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e12507 Background: T-DM1 is widely used in HER2 positive metastatic breast cancer (MBC) patients (pts), often for many cycles until progression. However, little is known about its long term toxicity. The aim of this study was to evaluate the safety profile of T-DM1 when delivered for ≥12 cycles. Methods: HER2 positive MBC pts who had received ≥12 cycles of T-DM1 across 18 Italian cancer centers were enrolled from January 2017 to September 2018. The 12 cycles cut-off was chosen based on the EMILIA trial median PFS (9.6 months), to identify a patient population treated with T-DM1 for longer time. Tumor and clinical characteristics were collected. Standard haematological tests, blood chemistries and side effects (nausea, vomiting, diarrhea, stomatitis, asthenia) were recorded cycle by cycle, according CTCAE criteria version 4. Haematological and laboratory toxicities were available for 86 patients, while other toxicities for all 115 patients. Results: Overall, 115 pts were enrolled. Median age was 54.5 (range 29.6–81.9); median time from diagnosis of metastatic disease to first T-DM1 cycle was 32.5 months. T-DM1 was administered as 2nd line and 3rd line of treatment in 45.2% and 27.8% of pts, respectively. Median number of cycles was 18 (range 12-59). Complete response, partial response and stable disease rates were 11.4%, 43% and 45.6%, respectively. Treatment related side effects are shown in table 1. Interestingly, no increased liver toxicity was observed in pts with liver metastases. Analysis of mean CTCAE grade by cycle showed that no relevant incremental toxicity was observed during long term T-DM1 therapy. Conclusions: T-DM1 is safe and well tolerated in these long responding pts. We found no relevant cumulative toxicity. Patients should be treated with T-DM1 as long as their tumor responds, as no safety issues are related to its long term use. [Table: see text]

504 Background: The effect of extended adjuvant endocrine therapy (ET) with aromatase inhibitors (AI) after sequential ET with tamoxifen (Tam) followed by AI for 5 years is still controversial. We conduct a clinical trial to assess different durations of ET of letrozole after tam. Methods: The GIM4 LEAD (Gruppo Italiano Mammella 4- Letrozole adjuvant therapy duration study, ClinicalTrials.gov:NCT01064635 ) was a prospective, randomized, Italian multicentric trial. Post-menopausal patients (pts) with hormone receptor positive early breast cancer free of recurrence after 2-3 years of adjuvant tam, were randomized in a 1:1 ratio to receive 3-2 years (short arm, S) or 5 years (long arm, L) of letrozole. The primary study end point was disease-free survival (DFS). Results: Between August 2005 and May 2010, 2056 pts were randomly assigned to receive 3-2 years (n=1030) or 5 years (n=1026) of letrozole. Main patients characteristics in the S and L arms were, respectively: median age 60 vs 61 years, node negative 56 vs 56%, (neo)adjuvant chemotherapy 53.4 vs 54.1%. The median follow-up was 10 years (IQR range: 8.6-11.4). The 8-year DFS was 80% (95% CI:77.3-82.7) and 85% (95% CI:82.9-87.6) in the S and L arm, respectively (hazard ratio, HR 0.82; 95% CI:0.68-0.98; p=0.031). This effect did not change in a multivariate Cox model that included nodal status, grading and age. No evidence of interaction between random assignment and nodal status, age and grading was observed. Among 1960 pts evaluable for toxicity, osteoporosis was diagnosed in 47 (4.8%) in S arm and 81 (8.3%) pts in L arm (chi-square=9.88; p=0.002). Bone fractures occurred in 5 (0.5%) and 9 (0.9%) pts in S and L arm, respectively ( p=0.29, Fisher exact test). Conclusions: After 2-3 years of adjuvant tam, extended treatment with 5 years of letrozole resulted in significant improvement in DFS compared to the standard duration of 2-3 years of letrozole. Clinical trial information: NCT01064635.

e12528 Background: Pts with ABC have a diverse clinical course and OS rates vary significantly among pts. New strategies had potentially changed the natural history of these pts, however data from clinical studies are still lacking and Real-World Studies (RWS) are crucial in clinical outcome evaluation. Methods: AMBRA is a longitudinal cohort study, aiming to describe the choice of first and subsequent lines of treatment in HER2-ve ABC pts receiving at least one CHT (SABCS 2016, P5-15-07 & P5-14-09) in the years 2012-2015. The present analysis is focused on the description of Progression-Free Survival (PFS) and OS according to the biologic subtype in the deceased population. So far, 791/1500 pts have been registered into the study and 255 (32.2%) are evaluable. Time to event analysis between subtypes was evaluated by Cox-Mantel Hazard Ratio and Logrank Test. DFS by Wilcoxon Rank-Sum Test. Results: Pts distribution according to molecular subtype was: Luminal A (86, 33.7%), Luminal B (107 (42.1%), TNBC (62, 24.3%). Median ages at diagnosis were 55.8, 52.9 and 55.1 years for the 3 subgroups, respectively. Mean DFS was significantly different according to the molecular subtypes: 87.28, 61.37 and 23.9 months. The difference between Luminal B and TNBC is statistically significant as well. Mean PFS of first-line therapy was 17.9 11.7 and 7.8 months respectively. Mean OS from first progression was 32.9 24.2 and 15.8 months respectively. Statistical details. Conclusions: Our data confirm in a RWS the different biological behaviour between Lum A and B. Metastatic life span is quite good for Luminal and disappointing for TNBC. Median time from last CHT and Death is quite short and similar.[Table: see text]

3116 Background: MBC is an incurable disease and therefore treatment focuses mainly on prolonging pts survival and improving quality of life. Eribulin (E) is a microtubule inhibitor that increased overall survival in pretreated pts. E peripheral N is reported in 13.9-35% of cases. PAINTER main objective was to survey tolerability of E in real life in MBC, while secondary endpoints were to investigate the relationships between specific genetic polymorphisms and incidence and severity of peripheral N. Methods: This is a multicenter, interventional, single-arm, phase IV study, that enrolled pts who received E after taxanes and antracyclines (dose 1.4 mg/m2 day 1, 8 every 21 days). PAINTER study follow-up is still ongoing. Genomic DNA was isolated from whole blood samples (Maxwell whole blood DNA kit. Promega). 15 SNPs (Single Nucleotide Polymorphisms) were genotyped by Taqman specific assays. For SNPs analysis, we selected pts with avaliable clinical data and who completed E treatment. N was evaluated by medical examination. The associations between peripheral N (any grade) and the selected polymorphisms were evaluated with Fisher exact test. Results: From May 2014 to June 2018, 180 pts were enrolled in the PAINTER study from 20 Italian hospitals and 135 were analysed for the present report. Pts and tumor characteristics were as follow: median age 62 years (31-85), ductal carcinoma 78.5%, visceral disease 70.4%, luminal type 62.6%, Her2 positive 20.3%, triple negative 17.1%, previous median treatment lines for MBC 5 (0-18), previous N reported in 17.8% of pts (sensory 87.5%, motor 12.5%). N (all grades) were reported in 33.4% of patients (G3-G4: 3%). Among the selected SNPs, one allelic variant (rs2233335 G/G versus G/T or T/T) in NDRG1 gene had a statistically significant association with N (p 0.0010). Conclusions: The data reported demonstrate for the first time that the allelic variant rs2233335 (G/T and T/T) in NDRG1 gene correlates with E induced N. These data, if corroborated, will allow a tailored treatment with E. Clinical trial information: NCT02864030. [Table: see text]

Background: The antibody-drug conjugate Trastuzumab emtansine (T-DM1, Kadcyla®) is standard of care in HER2+ breast cancer patients on clinical progression after Trastuzumab/Pertuzumab and taxanes. Despite considerable clinical benefits, most patients rapidly develop progressive disease due to adaptive resistance, the molecular bases of which remain largely unknown and/or controversial. Next generation sequencing (NGS) and digital PCR (dPCR) applied to serial biological samples obtained through liquid biopsy (LB) and re-biopsy (RB) offer a unique opportunity to intercept mutational trajectories and uncover molecular patterns linked to primary as well as adaptive resistance. Materials and methods: Tumor tissues (n=14), either from primary or metastatic lesions, and plasma samples (n=99) were collected, upon informed consent, from 9 breast cancer patients undergoing T-DM1 administration. Tissue (tDNA) and circulating tumor DNA (ctDNA) were extracted by the QIAmp DNA FFPE and CNA kits (Qiagen), respectively, and analyzed by ultra-deep sequencing and dPCR (IonTorrent S5 and QuantStudio 3D, LifeTechnologies) with commercial 400-gene panel and custom-designed dPCR assays. Genomic data were correlated with clinical imaging (CT/PET). Results: Six out 9 (66.7%) patients experienced progression within 1 year of treatment (mean 192±97 days), whereas the remaining 3 were stable at the last follow up (> 400 days). No correlation was found between outcome and HER2, ER or PR status in the latest available (prior to T-DM1) archival tissue, in which NGS revealed several pre-existing mutations, including some associated with resistance to ERBB2 blockade. LB analysis detected increases in both baseline and de novo occurring aberrations in 5/6 (83.4%) relapsing patients. As compared to clinical imaging, progression disease was anticipated by an average lead time of 1.9 months (range 0.7-2.8). Surprisingly, the sixth relapsing patient underwent rapid progression (3 months) in spite of decreased PIK3CA p.E545K in blood, further confirmed in the re-biopsy, thus suggesting heterogeneous response to T-DM1 across multiple cancer cell populations. Of note, we observed progressive accumulation of ERBB2 p.L755S (associated with Lapatinib resistance) in multiple biopsies of serial metastatic foci from a patient over 18 years of multimodal ERBB2 blockade. However, a single administration of T-DM1 resulted in ultra-fast (within few weeks) clearance of ERBB2 p.L755S ctDNA, and stabilization of two distinct 'bystander' TP53 ctDNAs (p.R273H and p.S241T). Conclusions: Non-invasive LB monitoring of a small cohort of T-DM1-treated patients provides proof of principle of intersecting mutational trajectories, anticipation and classification of resistance, as well as de novo appearance/clearance of resistance mutations. Thus, LB and RB may hint at disease evolution and successive lines of medical treatment. This work was supported by AIRC (Nuvenia Fellowship to MA, IG 19052 to PG), EU commission (grant #633937 – ULTRAPLACAD), and Regina Elena National Cancer Institute intramural funding. Citation Format: Allegretti M, Giordani E, Casini B, Romania P, Gasparro S, Russillo M, Gallo E, Buglioni S, Pescarmona E, Cognetti F, Ciliberto G, Giacomini P, Fabi A. Liquid biopsy and re-biopsy: Tracking mutational trajectories in HER2+ breast cancer patients undergoing T-DM1 treatment [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-01-19.

Clinical trials have shown the efficacy of trastuzumab-based adjuvant therapy in HER2-positive breast cancers, but routine clinical use awaits evaluation of compliance, safety, and effectiveness. Adjuvant trastuzumab-based therapy in routine clinical use was evaluated in the retrospective study GHEA, recording 1,002 patients treated according to the HERA protocol between March 2005 and December 2009 in 42 Italian oncology departments; 874 (87.23 %) patients completed 1-year trastuzumab treatment. In 128 patients (12.77 %), trastuzumab was withdrawn due to cardiac or non-cardiac toxicity (28 and 29 patients, respectively), disease progression (5 patients) or the clinician’s decision (66 patients). In addition, 156 patients experienced minor non-cardiac toxicities; 10 and 44 patients showed CHF and decreased LVEF, respectively, at the end of treatment. Compliance and safety of adjuvant trastuzumab-based therapy in Italian hospitals were high and close to those reported in the HERA trial. With a median follow-up of 32 months, 107 breast cancer relapses were recorded (overall frequency, 10.67 %), and lymph node involvement, estrogen receptor negativity, lymphoid infiltration, and vascular invasion were identified as independent prognostic factors for tumor recurrence, indicating that relapses were associated with advanced tumor stage. Analysis of site and frequency of distant metastases showed that bone metastases were significantly more frequent during or immediately after trastuzumab (18 months from the start of treatment) (35.89 vs. 14.28 %, p = 0.0240); no significant differences were observed in recurrences in the other recorded body sites, raising the possibility that the protection exerted by trastuzumab is lower in bone metastases.

Objective. An open pilot study to evaluate the effect of pregabalin (PGB) as add-on therapy on seizure control, quality of life, and anxiety in patients with brain tumour-related epilepsy (BTRE). Materials and methods. We recruited 25 consecutive patients with BTRE and uncontrolled seizures. At baseline and during follow-up, patients underwent a complete physical and neurological examination and were evaluated using the QOLIE 31P (V2), EORTC QLQ C30, Adverse Events Profile, and Hamilton Anxiety Rating Scale (HAM-A). At baseline, a seizure diary was given. Results. During follow-up, 17 patients underwent chemotherapy, none underwent radiotherapy, 9 had disease progression, and 3 died. Mean duration of follow-up was 4.1 months. Mean PGB dosage was 279 mg/day. At baseline, mean weekly seizure frequency was 5.3 (±10) and at last available follow-up visit was 2.8±5. This difference was statistically significant ( p=0.016). The responder rate was 76%. Ten patients dropped out; 4 as a result of seizure worsening, 1 as a result of unchanged seizure frequency, 3 as a result of a lack of compliance, and 2 as a result of side effects. Based on the QOLIE-31-P, a significant improvement of the subscale “seizure worry” ( p=0.004) and a significant decrease in distress scores related to AEDs and social life ( p=0.009 and p=0.008, respectively) were observed. A significant decrease in HAM-A score ( p=0.002) was documented. Conclusions. These data indicate that PGB may represent a valid alternative as add-on treatment in this patient population, based on its efficacy on seizure control and anxiety.

The majority of patients with hormone receptor-positive breast cancer are treated with oral endocrine therapies, which are administered in periods ranging from 5 to 10 years. Adherence, ie the degree a subject's behavior corresponds to the agreed recommendations, then becomes a significant problem, which can also affect distress levels. The aim of this study is to evaluate the level of adherence to endocrine therapy and distress in a sample of Italian women.The study is a descriptive cross sectional survey. Adherence was measured with the Morisky Medication Adherence 8-item Scale and distress was measured by the Distress Thermometer. Socio-demographic and clinical data were also collected and then processed.Adherence measured with MMAS-8 items scored 6.18 corresponding to an average level of adherence in the 151 patients examined. The only factors affecting adherence signi- ficantly were: level of education, marital status and, among the side effects of therapy, poor concentration and memory. The data analysis obtained from the Distress Thermometer showed a degree of discomfort equal to 4.71,For example, in younger patients' levels of distress are greater in relationships, whereas in married/defacto women and workers distress levels are greater in practical areas.Results from this study can be useful to identify patients at risk for non-adhe- rence and distress, and consequently to help, the oncology team. Despite this, the study of adherence and related-factors needs further investigation.La quasi totalità delle pazienti con carcinoma mammario positivo ai recettori ormonali, viene trattata con terapie endocrine orali, da assumere per periodi che variano dai 5 ai 10 anni. L’aderenza, ossia il grado con il quale il comportamento di un soggetto corri- sponde a quanto concordato con il medico, diviene quindi un problema rilevante, sul quale può incidere anche il Distress. L’obiettivo di questo studio è quello di valutare l’aderenza alla terapia endocrina ed il distress, in un campione di donne italiane.Nell’indagine quantitativa descrittiva, per la raccolta dati è stato utilizzato il questionario per l’aderenza MMAS-8-item, una scheda di raccolta dati socio-demografici-clinici ed il DistressThermometer. I dati sono stati elaborati mediante il programma SPSS.L’analisi dell’aderenza ha riportato, per le 151 pazienti prese in esame, un indice medio pari a 6.18. E’ inoltre emerso che il livello d’istruzione, lo stato civile e la difficoltà di concentrazione/memoria, incidono sull’aderenza. L’analisi dei dati ottenuti dal DistressThermometer ha evidenziato un grado di disagio pari a 4.71 che, per esempio,nelle pazienti più giovani è maggiore nell’area relazionale, mentre nelle donne coniugate/conviventi e in quelle lavoratrici è maggiore nell’area pratica.Lo studio mette in evidenza come il campione risulti mediamente aderente e con un livello di distress medio-basso. Queste informazioni possono essere utili per identifi- care le pazienti a rischio di non-aderenza e di distress,ed aiutare, di riflesso, il team di onco- logia. Nonostante questo, lo studio sull’aderenza e sui fattori ad essa correlati necessita di ulteriori indagini.

The discovery of human epidermal growth factor receptor 2 (HER2) and its role in the biology of breast cancer and the subsequent development of HER2-targeted therapies, have dramatically improved clinical outcomes for women with early-stage and advanced HER2-positive breast cancer (BC). HER-2 targeted therapies represent a major step forward in achieving the goal of delivering individualized targeted therapy for BC, and trastuzumab was the first anti-HER-2 strategy to be approved for treatment of HER-2 positive BC. This review discusses the treatment of metastatic HER2-positive BC and describes efficacy and safety of novel anti-HER2 target therapies in first-line metastatic settings and the future challenges include refining such treatments, reducing toxicity and simultaneously developing innovative therapies. Furthermore, combinations of trastuzumab and drugs targeting the downstream pathway are described. In the next future will be possible to use an ample armamentarium of combination therapies directed against HER2 and key signaling components integrated in the HER network. This approach will allow clinicians to tailor the management of the individual patient on the basis of tumor- specific biomarker profiles. There is an urgent need for prospective biomarker-driven trials to identify patients for whom targeting is cost-effective.

Background The aim of this analysis was to develop and validate a prognostic model for advanced breast cancer (ABC) with luminal subtype based on the combination of clinical, pathological and therapeutic predictors to provide a practical tool to evaluate patients' prognosis. Methods Clinical and pathological data were retrospectively correlated to progression-free and overall survival (PFS/OS) using a Cox model. Significant treatment variables were adjusted with the propensity score analysis. A continuous score to identify risk classes was derived according to model ratios. The performance of the risk-class model was tested for post-progression survival (PPS) and conditional survival (CS) as well. Results Data from 335 patients (3 institutions) were gathered (median follow-up 58 months). At multivariate analysis Ki67, Performance Status (PS) and number of metastatic sites were significant predictors for PFS, whereas Ki67, PS, brain metastases, PFS after 1st-line therapy, number of chemotherapy lines, hormonal therapy and maintenance were significant predictors for OS. The hormonal maintenance resulted to be prognostic after adjustment with propensity score analysis. A two-class model significantly differentiated low-risk and high-risk patients for 2-year PFS (31.5% and 11.0%, p 0.0001 ), and 3-years OS (57.1% and 4.8%, p 0.0001 ). A three-class model separated low risk, intermediate-risk, and high-risk patients for 2-year PFS (40.8%, 24.4%, and 11.0%, p 0.0001 ) and 3-year OS (68.1%, 24.8%, and 4.8%, p 0.0001 ). Both models equally discriminate the luminal ABC prognosis in terms of PPS and CS. Conclusions A risk stratification model including ‘ easy-to-obtain ' clinical, pathological and therapeutic parameters accurately separates luminal ABC patients into different risk classes.

Background There are no validated predictive markers for lapatinib and capecitabine in patients with trastuzumab-resistant HER2 positive metastatic breast cancer. Methods Data of 148 consecutive patients treated with lapatinib and capecitabine from March 2007 to December 2013 were collected from 13 Italian institutions. Estimates of progression-free survival (PFS) and overall survival (OS) were obtained with the Kaplan-Meier method and compared with logrank test. The association of clinicopathological variables and the outcome was studied by binary logistic regression analysis and Cox proportional hazard analysis. Results At a median follow-up of 41 months, median PFS and OS were 7 and 21 months, respectively. Patents with a PFS longer than 7 months had a significantly longer OS, compared with patients with a PFS equal to or shorter than 7 months (36 vs 15 months; p

Patients with cancer frequently use dietary supplementation and herbal therapies to control symptoms of disease and adverse effects of cancer therapy. Despite the widespread use of dietary supplementation and herbal therapies in oncology, robust scientific evidence in this area is lacking. Not only do these products need to be tested in large and well-designed observational or randomized studies, but their manufacturing process must be improved to achieve higher levels of standardization in product quality. Ginger is frequently used to counteract chemotherapy-induced nausea and vomiting (CINV), and some suggestions that it might be effective against CINV come from randomized and/or crossover clinical trials. However, several limitations in the methods of these studies limit their power and generalizability. The authors are conducting a randomized, double-blind study with a large sample size and homogeneous inclusion criteria in order to evaluate the efficacy of a well-standardized ginger extract in reducing nausea in patients with cancer. The widespread use of standardized herbal therapies and natural components among patients requires that scientific and rigorous research strategies are applied in this field to guide the physicians and the patients in safer use.

e21623Background: Fatigue is one of the most distressing symptoms of cancer pts. Incidence, characteristics, impact on quality of life and treatment of cancer-related fatigue in Italian oncological...

Testicular cancer (TC) is the most common tumor of young ales and its incidence has approximately doubled worldwide ver the past 40 years, without a comprehensible etiology for the bserved increase [1,2]. Both environmental and genetic factors are ikely to be involved [2]. Germ cell tumors (GCTs) are malignancies erived from primitive stem-cells and are divided into two cateories based on histology: tumors included pure seminoma and umors with some component of non-seminoma (NS), such as tertoma, embryonal carcinoma, choriocarcinoma and yolk sac tumor. CTs are curative diseases, with cure rates of over 80% [3]. However, 8% of patients with metastatic NSGCTs have poor-risk features hat result in cure rates of only about 50% at 5 years [3]. Negaive prognostic features are the non-seminoma histology together ith mediastinal primary site, the presence of non-pulmonary isceral metastases, or severe increase of serum tumor markers lphafetoprotein (AFP), human chorionic gonadotropin (HCG), and actate dehydrogenase (LDH). However the presence of a medistinal primary site and the presence of central nervous system CNS) metastases appear to confer the greatest risk of mortality. etastatic GCTs can be classified into good-, intermediate-, and

BackgroundSeveral studies have emphasized the importance of the maintenance of bone health in a comprehensive cancer care. However, no survey about approach to bone metastasis care is currently available. The ZeTa study provides a picture of the Italian oncologists' therapeutics habits in this area, in a real clinical-practice scenario.DesignThis study was based on online questionnaire-based interviews to Italian oncologists that included 145 questions. The aim was to collect information on the treatment of bone metastasis, the current use of bisphosphonates, the awareness of guidelines and the concerns about ONJ, the use of vitamin D supplementation.Results445 oncologists were contacted, 283 agreed to participate. The results show that the current management of bone metastasis is still sub-optimal, as the recommendations from current clinical guidelines are not completely followed by all specialists.ConclusionsThis survey highlights the urgent need to improve management of bone metastasis in cancer patients.

Background Preclinical data suggest that treatment with lapatinib reinduces sensitivity to trastuzumab in human epidermal growth factor receptor 2(HER2)-positive breast cancer cells. Patients and methods Between January 2007 and November 2010, 179 HER2-positive metastatic breast cancer patients were treated with lapatinib and capecitabine at nine Italian institutions. We evaluated the clinical outcome of 69 patients (38.5%) retreated with trastuzumab after lapatinib progression. Results Visceral metastases were identified in 51 (74%) and brain metastases in 16 patients (23%). All patients were pretreated with both trastuzumab- and lapatinib-based therapy. We observed with retreatment with trastuzumab-based therapy: 1 complete remission (2%), 18 partial remission (29%) and 10 stable disease ≥6 months (14%) and 47% of clinical benefit (CB). Median duration of response was 8.1 months [95% confidence interval (CI) 5.5–10.7]. No unexpected toxic effects occurred. At a median follow-up of 13 months, median progression-free survival was 4.9 months (95% CI 4.2–5.6) and overall survival (OS) 19.4 months (95% CI 14.0–25.0). Median OS was longer for patients experiencing CB (not reached versus 13.4 months for patients without CB, P = 0.002). Brain involvement was associated with lower median OS (17.3 versus 23.3 months for patients without brain disease; P = 0.021). Conclusion Retreatment with trastuzumab-based therapy showed CB in 47% of patients progressing during lapatinib-based therapy, leading to a prolonged OS.

Central nervous system (CNS) metastases from breast cancer (BC) represent an important cause of disease-related morbidity and mortality. For BC patients who develop CNS metastases, local control measures (both surgery and radiation) are essentially palliative and usually poorly effective, with systemic therapies often failing to achieve optimal control mainly due to the presence of the blood-brain barrier which hampers adequate penetration of therapeutic agents into the brain. However, recent evidence suggests that the status of the human epidermal growth factor receptor-2 (HER2) strongly influences the incidence of CNS metastases and the survival of BC patients from the time of development of CNS metastases, with HER2-positive (HER2+) patients generally experiencing higher rates of CNS metastases and prolonged overall survival compared to patients with HER2-negative disease. This phenomenon likely reflects the difficult CNS drug-penetration and improved control of extra-CNS disease following the clinical use of the anti-HER2 monoclonal antibody trastuzumab. Importantly, this HER2-based survival difference has important implications when planning the optimal treatment of BC patients with CNS metastases. To date, although no systemic therapy has been specifically approved for the treatment of CNS metastases from BC, several targeted agents are being clinically developed for this purpose. In the present review we will discuss the targeted therapies that are under investigation for the treatment of CNS metastases from BC, highlighting the different implications based on whether a given agent is being developed to target CNS metastases from HER2+ or HER2-negative breast cancer.

Background: The ErbB2-targeting monoclonal antibody trastuzumab has remarkable efficacy in metastatic breast cancer (MBC) patients (pts) with HER2 overexpression or amplification (HER2+), either alone or in combination with chemotherapy. However, the response rate to trastuzumab is modest and not all pts derive benefit from this treatment. Predictive mechanisms of sensitivity and/or resistance are largely unknown. Recently, preclinical and limited clinical data showed that aberrant MET expression in MBC is a predictor of poor prognosis and is involved in trastuzumab resistance. Aim of the present study was to investigate whether increased gene copy number of MET or its ligand, the hepatocyte growth factor (HGF), affect trastuzumab sensitivity. Patients and Methods: This retrospective study included 130 HER2+ MBC pts treated with trastuzumab as monotherapy (N=21) or in combination with chemotherapy (N=109). Main inclusion criteria were presence of at least one measurable lesion and availability of paraffin-embedded tumor tissue from primary cancer. MET and HGF gene copy number (GCN) were assessed by fluorescence in situ hybridization (FISH). Receiver operating characteristic (ROC) analysis was used for identifying the best MET and HGF mean GCN cut-off. Results: In the whole population response rate (RR), including complete (CR) and partial response (PR) was 49.2%, disease control rate, including CR+PR+ stable disease (SD) was 76.2%, median time to progression (TTP) 9.4 months, and median survival (OS) 28.3 months. MET FISH analysis was successfully performed in all 130 cases. Median MET mean GCN was 2.96 (range 1.66−8.40), with no gene amplification. ROC curve identified a mean of 3.72 MET GCN as the optimal cut-off value for discriminating between sensitive (CR+PR+SD) and refractory pts (pts with progressive disease [PD] at the first disease assessment). MET FISH+ (N=36, mean ≥3.72) had a significantly higher PD rate (44.4% versus 16.0%; p=0.001) and a significantly shorter TTP (5.7 versus 9.9 months; HR 1.74 95% C.I. 1.16−2.62; p=0.006) than MET FISH- pts (N=94, mean Conclusions: High GCNs of MET or HGF associate with an increased risk of trastuzumab failure in HER2+ MBC. These data support a further development of combining anti-HER2 with anti-MET strategies in MBC. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-13-07.

We conducted a prospective, observational study to verify the efficacy, tolerability and impact on quality of life, mood and global neurocognitive performances of oxcarbazepine monotherapy in patients with brain tumor-related epilepsy (BTRE). Patients were followed for 12 months. We recruited 25 patients (11 females 14 males; mean age 49.7) affected with BTRE (17 de novo patients and 7 in monotherapy with other antiepileptics) and introduced oxcarbazepine monotherapy because of uncontrolled seizures and/or side effects. At first visit, patients underwent neurological examination, Qolie 31P V2, EORTC QLQC30, Zung self-depression rating scale (ZSDRS) and adverse events profile. A seizure diary was given to each patient. Follow-up duration was 1-12 months (mean 7.1 months, 5 patients died and 10 dropped out). Totals of 16 patients underwent both chemotherapy and radiotherapy, 4 chemotherapy only, 1 radiotherapy only, and 4 did not undergo any systemic therapy. Mean dosage of oxcarbazepine was 1,230 mg/day (min 600, max 2,100 mg/day). McNemar's test showed a significant difference in seizure freedom rate (P = 0.002) between baseline and final follow-up in the intent-to-treat population. Six patients (24%) had serious side effects and one patient (4%) mild. Logistic regression revealed that, in our study, chemotherapy and radiotherapy did not affect the efficacy of OXC in seizure outcome (P = 0.658). The test evaluation at final follow-up showed a significant improvement in ZSDRS (P = 0.011) and no change over time. Oxcarbazepine seems to be efficacious in controlling seizures and in improving mood in patients with BTRE, but special caution should be taken when it is administered during radiotherapy.

We performed a case series analysis to evaluate the effects of levetiracetam (LEV) monotherapy on seizures, adverse events, cognitive functioning and quality of life (QoL) in patients with brain tumor-related epilepsy (BTRE). We also explored the possible effects of systemic therapies on the efficacy of LEV. Twenty-nine patients were followed (13 female, 16 male; age 24–75 years) with 12 months of follow-up. Patients were evaluated by QoL and neuropsychological tests. At final follow-up, mean LEV dosage was 1991.4 mg/day. Among patients who reached the final follow-up of 12 months (n = 15), 1 patient had ≥50% reduction of seizure frequency (SF), and 14/15 were seizure free. The difference in presence/absence of seizures between baseline and final follow-up was significant (p < 0.001). Responder rate was 100%. We observed five side-effects: four mild (reversible) and one severe. Logistic regression revealed that chemotherapy and radiotherapy did not affect the efficacy of LEV in seizure outcome (p = 0.999). The following statistically significant observations emerged by tests’ evaluation: less worry about seizures, effects of antiepileptic, and ability to maintain social functions. Our data suggest that seizure occurrence can be an important warning sign that the clinician should heed throughout the duration of the illness. Patients with BTRE represent a unique patient population that presents difficulties regarding management of two very different pathologies: epilepsy on the one hand, and brain tumor on the other. Our data indicate that LEV, in patients with BTRE, is safe and efficacious, with positive impact on QoL.

In order to evaluate the activity of gemcitabine as radiosensitizer for newly diagnosed glioblastoma multiforme (GBM), a prospective single-center phase II study was conducted.Eligible patients were required to have histologically proven GBM with evaluable and/or measurable disease after surgery. They were treated by standard cranial irradiation plus concomitant fixed dose rate gemcitabine given intravenously at 175 mg/m(2) weekly for 6 weeks. After chemo-radiotherapy, irrespective of tumor response, patients went on to receive oral temozolomide at 150-200 mg/m(2) for 5 days every 28 days.Twenty-three patients were enrolled. Median age was 57 years (range 43-72) and median Karnofsky performance status was 90 (range 70-100). Seventeen patients had received subtotal resection of the tumor, while six patients had biopsied-only tumors. Four patients responded to treatment (17.5%) with additional 14 (61%) experiencing stable disease for an overall disease control rate of 78.5%. Median progression-free and overall survival were 6.8 and 10.1 months, respectively. The concomitant radiotherapy-gemcitabine combination was well tolerated and severe adverse events were rare, consisting of grade 3 neutropenia and hypertransaminasemia in two cases each. Twenty patients were assessable for methylguanine methyltransferase (MGMT) promoter methylation, 11 of which were found methylated. In the methylated and unmethylated cohorts, disease control was obtained in 10/11 patients (91%) and 7/9 patients (77.5%), respectively.Concomitant radiotherapy-gemcitabine is active and well tolerated in newly diagnosed glioblastoma multiforme. Activity is observed both in tumors with methylated and unmethylated MGMT promoter.

The aim of this pilot study was to investigate the effects of levetiracetam monotherapy on seizure control, quality of life and neurocognitive performance in patients with brain tumor-related epilepsy. We present here preliminary data from 18 patients with follow-up of 6 months. We evaluated seizure frequency at baseline. We used administered Mini Mental State Examination (MMSE), Karnofsky Performance Status (KPS), Barthel index (BI), QOLIE 31P (V2), EORTC QLQ-C30 and Adverse Events Profile. After 6 months, 16 patients were seizure free (88.9%), 2 (11.1%) had reduction in seizure frequency >50%. Compared to baseline, we observed a worsening of performance (KPS p = 0.011; BI = 0.008) and global lower cognitive performance (MMSE p = 0.011); distress related to seizure frequency (p = 0.003) and medication effects (p = 0.046) were significantly lower. Levetiracetam caused mild and reversible side effects. These preliminary data on LEV monotherapy in patients with brain tumor-related epilepsy show that this antiepileptic drug is efficacious and well tolerated.

Though preclinical evidence supports the protracted use of trastuzumab to reach sustained anti-tumor activity, the activity of trastuzumab beyond disease progression remains controversial in HER-2 over-expressing (HER-2+) metastatic breast cancer (MBC) patients. We retrospectively evaluated a total of 59 patients with HER-2 + MBC treated at our institution with trastuzumab-based therapies. Our results were added to those obtained in similar observational studies and summary estimates for overall response (OR) and clinical benefit (CB) to first and second trastuzumab-based lines were calculated. In our series of patients we observed an OR of 59.3% and 27% for first and second trastuzumab-based lines, respectively, with a corresponding CB of 83% and 62.2%, respectively. Time to first and second progression were 9.5 months and 6.7 months, respectively. The combined analysis showed an OR of 50% for first trastuzumab-based regimen and 21.2% for second trastuzumab-based line. The corresponding values for CB were 77.6% and 42.6%, respectively. A second trastuzumab-containing regimen beyond progression yields a considerable rate of OR and CB in HER-2 + MBC patients. Randomized trials are warranted.

The recognition achieved in the late 1980s of human epidermal growth factor receptor 2 as an appealing therapeutic target for breast cancer has led to the development of targeted therapies for patients with human epidermal growth factor receptor 2-overexpressing breast tumors.The aim of the present review is to address the standard treatment of human epidermal growth factor receptor 2-positive metastatic breast cancer patients, which is currently based on the humanized monoclonal antibody trastuzumab and to describe the new treatment options available for patients progressing on trastuzumab-based therapies.A broad literature research was performed in order to review treatments, starting from the developmental phase of trastuzumab to the most recent biologic agents being tested in human epidermal growth factor receptor 2-positive disease.Trastuzumab combined with a taxane represents the first therapeutic option for human epidermal growth factor receptor 2-positive metastatic breast cancer. However, novel combinations of trastuzumab and chemotherapy still hold great interest for their remarkable activity and good tolerability. On the other hand, the dual epidermal growth factor receptor/human epidermal growth factor receptor 2 inhibitor lapatinib has been the first drug to be approved in combination with capecitabine for the treatment of patients who progress on trastuzumab-based therapies. Moreover, in the near future, trastuzumab plus another biologic agent targeting human epidermal growth factor receptor 2, either directly or indirectly, may represent an effective 'chemotherapy-free' combination for trastuzumab-refractory patients.

Objective Medical management of brain tumor-related epilepsy is complicated by interactions between antiepileptic and chemotherapeutic drugs. We studied the effect of temozolomide therapy on the disposition of the new antiepileptic drugs topiramate (TPM) or oxcarbazepine (OXC). Methods Fifteen patients chronically treated with TPM or OXC in monotherapy starting a chemotherapeutic treatment with temozolomide were enrolled in the study, of which ten were available for the final analyses. Blood samples were collected before temozolomide treatment (T0), at its end (T7) and after further 1–3 weeks (T14–T28). For each patient, more than one treatment cycle was studied. Topiramate and OXC mono-10-hydroxy derivative (MHD) plasma concentrations were determined by hplc coupled with ion spray mass spectrometer (TPM) or ultraviolet (MHD) detection. Results Mean TPM concentrations were 5.4 ± 2.4 μg/ml at T0 vs. 5.5 ± 2.4 μg/ml at T7 (n = 14), and 5.4 ± 2.4 μg/ml at T0 vs. 5.6 ± 2.8 μg/ml at T14–T28 (n = 14). Mean MHD concentrations were 16.4 ± 7.6 μg at T0 vs. 18.5 ± 9.0 μg/ml at T7 (n = 5), and 16.8 ± 7.0 μg/ml at T0 vs. 18.0 ± 8.7 μg/ml at T14–T28 (n = 8) (all comparisons not statistically significant; Student’s t-test for paired samples). Conclusion Temozolomide treatment did not affect TPM plasma concentrations in chronically treated patients. Data for MHD in OXC-treated patients were similar, but, due to the small sample size, results should be interpreted cautiously.These findings confirm that TPM (and possibly OXC) are a reasonable choice of antiepileptic drug in patients with brain tumor-related epilepsy.

Recent reports on large number of patients with brain metastases report that Whole Brain Radiotherapy (WBRT) and Radiosurgery (RS) should be the treatments of choice, particularly in multiple lesions cases. Among the prognostic factors, the cerebellar location was never considered, although this results in hydrocephalus, brain stem compression, ataxia, intracranial hypertension.We evaluated 44 patients with cerebellar metastases operated over 6 years. Primary lesions were: Lung (15), Breast (12), Gastrointestinal (9), Gut (3), Ovary (2), Melanoma (1), Salivary gland carcinoma (1), Unknown (1). Lesions were3 cm in 11 cases,or =3 cm in 33. Average KPS scoring at admission was 69.9. Twenty nine scoredor =70, 1570.Two patients died for surgical complications, 2 died within 1 months for other causes, 2 were lost to follow up. Eight had postoperative hematoma requiring reoperation, 1 had an occipital infarction. Average KPS scoring at discharge was 76.4, P0.002. Those patients that had complications scored less, the difference is significant (P0.008). Median survival was 8 months, 1 year survival rate 29.9%. Survival was correlated with either admission or discharge KPS (or =70 vs.70): P = 0.05 and P = 0.0001 respectively. None of the other parameters considered reached statistical significance.Open microneurosurgery is probably still the most effective therapy in improving survival and KPS in patients with large cerebellar metastases, given that the proper surgical technique is used and that complications do not occur. Specific data on cerebellar metastases as an independent subgroup are needed from radiosurgical series.

Purpose Unresponsiveness to erythropoiesis-stimulating agents, occurring in 30% to 50% of patients, is a major limitation to the treatment of chemotherapy-related anemia. We have prospectively evaluated whether intravenous iron can increase the proportion of patients with chemotherapy-related anemia who respond to darbepoetin. Patients and Methods Between December 2004 and February 2006, 149 patients with lung, gynecologic, breast, and colorectal cancers and ≥ 12 weeks of planned chemotherapy were enrolled from 33 institutions. Patients were required to have hemoglobin ≤ 11 g/L and no absolute or functional iron deficiency. All patients received darbepoetin 150 μg subcutaneously once weekly for 12 weeks and were randomly assigned to sodium ferric gluconate 125 mg intravenously (IV) weekly for the first 6 weeks (n = 73) or no iron (n = 76). Primary end point of the study was the percentage of patients achieving hematopoietic response (hemoglobin ≥ 12 g/dL or ≥ 2 g/dL increase). Results Hematopoietic response by intention-to-treat analysis was 76.7% (95%CI, 65.4% to 85.8%) in the darbepoetin/iron group and 61.8% (95%CI, 50.0% to 72.7%) in the darbepoetin group (P = .0495). Among patients fulfilling eligibility criteria and having received at least four darbepoetin administrations, hematopoietic responses in the darbepoetin/iron group (n = 53) and in the darbepoetin-only group (n = 50) were 92.5% (95% CI, 81.8% to 97.9%) and 70% (95% CI, 55.4% to 82.1%), respectively (P = .0033). Increase of hemoglobin during treatment period showed a time profile favoring darbepoetin/iron with statistically significant effect from week 5 on. The safety profile was comparable in the two arms. Conclusion In patients with chemotherapy-related anemia and no iron deficiency, IV iron supplementation significantly reduces treatment failures to darbepoetin without additional toxicity.

Preclinical evidence suggests that the cyclo-oxygenase-2 (COX-2) enzyme plays an important role in breast cancer progression. The aim of the present phase II study was to determine the activity and safety of the combination of the COX-2 inhibitor celecoxib with capecitabine in metastatic breast cancer (MBC) patients pretreated with anthracyclines and/or taxanes. Eligible patients received capecitabine 1,000 mg/m² twice daily on days 1–14 every 21 days and celecoxib 200 mg twice daily, continuously, until disease progression or unacceptable toxicity. About 42 pretreated MBC patients were enrolled into the study. Median number of previous chemotherapy lines for metastatic disease was 2 (0–3). Seven patients (19%) responded to treatment while disease stabilization occurred in 17 patients (40.5%). Overall, 20 patients (47.5%) achieved clinical benefit [objective responses (CR) plus stable disease (SD) ≥6 months]. Median time to progression (TTP) and median overall survival (OS) were 5.2 and 17.8 months, respectively. Treatment was very well tolerated: grade 3 toxicities were observed in only five patients, respectively, and no grade 4 adverse events were reported. Celecoxib was never discontinued for toxicity. Analysis of COX-2 expression in the 22 patients with available tissue revealed a significantly longer TTP and OS for patients whose tumors over-expressed COX-2. The combination of capecitabine and celecoxib is active and safe in far advanced MBC patients. Interestingly, this association resulted in a lower-than-expected toxicity, as compared to single-agent capecitabine. The clinical relevance of COX-2 as determinant of sensitivity to treatment with celecoxib should be further evaluated in larger series of patients.

In patients with newly diagnosed glioblastoma multiforme (GBM), concurrent chemo-radiotherapy with temozolomide is the new standard of care. In the present phase I study we investigated the association of gemcitabine, a cell-cycle antimetabolite with radiosensitizing properties, with radiotherapy (RT) in the first line treatment. Gemcitabine was delivered at a fixed dose-rate of 10 mg/m(2)/min weekly for 6 weeks starting 24-72 h prior to, and then concomitantly with RT (2.0 Gy per fraction, total dose 60 Gys). The primary end-point was the identification of dose-limiting toxicity (DLT), and maximum tolerated dose (MTD). Planned dose levels of gemcitabine started from 200 mg/m(2)/weekly (level 1), with sequential dose escalations of 25 mg/m(2). Ten patients were enrolled, all with evaluable disease after surgery. Six patients were male, median age was 55 years (44-75), and median baseline Karnofsky performance status was 85 (70-100). Four patients entered level 1, one patient being excluded from the study because of early disease progression. At this level, two of three patients developed progressive neurological deterioration, potentially related to the experimental treatment. On this basis gemcitabine dose was prudentially reduced to 175 mg/m(2)/weekly in the subsequent step (level -1). No DLT was encountered in the six patients enrolled at this level. Interestingly, at this dose only two grade three toxicities (one neutropenia and one raise in serum transaminases) were reported. Thus, fixed dose-rate gemcitabine at 175 mg/m(2)/weekly is the recommended regimen for further evaluation in a phase II study that is presently in progress.

Purpose of review The principal effort of this review was to elucidate the role of human epidermal growth factor receptor 2/neu expression in breast cancer, either as an independent prognostic factor or a predictive marker of response to antineoplastic therapy, in light of the most recent results obtained with the use of trastuzumab, in either the metastatic or the adjuvant setting. Recent findings Human epidermal growth factor receptor 2-overexpressing breast cancer is known to be associated with particularly aggressive disease and poor prognosis. On the other hand, human epidermal growth factor receptor 2/neu overexpression may predict response to endocrine therapy or chemotherapy. Nevertheless, trastuzumab increases the clinical benefit of first-line chemotherapy in patients with metastatic breast cancers that overexpress human epidermal growth factor receptor 2. Decades of randomized clinical trials on the front-line treatment of metastatic breast cancer have never been able to show so remarkable differences in survival as recent randomized trials comparing chemotherapy with chemotherapy plus trastuzumab in women with human epidermal growth factor receptor 2-overexpressing metastatic breast cancer have been able to do. Summary In the pretrastuzumab era, retrospective analyses have shown that human epidermal growth factor receptor 2 overexpression is an adverse prognostic factor associated with an increased risk of disease recurrence and death. In the trastuzumab era, this drug has changed the natural history of human epidermal growth factor receptor 2-positive breast cancer, either in the metastatic or, according to the most recent evidences, in the adjuvant setting.

Background Few prospective studies have assessed the role of bevacizumab and included a control arm with standard treatments for recurrent glioblastoma. We conducted a noncomparative phase II trial (AVAREG) to examine the efficacy of bevacizumab or fotemustine in this setting. Methods Eligible patients were randomized 2:1 to receive bevacizumab (10 mg/kg every 2 weeks) or fotemustine (75 mg/m(2) on days 1, 8, and 15, then 100 mg/m(2) every 3 weeks after a 35-day interval). The primary endpoint was 6-month overall survival (OS) rate (OS-6). No formal efficacy comparison was made between the treatment arms. Results Ninety-one patients were enrolled (bevacizumab n = 59; fotemustine n = 32). Median age was 57 years (range, 28-78 y), and patients had Eastern Cooperative Oncology Group performance status of 0 (n = 42), 1 (n = 35), or 2 (n = 14). OS-6 rate was 62.1% (95% confidence interval [CI], 48.4-74.5) with bevacizumab and 73.3% (95% CI, 54.1-87.7) with fotemustine. OS-6 rates were lower in bevacizumab-treated patients with MGMT promoter methylated tumors than in those with unmethylated tumors (50% and 85%, respectively), but higher in fotemustine-treated patients (87.5% and 50%, respectively). OS rates at 9 months were 37.9% (95% CI, 25.5-51.6) and 46.7% (95% CI, 28.3-65.7) with bevacizumab and fotemustine, respectively, and median OS was 7.3 months (95% CI, 5.8-9.2) and 8.7 months (95% CI, 6.3-15.4), respectively. Toxicity was as expected with the 2 agents. Conclusion Single-agent bevacizumab may have a role in patients with recurrent glioblastoma.

The management of elderly glioblastoma (GBM) remains controversial for under-representation in controlled trials, for modest tolerance of treatments, and higher rate of side effects. Age was identified as an important prognostic factor for survival, mainly in patients with poor performance status. The presence of co-morbidities (CM) represents an important issue in elderly because the correlation with frailty, and the role as predictor of disability and mortality. The aim of this study was to evaluate the impact of CM on outcome of elderly GBM. METHODS: Patients affected by GBM with age ≥ 65 years have been enrolled in a prospective study. For each patient, CM were identified with the Cumulative Illness Rating Scale (CIRS). RESULTS: Sixty-six elderly patients affected by GBM were enrolled into the study. The average age at diagnosis was 73 years (range 65-87). The median PFS at 12 months has been 8 months, with a rate of 29.1% patients free of progression at 1 year. The median OS has been 18 months (95% CI 13-23), with a survival rate of 35% at 2 years. The univariate analysis showed that the severity of CM is a strong predictor of disease progression (HR = 1.24, 95% CIs from 1.11 to 1.38, p = 0.000). Multivariate analysis confirmed that the severity of CM (HR = 1.24 for each increase of CIRS score, 95% CIs from 1.11 to 1.38, p = 0.000) is an independent predictor of disease progression. In addition, higher score of CM and age higher than 75 years are associated with short survival. DISCUSSION: We observed that high CM score is an independent predictor of disease progression and shorter survival. The evaluation of CM should drive therapeutic decisions in elderly GBM. In subgroups of elderly GBM without high score of CM, standard treatments should be considered. Further studies on elderly GBM are warranted to confirm these data.

The management of pT1a-b pN0 HER2-positive breast cancer is controversial and no data about the efficacy of trastuzumab in this setting are available from randomized clinical trials. The aims of this retrospective study were to assess how patients are managed in clinical practice in Italy, which clinical or biological characteristics influenced the choice of adjuvant systemic therapy and the outcome of patients.Data of consecutive patients who underwent surgery from January 2007 to December 2012 for HER2-positive, pT1a-b pN0 M0 breast cancer were retrospectively collected from 28 Italian centres. Analysis of contingency tables and multivariate generalized logit models were used to investigate the association between the baseline clinical and biological features and the treatment strategy adopted.Among 303 enrolled patients, 204 received adjuvant systemic therapy with trastuzumab, 65 adjuvant systemic therapy without trastuzumab and 34 did not receive adjuvant systemic therapy. At the multivariate analysis age, tumor size, proliferation index and hormone receptor status were significantly associated with the treatment choice. Five-year disease-free survival (DFS) probability was 95%, 94.3% and 69.6% for patients treated with adjuvant systemic therapy and trastuzumab, with adjuvant systemic therapy without trastuzumab and for patients who did not receive adjuvant systemic therapy, respectively (p

O6-methylguanine-DNA-methyltransferase (MGMT) has emerged as a relevant predictor of therapeutic response and good prognosis in patients with glioblastoma (GBM). Transcriptionally active MGMT rapidly removes the alkyl adducts, preventing the formation of cross-links and thereby causing resistance to alkylating drugs. Studies with pyrosequencing (PSQ) showed that this technique has a higher reproducibility and sensitivity than other techniques. However, the definition of a prognostically relevant threshold for the percentage of MGMT methylation remains one of the most critical issues in the use of PSQ analysis. The aim of this study was to define the cut-off value correlated with good favourable prognostic outcomes. We retrospectively analyzed 51 patients (33 males, 18 females) with GBM who underwent surgery or biopsy. The Receiver Operating Characteristics analysis showed that the best possible criteria for PSQ-detected percentage of MGMT methylation that predicted progression-free survival (PFS) and overall survival (OS) were 19% and 13%, respectively. Patients with ≤19% of PSQ-detected MGMT had a shorter PFS (HR: 0.24,p<0.01); those ones with ≤13% had a shorter OS (HR: 0.33,p<0.05). Our study reinforces the importance of MGMT in the management of GBM patients, but future studies with larger sample sizes are warranted to confirm our findings.

Estrogen receptors have recently been demonstrated at the cell surface. Unlike nuclear receptors, they are able to trigger rapid responses inside the cells. In this study, we evaluated the presence and the possible role of autoantibodies specific to estrogen receptor (anti-ER Abs) in the peripheral blood of breast cancer patients. Anti-ERα Abs were detectable in 22/48 (46%) patients' sera and their levels positively correlated with the percentage of Ki-67-positive breast cancer cells. Anti-ERα Abs purified from breast cancer patients' sera were able: (i) to recognize ERα epitopes expressed at the cell surface of ER-positive breast cancer cells, (ii) to trigger rapid extracellular signal-regulated kinase (ERK) phosphorylation, and (iii) to induce cell proliferation. Our results suggest that anti-ERα Abs can act as estrogen agonists playing a pathogenetic role as breast cancer-promoting factors. These autoantibodies could also be considered as possible peripheral blood biomarkers indicative of the breast cancer growth potential.

The efficacy of temozolomide (TMZ) plus radiation therapy (RT) in elderly patients with glioblastoma is unclear. We performed a large multicenter retrospective study to analyze prognostic factors and clinical outcome in these patients. Inclusion criteria were age ≥65 years, newly histologically confirmed glioblastoma, ECOG PS 0-2, adjuvant treatment with RT plus TMZ. We enrolled 237 patients; the average age was 71 and ECOG PS was 0-1 in 196 patients; gross total resection was performed in 174 cases. MGMT was analyzed in 151 persons and was methylated in 56 %. IDH1 was assessed in 100 patients and was mutated in 6 %. Seventy-one patients were treated with RT 40 Gy and 166 with RT 60 Gy. Progression-free survival and overall survival (OS) were 11.3 and 17.3 months, respectively. Overall survival was 19.4 vs 13.8 months for patients treated with RT 60 Gy and 40 Gy (p = 0.02); OS was 17.7 versus 16.1 months for patients treated with gross total resection vs partial surgery (p = 0.02); OS was 21.2 versus 13.6 months for methylated and unmethylated MGMT (p < 0.001). On multivariate analysis, gross total resection, RT 60 Gy, methylated MGMT and ECOG PS 0-1 were independent predictors of longer survival. Twenty-five patients (10 %) had grade 3-4 haematological toxicity during the concomitant treatment. We showed that, in elderly patients in good clinical condition treated with concomitant treatment, standard-course irradiation might be more effective than short-course irradiation. Methylated MGMT remains the most important prognostic factor.

The aim of this pilot observational study was to evaluate effect of cognitive rehabilitation training (RehabTr) on cognitive performances in patients with brain tumor-related epilepsy (BTRE) and cognitive disturbances. Medical inclusion criteria: patients (M/F) ≥ 18 years ≤ 75 with symptomatic seizures due to primary brain tumors or brain metastases in stable treatment with antiepileptic drugs; previous surgical resection or biopsy; >70 Karnofsky Performance Status; stable oncological disease. Eligible patients recruited from 100 consecutive patients with BTRE at first visit to our Center from 2011 to 2012. All recruited patients were administered battery of neuropsychological tests exploring various cognitive domains. Patients considered to have a neuropsychological deficit were those with at least one test score for a given domain indicative of impairment. Thirty patients out of 100 showed cognitive deficits, and were offered participation in RehabTr, of which 16 accepted (5 low grade glioma, 4 high grade glioma, 2 glioblastoma, 2 meningioma and 3 metastases) and 14 declined for various reasons. The RehabTr consisted of one weekly individual session of 1 h, for a total of 10 weeks, carried out by a trained psychologist. The functions trained were: memory, attention, visuo-spatial functions, language and reasoning by means of Training NeuroPsicologico (TNP(®)) software. To evaluate the effect of the RehabTr, the same battery of tests was administered directly after cognitive rehabilitation (T1), and at six-month follow-up (T2). Statistical analysis with Student T test for paired data showed that short-term verbal memory, episodic memory, fluency and long term visuo-spatial memory improved immediately after the T1 and remained stable at T2. At final follow-up all patients showed an improvement in at least one domain that had been lower than normal at baseline. Our results demonstrated a positive effect of rehabilitative training at different times, and, for these reasons, should encourage future research in this area with large, randomized clinical trials that evaluate the impact of a cognitive rehabilitation in patients with BTRE and cognitive deficits.

Alessandra Fabi,1 Diana Giannarelli,2 Paola Malaguti,1 Gianluigi Ferretti,1 Sabrina Vari,1 Paola Papaldo,1 Cecilia Nisticò,1 Mauro Caterino,3 Roy De Vita,4 Marcella Mottolese,5 Laura Iacorossi,6 Francesco Cognetti1 1Department of Medical Oncology, 2Biostatistic Unit, 3Service of Radiology, 4Operative Unit of Plastic and Reconstructive Surgery, Department of Pathology, Regina Elena National Cancer Institute, Rome, Italy; 5Department of Pathology, 6Department of Biomedicine and Prevention, University of Rome “Tor Vergata”, Rome, Italy Background: There is a deep need to improve the care of metastatic breast cancer (MBC) patients, since even today it remains an incurable disease. Taxanes are considered the most effective cytotoxic drugs for the treatment of MBC, both in monotherapy and in combined schedules, but the need for synthetic solvents contributes to the severe toxicities and may have a negative impact on the efficacy. Nanoparticle albumin-bound paclitaxel (Nab-paclitaxel) is a colloidal suspension of paclitaxel and human serum albumin initially developed to avoid the toxicities associated with conventional taxanes.Patients and methods: The aim of this prospective, single-center open-label, noncomparative study was to evaluate the efficacy and safety of nab-paclitaxel in MBC patients pretreated with taxanes. The patients were treated with nab-paclitaxel as a single agent, 260mg/m2 on day 1 of each 3-week cycle or 125mg/m2 weekly. The primary endpoint was the overall response rate (ORR). Secondary objectives were duration of response, clinical benefit rate, progression-free survival (PFS), overall survival, and safety.Results: A total of 42 patients (median age 48years, median Eastern Cooperative Oncology Group performance status 0, triple-negative MBC 19%, all pretreated with a taxane-based therapy, mainly in advanced disease) were enrolled in the study. The ORR was 23.8%, including one complete response (2.4%) and nine partial responses (21.4%); the disease control rate was 50%. The median duration of response was 7.2months. After a median follow-up of 9months, the median PFS was 4.6months. ORR and PFS were similar irrespective of the previous chemotherapy lines, metastatic sites, and biomolecular expression. Nab-paclitaxel was well tolerated, and the most frequent treatment-related toxicities were mild to moderate (grades 1–2).Conclusion: This real-life study shows that nab-paclitaxel has a significant antitumor activity and a manageable safety profile in patients pretreated with taxanes and experiencing a treatment failure after at least one line of chemotherapy. Keywords: nab-paclitaxel, metastatic breast cancer, anthracyclines

// Patrizia Vici 1, * , Anna Di Benedetto 2, * , Cristiana Ercolani 2 , Laura Pizzuti 1 , Luigi Di Lauro 1 , Domenico Sergi 1 , Francesca Sperati 3 , Irene Terrenato 3 , Rosanna Dattilo 4 , Claudio Botti 5 , Alessandra Fabi 6 , Maria Teresa Ramieri 7 , Lucia Mentuccia 8 , Camilla Marinelli 9 , Laura Iezzi 10 , Teresa Gamucci 8 , Clara Natoli 10 , Ilio Vitale 4, 11 , Maddalena Barba 1, 4 , Marcella Mottolese 2 , Ruggero De Maria 4 , Marcello Maugeri-Sacca 1, 4 1 Division of Medical Oncology B, “Regina Elena” National Cancer Institute, Rome, Italy 2 Department of Pathology, “Regina Elena” National Cancer Institute, Rome, Italy 3 Biostatistics-Scientific Direction, “Regina Elena” National Cancer Institute, Rome, Italy 4 Scientific Direction, “Regina Elena” National Cancer Institute, Rome, Italy 5 Department of Surgery, “Regina Elena” National Cancer Institute, Rome, Italy 6 Division of Medical Oncology A, “Regina Elena” National Cancer Institute, Rome, Italy 7 Division of Pathology, ASL Frosinone, Frosinone, Italy 8 Medical Oncology Unit, ASL Frosinone, Frosinone, Italy 9 Division of Pathology, “SS. Annunziata Hospital”, Chieti, Italy 10 Department of Experimental and Clinical Sciences, University “G. d'Annunzio”, Chieti, Italy 11 Department of Biology, University of Rome “Tor Vergata”, Rome, Italy * These authors have contributed equally to this work Correspondence to: Marcello Maugeri-Sacca, e-mail: maugeri@ifo.it Ruggero De Maria, e-mail: demaria@ifo.it Keywords: DNA damage and repair, triple-negative breast cancer, pathological complete response Received: September 09, 2015 Accepted: October 05, 2015 Published: October 17, 2015 ABSTRACT Response of cancer cells to chemotherapy-induced DNA damage is regulated by the ATM-Chk2 and ATR-Chk1 pathways. We investigated the association between phosphorylated H2AX (γ-H2AX), a marker of DNA double-strand breaks that trigger the ATM-Chk2 cascade, and phosphorylated Chk1 (pChk1), with pathological complete response (pCR) in triple-negative breast cancer (TNBC) patients treated with neoadjuvant chemotherapy. γ-H2AX and pChk1 were retrospectively assessed by immunohistochemistry in a series of pretreatment biopsies related to 66 patients. In fifty-three tumors hormone receptor status was negative in both the diagnostic biopsies and residual cancers, whereas in 13 cases there was a slight hormone receptor expression that changed after chemotherapy. Internal validation was carried out. In the entire cohort elevated levels of γ-H2AX, but not pChk1, were associated with reduced pCR rate ( p = 0.009). The association tested significant in both uni- and multivariate logistic regression models (OR 4.51, 95% CI: 1.39–14.66, p = 0.012, and OR 5.07, 95% CI: 1.28–20.09, p = 0.021, respectively). Internal validation supported the predictive value of the model. The predictive ability of γ-H2AX was further confirmed in the multivariate model after exclusion of tumors that underwent changes in hormone receptor status during chemotherapy (OR 7.07, 95% CI: 1.39–36.02, p = 0.018). Finally, in residual diseases a significant decrease of γ-H2AX levels was observed ( p < 0.001). Overall, γ-H2AX showed ability to predict pCR in TNBC and deserves larger, prospective studies.

Summary Background The magnitude of the survival benefit of aromatase inhibitors (AIs) after 2–3 years of tamoxifen as adjuvant hormonal therapy for early breast cancer is still unclear. We performed a literature-based meta-analysis, to look how much advantages adjuvant the “early switch” strategy add over standard tamoxifen for 5 years. Methods A pooled analysis of all phase-III trials was accomplished, and event-based relative risk ratios (RR) with 95% confidence interval (CI) were derived. Significant differences in primary outcome (EFS and RFS, event- and relapse-free survival), and secondary outcomes (OS, overall survival, deaths without progression, other cancers and toxicities), were explored. Magnitude outcome measures were absolute benefits and number of patients needed to treat. Heterogeneity test was applied as well. Results Five trials (8794 patients) were gathered. The risk of any event is reduced with AIs of 23%, with an absolute benefit of 3.8% (RR 0.67, 95% CI 0.59, 0.76). Again, RFS (RR 0.68, 95% CI 0.59, 0.79) or both LRFS and DFRS, were significantly improved with AIs. OS was significantly prolonged with AIs, with an absolute benefit of 1.2% (RR 0.76, 95% CI 0.62, 0.93), without significant heterogeneity. Bone fractures were significantly higher in patients receiving AIs (RR 1.50, 95% CI 1.12, 2.02), and endometrial cancer in patients who continued to receive tamoxifen (RR 0.32, 95% CI 0.13, 0.77), without significant heterogeneity. Conclusions The early switch strategy improves survival over standard tamoxifen for 5 years, with a different toxicity profile. The lack of significant heterogeneity in the analysis underscores the homogenous effect across all trials.

Purpose: To observe whether in pretreated metastatic breast cancer patients with HER2-positive disease vinorelbine plus trastuzumab can produce different overall response rate (ORR), time to progression (TTP), and overall survival (OS) from women with HER2-negative tumors treated with vinorelbine alone. Methods: Between June 2000 and January 2004, 68 consecutive women were enrolled: 33 patients received vinorelbine (V) alone, while 35 patients were given trastuzumab plus vinorelbine (T+V) according to HER2 expression determined by immunohistochemistry. In tumors scored +2, HER2 gene amplification was determined by fluorescence in situ hybridization. Results: In patients treated with V (HER2-negative tumors) the ORR was 27.3%, while in those given T+V (HER2 positive tumors) the ORR was 51.4%. The median duration of response was 8 months for women treated with V and 10 months for those who received T+V. Patients given T+V had a longer TTP (9 months) and OS (27 months) than those receiving V alone (6 months and 22 months respectively). Toxicity was mild in both groups. Concerning cardiotoxicity in T+V group, 7 patients (20%) had left ventricular systolic disfunction. Conclusion: Our data suggest that trastuzumab can change the natural history of HER2-positive metastatic breast cancer. In fact, when treated with trastuzumab, women with HER2-positive disease had better prognosis than patients with HER2-negative tumors. Conducting a formal phase III trial comparing vinorelbine alone vs vinorelbine plus trastuzumab in HER2-positive metastatic breast cancer women could be debatable.

BACKGROUND New aromatase inhibitors (AI) (second-generation: formestane and fadrozole; third-generation: letrozole, anastrozole, vorozole, and exemestane) have been tested in several controlled clinical trials after tamoxifen failure in metastatic breast carcinoma (MBC). They have resulted in better survival compared with megestrol acetate (MEG) in a number of studies. The authors performed a pooled analysis including all the Phase III trials published between 1996 and 2004 evaluating the AIs approved or not by the Food and Drug Administration (FDA) and the European Agency for the Evaluation of Medical Products (EMEA) as second-line endocrine therapy (ET) for patients with MBC. METHODS The overall response rate (ORR) and time to disease progression (TTP) were considered the primary end points, whereas toxicity was regarded as a secondary objective. Relative risk, 95% confidence interval, and heterogeneity were derived using 2 methods. RESULTS No significant differences in ORR and TTP were noted in the entire group of 9 trials comparing AI with MEG (3908 patients) and in the 6 trials comparing nonsteroidal AI and MEG (2415 patients). AI yielded significantly more hot flashes than MEG (P = 0.004) but caused significantly less toxicity than MEG in weight gain (P = 0.001), dyspnea (P = 0.008), and peripheral edema (P = 0.03). Significant heterogeneity for nausea, weight gain, dyspnea, and peripheral edema was registered. When steroidal AIs were excluded from the toxicity analysis, nausea maintained its strongly significant heterogeneity (P = 0.0002), whereas weight gain, dyspnea, and peripheral edema lost their significance. CONCLUSIONS This pooled analysis suggested that AIs in second-line ET for patients with MBC do not seem to add any significant benefit to MEG in terms of ORR and TTP. With regard to toxicity, the findings in the current study showed that weight gain, dyspnea, and peripheral edema are more frequent with the use of MEG, whereas hot flashes were more represented using AI. Cancer 2005. © 2005 American Cancer Society.

Background: The aim of the study was to assess the toxicity profile, activity in terms of response rate, time to progression, overall survival, and quality of life of pegylated liposomal doxorubicin (PLD) and gemcitabine combination in chemo-naive and pretreated metastatic breast cancer (MBC) women. Methods: Patients were eligible if they had disease progression to prior chemotherapy (anthracycline-including or not) for early breast cancer or MBC. Patients received PLD 25 mg/m2 intravenously on day 1 plus gemcitabine 800 mg/m2 intravenously on days 1 and 8 of each 21-day cycle. Results: Of 50 patients enrolled, 37 had received prior adjuvant chemotherapy (24 with an anthracycline) and 23 prior chemotherapy for metastatic disease (6 with an anthracycline). Two complete responses and 20 partial responses were achieved in 46 assessable patients (overall response rate: 47.8%). Responses were observed in 14 (46.6%) of 30 patients with previous anthracycline exposure. Median response duration was 7 months, median duration of clinical benefit 8 months, time to progression 7 months. At a median follow-up of 10 months, 79.4% patients were alive at 1 year. No neutropenic complication was observed. Non-hematological toxicities were mild. One patient previously treated with an anthracycline developed a transient decrease (26%) in the left ventricular ejection fraction, with cardiac function recovering within 6 months. Conclusion: Because of the non-overlapping toxicity profiles of both PLD and gemcitabine, this combination can be regarded as a reliable therapeutic option for patients who have failed previous treatments, including anthracycline, for MBC.

In 1996, a gap between the literature evidence for the prevention of chemotherapy-induced emesis and the prescription pattern in clinical practice was demonstrated in a drug utilization study. This study, carried out in 103 Italian oncological centers (77 new; 26 old that participated in the previous study) evaluates three different intervention strategies to implement these guidelines. In cancer patients submitted to chemotherapy, prescriptions of antiemetics were prospectively monitored for 2 consecutive weeks in 1999. Simple diffusion of guidelines was evaluated in an observational study in the 77 new centers, while the double combination of simple diffusion and “audit and feedback” strategy was randomly compared in the old centers with the triple combination of the same two strategies plus an “educational outreach visit.” Simple diffusion of guidelines improved the prescription but only for acute and delayed emesis induced by high-moderate emetogenic chemotherapy. No significant difference was detected in the prescriptions against cisplatin-induced emesis. The inappropriate use of 5-HT3 antagonists for prophylaxis of low emetogenic chemotherapy was found most frequently. Similar poor results were achieved by the audit and feedback strategy, while the educational outreach visit significantly increased the prescription of the optimal prophylaxis for cisplatin-induced acute and delayed emesis. A combination of interventions, including an educational outreach visit, seems to be a good strategy for transferring the results of antiemetic research to oncological practice.

To improve chemotherapy dose intensity and to optimize the use of granulocyte-colony stimulating factor, 506 patients with early breast cancer were randomly assigned to high dose epirubicin and cyclophospamide (EC) with or without prophylactic subcutaneously filgrastim, according to 5 different schedules: 480 microg or 300 microg daily or every other day, on day 8 through day 14, and 300 microg daily on days 8 and 12 of each chemotherapy course, Serum levels of lactate dehydrogenase (LDH) and alkaline phosphatase (AP) were significantly higher in patients given EC plus filgrastim than EC alone (P = 0.0001), the rate of G1-3 toxicity being 33.4% and 13.1% vs. 1.6% and 1%, respectively. No clinical evidence of filgrastim-related hepatic damage or significant difference in transaminase and gamma-GT elevation was seen between the two groups. LDH and AP closely resembled peripheral blood leukocytes count and increased with increasing leucocytosis, throughout the 5 schedules. Although no patient continued treatment for filgrastim-related side effects, and LDH and AP rises resolved spontaneously within 3 weeks following the chemotherapy course, physicians should be aware of the transient and innocuous change in serum chemistry associated to leucocytosis, since it could be misinterpreted as expression of disease activity.

Nausea and vomiting have a negative influence on the quality of life of patients receiving chemotherapy. The Consensus Conference held in 1997 outlined the therapeutic procedure to prevent delayed emesis that might otherwise be induced by chemotherapy. So far, no study has evaluated the correct management of delayed emesis in clinical practice. This study was performed in an attempt to verify the conformity of the delayed emesis therapy administered in some oncological centres with the Consensus Conference guidelines. A total of 149 patients were observed for a minimum of one up to a maximum of four chemotherapy cycles; analysis of the data took account of whether the chemotherapy had a high (HEC), moderate (MEC) or low (LEC) emetogenic potential. Among 42 patients who received HEC, 18 (43%) received antiemetic prophylaxis conforming to standards; 23 (54.7%) of these 42 had delayed emesis, only 8 (34.7%) of whom were treated with adequate antiemetic protection. MEC was administered to 72 patients, 46 (64%) of whom received adequate prophylaxis; delayed emesis was observed in 31 (43%) of the 72 patients, 20 (64.5%) of whom received antiemetic prophylaxis according to established guidelines. Of 35 patients treated with LEC, 22.8% manifested delayed emesis; a high percentage of these patients, 68.5%, received prophylaxis, even though it was unnecessary. Of all patients observed, only 50.3% received correct antiemetic protection. We deduce from the study that antiemetic treatment for delayed emesis in clinical practice needs more attention. Correct prophylaxis is necessary when HEC is given, and antiemetic protection for patients receiving MEC must be improved; among patients treated with LEC those at high risk must be identified so that overtreatment can be avoided.

BACKGROUND: RANO criteria, which evaluate both contrast enhancement and T2/FLAIR alterations, have been recently defined, but no prospective validation exists. We examined the radiological data of patients with recurrent glioblastoma treated with bevacizumab (BEV) or fotemustine (FTM) in the randomized phase II AVAREG-ML25739 (EUDRACT 2011-001363-46) trial. METHODS: All MRIs of the pts have been evaluated (BEV/FTM: 59/32) accordingly with RANO and Macdonald's criteria, both locally and centrally. RESULTS: 223 MRIs were analyzed. Concordance between RANO and Macdonald criteria was found in 96.3% of cases at local evaluation and in 95.5% at central revision. Concordances between local and central assessments were 72.5% with RANO criteria and 71.1% with Macdonald's criteria. At local evaluation, pts treated with BEV had a disease control rate (DCR = CR/PR/SD) of 0.75 (95%CI: 0.62-0.85) with RANO criteria, and 0.76 (95%CI: 0.63-0.86) with Macdonald criteria, vs 0.59 (95%CI: 0.41-0.76) and 0.63 (95%CI: 0.44-0.79) with FTM. Central evaluation showed a DCR of 0.80 (95%CI: 0.68-0.90) both with RANO and Macdonald criteria for pts treated with BEV vs 0.50 (95%CI: 0.32-0.68)with FTM. In the BEV arm, only 6.8% of patients showed an increase of T2/FLAIR without T1 contrast enhancement. CONCLUSIONS: After 4 years from RANO proposal, we showed that there is a good concordance of disease evaluation in recurrent glioblastoma pts treated either with BEV or FTM in academic centers.

The ATHENA international study investigated the safety and efficacy of bevacizumab plus first-line chemotherapy in locally recurrent/metastatic breast cancer in routine oncology practice. The present paper focuses on the outcomes of the Italian cohort of the study.A subgroup analysis was carried out to report on the safety (primary endpoint) and efficacy (secondary endpoint) outcomes of patients recruited from Italian Centers.A total of 278 patients were included. Median age was 57 years (range, 26-85), and ECOG performance status was 0 or 1 in 96% of the patients. Bevacizumab was predominantly combined with a taxane monotherapy: paclitaxel (41.4%), docetaxel (21.9%), or a taxane-based combination therapy (12.2%). The most frequent grade ≥3 adverse events previously associated with bevacizumab were hypertension (3.2%), proteinuria (2.9%), and cardiac disorders (0.7%). Median time to progression was 10.9 months. Median overall survival was 29.9 months, and 1-year survival probability was 85%. Objective responses were observed in 62.6% of the patients, and an additional 30% achieved stable disease.Results from the study support the safety and efficacy of bevacizumab in combination with chemotherapy for the treatment of locally recurrent/metastatic breast cancer in the context of routine oncology practice in Italy.