Citations

557 Background: Aromatase inhibitors (AIs) are a novel hormonal therapy for breast cancer. However, AIs can cause bone loss by blocking estrogen production. This study aims to assess the association between AIs and treatment-related bone loss in a large managed care population of women with breast cancer. Methods: Using medical and pharmacy claims data from over 5 million beneficiaries between 01/01/1998 and 01/31/2005, we identified 12,368 patients with ≥ 2 breast cancer claims in a 6-month period, who also had no bone metastasis and no prior osteoporosis or fracture claims. Patients who received anti-estrogen therapy were also excluded to remove the protective confounding effects. 1,354 patients receiving an AI (anastrozole, exemestane, letrozole) were compared to 11,014 controls who did not receive an AI with respect to their risk of bone loss. The observation start date for the AI and control groups was defined as the service date of the first AI claim and breast cancer claim, respectively. The bone loss endpoints analyzed were osteoporosis (including osteopenia) and clinical fractures. Results: The univariate analysis found that the prevalence of osteoporosis was 8.7% in the AI group vs. 7.1% in the control group, resulting in a statistically significant relative risk of 1.3 (95% CI=1.1–1.6, p=0.01). The prevalence of bone fracture was also statistically significantly elevated in the AI group compared to the controls (13.5% vs. 10.3%) with a relative risk of 1.4 (95% CI=1.2–1.6, p=0.001). Multivariate Cox proportional hazards regressions showed that after adjusting for age and comorbidities, the risk of bone loss remained statistically significantly higher in the AI group than the non-AI group, with 27% (95% CI=4%-55%, p=0.02) and 21% (95% CI=3%-43%, p=0.02) increase in the risk of osteoporosis and fractures, respectively. Conclusions: This retrospective longitudinal analysis of a large cohort of breast cancer patients corroborates previous findings from smaller clinical trials and demonstrates that AI therapies carry an increased risk of bone loss. Monitoring and treatment management strategies to alleviate bone loss risk are warranted in women receiving AI for breast cancer. [Table: see text]

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.

18037 Background: Platinum compounds are major chemotherapeutic agents in lung cancer and are metabolized by the glutathione pathway enzymes. We reported that genotypes of glutathione-related enzymes, especially GCLC, may be host factors in predicting survival of patients with stage IIIB/IV non-small cell lung cancer who were stable or responding from prior platinum-based chemotherapy (Yang et al., ASCO 2006). NCCTG investigators previously correlated allelic variants in 5-FU metabolizing genes with QOL in colorectal cancer patients (Sloan et al., ASCO 2004). We sought to evaluate the role of glutathione pathway genotypes on QOL. Methods: DNA samples were analyzed using 6 polymorphic DNA markers in the glutathione metabolic pathway. The contrasting genotypes in the analysis were GSTM1 and GSTT1 (null vs. present), GSTP1-I105V (AA vs. GA/GG), GSTP1-A114V (CC vs. CT/TT), GPX1 (CC vs. TT/TC), and GCLC (homozygous repeat 77 vs. heterozygous 7*). Forty-six patients completed the FACT-L and the UNISCALE QOL questionnaires at baseline and week-8, and we have results for all 6 genotypes. A clinically significant decline (CSD) in QOL was defined as a 10% decrease from baseline to week-8. A multivariate logistic regression model was used to evaluate the association of all 6 genotypes with a CSD in QOL. Results: Patients carrying the GPX1-CC genotype had a CSD in the UNISCALE (Odds Ratio (OR): 10.0; p=0.02), total FACT-L score (OR: 7.9; p=0.03), the FACT-L physical well being construct (OR: 13.7; p=0.02), and the FACT-L functional well being construct (OR: 5.3; p=0.05). Other constructs, i.e., emotional, social and family, and additional concerns were not significantly associated with the genotypes. Conclusions: Genotypes of glutathione-related enzymes, especially GPX1 may be inherited factors in predicting patients’ QOL after platinum-based chemotherapy. Further investigation to define and measure the direct or indirect effects of these genes on QOL is critical, particularly, via drug responses, toxicities, and disease recurrence. (This work was partly supported by NIH grants CA77118, CA80127, and CA84354.) No significant financial relationships to disclose.

11051 Background: A serious complication associated with breast cancer treatment is the increased risk for development of therapy-related acute myeloid leukemia (t-AML). To evaluate and possibly identify patients (pts) at high risk for development of t-AML, the Southwest Oncology Group asked whether dose-intensive adjuvant regimens for high risk breast cancer pts induced genetic damage to hematopoietic stem cells (HSC), defined by the emergence of clonal hematopoiesis, an early marker of HSC damage. Methods: 274 pts consented to the clonal hematopoiesis study objective of S0012, a randomized clinical trial of standard doxorubicin and cyclophosphamide followed by weekly paclitaxel (arm 1, 129 pts) vs. weekly doxorubicin and daily oral cyclophosphamide plus G-CSF followed by weekly paclitaxel (arm 2, 145 pts) as neoadjuvant therapy for inflammatory and locally advanced breast cancer. Two different clonality assays were used: the HUMARA (HUMan Androgen Receptor) Assay to estimate the incidence of early genetic damage by clonal proliferation and microsatellite instability (MSI) testing at 5 loci (Bat 26, Bat 40, APC, Mfd, D2S123), common ‘hotspots‘ in t-AML, to screen for loss of heterozygosity or defective DNA mismatch repair mechanisms. Blood samples were evaluated prior to treatment and at 6 and 12 mos post-surgery for emergence of clonal hematopoiesis. Results: Of the 274 pts enrolled, follow-up clonal hematopoiesis samples were available for 195 pts; 96 pts on arm 1 and 99 pts on arm 2. Both HUMARA and MSI results were negative for clonal hematopoiesis in 96% of samples analyzed. In 14 cases, the HUMARA assay suggested that a clonal population was present, but MSI analysis was negative. No cases were HUMARA+/MSI+. With a median follow-up of 19.6 mos, only one pt has developed t-AML 3 yr 5 mos post randomization. Her clonal hematopoiesis test samples at 6 and 12 mos following treatment were negative. Conclusions: Clonal hematopoiesis assays performed within the first year following neoadjuvant therapy and surgery on S0012 failed to identify an emerging clonal HSC population. Longer clinical follow-up will be necessary to define the positive predictive value of detecting clonal hematopoiesis in the 14 HUMARA+/MSI- cases as a harbinger of t-AML. No significant financial relationships to disclose.

6511 Background: In March 1998, the Common Toxicity Criteria (CTC) version 2.0 introduced the collection of attribution of adverse events (AE) to study drug. Collection of attribution adds time and cost to the clinical trial process, and reporting in the literature has varied. At ASCO 2006 results were presented from NCCTG trial 97–24–51 that showed ∼ 50% of events on the placebo arm were reported as attributed to study drug and 25% of the time the same event was not consistently attributed. We sought to validate these results in a second placebo controlled trial. Methods: Patients on the placebo arm of the phase III ACOSOG trial Z9001 (imatinib mesylate vs. placebo after resection of primary gastrointestinal stromal tumors) were evaluated since the reported AEs could not be due to study drug. Attribution was collected per CTCv3.0 as not related, unlikely, possibly, probably, or definitely related, and categorized as “unrelated” (not related or unlikely) and “related” (possible, probable, or definite). Patterns were evaluated using generalized estimating equations adjusting for multiple events per patient. Results: 202 patients and 2871 AEs were included. 52% of AEs were reported as “related”. Known imatinib AEs were more likely to be reported as “related”. The reported rate of AE relatedness varied by AE type. No patterns were observed by gender, age, PS, severity or visit of AE. When the same event was reported on the same patient on multiple visits, the attribution category changed at least once 33% of the time with 19% changing from “related” to “unrelated” or vice versa. Conclusion: 52% of events on the placebo arm of Z9001 were reported as attributed to study drug and 19% of the time the same event was not consistently attributed. These data provide further evidence that attribution is difficult to determine, unreliable, and of questionable value in interpreting randomized clinical trials. No significant financial relationships to disclose. [Table: see text]

1071 Background: N0234 is a phase II trial of gemcitabine at 1000 mg/m2 days 1 and 8 of a 21 day cycle and erlotinib at 150 mg daily in patients with previous therapy with either an anthracycline or a taxane for MBC. A partial response (PR) rate of 17% has been reported (ASCO 2005). Recent information suggests that over-expression of the EGFR pathway is frequent in patients with TNeg MBC. Methods: Tissue and serum were obtained for translational studies of ER, PR, HER2, and proteins related to EGFR pathway on tissue using immunohistochemistry; CK19, mammoglobin, and TTK on circulating tumor cells (CTCs). Markers were evaluated centrally, blinded to patient outcome. Complete data were available in 57 of 59 eligible patients; 20/57 patients (pts) were TNeg. Results: A PR rate of 25% and clinical benefit rate (PR + stable disease > 6 months)of 25% was observed in TNeg pts as compared to a PR rate of 14% (p = 0.30) and clinical benefit rate 22% (p= 0.75) for non-TNeg pts. Median progression free survival 72 days vs 98 days (p=0.13) and overall survival 227 days vs 738 days (p<0.001) were shorter for TNeg pts. Translational results for the EGFR pathway proteins and CTC analysis is forthcoming. Conclusions: The combination of gemcitabine and erlotinib appears to be as active in the non-TNeg and TNeg subset of patients on this trial. TNeg patients had an inferior clinical result, confirming the poor outcome seen in these patients. Data for the remaining biomarkers potentially predictive of activity will be presented. Supported by CA-25224, CA-37404. [Table: see text]

1048 Background: Previous trials with p plus gem show significant antitumor activity in MBC. Nab-p has lower toxicity compared to p with similar therapeutic effects. This study assessed proportion of confirmed tumor responses and toxicity profile of this combination. Methods: Single stage phase II study enrolled patients (pts) with measurable MBC eligible for 1st line chemotherapy (chemo). Pts treated (tx) with nab-p 125 mg/m2 followed by gem 1,000 mg/m2 days 1 and 8 of 21 day cycle. Dose modifications allowed for both drugs. Primary endpoint was proportion of confirmed responses; complete response (CR), partial response (PR) by RESIST criteria on two consecutive evaluations at least 6 weeks apart. 41 evaluable pts required to test the null hypothesis that the confirmed response rate was at most 40% against the alternative of at least 60%. Results: 50 pts enrolled 11/05 to 5/06. Median age 56 (29–86). 40 pts (80%) visceral disease, 34 (68%) ER positive, 28 (56%) PR positive, 1 (2%) HER2 positive, 1 (2%) prior trastuzumab treatment (tx). 25 (50%) had prior adjuvant chemo, including 15 (30%) prior taxane. Median follow-up 7 mos (3–12). Median of 6 cycles of tx completed (1–15). 41 pts discontinued tx, due to progression (41%), pt refusal (27%), adverse events (17%), alternate tx (7%). Confirmed response rate 48% (95% CI: 34–63%): 4 CR, 20 PR. Median duration of response 6.6 mos (95% CI: 5.7, not reached), median progression-free survival (PFS) 7.9 mos (95% CI: 5.3–9.3). Rate of overall survival (OS) at 6 mos 91% (95% CI: 84–100%), 6 month PFS 58% (95% CI: 45–74%). Median OS not reached. 30 pts required dose delays on total of 52 cycles, mostly due to hematologic AEs. 9 pts (19%) had grade (gr) 4 adverse event (AE), 32 (67%) had maximum gr 3 AE. Most common gr 3/4 AEs: neutropenia (52%), fatigue (26%), anemia (14%), dyspnea (14%), thrombocytopenia (12%). Four pts had gr 3 neuropathy. Conclusions: Nab-paclitaxel in combination with gem has clear activity in patients with MBC. Manageable hematologic, but no other significant toxicities. Study ongoing to correlate efficacy with caveolin-1 levels with results expected Spring 2007. Follow up study of this combination with an anti-angiogenesis agent is in development. No significant financial relationships to disclose.

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.

614 Background: An analysis of preoperative bilateral breast MRI at our institution suggests that approximately 1/3 of patients with newly diagnosed breast cancer may have a mammographically occult, but MRI-evident, contralateral breast abnormality. A number of these patients will have pathologic confirmation of carcinoma in the contralateral breast. Identification of risk factors to predict which patients are at high risk for having a mammographically occult contralateral carcinoma was performed. Methods: MRI results of 401 women with newly diagnosed breast carcinoma who underwent MRI were reviewed (overall group; OG). Patients with a contralateral abnormality identified only by MRI were analyzed to determine the incidence of contralateral carcinoma. In addition, the following risk factors were evaluated: Age at diagnosis, menopausal status, tumor size, nodal status, ipsilateral tumor histology, tumor grade, hormone receptor status, Her-2/neu receptor status, and whether the patient had a palpable vs. mammographically detected abnormality. Results: Pathologically confirmed contralateral carcinoma (CC) was found in 13 patients (3.2%). Similar percentages of patients in both groups (OG and CC) were noted in regard to tumor size, histology, grade, nodal status, Her-2/neu receptor status, and method of detection (palpable vs. mammographic). However, median patient age was 71 (CC) vs. 62(OG); 92% (12/13) were postmenopausal (CC) compared to 75% (OG); and 100% were ER positive (CC) vs. 81% percent (OG). Conclusions: Older, postmenopausal women who have ER + tumors may have a higher likelihood of having synchronous, contralateral, mammographically occult, MRI-detected breast carcinoma. Preoperative MRI may be beneficial in patients with similar risk factors; however, further follow up and additional experience is needed for confirmation of these findings. No significant financial relationships to disclose.