Decrease In LVEF Research Articles

Preoperative Right Ventricular Function in Patients with Organic Mitral Regurgitation

To assess the right ventricular (RV) function in patients with severe mitral regurgitation (MR); to find a relation between preoperative and postoperative parameters. RV function was echocardiographically assessed by determining the tricuspid annular plane systolic excursion (TAPSE) and the peak systolic velocity of the lateral tricuspid annulus (Sa) in 45 patients with severe organic MR (53.3% men, age 58 +/- 10 years). Mean NYHA class was 2.6 +/- 0.4, LVEF was 55.3 +/- 12%, RV end-diastolic diameter was 28.7 +/- 4.7, left ventricular end-systolic diameter (LVESD) was 44.6 +/- 12.6 mm, and LV end-diastolic volume (Simpson) was 160.6 +/- 50.3 ml. All patients underwent mitral valve replacement with posterior chordal sparing. Mean preoperative TAPSE and Sa were 19.4 +/- 4.3 mm and 10.3 +/- 3 cm/sec, respectively. RV dysfunction, defined as TAPSE < 22 mm, had 66.6% of the patients, and Sa < 11 cm/sec was found in 62.2% of the patients preoperatively. Preoperative TAPSE and Sa were significantly correlated (P < 0.00001, r = 0.61). Both TAPSE and Sa were correlated with the RV end-diastolic diameter (P < 0.01), LVESD (P < 0.05) left ventricular dp/dt (P < 0.05), and LVEF (P < 0.0001). Postoperative LVEF was 50% (P < 0.001), Sa 5.3 +/- 2 cm/sec (P < 0.001), and TAPSE 8.7 +/- 3.2mm (P < 0.001). Twenty-one patients (46.6%) reached the study end point of decrease of LVEF by more than 10%. Univariate predictors were age (P = 0.04), male gender (P = 0.01), TAPSE (P = 0.007), and Sa (P = 0.009), while a trend was found for regurgitation fraction (P = 0.058) and LV end-diastolic volume index (P = 0.09). By multivariate analysis, TAPSE (P = 0.01) and Sa (P = 0.01) were predictive for the study end point. The assessment of the RV function by echocardiography is a simple tool that provides prognostic information in patients with MR.

Preoperative Therapy with Pegylated Liposomal Doxorubicin, Cisplatin and Infusional Fluoruracil + Trastuzumab (±Endocrine Therapy) in Locally Advanced HER2 Positive Breast Cancer.

Abstract Background: Preoperative trastuzumab (T) and anthracyclines increase either pathological complete remission (pCR) and long term outcome in pts with locally advanced HER2 positive breast cancer. Pegylated liposomal doxorubicin (PLD) has been shown as active as conventional anthracyclines in advanced breast cancer albeit less toxic. Little is known about PLD activity as primary therapy in combination with T.Patients and methods: We tested a combination of PLD with cisplatin and infusional fluorouracil (CCF) and T in patients (pts) with HER2 positive T2-T4a-d N0-3 M0 breast cancer. PLD (25 mg/sqm), cisplatin (60 mg/sqm) and infusional fluorouracil (200 mg/sqm/day c.i.) q21 days for 8 courses. T was administered i.v. 6 mg/kg (after a loading dose of 8 mg/kg) every q21 days. Patients with ER and/or PgR≥10% tumors received endocrine therapy with letrozole (+ triptorelin q28 days if premenopausal). The endpoints were the rate of clinical response (CR) and of pCR defined as the absence of invasive or measurable tumor in the breast and in the axillary nodes and the tolerability of the combination.Results: Thirty-two pts entered the study and all are evaluable for pCR, CR and toxicity. Median age was 47 yrs (range 28-69). One pt had recurrent and 1 pt had bilateral cancer. Fifteen pts had hormone receptor positive (HR+ve), 15 had HR absent (HR-ve) tumors and 2 pts had ER 1-9% (HR poor) tumors. Thirteen pts (41%) had T4d cancer and 2 pts had T4b cancer. Twenty-six pts (86%) had clinically positive nodes.Overall 4 pts (13%) and 26 pts (81%) obtained a complete and a partial response, respectively with an overall CR rate of 94% [95%CI, 85%-100%]; no pt progressed. Thirteen pts [41% 95%CI, 24%-58%] obtained a pCR; in addition 1 pt had only isolated tumor cells and 2 pts had pT1a residual tumor. The pCR rate was 33% and 47% in patients with HR+ve and HR-ve tumors, respectively. Seventy-four percent [95%CI, 59%-90%]of pts had negative nodes at surgery.Among the 13 T4d cancers 7 pts obtained a pCR [54%, 95%CI, 27%-81%]. In particular 2/6 HR+ve (33%), 4/6 HR-ve (66%) and 1/1 HR poor T4d tumors achieved a pCR Treatment was completed in 21 pts, 11 pts discontinued treatment before completion of 8 cycles, although only 7 grade &amp;gt; 2 non haematological toxicity were observed, 3 of them in the same pt.No decrease of LVEF &amp;lt; 50% was observed.Conclusions: Our results indicate that CCF + T were active in a population of very locally advanced breast cancer yielding a pCR rate comparable to that observed with the combination of T + standard anthracyclines. Most interestingly, an impressive rate of pCR was observed in T4d tumors, suggesting an enhanced local delivery and increased activity of PLD. This result merits further investigations in larger series. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1097.

Cardiac safety of trastuzumab as adjuvant treatment for Japanese patients with early breast cancer

Recently, randomized trials revealed that trastuzumab as adjuvant treatment was effective in human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients. Safety information on adjuvant trastuzumab use in Japanese patients, especially cardiac toxicity data, is needed. We retrospectively reviewed 48 patients with early-stage HER2-positive breast cancer who were treated with curative surgery and adjuvant trastuzumab at the National Cancer Center Hospital East (Kashiwa, Japan). The cardiac safety as well as the short-term efficacy of trastuzumab were evaluated. The median age of the patients was 54 years. All patients received adjuvant or neoadjuvant cytotoxic chemotherapy. Twenty-seven patients (56%) received adjuvant radiation therapy. Forty-four patients (92%) received trastuzumab without concurrent cytotoxic chemotherapy and 4 patients (8%) on taxanes received trastuzumab concurrently. Twenty-five patients completed 1 year of trastuzumab treatment and 5 patients completed 2 years of trastuzumab treatment. Nine patients discontinued trastuzumab treatment, because of progressive disease (1 patient), decrease in left ventricular ejection fraction (LVEF; 2 patients), patient's refusal (4 patients), and other reasons (2 patients). There were five cardiac events. A decrease in LVEF to less than 50% was seen in 2 patients. The relationship between trastuzumab treatment and the cardiac events was unclear in 3 patients. The median follow-up time was 21.2 months. The disease-free survival (DFS) was 97.5% at 1 year and 92.9% at 2 years. The incidence of cardiac events caused by trastuzumab treatment was low in our analysis. Adjuvant trastuzumab treatment for up to at least 1 year should be safe for Japanese breast cancer patients.

Phase I evaluation of lapatinib (L) and epirubicin (E) in patients (pts) with anthracycline (anth)-naive metastatic breast cancer (MBC)

1107 Background: HER-2 alteration confers enhanced anth sensitivity in MBC, although HER-2 is not a target for anth. Topoisomerase 2A (Topo) is a target for anth. Topo amplification has been reported to occur only with HER-2 amplification, in approximately 1/3 of HER-2 amplified BC, providing a rationale for anth + trastuzumab(H) therapy in MBC with co-ampified HER-2/Topo. T+anth is cardiotoxic. L may have similar single agent activity, but less cardiotoxicity than H. L competes with anth for p-glycoprotein and might enhance its activity. The cardiac safety of L + anth needed to be established. Methods: We conducted a phase I evaluation of fixed dose lapatinib (1250 mg/day) with escalating doses of epirubicin (Epi-planned dose levels I-IV :75/80/90/100 mg/m2 ) in pts with HER-2±, anth-naive metastatic BC. Epirubicin was administered q3 weeks. A minimum of 3 (if no dose-limiting toxicity) and a maximum of 6 pts were treated per dose level. Ejection fractions were performed at base line and after every second cycle; BNP and troponin after every cycle. Results: 9 pts were treated, 3 level I, 6 level II. Dose level I was declared the maximum tolerated dose following two occurrences of dose-limiting toxicity in level II. 1 pt experienced febrile neutropenia,1 had &gt; 20% decrease in LVEF. To date there have been 3 PRs by RECIST out of 8 evaluable patients which represents a response rate of 37.5%. Conclusions: Using classic phase I criteria, the combination of L 1250 mg together with Epi 75 mg/m2 combination is relatively well tolerated and suitable for further investigation in a phase II study of HER-2+veTopo+ve MBC patients. We will conduct such a study in pts with HER-2+Topo+ metastatic BC. [Table: see text]

Benefits of dexrazoxane in female patients with stage II breast cancer treated with anthracycline-based adjuvant chemotherapy

e11626 Background: In Israel, the majority of patients receiving doxorubicin (A) are treated with dexrazoxan (D). A retro-active study was carried out on cardiac effects of A and D on female patients receiving adjuvant chemotherapy for Stage 2 breast cancer. Methods: 34 newly-diagnosed chemotherapy-naïve female patients with Stage 2 breast cancer, received anthracycline-based chemotherapy treatment A with D ± Herceptin (HER). Cardiotoxicity was assessed by echo-cardiograph pre- and post- treatment, and thereafter every 3 months for a period of 2 years, and was defined by presence of CHF or a reduction in resting LVEF to &lt;45% or to ≥15% below baseline echo-cardiograph. Results: 34 patients were eligible for assessment. The mean age was 52, ranging from 24 to 78. Chemotherapy regimen consisted of 4 cycles of A + cyclophosphamide + D ± HER (HER treatment over a period of one year) + paclitaxel (PAC) (12 courses). Of the 34 patients, 7 (20.5%) were Her2 new positive. 17 patients (50%) were estrogen (ER)/progesterone (PR) positive. 9 patients (26.4%) were triple negative. 2 of the Her2 new positive patients were also ER/PR positive. Average m2 per study population was 1.63 (mean range being 1.39 - 1.87). Average A dosage was 60mg/m2 and mean D dose was 391.2mg (between 333.6mg and 448.8mg). Ratio of A to D was 1:10. Echo-cardiograph pre- treatment ranged from 80% - 60%, a normal range according to the New York Health Association (NYHA). Post-treatment echo-cardiograph ranged from 70% - 45%. One patient from HER positive group (generally experiencing increased cardiotoxicity by 4%) showed decrease in LVEF by 14.3% (14.2% of Her2 new patients). Remaining patients showed no change. One patient from ER/PR positive group experienced a 12.3% reduction in LVEF, representing 5.88% of the ER/PR patients. Remaining ER/PR positive patients remained unchanged, with one patient showing increased LVEF from 60% to 70%. The triple negative patient showed no change in their echo- cardiograph results. Conclusions: This study confirms that no scientific or clinical-based evidence was found of anthracycline- based cardiotoxicity following administration of A plus D, in accordance with published medical evidence. D should be a standard of care for anthracycline-based chemotherapy. No significant financial relationships to disclose.

Translational study of the activity of liposomal doxorubicin formulations in hormone-refractory prostate cancer

e16026 Background: The efficacy of therapy for hormone-refractory prostate cancer (HRPC) is still unsatisfactory and new agents and therapeutic modalities are needed. The aims of the present work were to examine the in vitro activity and mechanisms of action of different doxorubicin formulations in HRPC cell lines and to assess the clinical potential of liposomal doxorubicin as second-line therapy in HRPC patients. Methods: Doxorubicin (Doxo), liposomal Doxo (Myocet) and pegylated liposomal Doxo (Caelyx) activity were assessed in vitro in PC3, DU145, and DU-R (partially resistant to docetaxel) cell lines by SRB test, and apoptosis was evaluated by TdT-assay and fluorescence image microscopy. On the basis of our in vitro results, a multicenter phase II trial was carried out in which a weekly administration of Myocet (25 mg/m2) and low-dose prednisone was given as second-line treatment after docetaxel failure. Objective responses were evaluated every nine weeks by PSA testing and by imaging for measurable lesions. Results: Myocet showed a higher cytotoxic activity than the other Doxo formulations in all cell lines, especially after a 72-h exposure, with already 70% of apoptotic cells at one tenth of the plasma peak concentration. Cytofluorimetry and fluorescence microscopy showed maximum Myocet concentration in the Golgi apparatus and at higher levels than those reached by the other Doxo formulations. The clinical trial completed the planned accrual of 43 patients and has achieved the principal endpoints of a PSA response (&gt; 50%) in more than 20% of patients and of stable disease, at 9 weeks, in 38% of patients. Toxicity was generally mild, with grade 2 leucopenia and grade 3 neutropenia observed in only 2 patients. No serious drug-related adverse events were reported, and there were no cases of heart failure or of &gt;10% decrease in LVEF. Conclusions: Myocet showed a higher activity on HRPC cells than the other Doxo formulations, which was probably due to a higher intracellular drug concentration, slower drug release and Golgi-dependent apoptosis. In the phase II study, Myocet and prednisone proved to be an effective and well tolerated regimen as second-line treatment for HRPC and warrant further evaluation. No significant financial relationships to disclose.

Phase II study of sunitinib in patients with recurrent and/or metastatic squamous head and neck carcinoma: The GORTEC 2006–01 study

6024 Background: Up to 90% of head and neck squamous cell carcinoma (HNSCC) express the vascular endothelial growth factor (VEGF) or the VEGF receptors (VEGFR) 1–3. Angiogenic factors could have prognostic implication making anti-angiogenic therapies an attractive treatment modality. Sunitinib inhibits multiple tyrosine kinase receptors including VEGFR1–3 and PDGFR. Methods: Palliative HNSCC in PD after platinum therapy received sunitinib 37.5 mg/day continuously. The primary endpoint was the disease control rate (SD, PR, CR) at 6–8 wks. A two-stage design was used (Simon; a = 0.15,b = 0.10, H0 = 10%, H1 = 25%) meaning that at least 6 patients out of 37 should achieve a SD. Dynamic contrast enhanced (DCE) magnetic resonance (MR) perfusion-weighted imaging before and 6 wks after treatment initiation was performed on a 3T system. Results: 37 pts (M/F:28/9;PS 0/1:5/32) were included.11 pts were not evaluable by imaging due to rapid clinical PD (7 pts) or toxicity (4 pts) and were considered in PD.PR was found in 1 pts, SD in 18, and PD in 18 (RECIST). Among the SD, 6 had a minor response and 5 had an unconfirmed PR (maximum % reduction in sum of the largest diameters: 2%, 4%, 7%, 10%, 16%, 17%, 30%, 45%, 48%, 65%, 73%). PR could not be confirmed due to PD within 4 wks (3 pts) or treatment termination due to toxicity (2 pts). 4 pts had MR DCE monitoring. In 3, a significant decrease in the volume transfer constant Ktrans measuring the tumor perfusion and endothelial permeability was found during sunitinib treatment. The main Gr3–4 toxicities (N pts) were fatigue (12), tumor bleedings (2), LVEF decrease (2), hypertension (2). Gr5 tumor bleedings occurred in 4 pts. Other local complications included apparition/worsening of tumor skin ulceration or tumor fistula in 15 pts. Conclusions: This trial met its primary endpoint with modest activity of sunitinib in HNSSC. The rate of complications (i.e., fatal bleedings) outlines the importance of a better patient selection. DCE-MRI may be useful to predict response. No significant financial relationships to disclose.

The Level of Cardiac Specific Overexpression of Adenylyl Cyclase Type 2 Dictates the Response to Chronic Pressure Overload

The major adenylyl cyclase (AC) isoforms in the heart are AC5 and AC6, which when overexpressed, exert different effects on the response to chronic pressure overload (CPO). Accordingly, the goal of this study was to examine the effects of overexpression (OE) of an AC isoform, which does not normally play a major role in the heart, eg, AC2, on the response to CPO. Two lines were generated: one with moderate AC2 OE of the transgene and the other with a higher level. The AC2 protein was 2 times greater in the line with higher OE. At least 6 WT and 6 AC2 OE from each group were subjected to transverse aortic constriction (TAC) or sham (S) operation for 1 week. With moderate AC2 OE, CPO did not affect the LV ejection fraction (EF) measured with echocardiography (75±1%) vs WT banded (72±1%), or with sham operated animals (76±1%). With higher AC2 OE, 1 week of CPO leads to a significant decrease in LVEF compared with WT (47±4 vs 72±1%) and increase in LVEDP (22.1±7.8 vs 3.5±0.5 mmHg). These were associated with more LV hypertrophy [LV weight/body weight (BW) ratio increased 121% vs 31%] and development of heart failure, as reflected by increased lung weight/BW (278%) vs WT (11%), and 3‐fold more fibrosis on histopathological examination. Thus, cardiac expression of AC2 at a moderate level does not affect the response to CPO adversely, but at a high level, results in more LV hypertrophy and reduced cardiac function leading to heart failure.

Phase II study of liposomal doxorubicin (Myocet®), docetaxel and trastuzumab combination as first line treatment of patients with her-2/neu positive locally advanced or metastatic breast cancer.

Abstract Abstract #3149 Objective: the aims of the study are to assess activity and safety of liposomal doxorubicin (Myocet®) in combination with Docetaxel and Trastuzumab as first-line treatment of patients with HER-2/neu positive MBC.&amp;#x2028; Methods: forty-six (46) non treated patients with metastatic HER2-overexpressing BC were planned to receive Myocet 50 mg/m2 (d1) and Docetaxel 30 mg/m2 (d2 and d9) plus Trastuzumab (d2, 4 mg/kg followed by 2 mg/kg weekly) for at least 6 cycles (up to a maximum of 8 unless occurrence of unacceptable toxicity or PD). Cycles were repeated every 21 days. Objective response was assessed according to WHO criteria every 3 cycles. To evaluate the tolerability WHO grading toxicity events were assessed at each cycle. Cardiotoxicity was defined as signs and/or symptoms of CHF and/or a decrease in LVEF below normal limit (&amp;lt; 50%) or a decline ≥ 15% from baseline value. To evaluate LVEF an echocardiography was done at baseline and at cycles 3, 6 and 8.&amp;#x2028; Results: we reported preliminary results of 46 patients enrolled. 41 patients completed at least 3 cycles and at first response evaluation Complete Response was seen in 2 pts (CR=4,9%), Partial Response in 22 pts (PR=53,7%), Stable Disease in 15 pts (SD=36,6%) and Progression Disease in 2 pts (PD=4,9%). The Overall Response Rate (ORR) was 58,6%.&amp;#x2028; 36 pts completed the planned chemotherapy (6 cycles): Complete Response was seen in 4 pts (CR=11,1%), Partial Response in 15 pts (PR=41,7%), Stable Disease in 9 (SD=25,0%) and Progression Disease in 8 pts (PD=22,2%). The Overall Response Rate (ORR) was 52,8%. 12 pts were entered in the follow up and for this subgroup median TTP was 13 months.&amp;#x2028; All 46 enrolled patients were included in the safety analysis. Most frequent toxicity events occurred during the study were: granulocytopenia Grade 4 in 16 pts (30.4%), leukocytopenia Grade 3 in 15 pts (32.6%), increase of transaminase levels Grade 1 in 14 pts (30.4%), alopecia Grade 4 in 16 pts (34.8%) and nausea Grade 2 in 13 pts (28.3%). In 2 patients LVEF dropped &amp;lt; 50% and other 2 pts registered a decrease of LVEF &amp;gt;15% with respect to baseline value. In the whole population LVEF mean value changed from 62.6 ± 4.9 at baseline to 61.0 ± 5.5 at cycle 3, to 62.9 ± 6.4 (cycle 6) and to 60.0 ± 8.1 (cycle 8).&amp;#x2028; Conclusion: these preliminary results suggest that the combination of non-pegylated liposomal doxorubicin, docetaxel and trastuzumab has shown a promising activity in first line MBC. The combination is safe with no significant change in LVEF values from baseline to the end of therapy. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3149.

The safety of dose-dense liposomal-encapsulated doxorubicin in association with docetaxel (MyTax) in breast cancer.

Abstract Abstract #2157 Background: Liposomal-Encapsulated Doxorubicin (LED) shows equivalent efficacy, better cardiac tolerability at higher cumulative dose than conventional anthracyclines in breast cancer treatment.&amp;#x2028; Methods: Sixteen pts were enrolled in a dose-finding study of LED (TLC-D99 Myocet ®) associated to Docetaxel (TXT). Twelve pts were treated with a fixed TXT dose (50 mg/m2) and TLC-D99 at three dose levels, 40-45-50 mg/m2, days 1 and 15 every 2 weeks using an intra- and inter-patient approach; four pts wrere treated at the TLC-D99 recommended dose (50 mg/m2). Cardiac monitoring of LVEF was performed every two cycles; Precursor Brain Natriuretic Peptide (proBNP) and cardiac Troponin (c-TnI) before and after 24 h chemotherapy was evaluated.&amp;#x2028; Results: Breast cancer (BC) disease extension: metastatic (MBC), 8; locally advanced BC, 5; T2-T3 BC, 3. Previous chemotherapy: untreated, 11 pts; adjuvant, 5 pts. Enrolled pts for each dose-level: I, 7; II, 9; III, 14. Newly treated pts: I dose-level, 7; II dose-level, 3; III dose-level, 6. Valuable cycles for each dose-level in a total 77 cycles: I, 14; II, 21; III, 42. DLTs were observed in 3 pts, 21%, and 3 cycles, 4%: 2 cardiac, characterized by a 19% LVEF decrease and a symptomatic arrhythmia; one G4 hematologic resistant to G-CSF. DLTs for each dose-level by pts and cycles, respectively: I, 14% (1/7 pts) and 7% (1/14 cycles); II, no DLT in 9 pts and 21 cycles; III, 14% (2/14 pts) and 5% (2/42 cycles). Cumulative G3-4 toxicities by pts and cycles, respectively: cardiac arrhythmia 6% and 1,3%, cardiac general (symptomatic LVEF decrease), 6% and 1,3%; alopecia 81% and 65%; neutropenia resistant to G-CSF, 6% and 1,3%. Cardiac DLTs were observed in 2 elderly pts (&amp;gt;65 y). The 2 cardiac DLTs were observed in 2 out of 3 pts with pre-existing diastolic dysfunction. No pathologic increase of c-TnI levels was detected. Seven pts showed increased pro-BNP after chemotherapy; 1 of these with increased pro-BNP after chemotherapy, persistent the day 1 of each subsequent chemotherapy showed a DLT;&amp;#x2028; G2 toxicities by patients and cycles, respectively: asthenia 37% and 18%, stomatitis/mucositis 12% and 5%, nausea 31% and 12%. Median rDI of TLC-D99 was 25 mg/m2/w and TXT 25 mg/m2/w for pts, respectively. Preliminary efficacy in 16 assessable pts: LA-BC and MBC, 1 CR (pCR) 7 PR (OR 62%), 4 SD and 1 PD; T2-T3 BC, 2 PR and 1 SD.&amp;#x2028; Conclusion: dose-dense TLC-D99/Docetaxel association can be safely recommended at the dose of 50 mg/m2 for each drug. Docetaxel intensification is ongoing. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2157.

Lapatinib (L) with weekly paclitaxel (P) as first-line therapy for patients (pts) with HER2+ metastatic breast cancer (MBC).

Abstract Abstract #3145 L, an oral tyrosine kinase inhibitor of EGFR/HER2, is active as monotherapy and in combination with chemotherapy for HER2+ MBC. In a planned subgroup analysis of a Ph III trial, EGF30001, L (1500mg QD) + P (175mg/m2 q3w), significantly improved overall response rate (ORR) and progression free survival (PFS) compared with P alone as initial therapy for HER2+ MBC. Here we report final results of a phase II, single-arm multicenter trial, EGF105764, assessing activity of L with weekly P in first line MBC.&amp;#x2028; Methods: Safety and efficacy of L (1500 mg QD)+P (80 mg/m2/wk x 3q wk) was evaluated in 57 pts with newly diagnosed, HER2 FISH+, Stage IV MBC. Primary endpoint was ORR.&amp;#x2028; Results and Discussion: All pts had ECOG PS ≤1, no pt received previous trastuzumab but 61% received prior adjuvant/neo-adjuvant chemo- or anti-hormonal therapy. Median time from prior chemotherapy was 63 weeks. No patient had suspected baseline CNS disease. At time of data cut-off, 41 (72%) pts progressed or withdrawn. The median duration of L treatment was 45 (range 2-87) wks, and 26 (range 0 to 80) wks for P. The investigator-assessed ORR was 77% (44/57), with 3 CR and 41 PR, (95% CI: 64.2, 87.3) with a median duration of response (DoR) of 42.3 wks (95% CI: 37.7, 64.1). The independently confirmed ORR was 51% (29/57), with 0 CR and 29 PR, (95% CI: 37.3, 64.4) with a median DoR of 39.7 wk (95% CI: 26.9, 50.0). CNS relapse was reported in 4/41 pts (10%). Most common AEs were diarrhoea (56%, ≥gr3: 5%), neutropenia (44%, ≥gr3: 26%), rash (40%, ≥gr3: 3%), fatigue (25%, ≥gr3: 0%), and neurological (25%, ≥gr3: 0%). Four pts had 1 dose reduction of L (2 due to diarrhoea) and 19 pts had ≥1 dose delay (6 due to diarrhoea). Dose reductions for P occurred in 7 pts; 45 pts had ≥1 dose delay (63% due to toxicity). There were no protocol defined LVEF decreases.&amp;#x2028; In the 86pt subset with HER2+ tumors in EGF30001, the investigator reported ORR was 63% in the L+q3w P and 38% for P+placebo. The safety profile of L+P used qw or q3w is comparable: diarrhoea all grades (56% vs 58%), rash all grades (40% vs 43%), and neurological events all grades (25% vs 26%). Neutropenia (all grades) was more common in the qw schedule of P (44% vs 26%), but the incidence of ≥gr3 was comparable (26% vs 21%, for qw vs 3qw respectively).&amp;#x2028; Conclusions: L + weekly P as first-line therapy for HER2+ MBC was well tolerated and produced a high, investigator assessed ORR of 77%. These data suggest that the combination of L and P (at any schedule) may be an option for newly diagnosed patients with HER2+ MBC. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3145.

Prognostic value of heart rate variability after acute myocardial infarction in the era of immediate reperfusion

The incidence and significance of impaired heart rate variability (HRV) after acute myocardial infarction (AMI) have not yet been evaluated in cohorts of patients in whom early reperfusion was systematically attempted. Therefore, HRV was evaluated in 412 unselected patients with AMI (311 men, mean age: 60+/-12 years, anterior AMI in 172 patients) treated with direct coronary angioplasty (PTCA) within 12 hours of symptom onset (mean 3.5+/-2.0 h). Standard deviation of normal RR intervals (SDNN), square root of the mean of the sum of the squares of differences between adjacent RR intervals (RMSSD) and left ventricular ejection fraction (LVEF, mean: 55+/-15%) were measured 11+/-9 days after AMI before discharge. Angiotensin-converting enzyme (ACE) inhibitors and beta-blockers were prescribed at discharge in 81.1% and 70.1% of patients, respectively. Mean SDNN was 94+/-30 ms (range 14-155). SDNN was <50 ms in 7% of patients. Mean RMSSD was 34+/-32 ms (range 2-234). RMSSD was <15 ms in 21% of patients. Low SDNN (<50 ms) was unrelated to gender, age, infarct location or extension of CHD but was related to low LVEF (p<0.001, logistic regression analysis). During mean follow-up of 4.3+/-3 years, there were 31 deaths; 24 were cardiac. SDNN was higher in long-term survivors (102+/-39 ms) as compared to nonsurvivors (81+/-33 ms, p=0.02) but RMSSD was unrelated to the long-term vital status. Four-year survival of patients with a SDNN <50 ms vs >50 ms was 80% vs 92%, respectively (p<0.001, Kaplan Meier analysis). Low SDNN (odds ratio OR=2.0, p<0.05) but not RMSSD was an independent denominator for long-term mortality as were low LVEF (OR=1.0 decrease in LVEF, p<0.01, proportional hazards model) and age (OR=1.1, p<0.001). Only 3/31 fatalities and 1/24 cardiac deaths were predicted by a SDNN <50 ms and only 5/31 fatalities by a RMSSD <15 ms. The incidence of severely depressed HRV in patients after AMI is low (<10%) in the era of early reperfusion of the infarct vessel using direct PTCA. Mortality in patients with a very low HRV when assessed by SDNN is substantial but the positive predictive value of this parameter is low.

Abstract 1104: Polymer Injection Therapy to Reverse Remodel the Papillary Muscles: Efficacy in Reducing Mitral Regurgitation in a Chronic Ischemic Model

Ischemic mitral regurgitation (IMR) relates to displacement of the papillary muscles from ischemic ventricular distortion. Recurrent IMR is frequent after annuloplasty, particularly when left ventricular remodeling continues to progress. Our hypothesis is that repositioning of the papillary muscles can be achieved by injection of polyvinyl-alcohol (PVA) polymer into the myocardium, in chronic MR with great left ventricle remodeling. Methods : we studied 8 sheep underwent ligation of circumflex branches to produce chronic ischemic MR over eight weeks. Once MR developed, PVA was injected into the myocardium underlying the infarcted PM. 2D and 3D echocardiograms were used pre infarct (baseline), pre PVA (Chronic MR) and post PVA. Hemodynamic data were obtained Results: One animal died, in the remaining 7 moderate MR developed. With PVA, the MR decreased significantly from moderate to trace-mild (vena contracta: 5.3 ± 0.9 mm vs 2.3 ± 0.9 mm, post MR vs post PVA; p&lt;0.001). This was associated with a decrease in infarcted papillary muscle-to-mitral annulus tethering distance (33.1 ± 4.6 to 27.4±4.1 mm, post MR vs post PVA, P&lt;0.05), tenting volume (2.1±0.3 to 1.6±0.4 mm, post MR vs post PVA, P&lt;0.05) and leaflet area (9.4 ± 0.8 to 8.2 ± 0.7 mm, post MR vs post PVA, P&lt;0.04). PVA was not associated with significant decreases in LVEF (41±2 % vs 39±2 %, p=ns). Conclusions : PVA polymer injections improve coaptation and reduce remodeling chronic MR without impairing LV systolic function. This new approach offers a potential alternative for relieving ischemic mitral regurgitation by correcting papillary muscle position, thus relieving tethering that causes ischemic mitral regurgitation.

Lapatinib or placebo plus letrozole as preoperative treatment of hormone receptor-positive HER2-negative operable breast cancer. Preliminary report of safety and activity of the double-blind randomized phase IIb LET-LOB study

623 Background: Crosstalk between hormone- and EGFR-family pathways is a possible cause of resistance to aromatase inhibitors (AI), as suggested by the increased expression of HER2, EGFR and MAPK in long-term estrogen-deprived breast cancer (BC) cells. Lapatinib (Lap) is an orally active small molecule inhibitor of EGFR and HER2 tyrosine-kinases. Combination of an AI and Lap in ER+/HER2- tumors could avoid the onset of resistance due to early stimulation of EGFR and HER2 pathways. To evaluate these effects, we designed an international multicenter phase IIb double-blind randomized trial in ER+/HER2- BC pts candidates for hormone neoadjuvant therapy. Methods: Postmenopausal pts with stage II-IIIa, HR+/HER2- BC are randomized to letrozole (Let; 2.5 mg/d) plus lapatinib (Lap; 1,500 mg/d) or placebo (P), given continuously for 24 weeks before surgery. Activity (with ultrasonographyc, US) and cardiac safety (with echocardiogram) assessment are performed after 12 and 24 weeks. Tissue biomarkers of hormone and EGFR-family related pathways are analyzed before and after treatment. An initial sample size of 42 pts will be enrolled assuming a 50% chance of cOR with Let+P and a 40% increase in cOR with the Let+Lap (equal to 70% absolute cOR). Additional 48 pts will be treated in case we observe 20 cOR in the first cohort (Simon's design). Results: 19 Italian and European centers are participating in the study. From April 2007, 28 pts have been randomized, and 15 pts were treated for at least 3 months (mo). Six pts completed the six mo treatment, and 4 underwent surgery. At diagnosis, mean US tumor size was 2.87 cm (range 2–6 cm). All pts were ER+ (73% ER+/PR+) and HER2-. No significant decrease in mean LVEF was observed at the 3-mo evaluation (60.9%-61.5%). No grade 3–4 toxicities were reported. A 34% absolute reduction in median longest US tumor diameter has been observed after 3 mo (15 pts) and 65% reduction has been obtained at 6 mo (6 pts). Updated blinded safety and activity results will be presented. Conclusions: The combination of Lap or P with Let in ER+/HER2-operable breast cancer was safe, without any early cardiac toxicity, and induced clear tumor shrinkage. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline

Trastuzumab-related cardiotoxicity in setting outside clinical trials: A mono-institutional experience

22116 Background: Since cardiac failure may occur in ordinary clinical practice at higher rate than in controlled clinical trials with strict entry criteria, we assessed the spectrum of cardiotoxicity during routine trastuzumab (T) treatment for breast cancer patients (pts) of our division. Methods: Data of 72 pts treated with trastuzumab-based therapy for at least 8 months were collected, unless they developed cardiotoxicity (median cumulative time 14: range 8–78 months). Pts characteristics were: potential cardiac risk factors in 15/72 pts, median FE 63% (range 50–80), prior anthracycline-based(A) therapy in 57 pts (79.2%), prior taxane-conteining (Tax) therapy in 37 pts (51.4%) (both 48.6%). Cardiac events (CEs) were defined as a decrease of LVEF to < 50% and/or of ≥ 20% from baseline; or symptoms of CHF according to NYHA class II-IV. LVEF at baseline was normal, performed every 3 months according to the local clinical practice and evaluated at 12 month. Results: CEs developed after a median of 10 months of T. Twenty-one pts (29.2%) experienced CEs. Thirteen of these (18.0%) (9 pretreated with A) developed CHF, NYHA class II-III (6 pts, 8.3%, class III). Two out of the 21 CEs pts had an asymptomatic reduction of < 50% LVEF. Sixteen out of the 72 pts (22.2%) had a ≥ 10% LVEF reduction from baseline (6/16 pts LVEF ≥ 20%). CEs occurred in 33.3% of the pts with a potential risk factor vs 28,1% of those without risk. There were no cardiac deaths. Among the 57 pts pretreated with A, 3 (8,6%) of those who also received Tax experienced cardiotoxicity class II-IV vs. 6 (27.3%) who did not (p=0.05). No pts treated with both A and Tax had a reduction of LVEF ≥ 20% vs. 22.7% of those pretreated with only A (p=0.01). CHF developed in7 cases in the first year, 4 in the second, and 1 in the third. Conclusion: According to our experience, cardiotoxicity of T based therapy is acceptable, but worse than that reported in the controlled clinical trials. No significant financial relationships to disclose.

A phase II evaluation of lapatinib (L) and bevacizumab (B) in HER2+ metastatic breast cancer (MBC)

1042 Background: In a preclinical HER2+ BC model, combination anti-HER2 and anti-VEGF therapy was more effective than either treatment alone, and increased VEGF expression is associated with worse outcome in HER2+ disease. B plus trastuzumab (T) has shown promising activity in patients (pts) with HER2+ MBC, however the cardiac toxicity of this regimen requires further evaluation. L, an oral dual inhibitor of EGFR and HER2, is approved in combination with capecitabine after T-based therapy for HER2+ MBC. L may have less cardiac toxicity and may be a safer and more effective alternative to T+B. This hypothesis was evaluated in a phase 2 trial of L+B in HER2+ MBC pts. Methods: This 50-patient single-arm study evaluated L (1,500 mg PO daily) plus B (10 mg/kg IV q2wk). The primary endpoint is progression-free survival (PFS) at 12 weeks with 84% power to detect a clinically significant PFS rate of 60%; secondary endpoints include toxicity and response per RECIST. Efficacy was assessed at Week 6, 12, and q12wks thereafter. HER2+ status was locally defined as HER2 FISH amplified or IHC3+. Serial evaluation of circulating tumor and endothelial cells and HER2 extracellular domain was performed. Results: Presently 31 pts are enrolled with a median of 4 prior MBC therapies (range 0–13); 30/31 received prior T (median duration 84 weeks, 14–250 weeks). The most commonly-reported AEs included diarrhea (61%), muscle pain (48%), fatigue (39%), nausea (28%), and emesis (29%). Two grade 2 asymptomatic LVEF decreases and one grade 3 GI hemorrhage were reported. At week 12, 16/21 patients were evaluable for efficacy; 3 pts had a partial response (PR), 10 pts had stable disease (SD), and 3 pts had progressive disease (PD), resulting in a 12-week PFS rate of 62%. At week 24, 5/9 (56%) pts have shown clinical benefit (CR, PR, SD ≥ 24 weeks); 2/2 pts remain in PR after 36 weeks. Conclusions: L+ B is well tolerated and has shown promising activity in heavily pretreated HER2+ MBC pts. Updated results from this ongoing trial will be reported. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration GlaxoSmithKline Genentech, GlaxoSmithKline GlaxoSmithKline AstraZeneca, Genentech, Genomic Health, GlaxoSmithKline Bristol-Myers Squibb, Genentech, GlaxoSmithKline, Novarits, Pfizer, Roche, sanofi-aventis

Usefulness of myocardial performance index and biochemical markers for early detection of anthracycline-induced cardiotoxicity in adults

Anthracycline therapy is limited by cardiotoxicity. Currently no diagnostic parameter is available allowing ubiquitous and reliable detection of preclinical anthracycline cardiomyopathy and prediction of prognosis. In 100 consecutive patients receiving anthracycline-based chemotherapy serial measurements of left ventricular systolic and diastolic function, Tei index (a Doppler echocardiographic parameter of global ventricular function), cardiac troponin T (cTnT) and NT-probrain natriuretic peptides (BNP) at baseline and during 1-year follow-up were performed. Mean ejection fraction (LVEF) significantly decreased immediately after completion of anthracycline therapy (mean dose 226.1 +/- 8.3 mg/m(2)) und further declined during follow-up (65.9 +/- 0.6% Vs. 61.6 +/- 0.7%; P < 0.001), while mean E/A ratio decreased after 6 months (P = 0.05). No patient presented with cardiac symptoms. The Tei index increased after therapy in the majority of patients (78.8%) compared with pre-therapy values indicating myocardial alteration in more patients than previously recognized. cTnT levels did not exceed the upper limit of the normal range in any patient. Seven patients had low-level elevations of cTnT. Only one of these patients developed a concomitant decrease in LVEF. Mean N-terminal-pro-BNP (NT-proBNP) levels did not significantly change after anthracycline administration. However, in 13 patients (15.3%) a marked, transient increase of NT-proBNP was obtained after the first anthracycline cycle without cardiac dysfunction presumably due to altered cardiac loading conditions during chemotherapy. Low to moderate doses of anthracyclines resulted in subclinical myocardial alteration in more patients than so far noticed. Clinical implications of increased Tei index remain to be determined in long-term. Our results do not support that assessment of cTnT or BNP levels may safely replace serial echocardiographic evaluation of systolic and diastolic function for the monitoring of anthracycline cardiotoxicity.

Persistent Reduction of Ischemic Mitral Regurgitation by Papillary Muscle Repositioning

Recurrent ischemic mitral regurgitation (IMR) is frequent despite initial reduction by annuloplasty because continued LV remodeling increases tethering to the infarcted papillary muscle (PM). We have previously shown that PM repositioning by an external patch device can acutely reduce IMR. In this study, we tested the hypothesis that IMR reduction persists despite possible continued LV remodeling. In 7 sheep, we used a chronic ischemic posterior infarct model that produces LV dilatation and MR over 10 weeks. An epicardial patch device was adjusted under echo guidance to reduce MR, with follow-up over a further 8 weeks and evaluation by 3D echo and sonomicrometry. In all 7 sheep, moderate IMR resolved with acute patch application and PM repositioning (6.5+/-1.8 mm to 0.6+/-1.3 mm proximal jet width, P<0.001) without decrease in LVEF (43+/-3% to 44+/-8%). Eight weeks after PM repositioning, MR was not significantly greater (0.6+/-1.3 mm versus 1.0+/-1.0 mm, P=NS) despite an increase in LV volumes in 3 animals (2 had increases of 50+/-15%). On average, LV volumes did not change significantly (ESV: 46+/-8 mL versus 49+/-15 mL; P=NS and EDV: 85+/-16 mL versus 89+/-30 mL; P=NS). LVEF was unchanged from acute to chronic patch (44+/-8% versus 43+/-8%). Contractility as end-systolic elastance did not decrease from the chronic MI to the acute and chronic patch stages, nor were there any significant changes in dP/dt, LV stiffness constant, or time constant of LV relaxation (Tau). PM repositioning is persistently effective in reducing moderate chronic IMR, even when LV volume increases. This may reflect structural stabilization by an external patch device of the papillary muscle-LV wall complex that controls mitral valve tethering.

Cardiac safety in patients (pts) with metastatic breast cancer (MBC) treated with lapatinib (L) and trastuzumab (TRA)

514 Background: Clearly defined standards for assessing cardiac toxicity do not exist for newer agents used as treatment for BC, e.g., tyrosine kinase inhibitors. To evaluate the usefulness of increased cardiac monitoring and cardiac function (LVEF) in pts treated with L+TRA, data from 4 trials were analyzed. Methods: From July 2003 to Dec 2006, 238 pts received L+TRA (n=203) or L+TRA with paclitaxel or docetaxel (n=35) for HER2-positive MBC. LVEF was evaluated at screening, every 8 weeks after starting L+TRA, and at withdrawal via multiple-gated acquisition scans or echocardiograms. Rate of symptomatic cardiac events (CE; NCI CTCAE Grade 3 or 4 LV systolic dysfunction) or asymptomatic LVEF decreases (=20% relative to baseline and below the institution’s lower limit of normal) were assessed. Results: None of the 238 pts had a symptomatic CE. Four pts had a single asymptomatic LVEF decrease and 1 pt had 2 asymptomatic LVEF decreases, totaling 6 decreases in 5 (2.1%) pts. These pts were women aged 36–64 years and had previously received anthracyclines (A; n=2), A+TRA (n=2), or unknown therapy (n=1). Median time to onset of LVEF decrease was 83 days; all but 1 decrease occurred within 75 days after initiating L+TRA (range: 18–221 days). Baseline LVEFs of 62%, 60%, 62%, 74% and 58% decreased to 47%, 46%, 45%, 45%, and 45%, respectively. L+TRA was temporarily interrupted in 3 pts and continued in 2 pts despite LVEF decrease. Per investigators, LVEF decrease resolved with no further sequelae in 4 pts (59%, 56%, 60%, and 50%) and was ongoing in 1 pt. Conclusion: Initial data indicate L+TRA or L+TRA with taxanes does not constitute a serious incremental cardiac risk and may not require more stringent cardiac monitoring than is used for A or TRA alone. The combined effect of HER2 inhibition with L+TRA appears not to increase the risk of CE in this population. No significant financial relationships to disclose.

Phase II trial of pegylated liposomal doxorubicin-cyclophosphamide combination as first-line chemotherapy in elderly metastatic breast cancer patients

19565 Background: Although the majority of metastatic breast cancer (MBC) patients (pts) responds to endocrine therapy, treatment failure is a concern, as well as front-line therapy for pts with ER/PR negative disease.The combination of anthracyclines (A) and cyclophosphamide (C) is active in younger pts, but cardiac toxicity of A in elderly MBC pts has to be considered. Pegylated liposomal doxorubicin (PLD) (Caelyx®) is active in MBC and has much less cardiotoxicity than A, and we present the preliminary data of the PLD/C in elderly MBC pts. Methods: This was a multicentric phase II trial. Inclusion criteria included: pts aged between 65 and 75, histologically proven measurable MBC, ECOG PS 0–1, LVEF = 50%, first-line chemotherapy for MBC. Prior adjuvant chemotherapy was allowed if stopped for = 6 or 12 months without and with anthracyclines, respectively. Endocrine therapy either in the adjuvant or metastatic setting had to be stopped for = 1 month. All pts gave a written informed consent. The treatment schedule was : PLD 40mg/m2 and C 500mg/m2 d1 every 4 weeks. Efficacy as well as response duration and tolerance were the primary and secondary end-points, respectively. Results: 35 patients were enrolled (Median age 71.3, range 65.6–75.9). A total of 166 cycles have been administered. The median number of cycles was 6 (range 1–9). No toxic death was reported, one patient died of diabetes mellitus decompensation. No congestive heart failure or decrease in LVEF was reported, although 1 pt experience grade 3 dyspnea and stopped treatment. Other (gr3–4) NCI-CTC toxicity included: neutropenia in 7 (gr3) and 3 (gr4) pts; gr3 mucositis (4). No febrile neutropenia was reported. Grade 3 hand-foot syndrome occurred in 1 pt, whereas treatment was stopped due to a generalized rash in 1 pt. An objective response (CR + PR) was achieved in 10 (28,6%) pts (1 CR and 8 PR), and a disease control in 24 (68.6%) with a progression free survival of 8.8 months and a median survival of 20.4 months Conclusions: The LPD-C combination is active in elderly MBC pts, with an acceptable toxicity profile. No significant financial relationships to disclose.