Background: The combination of the dual HER1/HER2 inhibitor lapatinib and capecitabine (LC) is a therapeutic option for patients (pts) with HER2-positive metastatic breast cancer (HER2 + MBC) after failure of trastuzumab-based therapy. No clinical and/or pathological factors have been identified as predictive markers of efficacy for LC. We conducted this retrospective analysis to investigate factors associated with progression-free survival (PFS) in pts with HER2 + MBC receiving LC. Patients and methods: Clinical and pathological data of 148 pts with HER2 + MBC treated from March 2007 to December 2013 with LC after failure of at least one prior trastuzumab-based treatment (given either in adjuvant or metastatic setting) were collected from 13 Italian institutions. PFS and overall survival (OS) were estimated by Kaplan Meier method and compared with log-rank test. A Cox multivariate analysis was performed to evaluate the association between clinical/pathological characteristics and risk of disease progression with LC. Results: At a median follow-up of 41 months (IQR 23-62), median PFS and OS were 7 and 21 months, respectively. Pts with PFS > 7 months had a significantly longer OS compared to those with PFS ≤ 7 months (36 vs 15 months; p < 0.001). In the multivariate analysis for PFS, HER2 luminal subtype (HR 0.53; C.I. 95% 0.29-0.95, p< 0.03) and progressive disease to prior trastuzumab at the first tumor assessment (HR 0.30; C.I. 95% 0.10-0.89, p< 0.03) were significantly associated with reduced risk of disease progression on LC, whereas visceral metastases before starting trastuzumab-based therapy were associated with higher risk of progression on LC (HR 2.11; CI 95% 1.08-4.12, p = 0.03). Stage at diagnosis, tumor grading, proliferation index, metastatic sites before starting LC, PFS after primary treatment for early breast cancer, PFS achieved with first-line trastuzumab and treatment with trastuzumab beyond progression were not associated with PFS on LC. Conclusion: Pts treated with LC who achieved PFS > 7 months had significantly longer OS. HER2 luminal subtype and rapid disease progression with prior trastuzumab were associated with a longer PFS with LC. The latter finding suggests that the underlying mechanisms of primary resistance are different for trastuzumab and lapatinib. Additional biological studies are needed to investigate predictive markers of sensitivity and resistance to LC.

Aim: Progress made in the treatment and better management of cancer pts has significantly improved overall survival. Early involvement of palliative care can translate into improvements in quality of care, QoL and survival.

ABSTRACT Aim: CRC pts have a median age of incidence > 65y although they are largely under-represented in phase III trials. This large population contains pts unfit for T, those suitable for monotherapy or for doublets and the impact of chemotherapy (CHT) outside clinical trial is unclear. Aim of the study was to retrospectively analyse T of elderly mCRC pts. Methods: Kaplan-Meir method was used for OS, the log-rank or Tarone-Ware test for diferences between subgroups, Cox's proportional hazard model to assess the impact of known prognostic factors and T. Results: 751 pts with mCRC observed from January 2000 to January 2013 were collected. Median age was 79y (75-93); Variables HR (CI95%) P value Sex 1.21 (1.01-1.46) 0.04 Age 1.75 (1.45-2.12) ECOG PS 2.51 (1.94-3.25) CT 2.14 (1.68-2.73) S of metastasis 2.48 (1.88-3.29) S of primary tumor 1.66 (1.31-2.11) Site of metastasis 1.33 (1.09-1.63) 0.006 Conclusions: These data show that in clinical practice treatment of metastatic disease has a positive effect on elderly pts OS, confirmed at multivariate analysis. KRAS analysis deserve further evaluation. Update results will be presented. Disclosure: All authors have declared no conflicts of interest.

Diarrhea in relation to the lapatinib–capecitabine regimen is a common and debilitating side effect which may interfere with optimal treatment delivery. We performed a post hoc analysis in human epidermal growth factor receptor 2-positive advanced breast cancer patients treated with a modified schedule in its administration, aimed primarily to evaluate grade (G) ≥2 diarrhea incidence and, secondarily, treatment efficacy.

Nutritional problems due to oral mucositis in patients with head and neck cancer un- dergoing concomitant radio-chemotherapy (RT/CT) significantly correlate with outcome. The aim of our prospective study was to investigate the impact of an early and intensive nutritional pro- gram, intensive dietary counseling, and enteral nutrition through a nasogastric tube on perfor- mance status and quality of life in head and neck cancer patients undergoing RT/CT. Thirty-five consecutive patients with locally advanced, unresectable head and neck cancer who were referred for RT/CT were enrolled. All patients were evaluated for nutritional status (PG-SGA score), serum prealbumin, ECOG performance status and quality of life (measured with EORTC QLQ- C30 version 3.0) before, at the end of, and 1 month after completion of RT/CT. Sixteen patients (46%) were compliant with the nutritional program. Placement of the nasogastric tube was sim- ple, safe and well tolerated by patients. The median duration of enteral nutrition was 31 days (range, 10-93 days). At the end of and 1 month after RT/CT, 94% of compliant patients had main- tained or improved their nutritional status, while in all noncompliant patients the nutritional sta- tus had worsened at the end of RT/CT, and 1 month later nutritional status had improved in only 1 of them (p<0.001). Nutritional status correlated significantly with ECOG performance status and quality of life. (Nutritional Therapy & Metabolism 2006; 24: 176-82)

e14043 Background: Maintenance treatment with B is considered an option for mCRC pts in responding pts after a first line CT + B, but few data are available on its real benefit on progression-free survival (PFS). Methods: Two-hundred-twenty mCRC pts treated with first line CT + B achieving a response [partial (PR) or complete (CR)] or a stable disease (SD) were considered eligible. 118 pts had received B maintenance (BM) whereas 102 did not (noBM). The two groups were homogeneous for main characteristics. First-line therapy in the BM vs noBM group included FOLFIRI regimen (96 vs 73 pts), FOLFOX (18 vs 28 pts) and FUFA (4 vs 1 pts). K-ras status was analyzed in 115 pts with an higher percentage of wild-type (wt) in the BM group (65 vs 50 pts, p= 0.04). A CR or PR have been achieved in 56% of pts in the BM group and 49% of noBM group, while a SD was observed in 34% and 31% of pts respectively for the BM and noBM group. The median number of BM cycles administered was 7 (range 3-25). PFS analysis of was conducted on the entire population comparing BM and noBM and by response to prior CT+B (PR and CR versus SD). Results: At a median follow-up of 18 months (1-109), the median PFS was 13 months (C.I.95%: 11-15) vs 8 months (C.I.95%: 7-10) p<0.0001, and the 1-year PFS 53.% vs 28% for BM and noBM respectively. According to the response, pts with CR/PR had a mPFS of 15 months (CI 95% 12-19) vs 10 months (CI 95% 10-12) p=0.004, and a 1-year PFS of 62.6% and 33.7% for the BM vs noBM group respectively. No difference in PFS was found in pts showing SD after first-line CT + B. Furthermore, no difference was observed in PFS comparing, in the BM group alone, CR/PR vs SD nor when the k-ras status was considered. Conclusions: Our retrospective analysis, shows that the maintenance therapy with B is correlated with a longer PFS in pts responding to the first line CT + B. Results from ongoing randomized phase III studies addressed to explore the issue of maintenance treatment are needed.

e15036 Background: It’s well known that in patients with hormone refractory prostate cancer (HRPC) who progressed after first line chemotherapy there are not a lot of therapeutic possibilities. Androgen and androgen receptor interactions are crucial for disease development and progression. In preclinical models the topoisomerase II inhibitor etoposide interfere with androgen mediated cell growth and reduce both intracellular and secreted PSA levels. So, etoposide can be considered not only classical cytotoxic drug but even an agent that directly targets androgen receptor function. Methods: 35 patients were enrolled. All had HRPC progressed after docetaxel and mitoxantrone, first and second line treatment respectively, and were almost asymptomatic (PS 0-1). Patients received oral estramustine (10 mg/kg/die) and intravenous etoposide (100 mg/mq/die 1-3 q21) until disease progression or grade 4 toxicity development. Disease progression was defined as rising PSA over 25% from base line or appearance of new lesions on radiological evaluation. PSA level was detected at every cycle. Median number of cycles administered was 4 (range 2-8). Results: 20 patients (57%) experienced a decreased level of PSA > 50% from baseline. Overall median time to progression was 15 weeks (range 3-35). Median survival of responders was 14 months, compared with 9 months for non responders. Observed toxicities (none more than grade 3) were thrombocytopenia, anemia, nausea and diarrhea, all easily manageable. Conclusions: We conclude that estramustine and etoposide is an active and well tolerated regimen in heavily pretreated and outpatient HRPC

BACKGROUNDA number of anaemic cancer patients are not responsive to treatment with recombinant human erythropoietin (rHuEPO). The aim of the present study is to investigate whether serum levels of tumour necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta, IL-6 and additional laboratory parameters, together with clinical variables, can predict the clinical outcome of treatment with rHuEPO in anaemic cancer patients.PATIENTS AND METHODSThirty-five cancer patients and 25 healthy controls were enrolled in this study. Patients were treated with epoetin alfa at the dose of 150 IU/kg s.c. three times a week for 12 weeks. If the haemoglobin (Hb) level failed to improve at least 2 g/dl above baseline by week 6 of treatment, dose was increased to 300 IU/kg s.c. for the remainder of the treatment period. All patients filled out the Brief Fatigue Inventory (BFI), a questionnaire for the self-evaluation of cancer-related fatigue. Serum samples from patients and control groups were frozen at -80 degrees C and TNF-alpha, IL-1beta and IL-6 were later examined by enzyme-linked immunosorbent assay.RESULTSFatigued cancer patients had significant higher levels of circulating TNF-alpha, IL-1beta and IL-6 than healthy controls. Responders (Rs) to erythropoietin had significant lower medium levels of TNF-alpha and IL-6 than nonresponders (NRs). Fatigued patients with a general BFI score > or =6 presented higher medium level of cytokines than nonfatigued patients (general BFI score <6), but each group responded similarly to treatment with rHuEPO.CONCLUSIONSHigh serum levels of TNF-alpha and IL-6 at the baseline are significantly correlated with a negative response to administration with rHuEPO. Thus, pretreatment evaluation of TNF-alpha and IL-6 serum levels can help to select those patients who are most likely to benefit from treatment with rHuEPO. On the contrary, Hb level, red blood cell count, lactate dehydrogenase and BFI score do not predict the outcome of treatment with rHuEPO.

e13572 Background: Cellular senescence, an irreversible cell growth arrest, is an intrinsic tumor suppressive mechanism, which restricts progression of early cancerous lesions in humans. We have demonstrated in a murine model for prostate cancer that complete inactivation of the tumor suppressor Pten elicits a senescence response, which significantly opposes tumorigenesis (Chen ZB, Nature 2005). Here we characterize Pten loss induced cellular senescence (PICS) as a novel type of senescence. Additionally, we show that compounds which target PTEN and MDM-2 can be used alone or in combination to potentiate the senescence pathway in tumors of genetically engineered mouse (GEM) and human xenografts models. Methods: Cell growth inhibition, western blot analysis and senescence assay (SA) were performed on LnCAP, MDA-PCa2b and PC3 cancer cell lines. Immunohistochemestry analysis and SA were performed in murine tumors. Cells were incubated with the PTEN inhibitor VO-OHpic (V) and the MDM-2 inhibitor, Nutlin-3 (N) at doses including the IC50 for each drug and cell type. In vivo evaluation of V and N were done both in Pten null prostate conditional mice (Ptenpc−/−) and human xenograft models. Results: PICS, represents a distinct type of senescence response that can be targeted for cancer therapy. PICS occurs at early time points after Pten inactivation and in the absence of cellular proliferation and DNA damage. Importantly, we have identified and developed for cancer therapy a novel PTEN inhibitor. Pharmacological inhibition of PTEN drives senescence in vitro and inhibits tumourigenesis in vivo in a human xenograft model. We also find that PICS is associated with enhanced mTOR-dependent p53 translation. In agreement with these mechanistic findings, N dramatically potentiate senescence and strongly inhibits tumorigenesis in Ptenpc−/− mice. Combination of V and N acts synergistically in inducing senescence in vitro and reducing cell growth. Conclusions: Taken together, our data identify a type of cellular senescence that can be triggered in non-proliferating cells in the absence of DNA damage . On the basis of this concept, we define a molecular framework for “pro-senescence” therapy against cancer. No significant financial relationships to disclose.

e20718 Background: Anemia, defined as a hemoglobin level < 12 g/dL, is frequent in cancer and affect quality of life and performance status. Of all the pretreatment possible causes of cancer-related anemia, unintentional weight loss, early indicator of malnutrition, is often underestimated or completely ignored. The aim of this study is to evaluate the possible pretreatment correlation between hemoglobin level, recent unintentional weight loss (≥ 5% in the last three months) and inflammatory status (C-reactive protein ≥ 10 mg/dL) in NSCLC. Methods: 56 consecutive outpatients with NSCLC (IIIB - IV stage), 68% males, 32% females, were enrolled. Criteria for eligibility included absence of comorbidity (diabetes, hepatic or renal failure) and not previous oncological treatment All patients were evaluated for hemoglobin level (Hb), percentage of involuntary weight loss (WL) and C- reactive protein (CRP) before chemotherapy. Results: 25% of patients had a Hb level < 12 g/dL, 38% referred a recent WL ≥ 5% and 54% had a CRP ≥ 10 mg/dL. Hb was WL-related (p = 0.001) and not CRP-related (p = 0.160), WL was CRP-related (p = 0.022). In the subgroup of patients, the differences of haemoglobin concentrations were minimal, but stastically significant only when inflammatory status was associated with WL. On Table we reported the mean concentrations of haemoglobin as measured in the subgroups of patients. Conclusions: Our data suggest that an early and intensive management of weight loss might prevent or reduce anemia in NSCLC before treatment. [Table: see text] No significant financial relationships to disclose.

20539 Background: Unintentional weight loss (WL) is an early indicator of malnutrition risk and is present in about 50% of cancer patients before treatment. Cancer-related malnutrition significantly correlates with quality of life (QoL) and outcome. Even if about 30% of all patients are malnourished before treatment, WL is frequently underestimated or completely ignored also in the management of older, though they are at increased risk of malnutrition, because of frailty and functional reserve limitation. The aim of this study was to evaluate the influence of WL on QoL in elderly cancer patients before chemo and/or radiotherapy. Methods: Between 2003 to 2007, 387 consecutive outpatients affected by solid tumor of different origin were submitted to nutritional screening before treatment; 104 of them (27%) were aged ≥ 70 years (median 73, range 70 - 85), 44 males, 60 females. All patients were evaluated for nutritional status (assessed with PG-SGA) and QoL (measured with EORCT QLQ-C30 v. 3.O). Results: At baseline, WL (median 6%, range 0 - 28) was observed in 62 older patients (60%), 37% of them had a WL ≥10%. The median PG-SGA score was 12 (range 2 - 20). Patients with WL had worse QLQ-C30 functional scales (FS 65 ± 25 vs 87 ± 10; p=0.001), symptom scales (SS 28 ± 24 vs 5 ± 10; p<0.001) and global health status too (GH 47 ± 21 vs 71 ± 9; p<0.001). In patients with WL ≥ 10% physical functioning scale reduced (PF 63 ± 26 vs 89 ± 9; p<0.001) and fatigue increased (FA 53 ± 34 vs 8 ± 16; p<0.001). Conclusions: Even if patients were heterogeneous, data demonstrated that the majority of new elderly cancer patients presenting to a medical oncologist are at risk of malnutrition or malnourished. WL was frequent and affected QoL. Our experience suggests that an early, careful and intensive pretreatment nutritional support might improve QoL. No significant financial relationships to disclose.