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10514 Background: Retrospective and preclinical studies suggest that smokers are at increased risk for LM from BC, possibly mediated by lung inflammation and the bioactive lipid, PGE2. To investigate this link in pts, we examined urinary PGE-M, a stable end metabolite of PGE2. Methods: A translational study was conducted, consisting of pts with LM (n=100), pts with mets but no known lung mets (NKL, n=100) and controls (CTRLS) with a history of BC (n=200). Pts receiving steroids and radiotherapy were excluded. Pts gave urine (PGE-M), blood (biomarkers), had BMI measured, and completed a validated questionnaire (smoking, NSAIDs, confounders). PGE-M was measured by mass spectrometry, normalized to urinary creatinine and compared between grps in both univariate and multivariate models, correcting for covariates. Results: From 09/2010 to 06/2011, 400 pts, med age 58 yrs (range 24-88) enrolled. There were no significant differences between grps in smoking and NSAID exposure (table). PGE-M (med; range) was highest among pts with LM (6.7; 0.7 - 43.4) compared to pts with NKL (4.6; 0.7 - 26.8) and CTRLS (4.2; 0.9 – 62.6, P24 pack year smoking history and LM had the highest co-variate-adjusted log PGE-M (P=0.03). In this model, age (P

e21172 Background: Reduced FDG avidity in metastasis of BC pts receiving HT may suggest a lower sensitivity of PET/CT in the detection of disease recurrence in these pts. We aim to evaluate the imp...

TPS124 Background: Src kinase plays an important role in BC cell survival within bone marrow. Src activation is associated with late-onset bone metastases (Zhang, Cancer Cell 09). In ER-negative BC, differential expression of various tyrosine kinases (TK), including KIT and ABL has been suggested. Therefore inhibition of TKs, including Src, represents a novel therapeutic approach. D is a potent inhibitor of 5 oncogenic TKs; BCR-ABL, SRC family, c-KIT, PDGFRβ and many EPH kinases (Shah, Science 04), with activity in CML and GIST. D inhibits VEGF-stimulated proliferation, has potent bone anti-resorptive activity and selectively inhibits basal-type BC growth. Preclinically, the combination of P + D showed greater antitumor activity than either single agent. In an ongoing phase II study we are investigating several biomarkers of response. Methods: Pts with measurable, HER2-negative MBC, and treated with ≤2 prior rx for metastatic disease, regardless of ER status, are eligible. Pts must have adequate renal, he...

1156 Background: Inhibition of SRC is a novel approach for MBC. Preclinically, the SRC inhibitor D + P had superior antitumor activity to either agent alone. We designed this phase I-II study to translate this observation. Methods: For phase I: pts with MBC, ECOG PS 0-1, normal hepatic, renal, marrow function were eligible. Pts with pleural/pericardial effusions were excluded. For phase II: pts had measurable, HER2-negative MBC, ≤2 prior rx for MBC. Cycle (C) consisted of wP 80 mg/m2 IV 3/4 weeks + D 70mg orally daily; escalating to 100 mg, 120 mg, and 150 mg in cohorts of 3 pts. Toxicity was assessed by CTCAE v3.0, response by RECIST. Results: 15 pts (14 females, 1 male) enrolled; median age 54 (range 35-74), median PS=1 (range 0-1). 11 (73%) pts rcvd prior adjuvant chemoRx. Pts rcvd a median of 3 prior rx for MBC (range 0-12). Pts rcvd median of 2 C of D + P (range 1-10). One DLT occurred at 150 mg (G3 fatigue); this cohort was expanded with no further DLTs to date. However, 1 pt had a skin reaction to ...

Background: D is an inhibitor of multiple tyrosine kinases; BCR-ABL, SRC family (SRC, LCK, YES, FYN), c-KIT, EPHA2, and PDGFRβ. Pre-clinical data show inhibition of BC cell lines; predominantly those of “basal-like” subtype or “triple-negative” (TN) and single agent activity has been seen in refractory MBC. In pre-clinical models, the combination of D and P had antitumor activity that was significantly better than either agent alone. We designed this phase 1 trial to translate this observation.Methods: Eligibility criteria included evaluable or measurable MBC with normal hepatic, renal, and bone marrow function, and ECOG PS 0-1. Prior taxane therapy (Rx), stable brain metastases and baseline neuropathy grade (G) ≤1 were allowed. Pts with pleural or pericardial effusions were excluded. wP 80 mg/m2 was given by 1-hr IV infusion 3 weeks out of 4 (1 cycle); D was given daily by mouth, starting with 70 mg and escalating 100 mg, 120 mg and 150 mg in cohorts of 3 pts, using a standard 3+3 dose escalation scheme. Supportive medications were given per institutional policy for wP. Where possible, pts discontinued inhibitors of CYP3A4. Safety assessments occurred q2 weeks; additional hematologic toxicity was assessed weekly. Toxicities were graded per CTCAE v3.0 and maximum tolerated dose (MTD) defined accordingly. Response was assessed after cycle 2 and every 3 cycles thereafter.Results: Nine evaluable pts (8 females, 1 male) have enrolled; median age 54 (range 35-67), median PS=1 (range 0-1). 6 pts received prior adjuvant chemoRx, 7 received prior chemoRx for MBC and only 3 were taxane-naïve. Pts received a median of 2 cycles (range 1-3). No dose limiting toxicity has been observed up to a daily D dose of 120 mg. The most common Rx-related toxicities have been hematologic and low G (table 1). 1 pt was admitted with G3 hypotension, urosepsis and G2 diarrhea, possibly Rx-related. Per protocol she continues on D 100mg. 5 of 6 (83%) pts treated with D ≥100mg developed diarrhea (2pts; G1, 3pts; G2). Other GI side-effects have been mild; 3pts G1 nausea, 1pt G2 vomiting. 8pts (89%) have complained of fatigue (6pts; G1, 1pt; G2, 1 pt; G3). 1pt developed G1 acneiform rash secondary to D. No pts have developed edema or effusions. 6 pts are evaluable for response; 2 stable disease and 1 partial response in a pt with TNBC who had received prior adjuvant taxane. Dose escalation continues.Conclusion: Our data show that treatment with wP and D is feasible in pts with MBC. The MTD has not yet been reached and dose escalation of D continues to the target dose of 150 mg daily. There is preliminary evidence of activity in TNBC. A phase II trial of wP and D will follow once a recommended dose level is reached.Common ToxicitiesAdverse EventTotal N(%)Grade 1 N(%)Grade 2 N(%)Grade 3 N(%)Grade 4 N(%)Grade 5 N(%)Anemia7 (78)5 (56)1 (11)1 (11) Leukopenia3 (33)2 (22)1 (11) Neutropenia1 (11) 1 (11) Thrombocytopenia1 (11)1 (11) Hypoalbuminemia2 (22)1 (11)1 (11) Alkaline Phosphatase2 (22)2 (22) ALT4 (44)3 (33)1 (11) AST5 (56)5 (56) Hyperglycemia8 (89)5 (56)3 (22) Hypophosphatemia3 (33) 2 (22)1 (11) Hypokalemia2 (22)1 (11) 1 (11) Diarrhea5 (56)2 (22)3 (33) Neuropathy7 (78)7 (78) Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5070.

Background: Adjuvant therapy for breast cancer (BCA) may be associated with an increased risk for osteoporosis. This prospective, observational study evaluates BMD changes in postmenopausal women undergoing adjuvant chemotherapy (CTX) for early stage BCA, in the absence of endocrine therapy.Methods: Women who have been postmenopausal for at least 5 years, and who were recently diagnosed with Stage 0-III BCA were eligible to undergo serial BMD if adjuvant endocrine therapy was not recommended. Study BMDs were performed at baseline, 1 and 2 years. All patients (pts) were counseled on calcium, vitamin D and weight bearing exercise. This study was designed to assess serial changes in BMD in the individual and to compare changes in those treated with CTX to those who received no systemic therapy (observation). The study was closed prior to reaching target sample size due to slow accrual.Results: Sixteen pts enrolled. Eleven pts received CTX with a dose dense anthracycline and taxane containing regimen and 5 pts received no systemic adjuvant therapy. Twelve pts, median age 63 (range 52-80), have completed the 1 year assessment and are reported here. Two pts treated with CTX and 1 pt on observation were on bisphosphonates at study entry. Baseline BMD mean in gm/cm2 at the lumbar spine (LS) was 1.112 (range 0.807-1.389) and total hip (TH) was 0.989 (range 0.760-1.213). At 1 year, mean BMD at LS was 1.078 (range 0.767-1.347) and TH was 0.956 (range 0.753-1.210). For all 12 pts at 1 year, the individual BMD changes in LS & TH BMD ranged from 10% loss to 2% gain, with 8 of the 9 CTX treated pts losing 1-10% of BMD and the 3 pts on observation staying within 2% of baseline. The mean dosage of dexamethasone used during CTX by the 9 CTX pts was 230 mg (range 156-288mg). The 3 observation pts had no exposure to steroids during the parallel time period.Conclusions: This prospective, observational study supports the hypothesis that adjuvant CTX, and/or its supportive medications, may be associated with acute changes in BMD in postmenopausal women. Patient follow up continues.Funded by Susan G. Komen for the Cure POP0402593 Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1066.

1131 Background: Capecitabine (C) is active in breast cancer and is usually dosed for 14 days (d) followed by a 7d rest (14 - 7). We described a mathematical method which predicts the optimal schedule for C to be 7d followed by a 7d rest (7 - 7) (Norton et al, Amer Assn Can Res. 2005). The MTD of C(7 - 7) is 2,000mg BID (Traina et al, J Clin Oncol. April 2008). Lapatinib (L) improves time to progression when added to C(14 - 7) in patients (pts) with HER-2-positive (+) metastatic breast cancer (MBC) that progressed after trastuzumab (T). To optimize this effective combination, we are testing C(7 - 7) + L in a phase II trial. Methods: Eligible pts have measurable, HER-2(+) MBC that has progressed after T. HER-2(+)=IHC 3+ or FISH>2. Pts have normal LVEF by MUGA, ECOG performance status (PS) 6 months, PFS. Using a Simon optimal 2-stage design, with alpha = 10%, power = 90% to discriminate between RR 10% and 25%, 21 pts will be accrued to the first stage. If >2 pts respond, 29 additional pts will be enrolled. If >7/ 40 pts respond, then C(7 - 7) + L will be considered worthy of further study. Results: As of January 5, 2008, 6 pts are enrolled and evaluable. Median (med) age 64 yrs (42–71), med ECOG PS 1 (0–1), ER/PR(+) 3, HER-2(+) 6, sites of MBC: bone (2), viscera (4), soft tissue (5). Med baseline LVEF 62% (51–68%). Prior tx: Adjuvant: CRx (5), hormone tx (3), T (3); MBC: CRx (2), hormone tx (1), T (3). After a med of 3 cycles (1–4), there were no grade 3, 4, or 5 events. Tx-related toxicity is: Gr 2 fatigue (1); Gr 1 AST (4), diarrhea (3), ALT (2), vomiting (1), hand-foot (1), fatigue (1). No withdrawls due to reduced LVEF. Two pts evaluable for response: PR = 1, SD [Table: see text]

590 Background: CMF (C 600 mg/m2, M 40 mg/m2, F 600 mg/m2) is an option for adjuvant therapy for patients with low risk early stage breast cancer. DD regimens as predicted by mathematical models of cancer growth and treatment response are superior. We previously demonstrated the safety of DD EC (epirubicin/cyclophosphamide) followed by paclitaxel at 10–11 day (d) intervals. We investigated the feasibility of administering DD adjuvant CMF every 14 d and then every 10–11 d in a 2-stage phase II trial. Methods: An initial cohort (A) was treated q 14 d with PEG-filgrastim (Neulasta) support. A second cohort (B) was treated every 10–11 d with filgrastim/Neupogen x 5 d and then, based on feasibility, modified (cohort C) to use 7 d filgrastim. The primary end point was feasibility defined as having ANC > 1.5 x 103/uL on day 1 of planned treatment for all 8 cycles with no grade 3 or higher non-hematologic toxicity. All three cohorts were tested using a Simon's two-stage optimal design with type I and type II errors set at 10%. This design would effectively discriminate between true tolerability (as protocol-defined) rates of< 60% and> 80%. Cohort A: 38 pts with early stage breast cancer were accrued from 3/2008 though 6/2008. Cohort B: 7 pts were accrued from June 2008 through August 2008. Cohort C: Is still open with 16 pts accrued from August 2008 through December 5, 2008. Results: Median age 51: range 38 to 78. Cohort A: 29/38 pts completed 8 cycles of CMF. The regimen was considered feasible. 2 other pts completed 7 cycles and were withdrawn for depression and grade 2 transaminitis. The 7 other pts completed between 1 and 6 cycles of CMF were withdrawn as follows: 3 personal, 1 (grade 3) bone pain, 2 allergy unrelated to CMF, and 1 seizure. Cohort B: 7 pts were accrued. 6 out of 7 pts could not complete 8 cycles of chemotherapy secondary to neutropenia and 1 secondary to grade 3 ALT elevation. Cohort C: Accrual has not been completed. 16 pts are currently enrolled. Conclusions: Dose dense adjuvant CMF is feasible at 14 d intervals with PEG-filgrastim support. Adjuvant CMF every 10–11 days with filgrastim given for 5 days beginning day 2 is not feasible. Accrual is ongoing for CMF at 10–11 days with filgrastim x 7 days. Updated results will be available for Cohort C. [Table: see text]

Abstract #3137 Background: The epitholones are a new class of antineoplastic agents which are microtubule inhibitors with low susceptibility to several mechanisms of drug resistance. Ixabepilone (BMS-247550, aza-epothilone B) has demonstrated efficacy as monotherapy or in combination with capecitabine (in anthracycline- and taxane-pretreated metastatic breast cancer) and has recently been approved for use in refractory breast cancer. A multicenter NCI-sponsored study was conducted to analyze the safety and efficacy of the combination of ixabepilone with trastuzumab in patients with metastatic HER2-positive breast cancer. Methods: This phase II nonrandomized study enrolled two cohorts of patients. Cohort 1 received no prior chemotherapy or trastuzumab for metastatic disease and cohort two received one or two prior trastuzumab-containing regimens for metastatic disease. Patients in each cohort received the same treatment regimen of ixabepilone and trastuzumab. Patients received ixabepilone 40 mg/m2 as a 3-hour continuous infusion on day 1 of a 21-day cycle plus trastuzumab once every 21 days. For the initial treatment of trastuzumab, patients received 8 mg/kg IV, and for all subsequent trastuzumab treatments 6 mg/kg. Treatment was continued until disease progression or unacceptable toxicity. Endpoints included response rate (RR), time to progression (TTP), toxicity, and predictive biomarkers. Results: 39 women entered the study (median age 51, range 29-74) with 15 patients in cohort 1 and 24 patients in cohort 2. A median of 7 cycles of therapy were administered in each cohort. In cohort 1, there were 12 partial responses (PR), and 1 patient with stable disease for 5 months (SD). In cohort 2, there were 8 PRs and 9 patients with SD. Across both cohorts, the overall RR was 51%, with a clinical benefit rate (CR + PR + SD for at least 6 months) of 56%. Treatment-related toxicities included neuropathy (grade ≥2, 55%), myalgias (grade ≥2, 20%), anemia (grade ≥2, 18%), neutropenia (grade ≥2, 23%), and elevated transaminases (grade ≥2, 10%). There were no episodes of grade 2 or higher cardiac toxicity. Biomarker data will be presented. Conclusion: This represents the first study of the combination of ixabepilone with trastuzumab for the treatment of metastatic HER2-positive breast cancer. These results suggest that the combination has an encouraging response rate as first- and subsequent- line therapy for metastatic breast cancer. Clinically significant neuropathy was the major toxicity, and appeared to be cumulative. Based on these results, further evaluation of ixabepilone plus trastuzumab is warranted. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3137.

9588 Background: ONJ is diagnosed with increasing frequency among IV bisphosponate (IVBP)-treated cancer pts, in the range of 1–10 per 100 treated pts depending on duration of therapy (Khosla 2007)...

3024 Background: A polysaccharide extract from Grifola frondosa (Maitake extract) has shown immunomodulatory effects in preclinical studies and potentials for anticancer immunotherapy. However whet...

567 Background: Dose dense, q2 wk AC-paclitaxel (T) is superior to q3 wk therapy (Rx) (Citron, JCO 2003). The risk of congestive heart failure (CHF) with ddAC-T is not increased at 2) ×4 then nab-p (260 mg/m2) x4 with pegfilgrastim on Day 2 plus B for one year (10mg/kg IV q2wk ×8 with chemoRx then B 15mg/kg q3wk); radiation & endocrine Rx per standard of care. MUGA obtained at baseline & mos. 2, 6, 9, 18. Pts with significant asymptomatic ↓LVEF during Rx may have B held per protocol. These pts are not counted as CEs but will have long-term cardiac monitoring. Accrual goal is 75 pts. If ≥3 CE (∼4.7%) or >1 cardiac death from LV dysfunction, B + ddAC-nab-p will not be considered safe. Results: 44 pts have enrolled, median (med) age 46.5 yrs (33–67). 28 pts have baseline & month 2 LVEF data: med baseline LVEF 68% (61–82), med LVEF at mo. 2 after ddAC+B 68% (53–75); 1 pt had an 18 point asymptomatic drop to 53% - B held but reinitiated in 4 wks with repeat LVEF 63%. 12 pts completed nab-p+B but none have reached the 6 mo. MUGA. Rx-related Gr 3/4 toxicity: neutropenia gr4 (6.8%), diarrhea gr3 (2.3%), hypertension gr3 (2.3%), neuropathy gr 3 (2.3%), fatigue gr 3 (2.3%), mucositis gr 3 (2.3%). 4 pts have withdrawn from study Rx, but only 1 due to toxicity including gr3 fatigue, mucositis & neuropathy. Conclusions: No LV dysfunction has been observed with B + ddAC-nab-p; this trial is on-going. Long-term follow-up and analysis of troponin, renin and circulating endothelial & tumor cells are planned. No significant financial relationships to disclose.

1045 Background: We have previously described a mathematical method to optimize chemotherapy dose and schedule (Norton et al, AACR 2005). Capecitabine (C) has activity in breast cancer when conventionally dosed for 14 days (d) q3 weeks (14/7). However, the predicted optimal dosing schedule for C using our model is 7d followed by a 7d rest (biweekly, 7/7). We tested this hypothesis in a Phase I/II study described below. Methods: Eligible patients (pts) have measurable, metastatic breast cancer (MBC), ECOG performance status (PS) =2 and normal organ function. There is no limit to number of prior chemotherapy (CRx) regimens. Pts with prior fluoropyrimidine for MBC are excluded. HER2+ pts must not be candidates for trastuzumab. C is given in divided daily doses for 7d followed by a 7d rest. A standard “3+3” dose escalation scheme employs flat dosing which begins at 1,500mg BID and increases by 500mg/dose level. Primary endpoint is the maximum tolerated dose (MTD), defined as the highest dose for which the incidence of dose-limiting toxicity (DLT) is [Table: see text] No significant financial relationships to disclose.

10587 Background: The epothilones, a new class of antineoplastic agents, promote tumor cell death by stabilizing microtubules and inducing apoptosis. Ixabepilone was selected from over 300 epothilone analogs due to its high in vivo efficacy, good metabolic stability and low protein binding. Methods: This international, multicenter, open-label Phase II trial was designed to assess the activity of ixabepilone in patients (pts) with highly resistant MBC who had progressed following taxane treatment. Eligible pts were aged ≥18 years with MBC (progressed on or within 4 months of taxane therapy [or within 6 months if adjuvant taxane only]). Pts were excluded if they had had ≥3 prior chemotherapy regimens for MBC or had ≥Grade 2 neuropathy. Ixabepilone (40 mg/m2 q3w) was administered as a 3-hour infusion for a maximum of 18 cycles, unless there was evidence of progressive disease and/or pts met discontinuation criteria. Toxicity was evaluated continuously. Results: Of 49 pts (median age 54 years, range 30–81), 86% of pts had received ≥2 prior chemotherapy regimens. Treatment-related adverse events (TRAEs) were manageable and mostly Grade 1 or 2 (45%). Treatment-related neuropathy was mostly sensory, mild-to-moderate, cumulative and reversible. Sensory neuropathy was managed mainly with dose reductions (12 out of 49 pts had their dose reduced due to neuropathy). Treatment-limiting or severe neuropathy generally resolved or lessened in intensity within 1–2 months after therapy discontinuation. Febrile neutropenia was reported in only 2 pts, in addition, 2 pts (4%) developed treatment-related infection with neutropenia. Only six pts (12%) required growth factor support for neutropenia during their treatment. Progressive disease was the most common reason for discontinuing the study (36%), with 16% discontinuing due to TRAEs. Conclusions: Ixabepilone demonstrates an acceptable safety profile, along with promising antitumor activity, in pts with clearly defined taxane-resistant MBC. [Table: see text] [Table: see text]

500 Background: Trastuzumab monotherapy has a 34% objective response rate (ORR) in patients with HER-2/neu IHC 3+ or FISH-positive first-line metastatic breast cancer (C. Vogel et al, JCO 20:719–726, 2002). Predicting response and survival to trastuzumab-based therapy is an unsolved problem. The HER-2/neu extracellular domain (ECD) is released after cleavage by the ADAM metalloproteinases, and the remaining membrane-bound internal domain is constitutively activated. Trastuzumab inhibits cleavage of the HER-2/neu ECD. Methods: A pooled analysis of 7 trials of first-line trastuzumab therapy (with or without chemotherapy) with serial serum HER-2/neu levels were included. The FDA-approved HER-2/neu ELISA (Oncogene Science/Bayer HealthCare) was used to determine serum HER-2/neu levels. A pretreatment and post-treatment serum (16–120 days) from 307 patients was available. 236 patients had data on overall survival. Kaplan Meier Life table analysis was performed to compare duration of response (DRP), time to progression (TTP), and overall survival (OS). Results: The median decrease in serum HER-2/neu levels for all patients was 31.0% (Range: 98% decrease to 239% increase). Patients with > 20% decrease in HER-2/neu levels had a significantly higher objective response rate (ORR, complete + partial response) and longer DRP, TTP and OS. The results were similar regardless of the timing of the second serum draw (≤ 30 days vs. > 30 days) after the start of trastazumab. Conclusion: Patients with < 20% decrease in serum HER-2/neu levels have decreased benefit from trastuzumab therapy. Patients who do not have a significant decrease in serum HER-2/neu levels should be considered for additional HER-2/neu-targeted therapies. [Table: see text] [Table: see text]

582 Background: DD q 2 weekly (w) AC → T is superior to conventionally scheduled (cs) AC → T and safe w/long follow-up (Hudis et al, SABCS 2005). With q 3 wk AC, adjuvant (adj) H is safe and effective (Romond et al and Perez et al, NEJM 2005). We therefore tested DD q 2 w AC → T + H × 1 year (y) as adj treatment (Rx) of patients (pts) with HER2/neu (+) BCA to determine cardiac safety. Based on the reported cardiac event (CE) rate of ≤ 4% in the randomized trials using cs chemotherapy (CRx) + H, we evaluated DD q 2 w AC → T + H with a 1° endpoint of cardiac safety defined as discontinuation (DC) of H due to 1) cardiac death or 2) congestive heart failure (CHF). The 2° endpoint is time to recurrence and overall survival. Methods: Pts with HER2/Neu IHC 3+ or FISH-amplified BCA were enrolled, regardless of tumor size or nodal status. Rx consisted of AC at 60/600 mg/m2 × 4 → T at 175 mg/m2 × 4 q 2 w w/pegfilgrastim 6 mg on d 2 + H × 1 y. Multi-gated radionuclide angiography scan (MUGA) is obtained at baseline and at months (mo) 2 (after AC × 4), 6 (after T × 4), 9, and 18. Pts w/baseline LVEF of ≥ 55% and w/o cardiac illnesses are eligible. Pts w/significant (sig) asymptomatic (asx) LVEF ↓ after DD AC based on mo 2 MUGA did not receive H, and pts w/sig asx LVEF ↓ during H had it DC’d. If the CE rate is > 4%, Rx is deemed not feasible. Results: From January 4, 2005 to November 1, 2005, 70 pts were enrolled. Median (med) age is 49 years (range, 27–72). Forty one of 70 pts (60%) had node (+) BC and 27/70 pts (40%) had (-) nodes. Med baseline LVEF is 68% (range, 55%-81%). As of January 9, 2005, all pts had mo 2 MUGA after DD AC and there is no sig LVEF ↓ and the med LVEF is 67% (range, 58%-79%). To date 39 pts had mo 6 MUGA w/med LVEF of 66% (range, 56%-75%) and one pt had a sig asx LVEF ↓ from baseline of 74% to 56%; H was DC’d. Twenty-three pts had mo 9 MUGA w/a med LVEF of 64% (range, 57%-69%). One patient had clinical CHF at mo 4 w/EF of 45% and improved sig w/cardiac medications. One had pneumonitis during radiation (RT). One had atrial fibrillation w/pericarditis after completion of RT. Discussion: DD AC → T + H appears to have an acceptable cardiac toxicity profile w/1/70 pts having a CE. Updated cardiac safety data will be presented. [Table: see text]

633 Background: We previously demonstrated that weekly T + HL after anthracycline based therapy was not feasible due to high incidence of grade (G) 3 diarrhea, which led to modification of the ALTT...

Abstract #2108 Background: DD q 2 weekly (w) AC → P + T x 1 year (y) has an acceptable safely profile w/ congestive heart failure (CHF) rate of 1/70 pts (Dang, JCO 2008). Lapatinib (L) is effective in HER2 (+) BC. We conducted a pilot study of dd AC → w P + T + L to determine its feasibility and cardiac safety. Methods: Enrolled pts had HER2 (+) BC; LVEF > 50%. Rx consisted of AC at 60/600 mg/m2 x 4 q 2 w (w/ pegfilgrastim 6 mg day 2) → P at 80 mg/m2 x 12 q w + T x 1 y; L (1000 mg daily beginning w/ P + T and continued x 1 y). MUGA is obtained at baseline and at months (mo) 2, 6, 9, and 18. Rx is considered feasible if 1) > 80% pts can complete the PTL phase without a dose delay or reduction and 2) the cardiac event rate (CHF or cardiac death) is < 4%. Pts can remain on-Rx w/ one dose reduction of L (1000 mg → 750 mg) for a G 3 event or < G 3 toxicity (unacceptable). Results: From March 2007 to April 2008, we enrolled 95 pts. Median (med) age was 45 years (range, 28-73). At a med follow-up of 7 months, 90 are evaluable. Of the 90 pts, 34 (37%) withdrew from study during the PTL phase; 29 for a 2nd event of G 3 or unacceptable < G 3 toxicities (15 G 3 diarrhea, 4 G 1/2 diarrhea, 1 G 3 rash, 2 G 2 rash, 1 G 3 dyspnea and also had G 3 diarrhea, 1 G 3 ↑QTc also had G 3 diarrhea, 1 G 3 ↑ALT also had G 3 diarrhea, 1 G 3 paronychia, 1 G 3 pneumonitis, 1 asymptomatic LVEF ↓, 1 myocarditis) and 5 for other reasons (2 personal reason, 1 PCP pneumonia, 1 progression, 1 P hypersensitivity). Overall, 25/90 (27%) pts had G 3 diarrhea and 31/90 (34%) pts required a dose reduction of lapatinib. Med LVEF at baseline is 67% (N=95), at mo 2 is 68% (N=90), at mo 6 is 65% (N=53), and mo 9 is 65% (N=28). To date there are no patient drop-outs due to significant LVEF declines after dd AC; one patient dropped during PTL out due to an asymptomatic LVEF decline. Discussion: L at 1000 mg/day is not feasible combined w/ weekly P and T by protocol stipulation (> 20% pts required L dose reduction) primarily due to excessive G 3 diarrhea. These results have led to the modification of Design 2 (Arm D) of ALTTO. We will report updated results. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2108.

This longitudinal prospective study describes the older breast cancer patient's perception of the cognitive impact of adjuvant chemotherapy.A total of 50 patientsor =age 65 with stage I to III breast cancer enrolled in this IRB-approved prospective study. Of the 50, 3 refused postchemotherapy testing and 2 had a cerebrovascular accident (CVA) during therapy, leaving 45 evaluable patients. The Squire Memory Self-Rating Questionnaire, given before and 6 months after chemotherapy, measured patients' perceptions of the ability to learn new information, of working memory, and of remote learning capabilities.Mean age was 70 years (range 65-84). Breast cancer stages were: I (33%), II (64%), III (2%). A 51% (23/45) of study participants perceived a decline in memory from before to 6 months after completion of chemotherapy. Patients who perceived a poorer memory than average before chemotherapy were more likely to report further memory deterioration after chemotherapy (19/30, 63%) than patients who perceived that their memory was average or better than average prior to chemotherapy (4/15, 27%). The memory domain most likely to be perceived as affected was the ability to learn new information (22/45, 49%) compared to remote memory (9/45, 20%) or working memory (13/45, 29%) capabilities.Approximately half of these older women perceived a decline in cognitive function from before to 6 months after chemotherapy. This perceived decline in cognitive function was most pronounced in patients with preexisting memory complaints. Further prospective study is needed to confirm these observations, correlate perceived memory changes with objective findings, and identify subgroups at special risk.

3072 Background: Flavopiridol is a cyclin dependent kinase inhibitor which enhances chemotherapy induced apoptosis. In vitro F enhances Doc-induced apoptosis in a sequence specific manner such that Doc must come before F (Motwani et al. Mol. Cancer Ther. 2:549–555, 2003). In vivoDoc must precede F by at least 4 hours in order to induce this effect. Methods: In view of this finding, we designed a phase I trial of weekly, sequential Doc followed by F in patients with advanced solid tumors. Docetaxel 35 mg/m2 was administered over 30 minutes, followed 4 hours later by escalating doses of F (20, 30, 40, 50, 60, and 70 mg/m2) administered weekly over one hour. This schedule was repeated for 3 weeks out of each 4 week cycle. We used standard eligibility criteria for this phase I trial including normal hepatic, renal, and bone marrow function, and Karnofsky Performance Status (KPS) ≥ 70%. Prior taxane therapy was allowed. Results: Eighteen evaluable patients have been enrolled: median age 56 (range 39–77), media...

PURPOSE: We conducted a phase II pilot study of dose-intensive adjuvant chemotherapy with doxorubicin followed sequentially by high-dose cyclophosphamide to determine the safety and feasibility of this dose-dense treatment and to estimate the disease-free and overall survival in breast cancer patients with four or more involved axillary lymph nodes. PATIENTS AND METHODS: Seventy-three patients received adjuvant treatment with four cycles of doxorubicin 75 mg/m2 as an intravenous bolus every 21 days, followed by three cycles of cyclophosphamide 3,000 mg/m2 every 14 days with granulocyte colony-stimulating factor support. RESULTS: Seventy-one patients were assessable, and all but two completed all planned chemotherapy. There was no treatment-related mortality. The most common toxicity was neutropenic fever, which occurred in 39% of patients. Median disease-free survival is 66 months (95% confidence interval, 34 to 98 months), and median overall survival has not yet been reached. At 5 years of follow-up, the disease-free survival is 51.7%, and overall survival is 60.0%. There is no long-term treatment-related toxicity, and no cases of acute myelogenous leukemia or myelodysplastic syndrome have been observed. CONCLUSION: Our pilot study of doxorubicin followed by cyclophosphamide demonstrates the safety and feasibility of the sequential dose-dense plan. Long-term follow-up, although noncomparative, is promising. However, this regimen is associated with a higher incidence of toxicity (and also higher costs) than the standard dose and schedule of doxorubicin and cyclophosphamide, and therefore it should not be used as conventional therapy in the absence of demonstrated improvement of outcome. Randomized trials testing the dose-dense approach have been completed but not yet reported. Because the sequential plan can decrease overlapping toxicities, it is an appropriate platform for the addition of newer active agents, such as taxanes or monoclonal antibodies.

616 Background: Q 14 day chemotherapy (CRx) was superior to q 21 day treatment in CALGB 97–41. (Citron et al, J Clin Oncol 2003 Apr 15;21(8):1431–9) Hence we hypothesized that even greater DD (q 10...

PURPOSE: This phase II study evaluated weekly trastuzumab and paclitaxel therapy in women with HER2-normal and HER2-overexpressing metastatic breast cancer. Efficacy was correlated with immunohistochemical and fluorescent in situ hybridization (FISH) assay results. PATIENTS AND METHODS: Eligible patients had bidimensionally measurable metastatic breast cancer. Up to three prior chemotherapy regimens, including prior anthracycline and taxane therapy, were allowed. Trastuzumab 4 mg/kg and paclitaxel 90 mg/m2 were administered on week 1, with trastuzumab 2 mg/kg and paclitaxel 90 mg/m2 administered on subsequent weeks. HER2 status was evaluated using four different immunohistochemical assays and FISH. RESULTS: Patients received a median of 25 weekly infusions (range, one to 85 infusions). Median delivered paclitaxel dose-intensity was 82 mg/m2/wk (range, 52 to 90 mg/m2/wk). The intent-to-treat response rate for all 95 patients enrolled was 56.8% (95% confidence interval, 47% to 67%). A response rate of 61.4% (4.5% complete response, 56.8% partial response) was observed in 88 fully assessable patients. In patients with HER2-overexpressing tumors, overall response rates ranged from 67% to 81% compared with 41% to 46% in patients with HER2-normal expression (ranges reflect the different assay methods used to assess HER2 status). Differences in response rates between patients with HER2-overexpressing tumors and those with normal HER2 expression were statistically significant for all assay methods, with CB11 and TAB250 antibodies and FISH having the strongest significance. Therapy was generally well tolerated, although three patients had serious cardiac complications. CONCLUSION: Weekly trastuzumab and paclitaxel therapy is active in women with metastatic breast cancer. Therapy was relatively well tolerated; however, attention to cardiac function is necessary.

Fluorescence in situ hybridization (FISH) is a quantitative technique which allows, by means of specific probes, to detect the t(9;22) translocation typical of chronic myeloid leukemia (CML) hematopoietic cells. We have evaluated FISH on interphase nuclei as a method for assessment of residual disease in bone marrow samples from 5 Philadelphia chromosome positive (Ph(+)) CML patients after 12 months therapy with interferon alpha; results were compared with findings obtained by conventional cytogenetics and by polymerase chain reaction (PCR). Our data indicate that FISH is more sensitive than cytogenetics for evaluation of residual disease, being positive in 1 out of 2 cases scored as Ph negative by cytogenetics, but is less sensitive than PCR which turned out to be positive in all patients. As additional advantage over conventional cytogenetics, FISH on interphase nuclei can be performed also on samples lacking metaphases or having poor chromosome spreading or unsatisfactory chromosome banding.

4096 Background: Flavopiridol (F), a potent cyclin dependent kinase inhibitor, potentiates docetaxel (Doc) induced apoptosis at nanomolar concentrations (300 nm). Significant tumor regression has b...

574 Background: The NCCN recommends serial bone mineral density (BMD) measurement with dual energy x-ray absorptiometry (DXA) to diagnose and treat AI-associated osteoporosis. The FRAX algorithm identifies additional patients with ORFR who may benefit from anti-resorptive therapy (ART). The TBS, which measures bone microstructure by DXA, is an independent indicator of ORFR. Here, we retrospectively evaluate the utility of a combined screening approach (BMD+FRAX+TBS) in identifying ORFR at baseline and following AI. Methods: Breast cancer patients > 60 years, treated with AI and no ART between 2006-12, who had serial DXA at Memorial Sloan Kettering Cancer Center were identified (n= 74). BMD, FRAX, and TBS were evaluated at baseline (