using the EORTC–QLQ‑C30 questionnaire, HRQoL was assessed at baseline and every 6 weeks thereafter until progression. The QLQ‑C30 consists of 30 items combined into 15 subscales, including a Global Health Status (GHS) where higher scores (range 0 to 100) indicate better HRQoL. This analysis included a protocol-specified time to definitive deterioration (TTD) analysis at a 5% decrease in QoL relative to baseline, with no subsequent increase above this threshold. We report additional sensitivity analyses using 10-point minimally important difference (MID) decreases in QLQ‑C30 score relative to baseline. Treatment arms were compared using a stratified logrank test and a Cox proportional hazards model adjusted for trial stratum (visceral metastases and previous hormone sensitivity), age, sex, race, baseline score and ECOG performance status, prognostic factors, and treatment history. Results: Baseline QLQ‑C30 GHS scores were not statistically significantly different across treatment groups (64.7 vs 65.3; difference -0.7 [95% CI; -4.3, 3.0]). The median TTD in HRQoL was 7.0 months (95% CI; 5.6, 8.3) for EVE+EXE vs 5.6 (95% CI; 4.2, 7.0) for EXE (P = .0792). Adjusted HR (0.80) approached significance (95% CI; 0.63, 1.02). At the 10-point MID, median TTD for EVE+EXE was 9.7 months (95% CI; 8.3, 11.2) vs 8.4 months (95% CI; 6.3, 12.5) for EXE. Adjusted HR was 0.90 (95% CI; 0.69, 1.18). Conclusions: These additional analyses demonstrate that in addition to significantly improving PFS, EVE+EXE does not compromise HRQoL.

559 Background: Current treatment options for postmenopausal patients with estrogen-receptor–positive (ER+) breast cancer (BC) who relapse or progress on a nonsteroidal aromatase inhibitor (NSAI) are limited. The BOLERO-2 trial supports the activity of everolimus (EVE; an oral mammalian target of rapamycin [mTOR] inhibitor) added to the steroidal aromatase inhibitor exemestane (EXE) to prolong progression-free survival (PFS) in this patient population. Long-term PFS and survival data are awaited. Methods: BOLERO-2 is a phase III double-blind, randomized, international trial comparing EVE (10 mg once daily) plus EXE (25 mg once daily) versus placebo (PBO) plus EXE in postmenopausal women with advanced ER+ BC progressing or recurring after NSAIs (letrozole or anastrozole). Patients were randomized (2:1) to EVE + EXE or PBO + EXE. The primary endpoint was PFS by local investigator assessment. Main secondary endpoints included centrally assessed PFS, overall survival (OS), safety, bone turnover, and overall response rate (ORR). Results: Baseline disease characteristics including tumor burden and prior cancer therapy were well balanced between treatment arms (N = 724). Median PFS was doubled and response rates were consistently improved with EVE + EXE (n = 485) vs PBO + EXE (n = 239) in interim analyses. Median PFS by local assessment was ~3 mo with PBO + EXE vs 6.9 mo (hazard ratio [HR] = 0.43; P < .0001) and 7.4 mo (HR = 0.44; P < .0001) with EVE + EXE at 7.5 mo and 12.5 mo follow-up, respectively. Fewer deaths were reported with EVE + EXE (17.2%) vs PBO + EXE (22.7%) at 12.5 mo follow-up. Safety profiles were consistent with previous reports for mTOR inhibitors. PFS data including 528 events (protocol-specified final analysis), and updated OS and safety data will be presented. Conclusions: Adding EVE to EXE markedly prolonged PFS in patients with NSAI-refractory advanced ER+ BC. There were fewer deaths among patients receiving EVE, and further follow-up will evaluate the effect of EVE on OS.

540 Background: Estrogen-receptor–positive (ER+) breast tumors can become refractory to aromatase inhibitor (AI) therapy. The mTOR pathway plays a critical role in hormone-resistant advanced breast cancer (ABC). Accordingly, the addition of everolimus (EVE) to exemestane (EXE) was evaluated in an international, phase III study (BOLERO-2) in patients with ER+ aBC refractory to letrozole or anastrozole. This report presents updated analyses from the population of Asian patients enrolled in this study. Methods: Eligible patients were randomized (2:1) to EXE (25 mg/day) with EVE (10 mg/day) or with matching placebo. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival, response rate, quality of life, and safety. Results: EVE + EXE significantly improved PFS versus EXE alone (HR = 0.44; 95% CI, 0.36-0.53; P < .0001) in the overall study population at median follow-up of 12.5 months. Of 143 patients of Asian origin (n = 106; 74% Japanese) enrolled in this study, 98 received EVE + EXE and 45 received EXE + placebo. At the time of database lock, 55 Asian patients (56%) in the combination arm had experienced disease progression compared with 34 patients (76%) in the EVE + placebo arm. Combination therapy reduced the risk of disease progression versus EXE alone by 44% among Asian patients (HR = 0.56; 95% CI, 0.37-0.87; P < .05). Commonly reported adverse events in the combination arm were consistent with previous clinical studies of mTOR inhibitors and included stomatitis (80%), rash (49%), dysgeusia (31%). Adverse events that occurred more frequently in the Asian subset versus Caucasians included stomatitis (80% vs 54%) and rash (49% vs 37%), whereas dyspnea (8% vs 24%) and asthenia (1% vs 17%) occurred less frequently in the Asian subset versus Caucasians. Conclusions: The addition of EVE to EXE significantly prolonged PFS in Asian patients versus EXE alone. Adverse events were higher in the combination arm but generally manageable. Combining EVE with an AI is a safe and effective treatment option for Asian women with non-steroidal AI resistant/refractory ER+ ABC.

1040 Background: Although sentinel lymph node biopsy (SLNB) is a common procedure in treatment of early stage breast cancer, SLN examination protocols have not been standardized. OSNA assay is a semi-automated lymph node examination method using molecular biological technique and has been valued as a tool for the intraoperative SLN examination with potential for standardization. Also, OSNA assay is quite unique in providing semi-quantitative result (++/+) reflecting volume of metastatic foci by measuring the amount of CK19mRNA in a lymph node. This study evaluated clinical utility of OSNA assay in the clinical setting at 10 institutes in Japan. Methods: 415 clinically node negative breast cancer patients scheduled for SLNB were enrolled. Each surgically-obtained SLN was applied to both postoperative pathological examination and OSNA assay; a central slice of each SLN with 1 mm thickness was applied to pathological examination for one section H&E staining, and the residual portion was applied to OSNA assay...

e11058 Background: The PI3K/Akt/mTOR pathway, a key regulator of cellular proliferation, cellular metabolism, and angiogenesis, is constitutively activated in aromatase inhibitor–resistant breast c...

9075 Background: The primary analysis at 12 months (12M) of the Z-/ZO-FAST studies demonstrated that the loss of bone mineral density (BMD) could be effectively prevented by zoledronic acid (ZA). B...

501^ Background: The study of tamoxifen or arimidex, combined with goserelin acetate, to compare efficacy and safety (STAGE) study recently reported a greater best overall tumor response rate (BORR) for anastrozole 1 mg/day plus goserelin 3.6 mg/month (A+G) versus tamoxifen 20 mg/day plus goserelin 3.6 mg/month (T+G) during 24 weeks of pre-operative breast cancer treatment. We report the preplanned exploratory analysis of Ki67 expression. Methods: STAGE is the first phase III, randomized, double-blind, parallel-group, multicenter study which enrolled premenopausal Japanese women with estrogen receptor-positive (ER+), HER2-, operable breast cancer. Tumor response was measured by caliper and MRI or CT. Ki67 indices (%), ER and progesterone receptor (PgR) Allred scores were determined from samples obtained at baseline (Day 0) and surgery (Wk 24). Ki67 ratio from baseline to Wk 24 was calculated; the estimate of reduction ratio between groups was compared by ANCOVA. A post hoc analysis explored any correlatio...

1120 Background: TAS-108, a novel steroidal antiestrogen, has demonstrated a favorable safety profile, including lower agonistic activity on uterus than tamoxifen and supportive effect on bone in preclinical studies. The potential tissue-specific effect of TAS-108 was investigated in postmenopausal breast cancer patients included in a randomized phase II study. (The clinical efficacy and safety results were presented at the 31st San Antonio Breast Cancer Symposium). Methods: Postmenopausal women aged 20–80 years with hormone receptor-positive metastatic breast cancer were eligible for this study and treated with oral TAS-108 (40, 80, or 120 mg/day) once a day. Endometrial thickness (ET) was measured by ultrasonography. The change in Bone Mineral Density (BMD) at lumber spine was assessed by dual energy X-ray absorptiometry. Hormone levels, bone metabolism markers, and serum lipid parameters were also measured at regular intervals. Wilcoxon signed-rank test was used to assess the significance of changes or percentage changes from baseline. Results: Ninety one patients with a median age of 62 years (range 44–80) were included in the analysis population. TAS-108 did not cause significant endometrial thickening (median baseline ET 3.3 mm, last point ET 3.6 mm; n = 36). In particular, after at least 1 year of treatment in 13 cases, no clinically significant increase in ET was found. No change was observed in median BMD (+0.74%; n = 20). Serum carboxy-terminal telopeptide of type I collagen (I CTP) levels remained unchanged although the decrease in osteocalcin levels was significant (p = 0.019; n = 49) in patients without bone metastasis. Median triglyceride levels significantly decreased from 104.0 to 85.0 mg/dl (p = 0.000) after 4 weeks of treatment, while there were no changes in other lipid parameters. An increase in sex hormone-binding globulin and testosterone levels were observed. Conclusions: TAS-108 may have no harmful effects within these parameters and could be used safely. However, further study in a greater number of cases is needed to identify the effect of the long-term use of TAS-108 on the uterus and bone. [Table: see text]

Purpose The purpose of this study was to investigate the activity of capecitabine and trastuzumab in patients with HER2-overexpressing metastatic breast caner resistant to both anthracyclines and taxanes. Method From June 2003 and May 2006, 40 female patients with measurable or assessable metastatic breast cancer were enrolled and data from 38 patients were reviewed extramurally and analyzed. Patients were treated with weekly trastuzumab given at a dose of 2 mg/kg/day over 90 min (4 mg/kg/day on the Wrst infusion) and capecitabine given at a dose 1,657 mg/m 2 /day during 21 days with a subsequent pause of 7 days. This cycle was repeated every 28 days. The primary endpoint was overall survival and secondary endpoints were progression-free survival and response rate. Result A median of 4.5 cycles (range 1–9 cycles) were delivered. The median age was 53 (range 30–69 years). Median overall survival and progression-free survival was 22.3 and 4.1 months, respectively. Survival rate at 1 and 2 year was 81.6 and 47.4%, respectively. Response rate was 18.4% (95% CI, 7.7–34.3%). All evaluable patients have responded with two CR (5.3%), 5 PR (13.2%), 20 SD (52.6%), 8 PD (21.1%) and 3 NE (7.9%). Regarding the hematological toxicities, grade 1/2/3 neutropenia, grade 1/2 anemia, grade 1 thrombocytopenia and grade 1/2 liver dysfunction were also common. No treatment-related death was reported. Conclusion The combination of capecitabine and trastuzumab is active and well-tolerated in patients with HER2overexpressing breast caner resistant to both anthracyclines and taxanes.

10592 Background: Cyclin-dependent kinases (CDKs) are expressed almost constantly but their activities change according to cell cycle phase. We studied the specific activity (SA; activity/expression) of CDKs to accurately evaluate their role in cell proliferation. We focused on the ratio of CDK2 SA to CDK1 SA because this ratio has been associated with rapid tumor growth in human breast cancer xenografts. Our goal was to investigate the prognostic significance of CDK2/1 ratio in node-negative breast cancer. Methods: We used a novel assay to measure SAs of CDK2 and CDK1 in 365 primary breast tumors. All tumors were histologically confirmed invasive breast cancer without lymph node involvement. The primary endpoint was relapse-free survival (RFS). Cut-off values for CDK2/1 ratio were defined as those points that best discriminated groups according to RFS. Tumors were grouped as low (136pts), intermediate (84pts), and high (145pts) CDK2/1 ratio. The median follow-up was 59 months (range 4–102). Results: Pts characteristics are described as follows: menopausal status: pre- 42%, post- 58%; tumor size: =20mm 48%, >20mm 52%; histologic grade (HG): I 28%, II 47%, III 23%; ER: (+) 57%, (-) 42%; PR: (+) 51%, (-) 48%. Pts with HG III or high CDK2/1 ratio showed significantly lower 5y-RFS rates than those with HG I/II or low/intermediate CDK2/1 ratio, respectively (HG: I 97%, II 91%, III 85%, P=0.040; CDK2/1 ratio: low 97%, intermediate 92%, high 85%, P=0.017). In univariate analysis, PR (- vs +, P=0.088) had a tendency to associate with relapse, and HG (III vs I, P=0.024) and CDK2/1 ratio (high vs low, P=0.011) also had a significant correlation with relapse. However, only CDK2/1 ratio showed a significant independent prognostic indicator in multivariate analysis (hazard ratio 2.86, 95% CI 1.25–6.58, P=0.01). More important, among women (n=185) with hormone receptor (HR) positive disease given adjuvant hormone therapy alone, who have had no useful factors to predict their outcomes, high CDK2/1 ratio was also associated with worse prognosis than low CDK2/1 ratio (5y-RFS 84% vs 100%, P=0.007). Conclusions: For patients with node- negative disease, especially those with HR positive tumors given adjuvant hormone therapy alone, the CDK2/1 ratio might be useful as a routine laboratory test to predict outcome. No significant financial relationships to disclose.

586 Background: Increased cyclin-dependent kinase 1 (CDK1) and reduced CDK2 activity reflects taxane chemosensitivity via regulation of SAC. Novel C2P device (Sysmex Inc.) measures CDK1/2 activity in human tissue within a few hours. We hypothesized that SAC functionality in breast cancer predicts taxane sensitivity. Methods: Biopsy samples obtained before preoperative therapy from 69 pts with primary breast cancer (median age 52, St II, 56%, St III, 40%, HER2 36%, HR 52%) ex vivo with paclitaxel (100 nM) for 24 h, then measured for CDK1/2 activity. Tumors with CDK1/2 ratio > 0.7 were denoted “responders” (CR, PR) based on preclinical testing. Clinical responses were evaluated with sonography. Results: 24 pts could not be evaluated because of unmeasurable or invalid CDK (n=3), no receipt of taxane (n=10), incomplete treatment/lack of imaging (n=10), or receipt of taxane as adjuvant therapy (n=1). Among the 45 evaluable pts, 30 obtained reading to determine the C2P-predicted response, which was significantly associated with the clinical response to preoperative therapy with paclitaxel, docetaxel, docetaxel/doxorubicin, paclitaxel/trastuzumab or lapatinib, or docetaxel/capecitabine (P=0.002; sensitivity 0.83; specificity 0.86; positive predictive value [PPV] 0.95; and negative predictive value [NPV] 0.60). For HER2- tumors, the sensitivity was 0.94; specificity 0.83; PPV 0.94; and NPV 0.83. We fit a series of logistic regression models to assess the relationship between C2P predicted response and clinical outcome. Each model included 1 clinical prognostic factor (HR status, stage, NG, histology, HER2) as well as the C2P prediction factor. In all 5 models C2P remained a statistically significant predictor of clinical response while adjusting for the other prognostic factor. Conclusions: CDK1/2 activity is a promising novel predictive marker to predict response to taxane- containing regimens for HER2- breast cancer. We could not predict taxane sensitivity in HER2+ tumors; this finding is consistent with preclinical findings that HER2 overexpression is involved in abnormal SAC functionality. Thus, the functional SAC reflects taxane sensitivity in HER2- tumors. We are planning a large prospective study to validate these findings. No significant financial relationships to disclose.

570 Background: The PReOperative Arimidex Compared to Tamoxifen (PROACT) trial has shown that preoperative (neoadjuvant) anastrozole (A) is an effective presurgical treatment for postmenopausal wom...