No abstract

#16 Rationale: It has been postulated that aromatase inhibitor (AI) therapy may sensitize ER+ breast cancer to lower doses of estrogen therapy as second-line endocrine treatment for advanced breast cancer (ABC). We therefore conducted a randomized trial of 30mg generic estradiol daily (10 mg t.i.d.- "recommended" dose) versus 6 mg (2 mg t.i.d - "experimental" dose).
 Materials and Methods: Major eligibility: Postmenopausal ER+ ABC treated with an AI with 24+ wks progression free survival, or relapse after 2+ yrs of adjuvant AI; RECIST measureable non-bone metastases or WHO assessable bone lesions, with elevated tumor markers >2X ULN. Major exclusions: History venous thrombosis, heart disease, uncontrolled hypercalcemia and fulvestant in the last 12 months. FDG PET scans were conducted at baseline and after 24 hours to assess metabolic flare as a predictor of response (pre-defined as a ≥12% increase in FDG uptake).
 Results: Sixty-six patients were enrolled (82% White, 15% Black); mean age 59 years, range 36-84. 34 received 6 mg and 32 received 30 mg. Estradiol levels will be provided at the meeting. There were more patients experiencing grade 3+ SAE on the 30 mg arm versus the 6 mg arm (11 vs. 4; P=0.06) with one venous thrombosis on each arm. There was no difference in total FACT-B QOL scores at one month by treatment arm, QOL decline was associated with more severe estrogen side effects, especially amongst patients on the 30 mg arm (P=0.006). Uterine bleeding was successfully controlled with intermittent progestin therapy. Clinical benefit rates (stable disease at least 24 weeks plus response - intent to treat population) were 25% (CI: 15-37%, 1PR and 7SD out of 32) on the 30 mg arm and 29% (CI: 19-42%, 3PR and 7SD out of 34) on the 6 mg arm. Patients with clinical benefit to estradiol could be retreated with original AI after progression and to date one PR out of three patients with repeat AI therapy noted. There were 44 patients evaluable for the interaction between PET -flare and response. Flare was seen in all responders (3/3), 9 of 13 patients with SD and only 3 of 30 patients with PD (p<0.0001). PPV for PET flare was therefore 12/15 (80%, CI: 61-92%) and NPV 27/31 (87%, CI: 76-94%). 
 Conclusions: The Protocol Review and Monitoring Committee closed the 30 mg arm early after they concluded that the 6 mg arm was as effective as the 30 mg arm with greater safety. We therefore recommend 6 mg as the appropriate dose for the palliative treatment of advanced ER+ breast cancer. FDG PET flare can be used to identify patients who have a high chance of clinical benefit.
 Supported by an AVON NCI Partners in Progress Award: Grant # P30 CA091842-S4. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 16.

3050 Background: Bevacizumab added to chemotherapy (CRx) prolongs PFS in pts with MBC. Data suggest that estrogen (E2) modulates VEGF-induced angiogenesis in physiologic and pathologic conditions. E2-induced VEGF expression may promote breast cancer growth therefore combination therapy with an aromatase inhibitor (AI) and an antibody to VEGF may be more effective than either agent alone. We performed a feasibility study testing B with L for the treatment (tx) of hormone receptor-positive MBC. Methods: Eligible pts have MBC and are candidates for AI therapy. Prior non-steroidal AI (NSAI) use without progression is permitted. Premenopausal pts undergo ovarian suppression/oophorectomy prior to tx. Therapy consists of L (2.5 mg daily) and B (15 mg/kg IV q3 weeks). The primary endpoint is frequency of Grade (Gr) 4 toxicity. Secondary endpoints include response rate, stable disease (SD) ≥ 6 mo and time to tumor progression. Using a two-stage design, 19 pts were accrued. Because <3 pts had Gr 4 toxicity, the 2nd stage is now enrolling an additional 23 pts. If <5 of the 42 pts have Gr 4 toxicity, the regimen will be considered feasible. Results: Thirty two pts are currently accrued and 28 are now evaluable. Medians: Age 49.5 yrs (32–77) and ECOG PS 0 (0–1). Sites of MBC: bone only 11/28, visceral 16/28, chest wall/soft tissue/lymph nodes 11/28. All are ER and/or PR (+); none are HER2 (+). Prior therapy: adjuvant CRx 20; adjuvant tamoxifen 14. Twenty five pts received an NSAI as first-line tx of MBC, starting a median of 23 wks (1–213) before B. Three pts received first-line tamoxifen; one pt had prior CRx for MBC. After a median of 8 cycles (1–20), tx-related toxicities: Gr 2: hypertension (HTN) 4, headache (HA) 4, proteinuria 3, fatigue 6, joint pain 5, hot flashes 1, epistaxis 1; Gr 3: HTN 5, HA 1, proteinuria 1. There has been no tx-related Gr 4/5 toxicity. Tx-related withdrawals: HTN 1 and headache 1. Twenty five pts are evaluable for response: PR 2, SD ≥ 6 mo 13, SD 4, progression 6. Conclusions: Combination L and B is well tolerated and will be studied in a randomized CALGB trial. Circulating endothelial and tumor cell data is reported separately. Supported in part by Genentech and Novartis. [Table: see text]

#4104 Background: Dose dense (dd) q2wk AC-paclitaxel (P) is superior to q3wk AC-P. Both regimens are associated with a &lt;1% incidence of CHF. In MBC, q3wk nanoparticle albumin-bound paclitaxel (nab-P) is superior to q3wk P and bevacizumab (B) improves progression-free survival when added to P. Based on the MBC data, B may be more effective when targeting minimal residual disease in the adjuvant setting and nab-P may offer superior efficacy with reduced toxicity. However, it is uncertain whether AC plus B increases the risk of CHF. We evaluated the cardiac safety of ddAC-nab-P with concurrent B as adjuvant therapy for BC.&#x2028; Methods: Based upon the accepted cardiac event (CE) rate of approximately 4% in trials with adjuvant trastuzumab, this study was designed with similar monitoring and tolerability thresholds. The primary endpoint is cardiac safety: symptomatic CHF or death from LV dysfunction. Secondary endpoints are toxicity, DFS, OS, and biomarkers for efficacy and toxicity. Eligible pts have resected HER2(-) BC and normal LVEF. B is administered concurrently (10 mg/kg IV q2wk x 8) with chemotherapy (AC at 60/600 mg/m2 q2wk x 4 then nab-P at 260 mg/m2 q2wk x 4) and continues at 15 mg/kg q3wk thereafter for a total one year of B therapy. Pegfilgrastim is administered Day 2 of each chemotherapy cycle. Radiation and endocrine therapy are administered per standard of care. MUGAs are obtained at baseline and mos 2, 6, 9 and 18. Although asymptomatic LVEF declines are not considered CEs, B may be held per protocol and long-term cardiac monitoring initiated. If 3 CEs or &gt; 1 cardiac death from LV dysfunction occur, B + ddAC-nab-P will not be considered safe.&#x2028; Results: The target accrual of 80 pts has been met. Median age is 47y (27-75). As of May 31, 2008, median follow-up is 14 mo (1-21) and 51 pts have completed 1y of planned therapy. No patients have developed symptomatic LV dysfunction at any point during study therapy. Sixteen pts have discontinued treatment due to toxicity: asymptomatic LVEF decline (N=3), hypertension (N=3), wound healing (N=3), headache (N=2), sensory neuropathy (N=2), pain (N=1), hypersensitivity reaction (N=1), and pneumonitis (N=1). Three pts had disease progression, and 8 pts withdrew consent.&#x2028; &#x2028; Conclusions: At the time of this analysis, no symptomatic LV dysfunction has been observed with B + ddAC-nab-P. Follow-up is ongoing. Correlative studies, including analysis of troponin, renin, and circulating endothelial and tumor cells, are underway. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4104.

#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.&#x2028; Methods: Enrolled pts had HER2 (+) BC; LVEF &gt; 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) &gt; 80% pts can complete the PTL phase without a dose delay or reduction and 2) the cardiac event rate (CHF or cardiac death) is &lt; 4%. Pts can remain on-Rx w/ one dose reduction of L (1000 mg → 750 mg) for a G 3 event or &lt; G 3 toxicity (unacceptable).&#x2028; 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 &lt; 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.&#x2028; Discussion: L at 1000 mg/day is not feasible combined w/ weekly P and T by protocol stipulation (&gt; 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.