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We have explored the therapeutic effects of anti-epidermal growth factor receptor monoclonal antibodies (MAbs) 225 and 528 on well established A431 epidermoid carcinoma xenografts, approximately 400 mm3 (1 cm in diameter) at the start of treatment. In previous reports we demonstrated that MAbs 225 and 528 prevented the growth of A431 cell xenografts in nude mice when treatment was begun on the day of tumor cell inoculation. Since anti-epidermal growth factor receptor MAb therapy of well established tumors was unable to retard growth, we explored combination therapy with MAb plus the chemotherapeutic agent cis-diamminedichloroplatinum (cis-DDP). Additive and concentration-dependent growth-inhibitory effects of MAb with cis-DDP were observed in cultures of A431 cells. Neither intensive treatment with 225 MAb (1 mg/mouse, i.p. on day 8 after tumor inoculation, and twice weekly for 4 weeks) nor a maximally tolerated single dose of cis-DDP [150 micrograms/25 g (6 mg/kg) mouse weight, i.p. on day 8] had significant effects on tumor growth. However, the two treatments in combination resulted in substantial xenograft growth inhibition, compared with both an untreated control group and animals treated with a single modality. When a second dose of cis-DDP (150 micrograms/25 g) was added after 10 days, combination therapy with 225 MAb produced striking antitumor effects. At the end of 1 month tumor xenografts had disappeared in all but one mouse, and no tumor relapses occurred during 6 months of observation. Identical results were obtained with anti-epidermal growth factor receptor MAb 528 in combination with cis-DDP. The results of these studies provide a novel approach to the treatment of well established tumor xenografts, which may have application in the therapy of human malignancies.

The epidermal growth factor receptor (EGFR) and one of its ligands, transforming growth factor alpha (TGF-alpha), are thought to function as a potential autocrine loop in non-small cell lung cancer (NSCLC). However, the expression pattern of EGFR and the TGF-alpha-related ligands have not been fully characterized in primary NSCLC and adjacent benign lung tissue. For this reason, we comprehensively examined the coexpression and differential expression of EGFR and its ligands, TGF-alpha, epidermal growth factor (EGF), and amphiregulin (AR), by Northern analysis, in paired samples of primary tumors and uninvolved lung. For those RNA species overexpressed in malignant lung, single cell expression patterns were studied by immunohistochemistry. Specimens were obtained from 57 consecutive patients who underwent resection of carefully staged resectable NSCLC and were followed prospectively. Most (112 of 114) tissue samples yielded high-quality RNA. EGFR was expressed in 82 of 88 (93%) tissue samples, while TGF-alpha was expressed in 62 of 72 (86%) samples, and AR was expressed in 64 of 70 (92%) samples. EGF was unexpressed in total cellular RNA in both tumor and uninvolved lung. In a comparison of RNA expression patterns in tumors and uninvolved lung, overexpression of EGFR was found in 45% (22 of 44) of tumors, while overexpression of TGF-alpha was seen in 61% (22 of 36) of tumors, and decreased expression of AR was seen in 63% (22 of 35) of tumors. Cell type and stage did not influence differential expression, indicating that this is a frequent event in primary NSCLC. Simultaneous overexpression of EGFR and TGF-alpha was seen in only 38% of tumors. Simultaneous overexpression of EGFR and decreased expression of AR were seen in only 21% of tumors. Thus far, the differential expression of EGFR, TGF-alpha, and AR does not correlate with either disease-free or overall survival. These findings indicate that histologically dissimilar tumors can express similar components of autocrine or paracrine growth factor loops. Differential expression of EGFR and its ligands in tumor specimens compared to uninvolved lung is a common event in NSCLC and may participate in tumor growth without necessarily influencing tumor progression or histology.

Zidovudine is a thymidine analogue that has been reported to have antiviral and antineoplastic activity in vitro.The case of a patient with acquired immune deficiency syndrome (AIDS) and a pulmonary non-Hodgkin lymphoma treated with zidovudine and no other treatment is presented.The patient achieved a prolonged partial remission of a pulmonary non-Hodgkin lymphoma while receiving zidovudine alone.Zidovudine may have antitumor effects in AIDS-related lymphomas and should be evaluated for its antitumor potential.

Background: The addition of trastuzumab to neoadjuvant chemotherapy has significantly improved pathological complete response (pCR) in patients with HER2-positive early breast cancer (BC). Lapatinib, a dual HER2/EGFR tyrosine kinase inhibitor, combined with chemotherapy has significantly improved progression free survival in patients with metastatic HER2-positive BC. Additionally, lapatinib combined with trastuzumab improved disease-free and overall survival in patients with metastatic HER2-positive BC. The NeoALTTO trial is testing the efficacy of lapatinib, trastuzumab or their combination together with paclitaxel when given as neoadjuvant therapy in patients with HER2-positive BC. Material and Methods: NeoALTTO is an international, multicenter, randomized study comparing the efficacy of lapatinib plus paclitaxel, versus trastuzumab plus paclitaxel, versus concomitant lapatinib and trastuzumab plus paclitaxel given as neoadjuvant treatment in HER2- positive primary BC. From January, 2008, to December, 2009, 455 patients were randomized from 99 participating sites. Patients were randomized to receive either lapatinib 1500 mg/d (154 pts), or trastuzumab 4 mg/kg IV loading dose followed by 2 mg/kg IV weekly (149 pts), or lapatinib 1000 mg/d with trastuzumab for a total of 6 weeks (152 pts). After this biological window, patients continued on the same targeted therapy plus weekly paclitaxel 80 mg/m2 for a further 12 weeks, until definitive surgery (total neoadjuvant therapy duration of 18 weeks). After surgery, patients received 3 cycles of adjuvant FEC followed by the same targeted therapy as in the biological window of the neoadjuvant phase for a further 34 weeks (to complete 52 weeks of anti-HER2 therapy). The primary objective of the study is to evaluate and compare among the three arms the rate of pCR, defined as the absence of invasive cancer in the breast at the time of surgery. Secondary objectives include objective response rate, safety, pathologic node-negative status, rate of conversion to breast conservation, disease-free survival and overall survival. All patients underwent tumor biopsies for comparative pharmacodynamic analyses before beginning therapy and on day 15 of the biological therapy window. A subset of patients also participated in PET/CT and circulating tumor cells substudies. Results: The last breast surgery was performed in May 2010. Data cleaning and analysis will be complete by November 2010 and results for safety and the primary objective (pCR) of this important phase III trial will be presented at the meeting. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr S3-3.

Background: Obesity has been associated with worse pathological complete response (pCR) to neoadjuvant chemotherapy (NACT) and overall outcome in breast cancer patients (pts). Our aim was to retrospectively evaluate body mass index (BMI) as a predictive factor of pCR to NACT in pts treated at our institution, taking into account tumor HER2 status and CT dose adjustment. Pts and methods: Pts with invasive breast cancer who received NACT followed by surgery at Vall d'Hebron University Hospital from January 2004 to December 2008 were analyzed. Pts were categorized as normal/underweight (BMI < 25 kg/m2), overweight (BMI of 25 to < 30 kg/m2), and obese (BMI ≥30 kg/m2). The overweight and obese groups were combined (BMI-high) and then compared with the normal/underweight group. Univariate and multivariate analyses were performed to assess the association between BMI and pCR (no invasive tumor in breast and nodes). Results: 256 consecutive pts were included. Median age was 52.5 years. According to BMI, 38.7% were normal/underweight and 59.4% were BMI-high. 23.4% of the pts had HER2 positive tumors (n=60), 84% received anthracyclines-and taxanes-based CT, and 46.6% of the HER2 positive pts were treated with trastuzumab. Drug dose was reduced in only five pts with a body surface area > 2m2. No statistically significant association was found between BMI and any tumor characteristics. In the univariate analysis, BMI-high was associated with worse pCR in the whole population (p=0.017), as well as in HER2 positive pts (p=0.013). In the multivariate analysis, BMI did not significantly predict pCR in the total population, although a trend was observed (p=0.098). In the HER2 positive subgroup, however, BMI was an independent predictive factor of pCR (p=0.001). Among luminal A [estrogen receptor positive and/or progesterone receptor positive and (Ki67 < 20% and histological grade 1 or 2)], luminal B [estrogen receptor positive and/or progesterone receptor positive and (Ki67 ≥20% or histological grade 3)], and triple negative tumors, BMI was not a predictive factor of pCR. Conclusions: Our results suggest that higher BMI is likely associated with worse pCR, particularly in HER2 positive pts. A better understanding of the molecular links between obesity and breast cancer is necessary to identify new predictive factors of pCR to NACT. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-03-04.

Background: The epidermal growth factor receptor (EGFR) plays a role in triple-negative (estrogen receptor-, progesterone receptor-, HER2-negative) breast cancer (TNBC). This randomized, phase II study investigated the combination of the EGFR monoclonal antibody cetuximab and cisplatin in the treatment of metastatic (m) TNBC. Methods: Patients (pts) with mTNBC who had received ≥1 prior chemotherapy regimen for metastatic disease, were randomized 2:1 to treatment with either: cetuximab (400 mg/m2 initial dose then 250 mg/m2 weekly) + ≥6x 3-weekly cycles of cisplatin (75 mg/m2, d1); or ≥6x 3-weekly cycles of cisplatin alone. In the cisplatin arm, pts with disease progression (PD) during the 6 cisplatin cycles could switch to cetuximab plus cisplatin and those with PD after the 6 cycles could receive cetuximab alone. The primary endpoint was best overall response. Simultaneous null hypotheses assumed that the overall response rate (ORR) in the combination arm was ≥20% and that the ORRs were equal in both arms. Secondary endpoints included progression-free survival (PFS), overall survival (OS) and safety. All statistical tests were performed at alpha-level 0.1 Results: 173 pts were included in the intention-to-treat population: 115 were randomized to cetuximab/cisplatin and 58 to cisplatin. The cetuximab/cisplatin and cisplatin arms were well balanced for patient and disease characteristics (randomization strata, 73% first and 27% second line in both arms). Differences included: age ≥65 years (19.1% vs 12.1%) and lung metastases (55.7% vs 44.8%). 30 pts receiving cisplatin alone switched to cetuximab/cisplatin after first PD. 79.6% of patients on cetuximab/cisplatin and 73.7% on cisplatin received ≥90% of the relative dose intensity of cisplatin. Adverse events (AEs) were manageable and in line with what was expected from the different agents (grade 3/4 AEs are shown in the Table). Grade 3/4 AEs (%) Adding cetuximab to cisplatin nearly doubled the ORR: 20.0% (95% CI 13.1%, 28.5%) vs 10.3% (95% CI 3.9%, 21.2%) (p=0.5 for testing ORR against 20.0%), with an odds ratio of 2.126 (90% CI 0.945, 4.786, p=0.11). Cetuximab/cisplatin was associated with a significant 32.5% reduction in the risk of disease progression compared with cisplatin alone HR 0.675 (95% CI 0.470, 0.969, p=0.032). Median PFS times were 3.7 and 1.5 months, respectively. The benefits of cetuximab/cisplatin over cisplatin on ORR and PFS were observed consistently across sub-groups (according to patient, disease and treatment characteristics), but sample sizes were small. OS results will be presented at the meeting. Conclusions: Adding cetuximab to cisplatin increased the ORR compared with cisplatin alone and significantly improved PFS in mTNBC. Safety was manageable. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD01-01.

1113 Background: VT has proven active in HER2+ MBC: Response rate (RR) and time to progression (TTP) in first- and second-line therapy: 51-84%, 7.5-17 months (m) and 51-66%, 3.5-9 m, respectively. However, all pts included in such studies were T-naive. In contrast, few data regarding the efficacy of VT in pts with prior T treatment (Tpt) has been reported and preclinical data do not support a synergism of V and T in T-resistant cell lines. Our aim was to describe the efficacy of VT in Tpt pts compared to a T-naive group and to study predictive factors of TTP in both groups. Methods: Medical reports of all pts receiving VT for MBC between 2001 and 2009 were selected. Those previously treated with T for MBC and/or relapsing ≤ 6 m after completion of adjuvant T constituted the Tpt group. Pts without previous exposure to T formed the T-naive subset. RR, clinical benefit rate (CBR), and TTP were analyzed. Baseline characteristics, along with time of prior T treatment in Tpt group, were analyzed as potential va...

1534 Background: Modulation of response to chemotherapy and prediction of efficacy to certain targeted therapies in TNBC is highly associated to BRCA1/2 mutations. We aimed to identify if TN phenotype in BC female patients added to family history is a useful predictor for detecting the presence of any of these mutations. Methods: We analyzed the mutation status of 227 consecutive unrelated female BC patients (probands) referred to our High Risk and Cancer Prevention Unit who had undergone full genetic testing of BRCA1/2 (direct sequencing and large rearrangements analysis). Univariate analyses were performed to compare the prevalence of mutations between TNBC and non-TNBC according to family history (breast/ovarian cancer in first/second degree relatives) and age at diagnosis (dichotomized at 50). A multivariate analysis was performed to identify predictors of finding a mutation. Results: Overall, 58/227 (26%) had a TNBC, 184 (81%) had a family history, and 190 (84%) were diagnosed before 50y. Twenty-one ...

1083 Background: We reported data from SOLTI-0701 demonstrating a clinical benefit with the oral regimen of SOR+CAP vs. PL+CAP in pts with advanced BC for progression-free survival (median, 6.4 vs. 4.1 mo; hazard ratio 0.58; 1-sided p=0.0006). Toxicities were comparable between treatment arms except for HFSR/HFS, which was not unexpected as HFSR and HFS are associated with SOR and CAP, respectively. Here we describe HFSR/HFS toxicity during this study. Methods: SOLTI-0701 is a multinational (Brazil, France, Spain) phase 2b study in HER2-negative pts with locally advanced or metastatic BC and ≤1 prior chemo regimen for advanced BC (n=229). Pts were randomized (1:1) to receive CAP (1,000 mg/m2 po, twice daily [BID], 14 of every 21 days) with PL or SOR (400 mg po, BID). The protocol recommended managing HFSR/HFS with symptomatic therapy, study drug (SOR, PL, CAP) interruption for grade (G) 2 toxicity, study drug interruption and dose reduction for recurrent G2 or G3 toxicity, and discontinuation for persiste...

1112 Background: In pts with MBC, retreatment with chemotherapy agents given previously in the early disease setting is a valid therapeutic option. Re-introduction of anthracyclines is limited by the risk of accumulative cardiotoxicity. Since NPLD is less cardiotoxic, administration of NLPD could be a potential strategy to re-introduce anthracyclines in MBC. In order to explore this hypothesis, we have analyzed the cardiotoxicity NPLD-containing regimes in pts with MBC previously exposed to D 360 mg/m2. Methods: Pts had PS 0-2, basal left ventricular ejection fraction (LVEF) >50%, adequate organ function, and prior exposure of D in the (neo)adjuvant setting at a dose of 360 mg/m2. No prior liposomal anthracyclines were allowed. LVEF was measured before initiating treatment with NPLD and at least at the time of treatment discontinuation. Cardiac events were defined as type A in case of signs and/or symptoms of congestive heart failure plus grade 3/4 LVEF decline; or type B including asymptomatic LVEF decli...

1073 Background: Two phase IIb trials in pts with advanced BC demonstrated activity for SOR plus standard chemotherapy for the primary endpoint of PFS. In Study A, median PFS for SOR + capecitabine (CAP) versus PL+CAP was 6.4 versus 4.1 mo (hazard ratio [HR] 0.58; 1-sided p=0.0006). In Study B, median PFS for SOR + paclitaxel (PAC) versus PL+PAC was 6.9 versus 5.6 mo (HR 0.79; 1-sided p=0.09). In both studies, randomization was stratified by visceral status with slight imbalances in some covariates. We performed MVA to assess the impact of imbalances and prognostic factors on PFS. Methods: Study A: Pts (N=229) with ≤1 prior chemo regimen for advanced BC were randomized to CAP (1,000 mg/m2 po, twice daily [BID], 14 of 21 days) + SOR (400 mg po, BID) or PL. Study B: Pts (N=237) with no prior chemo for advanced BC were randomized to PAC (90 mg/m2/wk IV, 3 wk on/1 wk off) + SOR (400 mg po, BID) or PL. MVA: Cox proportional hazards models of PFS stratified by visceral status were used for each study. Additiona...

2500 Background: LDE225 is a potent and selective inhibitor of Smo, a key signaling protein in the hedgehog (Hh) pathway. Activation of the Hh pathway is implicated in the pathogenesis of a wide ra...

3008 Background: RIDA is a non-prodrug rapamycin analog mTOR inhibitor, and DALO is a humanized monoclonal antibody targeting the IGF-1R receptor. In preclinical models, dual mTOR/IGF1-R inhibition...

3102 Background: Preclinical studies show that evasion of death receptor (DR)-mediated apoptosis may depend on intact growth factor signaling. DR agonists have not previously been combined with IGF-1R inhibitors in published clinical studies. The combination may yield synergistic targeted antitumor activity without added toxicity. This study combined 2 investigational, fully human monoclonal antibodies: conatumumab, a human DR5 agonist; and AMG 479, an IGF-1R antagonist. Methods: Eligible pts had locally advanced or metastatic chemotherapy refractory solid tumors, ECOG PS of 0 or 1, and adequate glycemic control if diabetic. Pts enrolled into 3 sequential dose cohorts and received conatumumab 1, 3, or 15 mg/kg IV and AMG 479 18 mg/kg IV on day 1 of each Q3W cycle. Dose escalation was based on

1043 Background: The use of bevacizumab, a vascular endothelial growth factor inhibitor, has been associated with an increase in risk of arterial thromboembolic events (ATE) and venous thromboembolic events (VTE) in some clinical trials. The aim of this systematic review and meta-analysis of randomized trials was to assess the overall risk of both grade 3-5 ATE and VTE associated with bevacizumab in patients with metastatic breast cancer (MBC). Methods: We selected all randomized phase III trials which compared chemotherapy with or without bevacizumab in MBC. For the analysis, we used a fixed-effects and random effects models to calculate the pooled event-based relative risk ratios (RR) with 95% confidence interval (CI). The Cochran's Q statistic and I2 statistics were first calculated to assess the heterogeneity among the proportions of the included trials. For this study, we collected all grade 3-5 events reported in these trials. We analyzed the overall RR for vascular events (ATE + VTE) because differ...

e11065 Background: Breast-conserving surgery (BCS) aims to obtain pathologically negative resection margins. Pts with PM may require S2. According to different series, the timing of aRx is related to BC pt prognosis. This study evaluated the impact of re-excision for PM on initiation of aRx and its correlation with pt prognosis. Methods: BCS patients with PM treated between 2000 and 2009 at Vall d'Hebron Hospital were identified. Clinical and pathological characteristics were collected; the time of S2 and aRx calculated from initial surgery (S1), and univariate analysis performed. Results: Of 53 pts, median age 53 yrs (range 29-87), 6 pts (11%) had immediate re-excision; 47 pts underwent S2: 18 (38%) had wider re-excision and 29 (62%) mastectomy. The median time from S1 to S2 was 3.13 weeks (range 0–18) and 8.83 weeks (range 2–24) from S1 to aRx. The median time to aRx for the 23 pts with early-S2 (≤ 3 weeks) versus the 30 pts with delayed-S2 (>3 weeks) was 6.98 weeks (range 2-17) and 8.98 weeks (range 3-...

601 Background: TNBC comprises 15%-20% of all breast cancers (BCs) and is associated with a poor prognosis. In the ixabepilone (Ixa) study CA163-080 (-080) (n = 161), 26% of the patients (pts) had ...

3030 Background: XL765 is a potent and selective inhibitor of class I PI3K isoforms, TORC1, and TORC2. XL765 has shown dose-dependent target modulation and tumor growth inhibition or shrinkage in multiple human xenografts. Methods: Pts receive XL765 twice daily (bid) or daily (qd) for 28-day cycles. Dose escalation follows a standard 3 + 3 design. PK and pharmacodynamic biomarker analyses are performed. Tumor response is assessed by RECIST every 8 weeks. A cohort of lymphoma pts will be enrolled to explore the potential utility of combined inhibition of PI3K and TORC1/2 in this disease setting. Results: 79 pts have been dosed with XL765; 52 pts on a bid regimen (30-240 mg/day) and 27 pts on a qd regimen (70-100 mg/day). On the bid schedule, 25 subjects have been treated at the established maximum tolerated dose (MTD) of 50 mg bid. The maximum administered dose (MAD) is 120 mg bid. On the qd schedule, the MAD is 100 mg and the preliminary MTD is 90 mg. The most common related adverse events (> 10% of pts) ...

3003 Background: The PI3K pathway is the most frequently aberrantly hyperactivated pathway in cancer. PI3K pathway inhibition is expected to have a strong impact on tumor survival and proliferation...

3005 Background: The PI3K pathway plays a major role in cancer cell growth and survival, and is frequently aberrantly hyperactivated in tumors. BEZ235 is a potent and highly selective reversible PI3K pathway inhibitor with antiproliferative and apoptotic activity in cancer cells. BEZ235 strongly inhibited activation of downstream effectors (e.g. Akt) and displayed antitumor activity in xenograft models harboring PI3K pathway alterations. In preclinical toxicology studies, BEZ235 treatment was well tolerated. Methods: This phase I, multicenter, open-label, single-agent, dose-escalation, study was conducted in pts with histologically confirmed, advanced, unresectable solid tumors. BEZ235 was administered once daily as a gelatin capsule either fasted or fed (10-1,100 mg) until unacceptable toxicity or disease progression. Dose escalation was guided by a Bayesian logistic regression model with overdose control. Anti-tumor activity of BEZ235 was assessed by CT and PET. Early efficacy data are based on central ...

1066 Background: Pertuzumab (P), a fully humanized monoclonal antibody, targets the dimerization epitope of human epidermal growth factor receptor (HER) 2, preventing dimerization of HER2 with othe...

3004 Background: XL147 is a selective inhibitor of class I PI3K isoforms. In preclinical cancer models, XL147 is cytostatic or cytoreductive as monotherapy and enhances the efficacy of targeted agents and chemotherapeutics. This open label, phase I dose escalation study assesses the safety, pharmacokinetics, pharmacodynamics and activity of XL147 in pts with advanced solid tumors and lymphoma. Methods: Using a standard 3 + 3 design, pts with solid tumors receive once daily XL147 on days 1-21 (21/7) or as a continuous daily dose (CDD) in 28-day cycles. Cycle 1 safety data determine dose-limiting toxicities (DLTs). Disease assessments occur every 8 weeks. The potential utility of pan-Class I PI3K inhibition in lymphoma pts will be explored. Results: 68 solid tumor pts have been treated: 41 on 21/7, 21 on CDD using capsules, and 6 on CDD using tablets. The MTD for 21/7 and preliminary MTD for CDD was 600 mg; MTD expansion in NSCLC and other solid tumor pts at 600 mg XL147 CDD is ongoing. Drug-related skin ra...

1036 Background: Improvement in progression-free (PFS: HR: 0.73; p=0.008) and overall survival (OS: HR: 0.74; p=0.026) was demonstrated with the combination of lapatinib (L) plus trastuzumab (T) in...

1091 Background: Bevacizumab, a vascular endothelial growth factor inhibitor, has shown to be active in patients with metastatic breast cancer (MBC) as first or second line therapy. In some tumor types, the addition of bevacizumab to chemotherapy increase the risk of gastrointestinal (GI) perforation compared with controls. The aim of this systematic review and meta-analysis of randomized trials was to assess the overall risk of GI perforation associated with bevacizumab in MBC. Methods: We selected all randomized trials which compared chemotherapy with or without bevacizumab in MBC. For the analysis, we used a fixed-effects and random effects models to calculate the pooled event-based relative risk ratios (RR) with 95% confidence interval (CI). The Cochran's Q statistic and I2 statistics were first calculated to assess the heterogeneity among the proportions of the included trials. For this study, we collected all events as reported in these trials. We did not consider differences in grade or outcomes. R...

Findings of increased numbers of epidermal growth factor receptors (EGF-R) and increased expression of transforming growth factor alpha (TGF-alpha) in surgical specimens of human renal cell carcinoma have led to the proposal that growth of these tumors may be regulated by TGF-alpha in an autocrine manner. In the studies presented here, we have examined this hypothesis using two human renal carcinoma cell lines, SKRC-4 and SKRC-29. We demonstrated that both SKRC-4 and SKRC-29 cells were growth stimulated by greater than 35% when cultured in the presence of TGF-alpha or EGF and were inhibited by 29% to 46% if cultured in the presence of anti-EGF-R monoclonal antibody 225. Treatment of cells with TGF-alpha enhanced the levels of expression of EGF-R mRNA and TGF-alpha mRNA. In addition, incubation of cells with monoclonal antibody 225 significantly elevated the levels of excreted TGF-alpha species in the culture medium. Our findings suggest that proliferation of human renal carcinoma cells may be regulated by endogenously produced TGF-alpha and that this regulatory pathway can be interrupted using antibody to its receptor, EGF-R.

6023 Background: Cediranib is an oral, highly potent and selective inhibitor of VEGF signaling, with activity versus VEGFR-1, -2 and -3. FDG-PET has previously been shown to provide early assessment of the effectiveness of anticancer treatment in solid tumors after chemotherapy. The objectives reported here were to assess the effects of cediranib on 1) tumor metabolic activity using FDG-PET (standardized uptake value, SUVmax) and 2) tumor size (RECIST longest diameter). Methods: Eligible pre-treated patients with metastatic or recurrent HNC or NSCLC received cediranib monotherapy 30 mg/day for 3 weeks, or until disease progression or unacceptable toxicity. Patients showing evidence of response (FDG-PET) or clinical benefit at day 22 could continue study treatment and were assessed on days 43 and 71 by RECIST/FDG-PET. Evaluable patients had baseline and at least one post-baseline measurement available. Results: A total of 19 patients were treated; 17 patients had baseline and day 22 FDG-PET and 18 patients had baseline and at least one post-baseline RECIST assessment. Consistent changes in FDG-PET were observed (Table). At days 22, 43 and 71, a total of 5 (29%), 7 (41%) and 6 (35%) patients had ≥25% decrease in SUVmax (FDG metabolic response), respectively. The combined (HNC/NSCLC) best mean % change in tumor size from baseline for all patients was -25.9%. Best responses of PR and SD were seen in 18.8% and 50% of HNC patients, respectively (Table). The most common adverse events were proteinuria (7 [37%]), fatigue, diarrhea and hypertension (each 6 [32%]). Conclusions: This study provided evidence of antitumor activity with cediranib monotherapy as measured by decreases in FDG uptake, reductions in tumor size and RECIST response rate. Cediranib 30 mg/day was generally well tolerated, with a manageable adverse event profile consistent with previous studies. Further studies are warranted in these tumor types. [Table: see text] [Table: see text]

1022 Background: Pertuzumab binds to the dimerization epitope of the HER2 receptor, inhibits HER dimerization and signal transduction, and induces ADCC. In 2 cohorts of pts (n = 66) with HER2-positive metastatic breast cancer which had progressed during trastuzumab therapy after ≤3 lines of chemotherapy with or without trastuzumab, pertuzumab plus trastuzumab has been shown to be active (CR 7.6%, PR 16.7%, SD ≥6/12 25.8%) (Gelmon et al. ASCO 2008, Abs 1026). To assess the activity of pertuzumab monotherapy in this clinical setting, the protocol was amended to include a 3rd cohort of pts. Methods: Pt selection was not changed except that ≥1 month between the last dose of trastuzumab and study start was required. Pts received pertuzumab monotherapy. If the tumor failed to respond or responded and then progressed, trastuzumab could be added to pertuzumab. 27 pts were to be recruited to ensure that ≥24 were fully evaluable for objective response and stabilization of disease ≥6 months. Standard 21-day schedules of the antibodies were given. Results: 29 pts were recruited. Tolerability was good: the major adverse events were mild diarrhea and rash with no clinical cardiac events. To date, 2 responses have been reported, and several pts have ongoing stabilization of disease. 14 pts have received trastuzumab plus pertuzumab following inadequate response (or response then relapse) on pertuzumab monotherapy. Of these 14, 2, having progressed during trastuzumab, failed to respond to pertuzumab monotherapy but underwent confirmed response when trastuzumab was added to the pertuzumab –possibly the first report of such a phenomenon and providing good evidence of an enhanced effect when the antibodies are combined. Updated results will be presented. Conclusions: Pertuzumab monotherapy is active against HER2-positive breast cancer which has progressed during trastuzumab-based therapy. The combination of the two antibodies appears to be more active than either antibody alone. The combination is also active in patients that had failed both antibodies given separately. In clinical studies, the use of the two antibodies combined is justified. [Table: see text]

e12000 Sorafenib is a potent multikinase inhibitor approved by the FDA and EMEA for the treatment of advanced renal cell carcinoma and hepatocellular carcinoma. As a single agent, sorafenib has been shown to have activity in pts with BC. Here, we review the TIES program, a compilation of currently ongoing investigator-sponsored phase IIb multinational, randomized, double-blind, placebo-controlled studies that aim to determine the optimal sequencing of pharmacologic agents for the treatment of BC. All studies will combine sorafenib with first- and/or second-line chemotherapy and/or hormonal therapy in pts with HER2-negative metastatic or locally advanced BC, enroll 220 pts, stratify pts by visceral vs nonvisceral disease, allow pts with evaluable and measurable disease, and include pts with treated brain metastases. The primary endpoint of all trials will be progression-free survival. Secondary endpoints will be safety, overall survival, objective response rate, duration of response, and time to progression. Some studies will also assess quality of life, pharmacokinetic sampling, and biomarkers. Additional information on four of the trials is shown below (Table). Patient characteristics and accruals will be reported. [Table: see text] No significant financial relationships to disclose.

3514 Background: JNJ-26854165 is a novel first-in-clinic oral Human Double Minute-2 (HDM-2) ubiquitin ligase antagonist. It increases the level of HDM-2 client proteins (e.g. p53) by inhibiting the association of HDM-2-client protein complex with the proteosome. Preclinical studies have demonstrated potent anti-proliferative and apoptosis-inducing activity of JNJ-26854165 in a broad range of p53 wild type and mutant tumor models. Methods: A 3+3 dose escalation study with the primary objectives to determine the adverse event (AE) profile, dose limiting toxicities (DLT) and maximum tolerated dose of JNJ-26854165 is ongoing. Secondary objectives include evaluation of PK and PD activity. Eligible patients have ECOG PS≤2 and adequate hematological, renal and hepatic function. JNJ-26854165 is administered orally once daily on a continuous schedule (21-day cycles). Sequential skin and tumor biopsies are taken, and evaluations for HDM-2, p53 and other pathway related markers are performed, including further molecular analyses for HDM-2 activity. Results: 37 pts have been treated at 9 dose levels (DL), 4–300 mg qd. AEs included nausea, vomiting, fatigue, anorexia, insomnia, electrolyte disturbances, liver function tests and creatinine elevations, and asymptomatic QTc prolongation, mostly grade 1–2. A DLT, grade 3 QTcF prolongation, was observed in one patient at DL 9. The patient was asymptomatic and the QTc prolongation recovered after treatment discontinuation. PK data showed dose-proportionality. After dosing at 300 mg, steady state Cmax and AUC0–24h were 2–3 μg/mL and ≈50 μg.h/mL, respectively, well exceeding the expected effective exposure modeled by preclinical studies. PD data showed engagement of the targeted pathway such as dose-dependent p53 upregulation in skin, upregulation of HDM-2 levels in tumors after treatment, and an increase in plasma MIC-1 levels. No objective responses have been observed so far. Conclusions: JNJ-26854165 was well tolerated at doses beyond the expected effective exposure modeled by preclinical studies. PD activity was observed at the 150–300 mg dose levels. The trial continues with cohort expansion at 300 mg. Updated results will be presented. [Table: see text]

3500 Background: XL147 is a selective inhibitor of Class I PI3K isoforms. In preclinical cancer models XL147 is cytostatic or cytoreductive as monotherapy and enhances the efficacy of targeted agents and chemotherapeutics. This open label, Phase 1 dose escalation study assesses the safety, pharmacokinetics, pharmacodynamics, and efficacy of XL147 in advanced solid tumors. Methods: For each 28 day cycle, patients (pts) receive XL147 on Days 1–21 (21/7) or as a continuous daily dose (CDD). Cycle 1 safety data determine dose-limiting toxicities (DLTs). Tumor response is assessed every 8 weeks. Results: As of December 2008, 39 pts have been treated: 36 on 21/7 across 7 dose levels (30–900 mg) and 3 on CDD at 100 mg. At 900 mg, 2 of 3 pts experienced a DLT of reversible grade 3 rash, and the MTD was established as 600 mg based on 15 pts. Drug-related toxicities included grade 3 skin rash (3 pts), grade 3 arterial thrombosis (1 pt), grade 2 transaminase elevation (1 pt), and grade 1 hyperglycemia (4 pts). XL147 exposure increased with dose from 30–400 mg and was similar from 400–900 mg. XL147 reached steady-state plasma concentrations by Day 15–20. Mean t1/2, z at steady-state ranged from 3.7–6.3 days. Doses ≥400 mg yielded exposures that exceeded the EC90 in xenograft models. A trend suggesting augmented food-induced changes in insulin was evident; however, glucose was minimally affected. XL147 reduced levels of phosphorylated PI3K pathway components in PBMCs, hair, skin, and tumor tissues in an exposure-dependent manner. In 2 pts dosed at the MTD, reductions of ≥70% in PI3K pathway signaling were observed in tumor tissue without compensatory upregulation of MEK/ERK phosphorylation. As of December 2008, 6 pts (3 NSCLC, 1 BCC, 1 NHL, 1 PC) continued on study >6 months including 3 >10 months (NHL, NSCLC, BCC). One pt with hormone refractory PC has sustained a normalization of PSA levels through 5 months. Conclusions: XL147 was generally well tolerated with the MTD for the 21/7 schedule defined as 600 mg. The most common drug-related toxicity was skin rash. Inhibition of PI3K pathway signaling has been demonstrated in tumor and surrogate tissues. Prolonged stable disease has been observed. [Table: see text]

e20527 Background: Elderly breast cancer (BC) patients (pts) are usually excluded from clinical trials. Nevertheless, with the increased use of trastuzumab (T) there is a need to assess and predict T-related cardiotoxicity in this population. Methods: Data were collected from women ≥70 years with BC and serial cardiac monitoring treated with T at our institution since 2005. Cardiovascular risk factors (CRF) were analysed together with left ventricular systolic function (LVEF) assessed at baseline and during T. Results: Thirty pts with early (10) or advanced (20) BC, median age 75.7 years (range 70–87), were identified. WHO performance status was 0–1 in 90% of pts. Median duration of treatment was 45 weeks (range 2–87). Basal LVEF was 63.8% (range 46.3–76). Five of 30 pts (16.6%) experienced asymptomatic cardiotoxicity defined as an absolute drop ≥10% with a final LVEF < 50% (13.3%, 4/30 pts) or any absolute drop >20% (3.3%, 1/30 pts). Four of 30 patients (13.3%) developed symptomatic cardiac heart failure. Median time to LVEF decline was 9 weeks (range 3–87). LVEF recovered to normal values in a median time of 4 weeks (range 3–48) in all but one patient. CRF are shown in Table 1 . Pts with T-related cardiotoxicity presented more often with history of cardiac disease (22.2% versus 9.5%), diabetes (22.2% versus 5%) and BMI>30 (68% versus 45%) as compared to the rest. No relevant difference was seen in terms of hyperlipemia, tobacco or hypertension. Previous or concomitant exposure to anthracyclines was not found as a risk factor either. Conclusions: Despite the limited numbers, this series shows that elderly BC pts treated with T experience reversible cardiac events similarly to those already described in younger pts. However, particular attention may be paid to cardiac history, diabetic and obese pts who appear more likely to develop T-related cardiotoxicity. [Table: see text] No significant financial relationships to disclose.

Background: Trastuzumab, a recombinant monoclonal antibody against the HER-2 receptor, has been shown to significantly improve disease-free and overall survival in women with HER-2 positive early breast cancer when given concurrently with or sequentially after chemotherapy. Materials and Methods: HERA is an ongoing international, multicenter, randomised phase III trial comparing one or two years of adjuvant trastuzumab given every three weeks with observation in 5,102 patients with HER-2 positive either node-negative (tumour size 1.0 cm) or nodepositive early breast cancer who had completed locoregional therapy and had received at least four cycles of standard neoadjuvant or adjuvant chemotherapy. Central confirmation of HER-2 positivity and LVEF 55% after completing chemotherapy and radiotherapy were required prior to randomisation. The second planned interim analysis of the 1 yr vs 2 yr trastuzumab comparison in the HERA trial was conducted on October 20, 2008. The Independent Data Monitoring Committee (IDMC) recommended that the study continue as planned without disclosing data on the 2 yr trastuzumab group. In the observation and the 1 yr trastuzumab groups, 827 disease-free survival events (DFS) have been observed at a median follow up of 48.4 months after randomization, and are the subject to the present update. Results: After release of the HERA and the combined B31 and N9831 results in 2005, a protocol amendment allowed for eligible observation patients to receive trastuzumab and data were continuously collected. Out of the 1698 observation patients, there were 885 observation patients who crossed over to trastuzumab. These late starter patients started trastuzumab at a median of 22.8 months (

Abstract #708 Background: A subgroup of HER2 overexpressing tumors also express p95HER2, a truncated fragment of the HER2 receptor that lacks the extracellular domain and retains kinase activity. Tumors expressing p95HER2 have a worse clinical outcome and are resistant to trastuzumab therapy (Scaltriti M. et al, JNCI 2007). The hypothesis that lapatinib, a small molecule inhibitor that targets the intracellular kinase domain of EGFR and HER2, would be active in these tumors was tested by correlating p95HER2 expression with clinical response to lapatinib in EGF20009, a lapatinib monotherapy study Methods: Archival tumor blocks were obtained from patients (pts) participating in study EGF20009. In this study, pts with untreated locally advanced or metastatic HER2 amplified breast tumors either received lapatinib 1500mg daily or 500mg BID (H.L. Gomez et al, J Clin Oncol 2008). Pre-treatment samples were analyzed for p95HER2 expression by immunofluorescence using 2 antibodies against HER2, binding to the intracellular and extracellular domain, respectively, plus a pan-cytokeratin antibody. Tumors were scored as p95HER2 positive (p95HER2+) [if any cytoplasmic staining was detected with the intracellular HER2 antibody and this staining co-localized with the pan-cytokeratin antibody], negative (p95HER2-) [no intracellular HER2 cytoplasmic staining) or non-evaluable (N/E) [no cytokeratin or HER2 staining by immunofluorescence]. The presence of p95HER2 was then correlated with response rate (RR), stable disease for over 100 days (SD) and progression-free survival (PFS) to lapatinib. A Cox-proportional hazards model was used to compare the groups. In order to correlate the presence of p95HER2 with HER2 extracellular domain in the serum, a quantitative determination of the 105 kD ECD level in serum (Oncogene Science HER2/neu Microtiter ELISA) has also been performed. Results: 68/105 tumors were evaluable for p95HER2 expression. Fourteen were p95HER2+ (20.5%) and 54 were p95HER2- (79.5%). The observed percentage of p95HER2+ tumors is concordant with published reports. Among the 14 pts with p95HER2+ tumors, 7 responded (RR: 50%) and 1 had SD for > 100 days for an overall clinical benefit rate of 57% (RR+SD). In the p95HER2- population (N=54), 24 pts responded (RR: 44.4%) and 16 pts had SD >100 days for an overall clinical benefit rate of 56% (RR+SD). PFS was similar in both groups, with a median PFS of 24 wks in pts with p95HER2+ and p95HER2- tumors (p=0.97, HR 1.1). These findings compare with the median PFS of 20.7 wks for the entire population in the trial (N=138pts). Further correlation of p95 status and HER2 ECD status of the tumors will be presented. Conclusion: These data demonstrate that lapatinib has similar activity in pts with p95HER2+ or p95HER2-, HER2 amplified breast tumors. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 708.

Abstract #6136 Background: The outlook for women with human epidermal growth factor receptor 2 (HER2)-positive early and advanced breast cancer has been significantly improved by the incorporation of trastuzumab (Herceptin®; H) into therapeutic regimens. H has a proven safety profile observed over 10 years of clinical experience in >500,000 patients (pts); however some concerns remain over cardiac dysfunction. This retrospective study reports detailed new analyses of pooled cardiac safety data from 6 metastatic breast cancer (MBC) trials. Methods: Reports of selected adverse events of symptomatic congestive heart failure (CHF) and cardiac rhythm disturbances (CRDs) as well as left ventricular ejection fraction (LVEF) declines were analysed. As definitions of CHF differed between trials, a detailed manual review of original data was performed, including serious adverse event reports. CRDs were identified based on Medical Dictionary for Regulatory Activities terms. LVEF declines were defined as decreases of ≥15 percentage points (pp) from baseline (BL) or ≥10 pp from BL to an LVEF of ≤50%. Results: In total, 882 MBC pts from 6 trials were evaluable for the pooled analysis: in 2 of the trials H was given as monotherapy (WO16229, MO16982) and in others H was combined with paclitaxel (BO15935), docetaxel (M77001), docetaxel and capecitabine (MO16419), and anastrozole (BO16216). There were 683 pts in the H group and 199 in the control group. Pt characteristics were well balanced between treatment groups. Symptomatic CHF was identified in 11 pts (1.6%) in the H group (including 1 death) and none in the control group. Of the 11 pts with CHF, 9 had received prior anthracyclines. Fifty-five CRDs (6.6%) were reported in 45 pts in the H group, with tachycardia (3.2%), palpitations (2.6%) and arrhythmias (0.6%) being the most frequent. With the exception of a single grade 3 event in each group, all CRDs were grade 1 or 2. Nearly all CRDs resolved with no sequelae (50/55 events; 91%). In the control group 2 pts (0.1%) experienced a CRD. The total number of pts evaluable for LVEF decline was 673 in the H group and 194 in the control group; 74 (11.0%) and 7 pts (3.6%), respectively, experienced a drop of ≥10 pp from BL to ≤50%. Eighty-nine (13.2%) and 9 pts (4.6%), respectively, had an LVEF decline of ≥15 pp from BL. Discussion: This pooled analysis of pts from 6 MBC trials demonstrates that H-based treatment in MBC is associated with a low incidence of symptomatic CHF (1.6%) and LVEF declines (11-13% of pts). Although CRDs were observed with H, the majority were of limited clinical significance. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6136.

A case of fat embolism syndrome is reported following an uncomplicated bone marrow harvest. The presenting symptoms were restlessness, shortness of breath and arterial hypoxemia. A lung perfusion scan ruled out the presence of a lung thromboembolism. The patient received supportive therapy and recovered within a few hours. We speculate that the larger gauge needle (13 vs 15) used to aspirate the bone marrow may have represented increased trauma to the iliac crest leading to fat embolism.

1015 Background: Lapatinib (L) is an oral, small-molecule inhibitor of EGFR and HER2 with a mechanism of action distinct from that of trastuzumab (T). Preclinical data suggest synergy between L and T. We studied L alone and in combination with T in pts with HER2+ MBC who progressed on T. Methods: Eligible women had received prior anthracycline and taxane therapy, had MBC with measurable lesions or bone-only disease, and had progressed on prior T-containing therapy. Pts were stratified by hormone receptor status and visceral/nonvisceral disease, then randomized to receive either L (1,500 mg QD) or L (1,000 mg QD) plus T (2 mg/kg weekly after 4 mg/kg loading dose). If pts progressed on the L arm, they could cross over to the L+T arm. The primary endpoint was PFS (investigator assessment), and secondary endpoints were clinical benefit rate (CBR) at 24 wks, RR, and OS. Results: 296 pts were randomized. All pts had received prior T; the median number of prior chemotherapy regimens was 6. Combination therapy si...

14508 Background: PI3K mutations are frequent in human cancer and play a role in the malignant phenotype and therapeutic resistance. NVP-BEZ235 is a small molecular mass compound in phase I clinica...

4129 Background: KRAS mutation status predicts sensitivity to anti-epidermal growth factor receptor (EGFR) agents in pts with refractory mCRC. In order to assess the efficacy of cetuximab alone and...

504 Background: The NOAH trial evaluated the addition of trastuzumab (H) to chemotherapy (CT) for pts with HER2-positive LABC. A significant improvement in pCR has been reported (Gianni. ASCO 2007; abs 532). Methods: 228 pts were randomized to receive 3 cycles of doxorubicin (60 mg/m2) and paclitaxel (150 mg/m2) q3w, 4 cycles of paclitaxel (175 mg/m2 q3w) and 3 cycles of CMF (C 600 mg/m2, M 40 mg/m2, F 600 mg/m2 d 1+8 q4w) with or without concomitant H (8 mg/kg loading dose then 6 mg/kg q3w for 1 year) before surgery. 171 (75%) core biopsies obtained before treatment were available for assays of c-Myc (by FISH), PTEN (by IHC) and IGF1R (by IHC) in addition to estrogen receptor (ER) and progesterone receptor (PgR). Results: The 171 pts with available biopsies were representative of the overall NOAH population, although with a lower incidence of ER+ tumors. Negative PgR status was strongly associated with pCR in the H group (51% vs 16% in PgR-positive tumors; p=0.008). Overall, 32 pts had c-Myc amplificatio...

22011 Background: The aim of our study was to investigate pretreatment serum CA-125 concentration as a prognostic factor in pts with EOC. Methods: A retrospective analysis was conducted on 219 pts ...

1538 Background: Women at risk of HBOS are recommended biannual/annual clinical breast examination (CBE), annual mammography (MX) and annual pelvic or transvaginal ultrasound (PTVUS) starting at ag...

19125 Background: Inhibition of the EGFR pathway has become an established strategy in NSCLC patients (pts) treatment. The aim of this study is to assess the value of predictive clinical variables ...

3520 Background: Agents that specifically inhibit the invasive phenotype of cancers are urgently required. AZD0530 is a potent, orally administered inhibitor of Src that has been shown preclinically to prevent phosphorylation of downstream mediators of motility and invasion, paxillin (Pax) and focal adhesion kinase (FAK), with inhibition of metastasis in vivo. Although Src activation is associated with poor prognosis, inhibition of Src activity in human cancers has never been demonstrated. Methods: Patients with cancer received AZD0530 in dose cohorts of 50 mg to 250 mg daily in this 2-part Phase I study. Paired tumor biopsies were acquired for investigation of Src inhibition. Part A defined MTD, toxicity profile and PK. Part B expanded the 50 mg, 125 mg and 175 mg cohorts to characterize changes in phosphorylation of the Src substrates Pax and FAK by evaluating intensity and localization of staining by IHC. Biopsy samples were assigned as pre- or post-AZD0530 treatment by an independent pathology panel blinded to treatment status, and tested for 80% concordance at a 10% alpha. Markers of bone turnover were collected. Results: There were 81 patients evaluable for safety assessment. The median number of prior therapies was 5 (1–27). Part A: DLTs occurred in 3 patients at 250 mg (leukopenia; septic shock (grd5) with renal failure; asthenia) and in 2 patients at 200 mg (febrile neutropenia; dyspnea). Part B confirmed the 50, 125 and 175 mg doses to be tolerable. The mean duration of AZD0530 treatment was 44 days (6–217); 11 patients were treated for longer than 3 months. The pathology panel found consistent modulation of phosphorylation and/or cellular localization of tumor Pax (P=0.067) and FAK (P=0.002) consequent to AZD0530 therapy. There was a dose response trend for reductions in Pax phosphorylation. Bone biomarker and PK data will be presented. Conclusion: For the first time, biomarkers have confirmed inhibition of Src in human cancers. AZD0530 is well tolerated at doses that demonstrate significant inhibition of Src activity. The trend for dose response changes in biomarkers of Src inhibition indicates that the MTD should be taken forward in further development. AZD0530 has a potential role in the prevention of metastases and invasion. No significant financial relationships to disclose.