Sparano, J. A.

1036 Background: Approximately 30% of human cancers have mutated Ras genes that produce proteins that remain in an active state causing uncontrolled proliferative signals. Post-translational modification of Ras include farneyslation catalyzed by FT. Tipifarnib (R115777) is an oral FTI active against human tumor cell lines and exhibiting modest single agent activity in pts with previously treated MBC. A previous phase I trial reported that CT inhibited farneyslation in peripheral blood mononuclear cells without affecting the pharmacokinetics of either agent. Objective: To evaluate objective response rate (ORR) of CT in taxane refractory MBC and to secondarily evaluate associated toxicity and progression-free survival (PFS). Methods: Pt with measurable MBC, previously treated (rx) with an anthracycline and relapse on a taxane or within 30 days (d). Study rx: T- 300 mg, po BID × 14 d plus C- 1,000 mg/m2, po BID × 14 d, followed by 7 d rest. Tumor reassessment was repeated q 3 cycles. The study was designed to detect improvement in ORR from 25% with C alone to 40% for the CT combination (90.5% power; type I error rate of 9.9%; 21 responses in 64 eligible pt needed to be promising. Results: 66/71 pt are available for primary analysis. Median age 50 yrs. Performance status: 0–1, 100%. ORR: PR-4.8% (3/62) [95% CI 0.01, 0.13], SD - 21% (13/62) [ 95% CI 0.12, 0.33]. Median survival - 10.6 months. Toxicity (%): anemia - 8(G3/4), neutropenia - 30 (G3/4), thrombocytopenia - 8 (G3/4), HFS-8 (G3), nausea/vomiting - 11(G3), diarrhea - 8 (G3), sensory neuropathy - 5 (G3). Conclusion: CT in taxane -refractory MBC has low antitumor activity without excessive toxicity. More mature data, including PFS, will be presented. No significant financial relationships to disclose.

270 Background: Neuropathy is a common and potentially enduring and disabling complication of adjuvant taxane therapy. Recent studies have identified candidate host single nucleotide polymorphisms (SNPs) associated with taxane-induced neuropathy (Schneider et al. ASCO 2011, abstr. 1000). We therefore sought to determine whether neuropathy was associated with breast cancer recurrence. Methods: This study included 4,950 eligible women with axillary lymph node positive or high-risk node-negative breast cancer who received up to 4 cycles of AC (doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2) every 3 weeks, followed by either: (1) paclitaxel 175 mg/m2 every 3 weeks x 4 (P3), (2) paclitaxel 80 mg/m2 weekly x 12 (P1), (3) docetaxel 100 mg/m2 every 3 weeks x 4 (D3), or (4) docetaxel 35 mg/m2 weekly x 12 (D1). Chemotherapy doses were based on actual body weight. Cox proportional hazards model were used to determine the relationship between neuropathy and disease free survival (DFS) and overall survival (OS) treating neuropathy status as a time dependent covariate and using a landmark analysis. Results: Of 4,702 patients who received at least 1 taxane dose, grade 2-4 neuropathy developed in 20%, 27%, 16%, and 16% in the P3, P1, D3, and D1 arms, respectively. In a model including age, tumor size, nodal status, treatment arm, neuropathy, and the neuropathy- treatment interaction, there was no relationship between neuropathy and DFS and OS in the entire population, for any of the individual treatment arms, or for any breast cancer subtypes, whether analyzed as a time-dependent covariate or using a landmark analysis. Baseline covariates associated with an increase rate of neuropathy included black race (25% vs. 19% grade 2-4, p=0.02) and obesity (21% vs. 19%, p=0.04), but not age. Conclusions: There was no association between taxane-induced neuropathy and DFS or OS in patients treated with contemporary AC-taxane therapy, including weekly paclitaxel. These findings show that taxane-induced neuropathy is not associated with outcome, thus suggesting that validation of SNPs predictive of neuropathy may be useful in identifying patients at higher risk for neuropathy but not taxane benefit and thereby improve therapeutic individualization.

Abstract Background: We have previously reported the results of surgical excision without irradiation for selected patients with DCIS in ECOG E5194, where the 5-year rates of local recurrence varied with age, grade, and lesion size (Hughes et al. J Clin Oncol 27:5319, 2009). New methods are needed to provide more accurate and reproducible assessment of recurrence risk. Methods: ECOG E5194 included 670 eligible patients with DCIS treated with surgical excision (≥ 3 mm negative margins) without irradiation, 228 of whom received tamoxifen. Patients had low or intermediate grade DCIS ≤ 2.5 cm, or high grade DCIS ≤ 1 cm. The Oncotype DX® assay was performed by quantitative RT-PCR using formalin fixed paraffin embedded tumor specimens from 327 patients (49% of the parent study). Recurrence Score® (RS) was calculated using the published algorithm. A new, prespecified DCIS Score™ was designed to predict recurrence using an optimized gene expression algorithm. The primary objective was to determine whether there was a significant association between the risk of an ipsilateral breast event (IBE) and the continuous DCIS Score in Cox models. 46 patients had an IBE (defined as ipsilateral local recurrence of DCIS [n=20] or invasive cancer [n=26]). Median follow-up was 8.8 years. Results: The 10-year IBE rates were 15.4% for low/intermediate grade DCIS and 15.1% for high-grade DCIS (as determined by central pathology review), and for invasive IBE, 5.6% and 9.8%, respectively. Comparison between local and expert grading showed substantial disagreement. Continuous DCIS Score was significantly associated with IBE (HR 2.34 per 50 units; 95% CI 1.15, 4.59; p=0.02) when adjusted for tamoxifen use (prespecified primary analysis) and with invasive IBE (HR 3.73; CI 1.34, 9.82; p=0.01). DCIS Score was significantly associated with outcome when evaluated by the prespecified risk groups (see Table). Similar results were observed with and without adjustment for tamoxifen use or for negative margin width. Features associated with IBE in multivariate models included menopausal status (HR 0.49; 95% CI 0.27, 0.90; p=0.02), tumor size (HR 1.52 per 5 mm; 95% CI 1.11, 2.01; p=0.01), and continuous DCIS Score (HR 2.41; 95% CI 1.15, 4.89; p=0.02). The standard RS, which is calculated using thresholding of many genes unlike the DCIS Score, was not associated with IBE or invasive IBE (p > 0.6). Conclusions: We have prospectively validated a multigene assay that quantifies recurrence risk and complements traditional clinical and pathologic factors in selected patients with DCIS treated with surgical excision without irradiation. The DCIS Score provides a new clinical tool for individualized selection of treatment for patients with DCIS. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr S4-6.

Abstract Abstract #6114 Introduction:
 Symptomatic patients (pts) with performance status (KPS) 70-80 with locally advanced or metastatic breast cancer (MBC) have worse prognosis than pts with good performance status and are often excluded from clinical trials. Ixabepilone (ixa), the first in a new class of antineoplastic agents, showed clinical benefit in 2 large clinical trials in combination with capecitabine (C) in MBC pts with tumors resistant to (study 046; JCO; 2007) or pretreated with anthracycline (A) and taxane (T) (study 048). In 048, ixa + C, compared to C alone, showed significant increases in PFS (HR 0.79 [0.69-0.90] and ORR (43% vs 29%). A trend toward increased OS was seen in 048 (HR 0.90 [0.78-1.03]) and 046 (HR 0.90 [0.77-1.05]) which did not reach statistical significance. In 046 and 048 trials, a survival benefit was seen with ixa + C in a predefined analysis in a subset of symptomatic KPS 70-80 pts (HR: 0.75 [0.58-0.98], 0.76 [0.60-0.96], respectively). We present a predefined pooled analysis of clinical outcomes in symptomatic pts from both studies to better evaluate the treatment effect in this subset.
 Methods:
 1973 pts with MBC previously treated with an A and T were randomized in phase III trials 046 and 048 to receive ixa (40mg/m2 IV over 3h Q3w) + C (1000mg/m2 PO BID x14d Q3w) or C alone (1250mg/m2 PO BID x14d Q3w). 606 pts from the 2 studies were KPS 70-80. Study outcomes included ORR, PFS and OS.
 Results:
 ORR, PFS and OS favored ixa + C in this pt population.
 
 In asymptomatic pts (KPS 90-100), similar improvement was observed in PFS and ORR; no benefit in OS was seen. Incidence of key treatment related grade 3/4 AEs for ixa + C in this subset of pts was similar to the overall population.
 Conclusions:
 In the pooled analysis, ixa + C demonstrates a survival benefit (2.8 mo) for symptomatic pts (KPS 70-80) failing A and T, which was consistently seen in this pt population in the individual studies as well, indicating that symptomatic pts can benefit from management of their disease and achieve overall clinical benefit with ixa combination. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6114.