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Background: In the era of targeted therapies, chemotherapy (CT) is still a valuable treatment option for patients (pts) with HER2 negative metastatic breast cancer (MBC). The identification of predictive and prognostic markers might improve treatment response and survival. Here we investigated the role of tumor subtypes, circulating tumor cells (CTCs), and mutations in genes or pathways of interest, in predicting response to CT and prognosis of HER2 negative MBC pts within AARES trial. Methods: AARES is an open label multicentric randomised phase 2 trial comparing a DNA-damaging (arm A: cisplatin 25 mg/m2/day, day 1-3 + cyclophosphamide 600 mg/m2 day 1) versus (vs) a non-DNA-damaging (arm B: capecitabine 1000 mg/m2 bid/day, day 1-14 + vinorelbine 60 mg/m2/day, day 1,8) CT regimen in pts with HER2 negative MBC. Archival tumor tissue samples and blood samples were collected at baseline. The Cell SearchTM system was used for CTCs isolation and enumeration and a cut-off of 5 CTC/7,5 ml was used. Tumor subtypes were based on locally assessed hormone receptors and HER2 status. The luminal-like subtype (Lum) was defined by ER or PR positivity, while the triple negative subtype (TN) by ER, PR, and HER2 negativity. Tissue samples were used for DNA extraction and next generation sequencing analysis using a target enrichment panel of 170 genes (TruSight 170, Illumina). Primary endpoint was objective response rate (ORR) assessed for the two treatment arms. Progression free survival (PFS) and overall survival (OS) were evaluated as secondary endpoints, and estimated with the Kaplan-Meier method. ORR, PFS and OS were correlated with CTC counts, tumor subtypes, and mutational status of genes/pathway of interest (PIK3CA, TP53, BRCA1, BRCA2, PI3K/AKT pathway (PI3K/AKT)). Results: AARES enrolled 102 pts from 2011 to 2016 across 9 Italian centers. Of these, 77 pts were evaluable for ORR. Median follow up was 32 months. Overall, median age was 57. The majority of pts had Lum tumors (73%), while 27% had TN. 86% of pts had visceral metastases, and 52% had 3 or more metastatic sites. 48% of pts received the study treatment as 1st line, 32% as 2nd line, and 19% as 3rd line. Out of the 77 pts with ORR data, 41 (53%) were CTC- and 36 (47%) CTC+. A larger proportion of pts with Lum tumors were CTC+ (54% n=30), while TN tumors were mainly CTC- (71% n=15). 49 pts had adequate tumor tissue for sequencing analysis. TP53 mutations (mut) were found in 33% of pts, BRCA1/2 mut in 14%, PIK3CA mut in 35%, and PI3K/AKT mut in 47%. ORR was 24% and 37% in arm A vs arm B, respectively (p= 0.2), and no difference in ORR was observed by tumor subtypes (Lum vs TN), and CTCs count (+ vs -). PFS and OS were assessable on the whole population (n=102) and did not significantly differ by treatment arms. Median OS (mOS) was higher in Lum pts compared to TN (24 months (mo) vs 15.4 mo, p=0.048) while median PFS (mPFS) did not differ according to tumor subtypes (p=0.28). Overall, CTCs count was not significantly associated with mPFS or OS however in pts with TN tumors and CTC-, mPFS and mOS were significantly longer (mPFS: 4.44 mo vs 2.56 mo in CTC- and CTC+ subgroups, respectively, p=0.00087 and mOS: 22.07 mo vs 3.57 mo in CTC- and CTC+ subgroups, respectively, p< 0.0001). On the other hand, no differences were observed in Lum pts categorized according to CTC status (p=0.83 for mPFS, p=0.54 for mOS). Finally, pts with PI3K/AKT mut had a significantly worse PFS compared to wild type in the overall population (p=0.0091) as well as in Lum (p=0.034) and TN pts (p=0.0052). Conclusions: CTCs and tumor subtypes were not predictive of response to CT regimens in HER2 negative MBC pts. A number of CTC >5 in TN MBC, and mutations in the PI3K/AKT pathway, identified a subgroup of pts with worse prognosis, potentially candidates for alternative treatments. Further studies are needed to confirm these results in a larger population. Citation Format: Emanuela Risi, Marta Pestrin, Chiara Biagioni, Dario Romagnoli, Ilenia Migliaccio, Francesca Galardi, Francesca De Luca, Matteo Benelli, Erica Moretti, Giuseppina Sanna, Luca Livraghi, Silvia Cappadona, Roberta Di Marsico, Domenico Amoroso, Angelo Martignetti, Angela S. Ribecco, Elena Rota Caremoli, Luigi Coltelli, Fabio Puglisi, Luca Malorni, Laura Biganzoli. Circulating tumor cells, immunohistochemical subtypes, and genes mutation as prognostic markers in HER2 negative metastatic breast cancer patients candidates to chemotherapy [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-05-45.

Ribociclib plus letrozole demonstrated manageable safety and efficacy profiles in hormone receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2-) advanced breast cancer (ABC) in the Phase 3b CompLEEment-1 trial.To evaluate the safety and efficacy of ribociclib plus letrozole in the Italian subpopulation with HR+, HER2- ABC from the CompLEEment-1 trial.Patients with HR+, HER2- ABC received ribociclib (600 mg/day, 3 weeks on/1 week off) plus letrozole (2.5 mg/day) while men and premenopausal women additionally received goserelin. Patients were allowed with ≤ 1 line of prior chemotherapy and an Eastern Cooperative Oncology Group performance status of ≤ 2. The primary outcome included safety and tolerability.Of the 554 Italian patients, 246 (44.4 %) patients completed treatment. The reasons for treatment discontinuation included progressive disease (PD; 36.6 %), adverse events (AEs; 11.9 %), and death (1.6 %). All-grade AEs and grade ≥ 3 AEs occurred in 98.9 % and 77.8 % patients, respectively. The most common treatment-related AEs were neutropenia (73.6 %), followed by leukopenia (32.1 %), and nausea (25.3 %). The overall response rate was 28.2 % (95 % confidence interval [CI], 24.4-32.1); clinical benefit rate was 71.7 % (95 % CI, 67.7-75.4); and median time to progression was 26.7 months (95 % CI, 24.8-non-estimable). Health-related quality of life scores were maintained during treatment.The safety and efficacy profiles of ribociclib plus letrozole in the Italian subpopulation was found to be consistent with the CompLEEment-1 global population result, MONALEESA-2, and MONALEESA-7 outcomes, which reaffirm ribociclib plus letrozole as the frontline treatment option in patients with HR+, HER2- ABC.NCT02941926 (30 November 2016).

Background: Approximately 10-30% of patients (pts) with metastatic breast cancer (BC) are diagnosed with central nervous system (CNS) metastases, which are a major cause of morbidity and mortality, and are associated with a poor prognosis. Due to improving diagnostics and treatments in BC, and therefore longer pt survival, more CNS metastases in breast cancer pts are readily detected. However, pts with CNS metastases are often excluded from clinical trials. Ribociclib (RIB), an oral, selective cyclin-dependent kinase 4/6 inhibitor, is approved for use in combination with endocrine therapy (ET) in women with HR+, HER2- ABC. Here, we present a subgroup analysis of pts with CNS metastases at baseline from the Core Phase of CompLEEment-1 (NCT02941926), a Phase IIIb trial of RIB in combination with letrozole (LET) in pts with HR+, HER2- ABC. The eligibility criteria for this study allowed a broader and more diverse pt population than those of previous Phase III trials of RIB + LET, to reflect a typical real-world clinical setting. Methods: CompLEEment-1 included women of any menopausal status and men with HR+, HER2- ABC treated with ≤1 line of prior chemotherapy and no prior hormonal therapy for advanced disease. Pts received RIB (600 mg QD, 3 weeks on/1 week off) in combination with LET (2.5 mg QD, continuous). Men and premenopausal women received a luteinizing hormone-releasing hormone agonist (3.6 mg goserelin or 7.5 mg leuprolide, Q28D). This subgroup analysis assessed the primary outcomes (safety and tolerability) and secondary outcomes of time to progression (TTP), overall response rate (ORR), and clinical benefit rate (CBR) in pts with CNS metastases. Results: At the data cutoff date (November 8, 2019), 51 pts with CNS metastases (1.57%; total pt population N = 3,246) had been evaluated: median age was 56.0 years, 30 (58.8%) pts were postmenopausal, and ECOG PS Citation Format: Paul Cottu, Michelino De Laurentiis, Paolo Marchetti, Luigi Coltelli, Nadia Califaretti, Marc Debled, Shekar Patil, Ella Evron, Francois Duhoux, Lakshmi Menon-Singh, Jiwen Wu, Katie Zhou, Javier Salvador Bofill. Ribociclib + letrozole in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2−) advanced breast cancer (ABC) and central nervous system metastases: Subgroup analysis of the phase IIIb CompLEEment-1 trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS14-07.

Introduction. Several studies have evaluated cardioprotective strategies to prevent myocardial dysfunction in patients who are receiving cardiotoxic therapies. Angiotensin-converting enzyme inhibitors and β-blockers are recommended first-line agents for heart failure. However, the optimal approach still represents a controversial issue. We hypothesized whether pharmacological cardioprevention could reduce subclinical heart damage in patients with breast cancer who are being treated with an anthracycline-based chemotherapy. Patients and methods. The SAFE trial was a 4-arm, randomized, phase 3, double-blind, placebo-controlled, national multicentric study conducted at eight oncology departments in Italy. The study recruitment was conducted between July 2015 and June 2020. A prespecified interim analysis on 174 women at 12 months was reported in 2020. Patients were eligible for trial inclusion if they had indication to receive primary or postoperative systemic therapy using an anthracycline-based regimen. Patients with a prior diagnosis of cardiovascular disease were excluded. Cardioprotective therapy (bisoprolol, ramipril, or both drugs compared with placebo) was administered for one year from the initiation of chemotherapy or until the end of trastuzumab therapy in case of ERBB2-positive patients. Doses for all groups were systematically up-titrated up to the daily target dose of bisoprolol (5mg, once daily), ramipril (5mg, once daily), and placebo, if tolerated. The primary end point was defined as detection of any subclinical impairment (worsening 10%) in myocardial function and deformation measured at 24 months using 3-dimensional (3D) echocardiography, left ventricular ejection fraction (LVEF), and global longitudinal strain (GLS). ClinicalTrials.gov identifier: NCT2236806. Results. 262 women (median age, 48 years; range, 24-75 years) were enrolled and treated in the study. We analyzed patients who had completed the pre-planned cardiological assessment at 24 months. Baseline demographic, tumor, and cardiovascular profiles were similar between groups. All patients received an anthracycline-based chemotherapy, 215 patients received at least three cycles of anthracyclines (range 1-6), 223 patients received also a taxanes-based chemotherapy, and 84 cases were treated with adjuvant trastuzumab. Sixty patients were treated with neoadjuvant chemotherapy, 157 cases received adjuvant endocrine therapy, and 128 patients had postoperative radiation therapy. GLS worsened 10% or greater in 68% of patients enrolled in the placebo arm, 15%, 13%, and 13% in the ramipril, bisoprolol, and ramipril plus bisoprolol arms, respectively (P < 0.05). A reduction of 10% or greater in 3D-LVEF was observed in 19% in the placebo arm, 11% in the ramipril arm, 11% in the bisoprolol arm, and 7% in the ramipril plus bisoprolol arm (P < 0.05). Study drugs were well tolerated with no serious adverse events, the ramipril plus bisoprolol arm showed significantly more toxic effects and had a significantly higher rate of allocated treatment discontinuation as compared to the other arms. Conclusions. Cardioprotective pharmacological strategies in patients who were affected by breast cancer and were receiving an anthracycline-based chemotherapy are well tolerated and protect against cancer therapy–related LVEF decline and heart remodeling. Citation Format: Icro Meattini, Carlotta Becherini, Luca Visani, Calogero Saieva, Viola Salvestrini, Francesca Martella, Carlotta Bacci, Elena Molinara, Mario Airoldi, Maria Riccarda Del Bene, Domenico Amoroso, Luigi Coltelli, Isacco Desideri, Vieri Scotti, Marco Bernini, Lorenzo Orzalesi, Jacopo Nori, Simonetta Bianchi, Giuseppe Barletta, Lorenzo Livi. Beta blockers and/or ACE inhibitors as cardioprotective strategy for patients affected by nonmetastatic breast cancer who are receiving an anthracycline-based chemotherapy (SAFE - NCT02236806): final results of a randomized trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD8-03.

To investigate pharmacogenetic interactions among VEGF-A, VEGFR-2, IL-8, HIF-1α, EPAS-1, and TSP-1 SNPs and their role on progression-free survival (PFS) in metastatic breast cancer (MBC) patients treated with bevacizumab plus first-line paclitaxel or with paclitaxel alone. Analyses were performed on germline DNA, and SNPs were investigated by real-time PCR technique. The multifactor dimensionality reduction (MDR) methodology was applied to investigate the interaction between SNPs. The present study was an explorative, ambidirectional cohort study: 307 patients from 11 Oncology Units were evaluated retrospectively from 2009 to 2016, then followed prospectively (NCT01935102). Two hundred and fifteen patients were treated with paclitaxel and bevacizumab, whereas 92 patients with paclitaxel alone. In the bevacizumab plus paclitaxel group, the MDR software provided two pharmacogenetic interaction profiles consisting of the combination between specific VEGF-A rs833061 and VEGFR-2 rs1870377 genotypes. Median PFS for favorable genetic profile was 16.8 vs. the 10.6 months of unfavorable genetic profile (p = 0.0011). Cox proportional hazards model showed an adjusted hazard ratio of 0.64 (95% CI, 0.5–0.9; p = 0.004). Median OS for the favorable genetic profile was 39.6 vs. 28 months of unfavorable genetic profile (p = 0.0103). Cox proportional hazards model revealed an adjusted hazard ratio of 0.71 (95% CI, 0.5–1.01; p = 0.058). In the 92 patients treated with paclitaxel alone, the results showed no effect of the favorable genetic profile, as compared to the unfavorable genetic profile, either on the PFS (p = 0.509) and on the OS (p = 0.732). The pharmacogenetic statistical interaction between VEGF-A rs833061 and VEGFR-2 rs1870377 genotypes may identify a population of bevacizumab-treated patients with a better PFS.

Background: Real world data have the potential to demonstrate the applicability of the results of randomized studies in the general population. SUPER trial was conducted in order to assess the activity, the efficacy and the safety of the combination of pertuzumab, trastuzumab and chemotherapy in clinical practice.Material and methods: Patients diagnosed with HER2 positive metastatic breast cancer (mBC) and treated with pertuzumab, trastuzumab and chemotherapy were accrued at 18 italian hospitals. Data were retrospectively collected in the time frame between pertuzumab availability in clinical practice and study approval in 2016, and prospectively collected thereafter. Results: Overall 342 HER2 positive mBC were accrued. 172 patients had relapsed disease and 56.4% of them received neo/adjuvant trastuzumab. 205 patients received docetaxel. Objective response rate was 76.3% (95%CI: 71.4–80.7). Median progression free survival (PFS) and overall survival (OS) were 24.3 months (95% CI: 20.0–28.9) and 70.2 months (95% CI: 61.4–79.0) respectively. Triple positive patients treated with endocrine therapy in addition to pertuzumab and trastuzumab maintenance had a significant longer PFS and OS than patients who did not. mPFS was 31.2 months and 13 months respectively (HR=0.47; 95% CI: 0.33–0.66; pConclusions: SUPER suggests that results of first-line treatment with pertuzumab, trastuzumab and chemotherapy in unselected patients are consistent with findings from CLEOPATRA trial.Moreover, as expected from real world evidence, new insights have emerged.

Background Metastatic breast cancer (MBC) is highly prevalent in middle-aged or elderly patients. Eribulin is a nontaxane microtubule inhibitor, approved for the treatment of pretreated MBC. This multicentric study (sponsored by GIOGer, Italian Group for Geriatric Oncology) was designed to assess the efficacy and tolerability of eribulin, according to parameters usually used in geriatric oncology. Subjects, materials, and methods An observational study was conducted on 50 consecutive elderly patients with MBC. The primary endpoint was to evaluate the change in items score of comprehensive geriatric assessment (CGA) and health-related quality of life (HRQL). Italian versions of the CGA and HRQL questionnaires were administered at baseline, before the third and fifth cycles, and then every three cycles until treatment discontinuation. Secondary endpoints were efficacy and safety. Results Overall, both EQ-5D scores and EQ-5D-3 L visual analogic scale did not significantly change from baseline; the percentage of subjects without problems doing usual activities tended to decrease during treatment (p for linear trend .018), and the percentage of patients with minor problems performing usual activities tended to increase (p for linear trend.012). Among CGA items, Instrumental Activities of Daily Living tended to decrease during treatment and Geriatric Depression Scale tended to increase. After 12 months follow-up, 24 patients (out of 47) showed clinical benefits; median progression-free survival was 4.49 months (2.10-10.33) and median OS was 7.31 months (3.70-14.03). The treatment was associated with mild toxicity. Conclusion Eribulin treatment preserved quality of life and geriatric parameters included in the CGA, except for instrumental functioning and geriatric depression, in elderly patients with MBC. Implications for practice A collaboration between oncologist and geriatric specialists is essential in the management of patients with metastatic breast cancer, who are frequently elderly or frail. The assessment of geriatric parameters in the decision-making process can contribute to direct toward the most appropriate therapeutic plan and preserve the quality of life of patients. Eribulin does not seem to affect quality of life or worsen the overall geriatric status; therefore, it can be considered a suitable option for elderly patients with metastatic breast cancer.

Background: several studies have evaluated cardioprotective strategies to prevent myocardial dysfunction in patients receiving cardiotoxic therapies. However, the optimal approach still represents a controversial issue. The SAFE trial (ClinicaTrials.gov identifier: NCT2236806) is a four-arm, randomized, phase 3, double-blind, placebo-controlled study. The objective is to determine whether pharmacological cardioprevention could reduce subclinical heart damage in breast cancer patients treated with anthracycline-based chemotherapy. This is a subgroup analysis focused on the impact of postoperative breast radiation therapy (RT) of the recently published pre-specified interim analysis on the first 174 patients who had completed cardiac assessment at 12-month. Methods: patients were eligible for trial inclusion if they had indication to primary or postoperative systemic therapy using an anthracycline-based regimen. Patients with prior diagnosis of cardiovascular disease were excluded. Cardioprotective therapy (bisoprolol, ramipril, or both drugs, as compared to placebo) was administered for 1 year from the initiation of chemotherapy or until the end of trastuzumab therapy in case of HER2 positive patients. The primary endpoint was defined as detection of any subclinical impairment (worsening ≥10%) in myocardial function and deformation measured with standard and 3-dimensional (3D) echocardiography, left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS). Results: at 12-month, 3D-LVEF worsened by 4.4% in placebo arm and 3.0%, 1.9%, 1.3% in ramipril, bisoprolol, ramipril plus bisoprolol arms, respectively (P = .005). GLS worsened by 6.0% in placebo arm and 1.5%, .6% in ramipril, and bisoprolol arms, respectively; whereas it was unchanged (.1% improvement) in ramipril plus bisoprolol arm (P < .001). The percentage of patients showing a reduction ≥10% in 3D-LVEF was 19% in placebo arm, 11.5% in ramipril arm, 11.4% in bisoprolol arm and 6.8% in ramipril plus bisoprolol arm; 35.7% patients receiving placebo showed a ≥10% GLS worsening compared to 15.9% (ramipril), 13.6% (bisoprolol), and 13.6% (ramipril plus bisoprolol) (P = .025). Concerning differences in 3D-LVEF changes from baseline to end of treatment, bisoprolol-containing arms showed significant benefit in patients not receiving RT (P = .09), in patients receiving right-sided breast RT (P = .0001), and with lesser extent, in patients receiving left-sided RT (P = .041). No significant benefit was shown in ramipril-containing arms. Concerning differences in GLS changes from baseline to end of treatment, bisoprolol-containing arms showed significant benefit in patients not receiving RT (P = .0001) and in patients receiving right-sided breast RT (P = .0001), while no benefit was shown in patients receiving left-sided breast RT (P = .270). Ramipril-containing arms showed significant benefit in patients not receiving RT (P = .035) and in patients receiving left-sided breast RT (P = 0.14), while no benefit was shown in right-sided breast RT (P = .260). Conclusions: at the interim analysis, cardioprotective pharmacological strategies in patients affected by breast cancer receiving an anthracycline-based chemotherapy are well tolerated and seem to protect against cancer therapy-related LVEF decline and heart remodeling. This favorable effect seems to be reduced in patients receiving postoperative left-sided breast RT, thus calling for further investigations on potentially radiation-related early subclinical heart damage. Citation Format: Icro Meattini, Giuseppe Barletta, Carlotta Becherini, Luca Visani, Francesca Martella, Mario Airoldi, Domenico Amoroso, Luigi Coltelli, Chiara Bellini, Giulia Stocchi, Victoria Lorenzetti, Carolina Orsatti, Lucia Angelini, Lorenzo Livi. Cardioprotective strategy for non-metastatic breast cancer patients receiving an anthracycline-based chemotherapy: subgroup analysis focused on impact of postoperative breast radiation therapy of the preplanned interim analysis of the phase 3 SAFE trial (NCT2236806) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD5-02.

Background: Around 20% of breast cancers (BC) are HER-2+. Trastuzumab (T) has dramatically changed the outcome of HER-2+ BC patients (pts), both in early and in advanced settings. The combination of Pertuzumab (P) plus T and docetaxel, used as first-line treatment for HER-2+ metastatic BC (MBC) in the phase III CLEOPATRA study, significantly prolonged progression free survival (PFS) and overall survival (OS). In order to verify the results of the Cleopatra trial in unselected pts, we performed a multicenter, retrospective-prospective, observational study, in HER-2+ MBC pts candidate to receive first line therapy with P plus T plus taxanes. Methods: We analyze the outcome of all HER-2+ MBC pts treated with P+T and taxanes, as first line therapy since the availability of P in Italy (2013), at 13 general and university hospitals. Results: Until June 6th data from 217 HER-2+ MBC pts were recorded. Main pts' characteristics were: median age 54 y (28-80), median ECOG PS 0 (0-2), hormonal receptor positive 152 pts (70%), 60 pts (27.6%) received neo/adjuvant chemotherapy (CT) + T and 75 pts (34.5%) adjuvant endocrine therapy. Most common metastatic sites: bone 121 pts (55.7%), liver 85 pts (39.2%), lung 61 pts (28.1%), soft tissues 133 pts (61.3%); 8 pts had CNS involvement. Seventy-eight pts (35.9%) had bone and/or soft tissues disease only; 108 pts (49.7%) had metastatic disease on presentation. Median number of metastatic sites was 3 (1-8). 144 pts (66.3%) and 72 pts (33.2%) received docetaxel (D) and paclitaxel (P) respectively. Median number of CT cycles was 6 for both drugs (D range 1-13; P range 1-18). Up to now 23 pts are still on CT and 86 on maintenance; ORR in evaluated pts (189) is 80.9% (47 and 106 pts obtained CR and PR respectively), 11 pts experienced PD during CT; 113 pts (58.2%) received endocrine therapy during maintenance.Median PFS is 14.7+ months (0.3+ - 53.2+). Most common adverse events are reported in table 1 Table 1Adverse EventAll grades N (%)Grade 3-4 N (%)Leukopenia39 (18)10 (4.6)Neutropenia42 (19.3)16 (7.3)Anemia50 (23)2 (0.9)Febrile Neutropenia7 (3.2) Diarrhea103 (47.4)10 (4.6)Asthenia127 (58.5)5 (2.3)Peripheral Neuropathy80 (36.8)3 (1.3)Stomatitis67 (30.8)2 (0.9) Nail changes, nausea, alopecia, rash and arthro-myalgia were also reported. Three pts interrupted CT due to symptomatic drop of left ventricular ejection fraction (LVEF); 2 pts interrupted maintenance P due to rash and dyspnea respectively, 16 stopped P and T due to drop in LVEF, 1 due to occurrence of ALL and 1 refused to continue. Conclusions: Our preliminary results highlight the activity and safety of the combination of CT plus P and T in unselected HER-2+ MBC patients. The study is ongoing and updated results will be presented. Citation Format: Garrone O, D'Onofrio L, Blondeaux E, Bertolini I, Giarratano T, Beano A, Saggia C, Cazzaniga M, LaVerde N, Collovà E, Milani A, De Conciliis E, Coltelli L, Airoldi M, Del Mastro L, Cursano MC, Michelotti A, Vandone AM, Guarneri V, Donadio M, Riva F, Nuzzo A, Merlano MC. Moving from the CLEOPATRA study to real life: Preliminary results from the G.O.N.O. SUPER trial [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-21-29.

IMPORTANCE: Several studies have evaluated cardioprotective strategies to prevent myocardial dysfunction in patients who are receiving cardiotoxic therapies. However, the optimal approach still represents a controversial issue. OBJECTIVE: To determine whether pharmacological cardioprevention could reduce subclinical heart damage in patients with breast cancer who are being treated with anthracycline-based chemotherapy. DESIGN, SETTING, AND PARTICIPANTS: The SAFE trial was a 4-arm, randomized, phase 3, double-blind, placebo-controlled, national multicentric study conducted at 8 oncology departments in Italy. It was a prespecified interim analysis on the first 174 patients who had completed cardiac assessment at 12 months. The study recruitment was conducted between July 2015 and June 2020. The interim analysis was performed in 2020. Patients were eligible for trial inclusion if they had indication to receive primary or postoperative systemic therapy using an anthracycline-based regimen. Patients with a prior diagnosis of cardiovascular disease were excluded. INTERVENTIONS: Cardioprotective therapy (bisoprolol, ramipril, or both drugs compared with placebo) was administered for 1 year from the initiation of chemotherapy or until the end of trastuzumab therapy in case of ERBB2-positive patients. Doses for all groups were systematically up-titrated up to the daily target dose of bisoprolol (5 mg, once daily), ramipril (5 mg, once daily), and placebo, if tolerated. MAIN OUTCOMES AND MEASURES: The primary end point was defined as detection of any subclinical impairment (worsening ≥10%) in myocardial function and deformation measured with standard and 3-dimensional (3D) echocardiography, left ventricular ejection fraction (LVEF), and global longitudinal strain (GLS). RESULTS: The analysis was performed on 174 women (median age, 48 years; range, 24-75 years) who had completed a cardiological assessment at 12 months and reached the end of treatment. At 12 months, 3D-LVEF worsened by 4.4% in placebo arm and 3.0%, 1.9%, 1.3% in the ramipril, bisoprolol, ramipril plus bisoprolol arms, respectively (P = .01). Global longitudinal strain worsened by 6.0% in placebo arm and 1.5% and 0.6% in the ramipril and bisoprolol arms, respectively, whereas it was unchanged (0.1% improvement) in the ramipril plus bisoprolol arm (P

// Anna Solini 1 , Vittorio Simeon 2 , Lisa Derosa 3 , Paola Orlandi 1 , Chiara Rossi 1 , Andrea Fontana 3 , Luca Galli 3 , Teresa Di Desidero 1 , Anna Fioravanti 1 , Sara Lucchesi 4 , Luigi Coltelli 4 , Laura Ginocchi 4 , Giacomo Allegrini 4 , Romano Danesi 1 , Alfredo Falcone 3 , Guido Bocci 1 1 Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy 2 Laboratory of Pre-clinical and Translational Research, IRCCS - CROB Referral Cancer Center of Basilicata, Rionero in Vulture, Potenza, Italy 3 Oncology Unit 2, University Hospital of Pisa, Pisa, Italy 4 Division of Medical Oncology, Pontedera Hospital, Azienda USL of Pisa, Pontedera, Italy Correspondence to: Guido Bocci, e-mail: guido.bocci@med.unipi.it Keywords: survival dimensionality reduction analysis, P2X7 receptor, VEGFR-2, polymorphisms, prostate cancer Received: April 07, 2015 Accepted: August 10, 2015 Published: August 21, 2015 ABSTRACT VEGFR-2 and P2X 7 receptor (P2X 7 R) have been described to stimulate the angiogenesis and inflammatory processes of prostate cancer. The present study has been performed to investigate the genetic interactions among VEGFR-2 and P2X 7 R SNPs and their correlation with overall survival (OS) in a population of metastatic prostate cancer patients. Analyses were performed on germline DNA obtained from blood samples and SNPs were investigated by real-time PCR technique. The survival dimensionality reduction (SDR) methodology was applied to investigate the genetic interaction between SNPs. One hundred patients were enrolled. The SDR software provided two genetic interaction profiles consisting of the combination between specific VEGFR-2 (rs2071559, rs11133360) and P2X 7 R (rs3751143, rs208294) genotypes. The median OS was 126 months (95% CI, 115.94–152.96) and 65.65 months (95% CI, 52.95–76.53) for the favorable and the unfavorable genetic profile, respectively ( p < 0.0001). The genetic statistical interaction between VEGFR-2 (rs2071559, rs11133360) and P2X 7 R (rs3751143, rs208294) genotypes may identify a population of prostate cancer patients with a better prognosis.

Importance The combination of a triple-drug chemotherapy regimen with an anti–epidermal growth factor receptor (EGFR) agent as a first-line treatment of metastatic colorectal cancer (mCRC) showed promising activity along with safety concerns in single-arm phase 2 trials. The role of maintenance following chemotherapy and anti-EGFR and the optimal regimen to be adopted are not established. Objectives To evaluate the activity and safety of cetuximab plus modified FOLFOXIRI (mFOLFOXIRI) and explore the role of maintenance with cetuximab or bevacizumab in RAS and BRAF wild-type mCRC. Design, Setting, and Participants In a prospective, noncomparative, open-label, multicenter, randomized phase 2 trial, patients aged 18 to 75 years with unresectable, previously untreated RAS and BRAF wild-type (before amendment, KRAS wild-type) mCRC were recruited from 21 oncology units in Italy from October 19, 2011, to March 1, 2015 (followed up through May 31, 2017). In total, 323 patients were screened and 143 were randomized to 2 treatment arms to receive as a first-line induction a regimen of mFOLFOXIRI plus cetuximab followed by cetuximab (arm A) or bevacizumab (arm B) until disease progression. Primary analyses were conducted in a modified intention-to-treat population. Interventions mFOLFOXIRI plus cetuximab repeated every 2 weeks for up to 8 cycles, followed by maintenance with cetuximab or bevacizumab until disease progression. Main Outcomes and Measures The primary end point was the 10-month progression-free rate (PFR); secondary end points included progression-free and overall survival, response rate, rate of metastases resection, and adverse events. Results Of 143 patients randomized, 116 (81.1%) (median [interquartile range (IQR)] age, 59.5 [53-67] years; 34 [29.3%] women) had RAS and BRAF wild-type mCRC. At a median (IQR) follow-up of 44.0 (30.5-52.1) months, 10-month PFRs were 50.8% (90% CI, 39.5%-62.2%) in arm A and 40.4% (90% CI, 29.4%-52.1%) in arm B. The overall response rate was 71.6% (95% CI, 62.4%-79.5%). Main grade 3/4 adverse events were neutropenia (occurring in 36 patients [31%]), diarrhea (in 21 patients [18%]), skin toxic effects (in 18 patients [16%]), asthenia (in 11 patients [9%]), stomatitis (in 7 patients [6%]), and febrile neutropenia (in 3 patients [3%]). Conclusions and Relevance Although neither of the 2 arms met the primary end point, the findings indicate that a 4-month induction regimen of mFOLFOXIRI plus cetuximab is feasible and provides relevant activity results, leading to a high surgical resection rate. Trial Registration clinicaltrials.gov Identifier:NCT02295930

Background The phase IIIb international study C-1 (NCT02941926) aims to assess the safety and efficacy of RIBO + LET in men and women who have not received prior ET for HR+, HER2– ABC. Overall more than 3000 pts were enrolled. Here we present interim efficacy and safety results from the Italian cohort. Methods Pts with HR+, HER2– ABC, ≤1 line of prior chemotherapy, and no prior ET for ABC received RIBO (600 mg/day, 3 wk on/1 wk off) + LET (2.5 mg/day). Men and premenopausal women received concomitant goserelin. The primary endpoint was safety and tolerability. Secondary endpoints included time to progression (TTP), overall response rate (ORR) and clinical benefit rate (CBR). Results From April 2017, to December 2017, 554 pts were enrolled in the C-1 trial in Italy. Median age was 58 years (range 20–87); 1,1% (6) of pts were male, 29,1% were premenopausal women and 69.3% post-menopausal. 2,3%(13) of pts presented CNS metastases and 4,5% (25) skin involvement at study entry. At the cut-off date for this Analysis (August 8, 2018) 66,1% of the pts were still on treatment, 29,8% discontinued, mainly for progression (18,4%) or AEs (10,3 %). The most common all-grade any-cause AEs were neutropenia (69,7%), nausea (29,6%), and leukopenia (28,7%). Grade 3 or 4 elevations in ALT and AST levels were reported in 6,4% and 4,3%, respectively. Prolongation of the QTcF interval to more than 480 msec occurred in 3.1% of patients. 30,3% of patients required a dose reduction (24% one dose, 24,9% due to AEs). ORR was 20,4% (95% CI, 17,1%-24%) and CBR was 69,7% (95% CI, 65,7%-73,5%). TTP was not reached. Conclusions This interim analysis confirm the predictable and manageable safety profile of RIBO in combination with LET as first-line treatment for HR+, HER2– ABC. The Italian C-1 cohort is the largest hormono-sensitive Italian population ever published with a CDK 4/6 inhibitor, including 6 male patients and 13 patients with CNS metastases that could give valuable information on this patient’s subgroups that still represent an unmet need. Clinical trial identification EudraCT: 2016-003467-19, release date 2016-12-08 Protocol n. CLEE011A2404 NCT02941926. Legal entity responsible for the study Novartis Pharma AG. Funding Novartis Pharma AG. Disclosure M. De Laurentiis: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Celgene; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: astrazeneca; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: eisai; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Eli Lilly; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Amgen. M. Mazza: Honoraria (self): Novartis; Honoraria (self): Pfizer; Honoraria (self): istituto gentili; Honoraria (self): Celgene; Honoraria (self): astrazeneca. M. Mansutti: Honoraria (self): Novartis; Honoraria (self): Pfizer; Honoraria (self): Celgene. R. Masetti: Honoraria (self), Advisory / Consultancy: genomic Health; Honoraria (self), Advisory / Consultancy: medtronic. Z. Ballatore: Honoraria (self), writing engagement and public speaking: Ipsen. R. Torrisi: Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Lilly; Honoraria (self), Advisory / Consultancy: MSD. A. Michelotti: Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: astrazeneca; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: eisai; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Celgene; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: teva; Advisory / Consultancy: Pfizer. A. Zambelli: Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: astrazeneca. D. Generali: Honoraria (self): Novartis; Honoraria (self): Lilly; Honoraria (self): Pfizer; Honoraria (self): Roche. P. Vici: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer. A. Fabi: Honoraria (self), Speaker Bureau / Expert testimony: Roche; Honoraria (self), Speaker Bureau / Expert testimony: Novartis; Honoraria (self), Speaker Bureau / Expert testimony: astrazeneca; Honoraria (self), Speaker Bureau / Expert testimony: Pfizer. P. Marchetti: Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: bms; Honoraria (self), Advisory / Consultancy: astrazeneca; Honoraria (self), Advisory / Consultancy: incyte; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: molteni; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: MSD. S. Spazzapan: Honoraria (self), Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Celgene; Travel / Accommodation / Expenses: gentili; Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (institution), principal investigator of trials: Novartis; Honoraria (self), Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Speaker Bureau / Expert testimony: Takeda; Honoraria (self), Speaker Bureau / Expert testimony: Pierre Fabre; Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses, principal investigator of trials: Roche; Honoraria (self), Travel / Accommodation / Expenses: tesaro; Honoraria (self), Speaker Bureau / Expert testimony: astrazeneca; Research grant / Funding (institution), principal investigator of trials: abbvie. A. Frassoldati: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Honoraria (self), Speaker Bureau / Expert testimony, plus writing engagement: astrazeneca; Honoraria (self), Speaker Bureau / Expert testimony: Pfizer. G. Sarobba: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Amgen; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: teva. D. Grasso: Full / Part-time employment: Novartis; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: astrazeneca; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Celgene; Honoraria (self), Travel / Accommodation / Expenses: pierrefabre. C. Zamagni: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Celgene; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: astrazeneca; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: teva; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: istituto gentili; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: eisai; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Amgen; Honoraria (self), Advisory / Consultancy: eliLilly; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: tesaro. All other authors have declared no conflicts of interest.

Purpose To investigate the cardiac safety of adjuvant Non-Pegylated Liposomal Doxorubicin (NPL-DOX) combined to Cyclophosphamide (CTX) and followed by weekly Paclitaxel, in older patients (≥65 years) with diagnosis of high risk breast cancer. The main end point of this prospective study was the detection of early episodes of symptomatic congestive heart failure (CHF). Methods The cardiac function was evaluated by left ventricular ejection fraction (LVEF) measurements with repeated echocardiograms, performed 2 weeks before the beginning of chemotherapy and every 6 months, until 30 months after the study entry; then yearly for at least 5 years. Results Forty-seven patients were enrolled from two Italian Divisions of Medical Oncology. Final results revealed no early episodes of symptomatic CHF within the first 12 months from the enrolment. Only two cardiac events were observed: an episode of atrial flutter after the first cycle of NPL-DOX and CTX, with a quick return to normal rhythm, and a grade 3 (scored to NCI-CTCAE, version 3.0) CHF episode, 18 months later chemotherapy start. No other relevant toxicities were reported. Conclusions This adjuvant combination including NPL-DOX in elderly patients, resulted in a low rate of cardiac toxic effects. Comparative trials should be encouraged to confirm these findings.

e13006Background: Approximately 20% of breast cancers (BC) are HER-2+. Trastuzumab (T) has dramatically changed the outcome, both in early and in advanced settings in HER2+BC. Pertuzumab (P) plus T...

e12510 Background: Approximately 20% of breast cancers (BC) are HER-2+. Trastuzumab (T) has substantially improved the outcome, both in early and in advanced settings, in HER-2+BC. Pertuzumab (P), combined with T and taxanes, ameliorated progression free survival (PFS) and overall survival (OS) in the phase III CLEOPATRA study. In order to verify the results of the trial in unselected patients (pts), we performed a multicenter, retrospective-prospective, observational study, in HER-2+ metastatic BC (MBC) pts. Methods: We analyze the outcome of all HER-2+ MBC pts treated with P+T and taxanes, as first line therapy since the availability of P in Italy, at 11 general and university hospitals. Results: Up to February 1stdata from 103 HER-2+ MBC pts were recorded. Main pts’ characteristics were: median (M) age 52 y (28-78), m ECOG PS 0 (0-2), ER/PgR positive 68 pts (66%). Most common metastatic sites: liver 51 pts (49.5%), bone 64 pts (62.1%), lung 26 pts (25.2%). Thirty pts (29.1%) had bone and soft tissue disease only; 78 pts (75.7%) had metastatic disease on presentation. m number of metastatic sites was 3 (1-7); 25 pts (24.3%) received neo/adjuvant chemotherapy (CT) + T and 36 pts (34.9%) adjuvant endocrine therapy; 71 pts (69%) and 32 pts (31%) received docetaxel (D) and paclitaxel (P) respectively. m number of CT cycles was 6 for both drugs (D range 3-12; P range 1-18).At the time of the present analysis 12 pts are still on CT and 78 on maintenance; response is available for 91 pts and ORR is 80.2% (22 pts and 51 pts obtained CR and PR respectively), 6 pts experienced PD during CT. Median PFS is 13.9 months (1.5+ - 33.8+).Among hematological toxicities leucopenia (any grade) was recorded in 29 pts (28.1%), g 3 febrile neutropenia in 6 pts (5.8%). No change of left ventricular ejection fraction (LVEF) was recorded during CT; 4 pts interrupted maintenance P due to drop in LVEF and 1 due to rash. Onicopathy, nausea, alopecia, rash and arthro-myalgia were the most common non-hematological toxicities. Conclusions: Our preliminary results highlight the activity and the safety of the combination of CT plus P and T in unselected HER2+ MBC patients. The study is ongoing and updated results will be presented.

Aim: To investigate pharmacogenetic interactions among VEGF-A, VEGFR-2, IL-8, HIF-1α, EPAS-1 and TSP-1 SNPs and their role on progression-free survival in a population of metastatic breast cancer patients treated with bevacizumab in combination with first-line paclitaxel. Patients & methods: Analyses were performed on germline DNA obtained from blood samples and SNPs were investigated by real-time polymerase chain reaction technique. The multifactor dimensionality reduction methodology was applied to investigate the interaction between SNPs. Results: One hundred and thirteen patients were enrolled from eight Italian Oncology Units ( clinicaltrial.gov : NCT01935102). The multifactor dimensionality reduction software provided two pharmacogenetic interaction profiles consisting of the combination between specific VEGFR-2 rs11133360 and IL-8 rs4073 genotypes. The median progression-free survival was 14.1 months (95% CI: 11.4–16.8) and 10.2 months (95% CI: 8.8–11.5) for the favorable and the unfavorable genetic profile, respectively (HR: 0.44, 95% CI: 0.29–0.66, p < 0.0001). Conclusion: The pharmacogenetic statistical interaction between VEGFR-2 rs11133360 and IL-8 rs4073 genotypes may identify a population of patients with a better outcome.

1086 Background: Previous retrospective studies have attempted to identify a possible role of VEGF single nucleotide polymorphisms (SNPs) to predict BV efficacy in terms of OS and PFS in MBC pts with conflicting results (Schneider 2008, Grimaldi 2011, Lambrechts 2011). Methods: On the basis of these preliminary data, we decided to assess in a MBC population if different VEGF, VEGFR-2, IL-8, IL-6, HIF-1alfa, EPAS-1 and TSP-1 genotypes could predict first line BV + paclitaxel (P) response in terms both of OS and PFS. Analyses were performed on germline DNA obtained from blood samples. Fourteen polymorphisms were investigated by real-time PCR technique. Both single and combinations of SNPs were investigated. The multifactor dimensionality reduction (MDR) methodology was applied to identify a genetic interaction profile for PFS ( http://sourgeforge.net/projects/mdr/ ). Results: 102 pts have been enrolled from 8 Oncology Units. Main pts characteristics are: median age 59 years (range 32-81), ECOG-PS 0/1 in 78%/22%, hormone receptor positive 83%, previous adjuvant chemotherapy 68%, disease free interval (DFI) < 12 months 27%. After a median follow up of 17.4 months (1.9-54.7), mPFS was 11.6 months (95% CI: 10.6-12.6) and mOS was 32.4 months (95% CI: 25.9-38.9). None of SNPs were individually associated with PFS. Conversely, a genetic interaction profile consisting of VEGFR-2 rs11133360 and IL-8 rs4073 was significantly associated with PFS. mPFS was 14 months (95% CI: 11.7-16.3) and 10.9 months (95% CI: 9.3-12.4) for the favorable and unfavorable genetic profile, respectively (HR=0.63, 95% CI: 0.4-0-99, p= 0.046). Furthermore, at the multivariate analysis hormone receptor positive (HR=0.22, 95% CI: 0.12-0-41, p12 months (HR= 0.4, 95% CI: 0.2-0.82, p= 0.011) and BV maintenance (HR=0.63, 95% CI: 0.25.0.71, p=0.001) were significantly associated with a better PFS. Conclusions: Genetic interaction between VEGFR-2 rs11133360 and IL-8 rs4073 polymorphisms could predict BV response in terms of PFS. With a longer follow-up correlations with OS will be investigated. Prospective study is planned. Study supported by the non-profit foundation F.A.R.O.

Recent data reported an association between VEGF-A genotype of tumors and median overall survival as well as grade 3 or 4 hypertension when using bevacizumab in metastatic breast cancer. In the present case we report a discordant VEGF-A genotype between tumor and normal tissue in a patient with a responsive hepatic lesion of chemoresistant breast cancer treated with bevacizumab and paclitaxel. Moreover, we show that, despite the very low VEGF-A protein expression, the neoplastic lesion was well vascularized and responded to bevacizumab therapy. The discordance of VEGF-A polymorphisms in tumor and germline DNA may suggest the importance of obtaining both information in order to predict a superior overall survival or a lower risk of hypertension in patients treated with taxanes and bevacizumab.

11021 Background: women treated with tamoxifen for ER-positive early breast cancer are at a two to seven fold increased risk of endometrial cancer. Even though published data fail to support the use of transvaginal ultrasound (TVU) for screening of endometrial cancer, this is still a very common clinical practice in this subset of patients (pts). Methods: we have conducted a retrospective analysis to investigate the value of TVU in early detection of tamoxifen-related endometrial cancer. The screened population consists of pts treated with adjuvant tamoxifen in our institution from January 1999 up to December 2003 receiving a TVU annually or in case of gynaecologic symptoms. Results: 491 evaluated pts performed a total of 1634 TVUs in asymptomatic conditions. FIGO stage I endometrial cancers have been diagnosed in 3 patients (0.32%) who are still alive after total hysterectomy. A vaginal bleeding anticipated the examination in 33 women (3.2%) and represented the first symptom in two cases of tumor. Only one endometrial cancer has been detected with the screening procedure. Median increase of endometrial thickness has been 7.6 mm (range 1–34 mm) and those patients with abnormal images at TVU underwent an hysteroscopy with endometrial biopsies (169) resulting in a benign histology (polyps, cystic atrophy, hyperplasia) in most cases. Conclusions: therefore we have performed more than 1500 transvaginal ultrasound to detect only one asymptomatic cancer so we agree with literature in supporting that women receiving tamoxifen should undergo only an annual gynaecologic examination reserving the TVU to patients with vaginal bleedings or discharges. No significant financial relationships to disclose.

870 Background: Gemcitabine (G) and Capecitabine (C) are both actives in metastatic breast cancer (MBC). Methods: To define the maximum tolerated dose of this combination we designed a phase I stud...