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Background: Palbociclib (PD-0332991) is an orally active, potent and highly selective inhibitor of CDK4/6 that prohibits progression of the cell cycle from G1 into S phase and has shown activity in ER positive breast cancer in vivo and in vitro. Recently, in phase 2 settings, palbocilcib extended PFS in combination with letrozole as first-line hormonal treatment for advanced breast cancer (ABC) (Finn R.S. et al. Cancer Res., Dec 2012; 72: S1-6) and showed single agent activity in patients with ER positive ABC relapsed to several lines of therapy (DeMichele A. et al., ASCO 2013). Given pre-clinical evidence on the relevance of Cyclin D-CDK4/6-E2F signalling in the development of acquired resistance to hormonal therapy, CDK4-6 inhibition might be a strategy to overcome resistance in tumors who have progressed after hormonal therapy for metastatic disease. Study design: This is an investigator initiated, open-label, multicenter, randomized, Phase 2 trial for patients with ER+ HER2 negative ABC who have experienced progression on first or second line hormonal therapy. Other eligibility criteria include: ≤1 previous line of chemotherapy for ABC; measurable disease; and available archival tumor tissue for translational studies. Consenting patients are randomized (1:1) to receive, until progression of disease, unacceptable toxicity or consent withdrawal, either ARM A) palbociclib 125 mg/d orally for 3 weeks followed by 1 week off treatment or ARM B) palbociclib in combination with the hormonal therapy to which the patient has experienced progression in the previous line of treatment (anastrozole 1 mg/d, letrozole 2.5 mg/d, exemestane 25 mg/d, fulvestrant 500mg/4 weeks). Patients are stratified according to: number or prior lines of hormonal therapy (1 vs. 2); disease site (visceral vs. non visceral); duration of prior line of hormonal therapy (>6 vs. ≤6 months); treating center. The primary endpoint is clinical benefit (CB) (i.e. complete response, partial response, stable disease≥ 24 weeks), based on local assessment of response using RECIST 1.1 criteria. Key secondary endpoints are: objective response rate, duration of response, time to progression, progression-free survival, overall survival and assessment of exploratory tissue markers of response. Statistical methods: A two-stage optimal phase 2 design is used to assess the activity of each of the two treatment regimens. Assuming P0≤20% (inactivity), P1≥ 40% (activity) and α = 10%, a sample size of 50 evaluable patients per treatment arm is required for a statistical power equal to 90%. In case of inactivity, enrolment could be stopped in each arm after 25 evaluable patients. This study does not provide adequate power for a two arm comparison. Target accrual: the study is actively recruiting in 3 Italian centers and is expected to involve additional 7 centers in Italy by the end of 2013. The first patient was enrolled in October 2012 and, as per June 2013, a total of 9 patients have been enrolled, 8 remain on treatment. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT2-6-01.

Background The human epidermal growth factor receptor 2 (HER2) and p53 pathways may be involved in chemotherapy sensitivity and/or resistance. We explore the value of HER2 and p53 status to foretell docetaxel sensitivity in advanced breast cancer. Methods HER2 and p53 expression was analysed in 36 (median age 55 yrs; range 37-87) metastatic breast cancer patients receiving docetaxel-based first-line chemotherapy. HER2 was determined by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), p53 was tested by IHC. We correlate the expression of study parameters with pathologic parameters, RECIST response and survival. The standard cut-off value of 2 was used to determine HER2 overexpression while p53 mean expression level was used to divide low/high expressors tumors. Results Median time to progression and overall survival were 9 (range 2 - 54) and 20 (range 3 - 101) months. Overall response rate was 41.6%. Nine cases showed HER2 overexpression. HER2 was more frequently overexpressed in less differentiated (p = 0.05) and higher stage (p = 0.003) disease. Mean FISH-HER2 values were significantly higher in responder than in non-responder pts (8.53 ± 10.21 vs 2.50 ± 4.12, p = 0.027). Moreover, HER2 overexpression correlates with treatment response at cross-tabulation analysis (p = 0.046). p53 expression was only associated with higher stage disease (p = 0.02) but lack of any significant association with HER status or docetaxel response. No significant relation with survival was observed for any parameter. Conclusion Our data seem to indicate that FISH-determined HER2 status but not p53 is associated with docetaxel sensitivity in metastatic breast cancer.

Introduction sorafenib, a tyrosine-kinase inhibitor, is widely used in the treatment of advanced hepatocellular carcinoma. Drug-related toxicities are generally mild but sorafenib, as other similar agents, may induce elevation of systemic arterial blood pressure levels in relation to an interaction with cardiovascular system probably mediated by HIF pathway. This side effect may be particularly critical for patients with underlying serious heart disease as it can induce acute heart failure, a life-threatening condition, and usually such patients are excluded from active treatment with tyrosine-kinase inhibitors. We report the case of a patient affected by advanced hepatocellular carcinoma and serious impairment of cardiac function treated with sorafenib without any worsening of heart function. To our knowledge this is the first report of this kind in the literature. Case presentation We report the case of a 74-year-old patient affected by advanced multifocal HCV-cirrhosis related hepatocellular carcinoma and severe post-ischemic fall of left-ventricular function with serious risk of cardiac functional impairment. The patient presented with an ECOG performance status of 0. Blood chemistry tests showed a substantial elevation of α-fetoprotein values and slight increases of bilirubin, of γ-GT and of GOT; the absence of encephalopathy and ascites and the normality of coagulation parameters and of albumin led to classify the patient into the functional class Child-Pugh A. The patients was successfully treated with sorafenib at the reduced daily dose of 400 mg for long-time without any worsening of heart function. Conclusion The presented case can offer to oncologists a clinical support to take into consideration when deciding to treat with sorafenib advanced hepatocellular carcinoma patients presenting with serious impairment of cardiac function that are usually excluded from an active treatment.

Background Elderly patients with advanced non-small-cell lung cancer (NSCLC) with poor performance status (PS) are a special population requiring particular attention. Single-agent oral vinorelbine could be an attractive option. Patients and methods A total of 43 patients with stage IIIB–IV NSCLC and Eastern Cooperative Oncology Group (ECOG) PS of two or more with good functional status were prospectively recruited. Oral vinorelbine was administered at the dose of 60 mg/m2 on days 1–8 every 3 weeks. Primary end points were response rate and safety. Results Overall response rate was 18.6% with 8 partial responses; 18 of 43 (41.8%) experienced stable disease lasting >12 weeks and 17 of 43 (39.6%) disease progression for an overall clinical benefit of 60.4%. Median time to progression was 4.0 (range 2–22) months and median overall survival 8.0 (range 3–35) months. Treatment was well tolerated. Of 187 cycles, we did not observe any grade 3/4 toxicity with the exception of a single not-febrile G3 neutropenia. Regardless of severity, main toxic effects observed were nausea in 48.1% and vomiting in 22.9% of patients, anemia in 43.2%, fatigue in 32.6% and leukopenia in 23.2%. Conclusion Single-agent oral vinorelbine is extremely safe in elderly patients with advanced NSCLC and ECOG PS of two or more and may represent a valid option in this very special population.

e16008 Background: Deregulation of the normal cell cycle is a frequent event in human tumors and plays an important role in malignant transformation. p27kip1 is a negative regulator of the G1 phase, is frequently lost in tumor cells and, in some cases, its alteration is coupled with oxidative DNA damage. Methods: We evaluated the expression of p27kip1 and the extent of endogenous oxidative DNA damage (by means of 8-hydroxydeoxyguanosine [8-OHdG] levels) by immunostaining in a series of 125 (median age 64[range23–86]yrs) renal cell carcinomas (RCCs); furthermore, the prognostic significance of their alterations was tested. Median values of expression were used as cut-off. p27kip1 expression was also evaluated by Western Blot in a second series of 34 fresh-frozen RCCs. Results: to date, median follow-up is 29[range 4 - 104] months. p27kip1expression was lost in a significant fraction of tumors (55%) with a median percentage of positive cells of 20% [range 0–60%). Loss of p27kip1 staining correlated with higher tumor grade (p=0.049). Recurrence (p=0.007) and death (p=0.006) from RCCs were significantly more frequent in patients p27kip1-negative compared with positive ones. Kaplan-Meier analysis showed a significant separation between high vs low p27kip1 expression groups for both disease-free (p=0.011) and overall (p=0.002) survival. At multivariate analysis, loss of p27kip1expression was the only independent risk predictor for recurrence (HR=4.326, p=0.014) and death (HR=4.915, p=0.012) from RCCs when tumor size, tumor grade and stage were included. No significant correlation with clinical or pathological parameters and outcome was found for 8- OHdG. p27kip1 total protein levels showed a variable behaviour at WB analysis with a modest trend toward a global reduction but an elevation in some cases. Conclusions: loss of p27kip1 is frequent in human RCCs and is a powerful predictor of poor outcome. p27kip1 alteration are not related to endogenous oxidative DNA damage. The behaviour of p27kip1at WB analysis is probably related to the elevation of the cytoplasmatic (and inactive) fraction. No significant financial relationships to disclose.

19085 Background: Elderly patients with advanced non small cell lung cancer(NSCLC) with poor PS are a special population requiring particular attention. Single agent oral vinorelbine could be an at...

1085 Background: Fulvestrant (F) is a pure anti-estrogen agent available for the HT of post-menopausal ormone-sensitive advanced breast cancer (ABC). Aim of the study is to analyze the effect(s) of F treatment on lipid profile, endometrial mucosa and coagulation indices (CI). Methods: 24 pts (mean age 66.2 ± 9.5 yrs) with hormone-sensitive ABC were enrolled. All patients (data on 21 pts) received at least one previous HT course, with 90.5% receiving =2 HT courses. Last HT was exemestane in 13/21, letrozole in 5/21 and other in 3/21 with a median withdrawal time of 19 days (range 3–1,456). All pts but one received at least one previous CT regimen, with 60% receiving =2 CT regimens. Complete fasting lipid blood profile and CI were assessed before F administration, every 3 months and at discontinuation. Endometrial mucosa thickness was evaluated before F administration and at end-study time. All patients referred no significant dietary changes during treatment. Pts receiving statins were excluded. Results: pts received a median of 6 F injections (range 3–14). We observed SD in 10/21 pts and PD in 11/21 pts with a mean TTP of 6.2 ± 2.9 months. Total cholesterol (C) levels significantly decreased during F treatment (214.1 ± 48.7 vs 194.0 ± 41.0 mg/dl; p=0.0084) together with LDL-C (119.5 ± 40.7 vs 104.2 ± 30.4 mg/dl; p=0.0067). HDL-C (62.4 ± 17.8 vs 64.3 ± 19.5 mg/dl; p = ns) and triglycerides (152.4 ± 64.5 vs 148.2 ± 61.6 mg/dl; p=ns) did not show significant changes. Subgroup analysis demonstrated a reduction in both pts receiving = 6 (n=17) or >6 (n=11) injections (204.6 ± 45.3 vs 186.6 ± 41.2 mg/dl, p=0.014 and 219.5 ± 48.9 vs 203.9 ± 33.3 mg/dl, p=ns respectively). All CI and mean endometrial mucosa thickness value did not vary. Conclusions: We observed a clear lipid lowering effect of F in our study population. We suggest a possible effect of F on lipid metabolism. Lipid lowering effect of F it’s evident during the first six months of treatment lasting in pts continuing therapy. No significant financial relationships to disclose.

1132 Background: The addiction of trastuzumab to standard chemotherapy has improved the outcome of HER-2-positive metastatic breast cancer (MBC) pts. Oxaliplatin and docetaxxel are among the most active agents in MBC pts pretreated with anthracyclines. In vitro studies showed synergistic effect of the combination. We investigated the feasibility and the safety of the 3-drug combination given as first line chemotherapy (CT) in HER-2-positive MBC. Methods: HER-2-positive MBC pts were prospectively enrolled to receive a first-line treatment consisting of trastuzumab 8 mg/kg loading dose iv (followed by 6 mg/kg) on day 1, docetaxel 75 mg/sqm iv on day 1, and oxaliplatin 70 mg/sqm on day 2 every 21 days. All pts received peg-filgrastim 6 mg on day 3 to prevent bone marrow toxicity. Pts received up to 9 cycles of CT. Primary end points were overall response rate (ORR) (according to RECIST criteria), clinical benefit (CB), and tolerability. Cardiac function was evaluated by echocardiography at baseline, each 3 courses and at the end of treatment. Results: To date, 13 pts have been enrolled (median age 59 yrs [range 34–70]; ECOG PS 0) representing the first-step accrual according to Minimax design. Ten pts had previously received anthracyclines as adjuvant treatment and 11 pts presented with visceral metastasis. All pts received at least 6 cycles of treatment with 7 pts continuing up to 9 cycles. Response and toxicity data are available for all pts. Two pts experienced CR, 7 pts PR, and 4 pts showed SD (lasting more than 6 months in 3 cases) with an ORR of 70% and a CB of 100%. No pts progressed during treatment. No grade 4 toxicity was observed. Most common grade 3 toxicities were diarrhea (18%), nausea/vomiting (22%), mucositis (11%). In particular, 2 episodes of febrile neutropenia were reported and no grade 4 haematologycal toxicity was observed. No significative reduction of LVEF were reported. Conclusions: The combination of trastuzumab, oxaliplatin, and docetaxel (HOT combination) showed promising activity and was well tolerated as first-line treatment in pts with HER-2-positive MBC. Peg-filgrastim profilaxis improved safety profile. No significant financial relationships to disclose.

The dystroglycan (DG) complex is a transmembrane glycoprotein that forms a continuous link from the extracellular matrix to the actin cytoskeleton. Deregulated expression of DG has been reported in a variety of human malignancies and related to tumor aggressiveness. In this study expression of the DG subunit was evaluated by immunostaining in a series of renal epithelial cancers and its relation with traditional prognostic indicators and with the clinical outcome of the patients was evaluated. alphaDG expression was undetectable in a significant fraction of tumors (54%). In renal cell carcinomas (RCC) loss of alpha-DG staining correlated with higher tumor grade (p = 0.02) but not with tumor stage nor tumor size. In clear cell RCC patients loss of alphaDG staining correlated with an increased risk of recurrence (p = 0.002 by log-rank test) and death (p = 0.004) also when patients with lower grade or stage tumors were analyzed separately. In a multivariate analysis loss of DG staining confirmed to be and independent predictor of shorter disease-free (p = 0.001; RR = 4.9) and overall (p = 0.009; RR = 4.9) survival stronger than tumor grade and size. These findings demonstrate that loss of alphaDG expression, which correspond to loss of a functional DG complex, is a frequent event in human renal tumorigenesis and is an independent predictor of early recurrence and death for patients with clear cell RCC.