Citations

1055^ Background: Key properties of QoL instruments in a clinical trial setting are reliability, the ability to detect a change, and content validity. Using data from the Study 301 phase III breast cancer trial, we report here content validity and ability to detect a change for the EORTC QLQ-C30 and breast cancer-specific QLQ-BR23 questionnaires. Methods: Patients with locally advanced or metastatic breast cancer were randomized to 21-day cycles of either eribulin mesylate 1.4 mg/m2 given on Days 1 and 8, or capecitabine 1.25 g/m2BID orally on Days 1-14. QoL questionnaires were completed at baseline and at 6 weeks, 3, 6, 12, 18, and 24 months. Objective tumor response was evaluated (complete response [CR]; partial response [PR]; stable disease [SD]; progressive disease [PD]). Univariate and multivariate longitudinal analyses using weighted generalized estimating equations were employed to assess the responsiveness of the QoL scales to objective tumor response. Results: 1,102 patients were randomized (554 eribulin, 548 capecitabine). Global health status (GHS)/QoL scores were low at baseline (55). GHS/QoL scores were highest for patients with CR (70.8), followed by those patients with PR (63.5), SD (60.5), and PD (58.1). Physical functioning followed the same pattern: CR (98.3); PR (79.1); SD (72.8); PD (71.0). Role and social functioning scores were also responsive. Pain increased, while fatigue and body image worsened, with poorer tumor responses. Using the weighted generalized estimating equations, there were improvements in physical (34.78; p<0.01), cognitive (27.29; p<0.01), and social (22.04; p<0.01) functioning, and future perspective 11.47 (p<0.01), in patients who responded (CR and PR) to treatment compared with non-responders. Pain decreased significantly by 28.62 (p<0.01) on a 0-100 scale. Patients who responded also gained appetite and had fewer breast symptoms. Conclusions: These results suggest content validity of the EORTC QLQ-30 and QLQ-BR23 questionnaires as they correlate with changes in objective tumor assessments. Clinical trial information: NCT00337103.

1037 Background: Folate receptor alpha (FRA the product of the FOLR1 gene) has been identified as a potential prognostic and therapeutic target in a number of cancers. A correlation has been shown between intense expression of FRA in breast tumors and poor prognosis, yet little is known about FOLR1/FRA expression across clinically relevant breast cancer subtypes. Methods: 131 breast cancer tumors including 4 benign, 33 ER+, 26 HER2+, and 68 triple negative (TN) were constructed into tissue microarrays (TMAs). FRA expression was analyzed by immunohistochemistry (IHC) using a high affinity FRA antibody. Tumor membrane staining intensity was scored by a pathologist as negative (0), weak (1+), moderate (2+) and strong (3+). The percent of cells within each tissue core stained at each intensity was recorded to calculate an H-score. The H-score is a weighted score that captured both the proportion of positive staining and intensity for each tumor. H-score values can range from zero (no membrane staining) to a maximum of 300 (100% membrane staining at 3+). H-scores for each patient sample were averaged over 3 TMA cores. The mean H-scores for each tumor subtype and the percentage of 3+ staining in >30% of tumor cells were compared by a Mann-Whitney test. The distribution of FOLR1 mRNA was completed using a TCGA RNA-seq dataset from 691 breast tumors classified as ER+, HER2+ and TN. FOLR1 levels of TN versus ER+ and HER2+ were compared by a Mann-Whitney test. Results: The mean H-score for the benign tumors was 0, ER+ (13.31), HER2+ (39.36), TN (119.02). The median H-score for the benign tumors was 0, ER+ (0), HER2+ (7.5), TN (127.5). The TN tumors mean and median H scores were significantly higher than benign, ER+ or HER2+ (p<0.001). The largest percentage of 3+ staining in >30% of tumor cells was observed in TN tumors (36.7%) and lowest in ER+ tumors (0%) (p<0.001). TN tumors had significantly higher levels of FOLR1 mRNA compared to ER+ and HER2+ subtypes (p<0.0001). Conclusions: Our data indicate that expression of FRA is highly prevalent in TN tumors and is supported by FOLR1 mRNA levels. Anti-FRA therapy may represent an important therapeutic intervention in TNBC who to this point have no active targeted treatment options.

1007 Background: Determining optimal adjuvant chemotherapy for early stage breast cancer depends on efficacy and toxicity. We sought to determine if T is equivalent to AC but with reduced toxicity. Methods: Pts with operable breast cancer with 0-3 positive nodes were enrolled on a 2x2 factorial design study which addressed (1) superiority of 6 vs. 4 cycles of therapy (previously reported, Shulman, JCO 2012) and (2) equivalence of single-agent T to standard AC, defined as upper bound of 95% confidence interval (CI) of hazard ratio (HR) of T vs. AC < 1.30 for the primary endpoint of relapse-free survival (RFS). A planned target of 567 RFS events required 4,646 pts with 4 yrs FU. At activation in 2002, T (80mg/m2) was q1wk for 12 or 18 wks and AC (60/600 mg/m2) was q3wk for 4 or 6 cycles. In 2003 (570 pts enrolled) schedules were revised to 4 or 6 cycles q2wk for both T (175 mg/m2) and AC. The 6-cycle arms were dropped in 2008 (3,171 pts enrolled) due to slow accrual. Relative effectiveness of T to AC is shown by hazard ratio (HR). Logrank p-values are measures of discordance but are not relevant for the equivalence question and are not adjusted for multiple comparisons. Results: After enrolling 3,871 pts, the study closed in 2010 due to slowing accrual. With a median follow-up of 6.1 yrs there are 437 RFS events. The HR of 1.26 (95% CI: 1.05-1.53; p = 0.02) does not allow a conclusion of equivalence of T with AC. With 266 deaths the HR for overall survival (OS) is 1.27 (95% CI=1.00-1.62; p = 0.05), favoring AC. The estimated absolute advantage of AC at 5 yrs is 3% (91 vs. 88%) for RFS and 1% (95 vs. 94%) for OS. All 9 treatment-related deaths were in pts receiving AC and are included in the survival analysis. The incidence of Grade 3+ toxicity for AC vs T was 33% vs. 4% for hematologic toxicity and 36% vs 22% for non-hematologic toxicity. Conclusions: This trial did not show equivalence of T to AC, a conclusion that is very unlikely to change with additional follow-up. T was less toxic than AC. Clinical trial information: CDR0000069444/NCT00041119.

520 Background: There is considerable interest in developing HER2 testing criteria for adjuvant H. We used the 21-gene assay to examine the relationship of HER2 mRNA to benefit from H. Methods: N9831 compared adjuvant chemotherapy AC-T to concurrent chemotherapy-trastuzumab AC-TH in stage I-III HER2+ breast cancer. Recurrence Score (RS) and HER2 mRNA expression were determined by Oncotype DX (neg<10.7, equiv 10.7 to <11.5, and pos ≥11.5 log2 expression units). Cox regression was used to assess the association of HER2 expression with H benefit for distant recurrence. Results: Median follow-up: 7.4 yrs. Of 1,940 total pts, 901 had consent and sufficient tissue. HER2 by RT-PCR was neg in 130 (14%), equiv in 85 (9%), and pos in 686 (76%) pts. Concordance between HER2 assessments was 95% for RT-PCR vs central IHC (>10% + cells = +), 91% for RT-PCR vs central FISH (≥2.0 = pos) and 94% for central IHC vs central FISH. In the primary analysis, the association of HER2 expression with H benefit was marginally non-significant (P=0.057). In hormone receptor pos pts (local IHC) the association was significant (P=0.002). The association was nonlinear with the greatest estimated benefit at lower and higher HER2 mRNA expression levels. The observed treatment benefit in low HER2 pts was not due to imbalance between arms in RS and individual gene expression values. Conclusions: Concordance among HER2 assessments by central IHC, FISH, and RT-PCR was high. Association of HER2 mRNA expression with H benefit was marginally non-significant. A consistent benefit of trastuzumab irrespective of mHER2 levels was observed in the pts with either IHC+ or FISH+ tumors. Benefit was observed in pts with high HER2 by RT-PCR but also observed for the small groups of pts with negative results by quantitative RT-PCR or FISH (Table). Plausible mechanisms for this observation will be discussed. [Table: see text]

e13501 Background: Loss of estrogen receptor alpha gene expression has been associated with insensitivity to endocrine therapy in human breast cancer patients. Histone deacetylase (HDAC) inhibitors have recently been found to restore sensitivity to the estrogen receptor by modulation of the estrogen and progesterone receptors. This had been shown with both aromatase and tamoxifen refractory and in triple negative cell lines . We performed a Phase I study of the combination of LBH589 (panobinostat) and letrozole to evaluate safety and tolerability in patients with metastatic breast cancer prior to the performance of a phase II trial. Methods: We enrolled postmenopausal women with metastatic breast cancer, ECOG PS 0 or 1, ANC>1500/mm3, platelets>100,000/mm3, normal total bilirubin, and ALT/AST adequate laboratory tests were eligible. Letrozole dose was 2.5 mg/day orally. Dose of LBH589: Level 1, 20 mg orally three times weekly; Level 2, 30 mg orally three times a week. Results: 12 patients (dose level 1:6 patients, dose level 2: 6 patients) have been enrolled. 43 cycles of treatment have been given to these12 patients. Initial cohort of 3 patients at the 20 mg dose level had no dose limiting toxicity (DLT). At the 30 mg dose level 3/6 patients had DLT (thrombocytopenia grade 1: 2 pts; grade 3:1 pt; grade 4: 1 pt; and diarrhea grade 3: 1 pt. One pt at the 30 mg dose level has a confirmed partial response and remains on study after 6 cycles of treatment. Subsequent cohort of 3 patients had 1 dose DLT with doubling of the creatinine. The main DLT was thrombocytopenia in 3/6 pts at the 30 mg dose level. Conclusions: The recommended dose for phase II testing of LBH589 is 20 mg orally 3 times per week in combination with standard dose letrozole.

1021 Background: At 5 years, AT did not improve disease free survival or overall survival and RS was a more accurate predictor of relapse than standard clinicopathologic characteristics for patients with hormone receptor (HR) positive tumors. Methods: A Phase III Intergroup trial tested adjuvant AT vs. AC. Women with 1-3 N + or N - and T-size > 1cm were randomized to 4 cycles of AT (60 mg/m2/60 mg/ m2) or AC (60 mg/m2/600 mg/m2) q 3 wk x 4. Patients(pts) with ER + and/ or PR + tumors received tam for 5 yrs. Pts were stratified by nodal, HR (ER+ PR+, ER+PR-, ER-PR+, ER-PR-, ER/PR unk) and menopausal status. The primary endpoint was DFS. A sample of 465 pts with HR + breast cancer with 0 to 3 positive axillary nodes who did (N =116) or did not have a recurrence had tumor tissue evaluated using the 21- gene assay. Grade and HR expression were evaluated locally and centrally. Results: 2952 pts were randomized between 7/30/98 and 1/21/00. 2883 were eligible and analyzable. Arms were balanced for age, HR, menopause, nodes, surgery, grade and T-size: median age 51; 64% ER +; 65% LN-; grade: 10% low, 38% int., 46% high; and median T-size - 2.0 cm. At a median follow-up of 11.5 years the DFS/OS results are shown in the table below. RS was a highly significant predictor of recurrence including node negative and node positive disease (P < .0001) and predicted recurrence more accurately than clinical variables. Conclusions: At 11.5 yrs. median follow-up, there remains no difference in DFS or OS, although there continue to be fewer events in the AT arm in the prespecified ER/PR negative subgroup. At 10 years, the RS continues to be a more accurate predictor of relapse than standard clinical features. [Table: see text]

1005 Background: We previously reported that in the E5194 clinical trial patients with ductal carcinoma in situ (DCIS) treated with wide local excision (WLE) without radiation (RT), the DCIS Score was significantly associated with 10 year risk of an ipsilateral breast event (IBE - recurrence of in situ or invasive carcinoma), whether evaluated as a continuous or categorical variable (P=0.02 for both). Here we evaluate correlation between DCIS Score and clinicopathologic (CP) features and if DCIS Score provides independent recurrence risk information. Methods: The study population included 327 women with DCIS prospectively selected for treatment with WLE without RT, including low-intermediate grade tumors ≤2.5 cm or high-grade ≤1 cm. CP variables included age, menopausal status, tamoxifen treatment (used in 29%) and expert centrally determined tumor size, grade, comedo necrosis, tumor type, and margin status. The association between DCIS Score and CP variables was examined by spearman rank correlation, and proportional hazards regression models were used to determine variables significantly associated with IBE. Results: Lesion size (p=0.009) and menopausal status (p=0.03) were significantly associated with IBE, while grade (p=0.69) and comedo necrosis (p=0.47) were not. DCIS Score was significantly associated with IBE after adjustment for CP features and tamoxifen use (p=0.02). DCIS Score was moderately correlated with grade (rs=0.46; 95% CI 0.37,0.54), percentage comedo necrosis (rs=0.49; CI 0.41,0.57), and lesion size (rs=0.18; CI 0.08,0.29) but not other features. Exploratory analyses in all CP subgroups, including the multicomponent Van Nuys Prognostic Index, showed a wide range of DCIS Scores in each subgroup. Concordance of the grades among readers was low: local vs parent central, 68%; local vs central nuclear grade, 45%; parent central vs central nuclear grade, 37%. Conclusions: DCIS Score is moderately correlated with grade, comedo necrosis, and tumor size. DCIS Score provides recurrence risk information independent of these features and identifies subjects with DCIS who are at high risk for local invasive and in-situ local recurrence after WLE alone.

TPS1140^ Background: NKTR-102 is a topoisomerase I inhibitor-polymer conjugate that hydrolyzes to provide continuous exposure to SN-38. A phase 2 trial of single-agent NKTR-102 was conducted in pts with 3rd-line MBC; 2 schedules (q14d; q21d) investigated a dose of 145 mg/m2. ORR was 29% (including 3% CR) with the prior ATC subset demonstrating an ORR of 31%. Dosing q21d was better tolerated; in this arm, median PFS and OS equaled 5.3m and 13.1m, respectively. Trial Design: Pts will be randomized 1:1 to receive single-agent NKTR-102 or TPC in an open-label, randomized, multicenter phase 3 study in pts with advanced breast cancer. Key Entry Criteria: Adult females, with ECOG 0 or 1 with adequate liver, kidney and marrow function. All pts must have received prior therapy with ATC (these drugs can be administered in the neo/adjuvant or locally advanced/metastatic setting). Prior A is not mandated if contraindicated. Prior toxicities must have resolved to ≤ Grade 1 (except sensory neuropathy ≤ Grade 2; complete resolution of prior diarrhea). Pts with brain metastases may be eligible, if lesions are stable for prior 3 weeks without steroids. Methods: Primary efficacy endpoint is OS. Secondary endpoints include: ORR by RECIST v1.1, clinical benefit rate (ORR+SD > 6 months), PFS and QoL. NKTR-102 is given IV at 145 mg/m2 over 90-min every 21 days without premedications. Pts randomized to TPC receive 1 of the following: eribulin, ixabepilone, vinorelbine, gemcitabine, paclitaxel, docetaxel or nab-paclitaxel (the agent must be available at the treating institution). Pts are stratified by region, prior eribulin and receptor status (TNBC, Her2+ or Other). Target Accrual: ~840 pts will be required for sufficient events to occur in the planned follow-up time; OS will be compared using a two-sided log-rank test; 1 interim analysis will occur when 50% of the deaths are reported. PK sampling is performed in a subset of pts. CTCs (isolated by Apocell ApoStream technology) are serially assessed for potential predictive markers of response and toxicity. Enrollment is expected to remain open until late 2013.

LBA1000 The full, final text of this abstract will be available at abstract.asco.org at 12:01 AM (EDT) on Monday, June 4, 2012, and in the Annual Meeting Proceedings online supplement to the June 20, 2012, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Monday edition of ASCO Daily News.

605 Background: Pre-clinical and nonrandomized clinical data support synergy of the combination of bevacizumab and trastuzumab. We conducted a randomized double-blinded phase III trial of chemotherapy/trastuzumab ± bevacizumab to evaluate efficacy (PFS after treatment initiation) of the addition of bevacizumab in first-line treatment of HER2+ MBC. Methods: Days 1, 8 and 15 paclitaxel ± carboplatin were administered with trastuzumab and either placebo or bevacizumab 10 mg/kg every 2 weeks for a total of 6 months. Antibody therapy was then continued without chemo every 3 weeks, until disease progression or unacceptable toxicity. Disease assessments were performed every 3 months. Results: Ninety-six of the planned 489 analyzable patients (pts) were accrued between 2007 and 2009, at which time the study terminated due to poor accrual. Seventy % of pts were post-menopausal, 60% had ER+/HER2+ BC. Median age was 55 years (28-80). Outcomes and toxicities are summarized on the tables below. Median follow-up was 30 months. Conclusions: The combination of chemotherapy, trastuzumab, and bevacizumab did not significantly increased toxicity, and was overall safe and well tolerated. No significant differences in clinical benefit were observed between both treatment arms. Data on CTCs and Quality of Life will be presented at the meeting. This study was conducted by the Eastern Cooperative Oncology Group (Robert L. Comis, MD, Chair) and supported in part by Public Health Service Grants CA23318, CA66636, CA21115, CA32291, CA31946, CA49957, CA27525, CA14548, CA17145, CA32102, CA25224, CA49. [Table: see text] [Table: see text]