Perez, Edith A.

CRA1002 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.

6023 Background: The addition of trastuzumab (H) to a standard adjuvant therapy regimen (doxorubicin, cyclophosphamide, and paclitaxel; AC→T) is associated with a 52% reduction in risk (p < 0.0001) of disease recurrence in patients with HER2 positive operable breast cancer (Romond et al, NEJM 2005). A cost-effectiveness analysis was performed to assess the lifetime clinical and economic implications of this important clinical finding. Methods: A Markov model with three health states (disease-free survival [DFS], recurrence, and death) was used to estimate the likely cost-effectiveness (CE) for a 50 yr old woman. Efficacy results from both trials (NCCTG N9831/NSABP B-31) were used through 4 years, and projections of time to recurrence and death were based on the literature (EBCTCG, Lancet 2005). After 4 years, annual transition probabilities to recurrence and death are assumed to be the same in both arms. Cardiotoxicity was higher with H (Perez EA, ASCO 2005). Actual total dose of H was used which was lower than scheduled dose. Incremental costs associated with addition of H to adjuvant therapy were estimated using average wholesale prices, Medicare reimbursement rates and other published data. These costs included testing for HER2 status, drug and administration costs for H, cardiac monitoring, treatment of cardiotoxicity, treatment following recurrence, and end-of-life costs for dying patients. Utility estimates were derived from the literature. Results: Over a lifetime, the cost per quality-adjusted life year gained (QALY; discount rate 3%) is $27,800, with a range of $17,900 to $39,100 under multi-way sensitivity analysis. Projected life expectancy from the Markov model is 3 years longer for H patients (19.4 v 16.4 yrs). Over a 20-year horizon, addition of H to AC→T is estimated to cost an additional $46,300 on average, with an expected gain of 1.28 QALYs-a cost/QALY of $36,100. The key drivers of CE are the cost of treatment and the improvement in DFS. Conclusion: The model projects a cost-utility ratio that is below that of many treatments used for oncology patients. The use of trastuzumab in the adjuvant setting for HER2+ breast cancer is projected to be cost-effective. [Table: see text]

6006 Background: In March 1998, the Common Toxicity Criteria version 2.0 was implemented and introduced the collection and reporting of attribution of adverse events to study treatment. Collection and reporting of attribution adds time and cost to the clinical trial process, and its use while reporting adverse events (AE) in the literature has varied. We investigate whether attribution adds value to the interpretation of AE data. Methods: Patients on the placebo arm of trial 97–24–51 (CAI vs. Placebo) were chosen since the true relationship of the event to the study treatment is known (“unrelated”). Attribution was collected per CTCv2.0 and categorized as “not related” (not related or unlikely) and “related” (possible, probable, or definite). All reported AEs and the maximum severity for a given AE were evaluated. Patterns were evaluated using generalized estimating equations adjusting for multiple events per patient. Changes in attribution over time for the same event were computed. Results: 84 patients on the placebo arm experienced a total of 1013 AEs. 47% of AEs were reported as “related” with 36% reported as possibly related. Known CAI AEs were more likely to be reported as “related” (p = 0.005). Pulmonary AEs were more likely to be reported as “not related” (p = 0.0006). No patterns were observed by gender, age, PS, severity or treatment cycle of AE. When the same event was reported on the same patient in multiple cycles, the attribution category changed at least once 36% of the time with 25% changing from “related” to “unrelated” or vice versa. Conclusion: Almost 50% of events on a placebo arm of a phase III trial were reported as being attributed to study treatment and 25% of the time the same event was not consistently attributed. These data suggest that attribution is difficult to determine, unreliable, and thus its value in large phase III trials is questionable. [Table: see text] No significant financial relationships to disclose.

13013 Background: The glutathione metabolic pathway is directly involved in the inactivation of platinum compounds. Our earlier work indicated that genotypes corresponding to varied glutathione-related enzyme activities may predict survival in patients with advanced lung cancer. Herein, we evaluated the role of glutathione-related genotypes on clinical outcomes in stage IIIB/IV non-small cell lung cancer patients who were stable or responding from one prior platinum-based chemotherapy. Methods: DNA samples from patients who had tumor regression or stable disease after treatment with one platinum based chemotherapy regimen were analyzed using 6 polymorphic DNA markers that encode 5 important enzymes in the glutathione metabolic pathway. The contrasting genotypes used in the analysis were GCLC (homozygous repeat 77 vs. heterozygous 7*), GPX1 (CC vs. other), GSTP1-I105V (AA vs. other), GSTP1-A114V (CC vs. other), GSTM1 (null vs. present), and GSTT1 (null vs. present). Multivariable Cox proportional hazards models adjusted for age, gender, treatment arm, ECOG performance status, stage, and prior tumor response, were used to evaluate the prognostic significance of the genotypes at each locus. Results: Data from 112 patients with a median follow-up of 10.6 (range: 0.4–56.3) months was used. No significant difference in time to disease progression was observed for any of the genotypes. Among the 6 genomic DNA markers, the GCLC genotype was an important prognostic factor for overall survival after adjusting for other factors. In particular, patients carrying a 77 repeat genotype (homozygous) had a significantly worse survival (Hazard ratio = 1.67, 95% CI: 1.05–2.63). Conclusions: Genotypes of glutathione-related enzymes, especially GCLC, may be used as host factors in predicting patients’ prognosis after platinum-based chemotherapy. Further investigation to define and measure the effects of these genes in chemotherapeutic regimens is needed. (This work was partly supported by NIH research grants CA77118, CA80127, and CA84354.) No significant financial relationships to disclose.

LBA537 Background: Between 10-1-02 and 12-01-05, SWOG 0012 accrued patients to a two-arm randomized trial, with formal participation from NCCTG and CTSU participation by other cooperative groups. Arm 1 gave A at 60 mg/m2 and C at 600 mg/m2 q 3 wk IV for 5 cycles, arm 2 A at 24 mg/m2/wk × 15 IV and C at 60 mg/m2/day PO for 15 wk with G at 5 mcg/kg/day × 6/7 weekly. Both groups then received T at 80 mg/m2/wk × 12, and proceeded to surgery with pCR by NSABP criteria at the primary site as the endpoint. A total of 372 were randomized, and we report here on 265 patients (pts) evaluable for outcome, including those who did not proceed to surgery. In arm 1, pCR was seen in 17% vs 27% in arm 2 (p = .06); when adjusted for hormone receptor status (ER-PR- in 49% on arm 1, 41% on arm 2) and disease type (locally advanced vs inflammatory), the odds ratio in favor of arm 2 is 1.98 (95% CI 1.05–3.74, p = .034). For ER- PR- pts, pCR rates for Arm 1 vs 2 were 26 vs 43%, while for those with ER or PR+, pCR rates were 9 vs 14%. Inflammatory pts showed a striking difference in pCR rates for arm 1 vs arm 2 (12 vs 33%, p = .033). HER 2 status (+ in 29%) did not predict response or interact with treatment. Grade 3/4 toxicities (arm 1 vs 2, %) were as follows: hand-foot syndrome (0 vs 13), neutropenia (47 vs 16), neutropenic infection (1.8 vs 0.6), stomatitis (2 vs 11), and nausea/vomiting (11 vs 5). Toxicity from T was grade 3 neuropathy in 10%, with grade 3 or 4 neutropenia in 12%. There were no treatment-related deaths. Continuous or “metronomic” chemotherapy with AC is superior to standard intermittent AC, and the pCR rate reported for the continuous arm is the highest reported in a cooperative group experience for this patient population. [Table: see text]

660 Background: Patients (pts) with MBC previously treated with an anthracycline, a taxane and capecitabine have very limited treatment options. Ixabepilone is the first semi-synthetic analog in a new class of cytotoxic agents, the epothilones. It has shown activity in breast and other tumors. Methods: This single-arm Phase II trial was designed to assess the objective response rate (ORR) of ixabepilone in MBC pts resistant to an anthracycline, a taxane and capecitabine. Pts had to be resistant to each regimen as defined by progression within 8 wks in the metastatic setting or recurrence within 6 months (mo) of adjuvant anthracycline/taxane. Capecitabine must have been given in the metastatic setting. Response was assessed by an independent radiology review committee (IRRC; primary analysis) and by each investigator per RECIST. Ixabepilone was administered IV at 40 mg/m2 over 3 h every 3 wks. Results: A total of 126 pts were treated: median age 51 yrs (range 30–78), Karnofsky PS range 70–100% and 70% pts had baseline liver metastases. 88% pts had received ≥2 prior metastatic regimens. 113 pts were response evaluable (had target disease by IRRC and met eligibility criteria for prior therapy). Median duration of response was 5.3 mo. Stable disease (SD) was the best response in 50% pts and 14% pts had SD ≥6 mo duration. Median PFS was 3.1 mo. Pts received a median of 4 cycles (range 1–16). The most common Grade 3/4 treatment-related adverse events were sensory peripheral neuropathy (14%), fatigue (10%), myalgia (7%), and stomatitis (6%). The neuropathy was cumulative and reversible. Time to resolution (to Grade 1 or baseline) for Grade 3/4 neuropathy was 5.4 wks by Kaplan-Meier analysis. Grade 3/4 neutropenia and thrombocytopenia occurred in 54% and 7% of pts, respectively. Febrile neutropenia was reported in 3% pts. Conclusions: Ixabepilone demonstrates promising clinical activity and a manageable safety profile in patients highly resistant to standard chemotherapy. [Table: see text] [Table: see text]

577 Background: BAY 43–9006 targets the ras/raf signaling pathway and inhibits VEGFR-2, VEGFR-3 and or PDGFR-β growth factors. A study was conducted to assess anti-tumor activity and the toxicity profile in patients (pts) with metastatic breast cancer (MBC). Methods: A two-stage phase II study was conducted with pts with MBC who had measurable disease and were candidates for 1 st or 2 nd line chemotherapy and had previously received an anthracycline and/or a taxane in the neoadjuvant, adjuvant, or metastatic setting. Pts started with a dose of 400 mg twice daily on days 1–28 of each 4 week cycle. Based on interval adverse events (AEs), a dose reduction was considered as 400 mg given one time daily. Primary endpoint was tumor response defined as a complete or partial response (PR) according to RESIST. The study required 40 pts, but was to be terminated if 0 or 1 responses occurred among 1 st 20 eligible pts. Results: 23 pts enrolled with a median age of 54 (range 37–70) but 3 were declared ineligible. All 23 pts were included in all analyses except efficacy analysis as stated per protocol. Fifteen (65%) had visceral metastasis; 22 (96%) had prior anthracycline treatment (tx); 16 (70%) had prior taxane tx.; 10 (44%) had received prior chemotherapy for metastatic disease and 14 (61%) had a prior relapse free interval of 12 months (mos) or more. Pts received tx for a median of 2 cycles (range 1–8) with a median follow-up of 7.2 mos. Dose reductions were due to dermatitis/skin rash (3), hand/foot skin reaction (2), hypertension (1) and cramping hands/feet (1). No grade 4 AEs occurred and grade 3 AEs included acne (2), hand/foot skin reaction (1), neutropenia (1), cough (1), wound infection (1), and prolonged PTT (1). Among the 20 pts eligible for efficacy analysis one pt (5%; 95% CI 0.5–20.5%) achieved a PR with duration of 3.6 mos and one pt achieved stable disease for at least 6 mos. The 6-month overall survival rate was 81% and the progression-free survival rates were 53% at 2 mos, 24% at 4 mos and 6% at 6 mos. Median time to progression was 2 mos. Based on the lack of sufficient response, we did not proceed with the 2nd stage of this study. Conclusion: Treatment with oral BAY 43–9006, while well tolerated, does not have sufficient activity to warrant further testing as a single agent in this disease setting. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech Genentech

573 Background: This study evaluates whether concurrent epirubicin/taxane (ET) improves disease-free survival (DFS) at 3 yrs compared to the sequential combination of epirubicin/cyclophosphamide followed by a taxane (EC>T) in pts with operable node (+) breast cancer. Methods: Eligible pts were randomized to receive either ET (E 75 mg/m 2) for 8 cycles q21 days or EC>T (E 90 mg/m 2, C 600 mg/m2) for 4 cycles, followed by 4 cycles of a taxane q21 days. Choice of T (paclitaxel 175 mg/m2 or docetaxel 75 mg/m 2) was at the physician’s discretion. The primary endpoint is DFS. A 0.10 increase in the probability of DFS at 3 yrs for the ET arm would be considered clinically relevant. To detect 82 events, 300 subjects per arm are required to provide 90% power at 5% significance level. Results: 617 pts were enrolled from Nov 2000 to June 2003; 308 pts received ET and 309 pts received EC>T. Both treatment arms were well balanced with respect to age, nodal+, ER status, Her-2+ and PS; median age 52.5 (42%<50 years old); 70% ER+; 61% LN (1–3); 16% Her-2+; 87% PS 0. Total of 2206 cycles of treatment were given to ET compared 2314 cycles of treatment to EC>T. At 30 months of median follow-up there were DFS 102 events occurred; 47 events in ET arm (16%) and 55 events in EC>T arm (18%); 63 total deaths; 29 deaths in ET arm and 34 deaths in EC>T arm. The most common toxicities include alopecia (50%), fatigue (31%), nausea and vomiting (30%), dyspepsia (27%), febrile neutropenia (15%), constipation (12%), diarrhea (10%), arthralgia (11%), stomatitis (10%). In cardiac safety f/u, only one pt in ET arm remained LVEF drop >15. Conclusions: Epirubicin can be combined with taxanes in both sequential and concurrent therapies and both regimens are effective and well tolerated. The study is sponsored by Pfizer Inc. No significant financial relationships to disclose.

523 Background: Adjuvant trastuzumab (Herceptin [H]) with chemotherapy improves outcome in HER2+ breast cancer (BC). Preclinical studies suggest H may enhance RT. We herein assess if H given with adjuvant RT increases adverse events (AE) after breast conserving surgery or mastectomy. Methods: N9831 randomized 3505 women with pT1–3N1–2M0, pT2–3N0M0, or pT1cN0M0 (ER/PR negative) HER2+ BC to doxorubicin (A) and cyclophosphamide (C) followed by weekly paclitaxel (T), AC→T→H, or AC→TH→H. Post-lumpectomy breast ± nodal RT was recommended, as was post-mastectomy chest wall + nodal RT (>3 nodes +); internal mammary RT was prohibited. RT started within 5 weeks of completion of T and allowed concurrently with H. 2324 eligible patients were enrolled on study prior to April 25, 2004: 1460 patients receiving RT are available for analysis of RT-associated AEs. Also, 1286 patients on +H arms who completed T (908 +RT and 378 -RT) are available for analysis of clinical cardiac events (CE). Rates of RT-associated AEs were compared across treatment arms, and rates of CE were compared for +RT vs -RT patients within +H arms. All reported p-values are for chi-squared statistics. Results: With a median follow-up of 1.5 years, significant differences among arms in RT-associated AEs were not identified. No significant differences across arms in +RT patients existed in the incidence of skin reaction (p=0.78), pneumonitis (p=0.78), dyspnea (p=0.87), cough (p=0.54), esophageal dysphagia (p=0.26), or neutropenia (p=0.16). There was a significant difference in +RT patients in the incidence of leukopenia (p=0.02) with higher incidence rates in the arms receiving H. RT did not increase the frequency of CE. In the AC→T→H arm, the incidence of CE was 2.2% in +RT patients versus 2.9% in -RT patients. In the AC→TH→H arm, the incidence of CE was 1.5% in +RT patients versus 6.3% in -RT patients. No difference in CE was seen between left- and right-sided RT fields in +RT patients in either +H arm. Conclusion: Concurrent administration of adjuvant RT with H in early stage breast cancer patients is not associated with an increased incidence of acute RT AEs. Further follow-up is required to assess late AEs. No significant financial relationships to disclose.

504 Background: CYP2D6 genetic variants and concurrent administration of potent inhibitors (Inh) of the enzyme markedly reduce the plasma concentrations of endoxifen (Jin. JNCI 2005;97:30–9). We have shown that genetic variation in CYP2D6 is associated with a higher risk of relapse in Tam treated patients (pts) (Goetz. JCO 2005;23:9312–18), but the impact of CYP2D6 inhibition on Tam clinical outcome is unknown. Methods: Using the North Central Cancer Treatment Group 89–30–52 adjuvant Tam trial (1989–1994), we evaluated the effect of co-administration of CYP2D6 Inh and CYP2D6*4 genotype on relapse in pts receiving tam alone. Patient charts were reviewed at each randomizing site to record the following known CYP2D6 Inh: fluoxetine (F), paroxetine (P), sertraline (S), cimetidine (C), amiodarone (A), doxepin (D), ticlopidine (T) and haloperidol (H). Poor metabolizers (PM) were defined as pts who were CYP2D6 *4/*4 and/or known to receive a CYP2D6 Inh. Intermediate metabolizers (IM) were defined as WT/*4 without CYP2D6 Inh, and extensive metabolizers (EM) as WT/WT without CYP2D6 Inh. The association between CYP2D6 status and Tam clinical outcome was determined using the log-rank test. Multivariate Cox modeling was performed using traditional prognostic factors. Results: CYP2D6*4 genotype was obtained in 190 of 256 eligible pts, with a CYP2D6*4/*4 genotype frequency of 6.8% as described previously (Goetz JCO 2005). Medication history was available in 171/256 eligible pts and in 143/190 pts with CYP2D6 genotype. Eleven of 173 patients were concomitantly administered these CYP2D6 Inh: F(2), P(2), S(2), H(1), C(4), and D(1). The median duration of use was 2.5 yrs. Twenty-four pts met criteria for PM [13 by *4/*4 genotype and 11 by CYP2D6 Inh (7 WT/WT, 1 WT/*4, and 3 unknown genotype)], 21 for IM, and 102 for EM. Compared with either IM or EM, PMs had significantly worse time to recurrence and disease free survival in both the univariate (HR 2.5, p=0.02; and 2.2, p=0.01) and multivariate (HR 2.7, p=0.01; and HR 2.2 p=.02) analyses utilizing tumor size, nodal status, and tumor grade. Conclusion: Our data indicate that CYP2D6 status can be used to identify pts who should receive tam therapy and tam treated pts should not be co-administered potent CYP2D6 inhibitors. No significant financial relationships to disclose.