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Cardio-oncology is now part of the standard clinical approach for patients with cancer and cannot be overlooked anymore. While its scientific background is solid and its clinical relevance is well known, its application in daily practice varies greatly among hospitals. To provide the best cardio-oncology care to cancer patients and to make cardio-oncology's clinical use uniform, we developed a shared multidisciplinary proposal for a dedicated clinical pathway. Our proposition presents the minimum requirements needed to which this path caters for, identifies patient categories to be entered into the path, highlights the role of a specific inter-hospital clinical and imaging network and indicates follow-up strategies during and after oncological treatments. The proposed pathway is based on some key elements and is easily adaptable to different hospitals with minimal changes.

Background Despite endocrine therapy is the mainstay of treatment for HR+/HER2- metastatic breast cancer (MBC), patients with high disease burden or those at risk of visceral crisis are still offered first-line chemotherapy (CT). Chemotherapy is generally followed by maintenance hormonal therapy. The MAIN-A study is an investigator-driven, randomized phase III trial designed to compare maintenance everolimus (EVE) combined with aromatase inhibitors (AI) versus AI alone in pts with disease control after first-line CT.Methods Postmenopausal pts achieving disease control (stable disease, partial response or complete response) after first-line CT were randomly assigned to EVE 10 mg po daily plus AI or to AI alone. Primary aim was PFS in the ITT. We present here overall survival (OS) results and the impact of tumor characteristics on PFS.Results 110 pts were randomized to EVE+AI (n=52) or to AI (n= 58). Primary aim results have been already presented (Guarneri V, ESMO Breast 2019), showing a non-significant prolongation of median PFS in the ITT population for EVE+AI (9.9 mos vs 7.2 mos, HR 0.764, 95% CI 0.501-1.164. Patients with visceral metastases tended to experience shorter PFS as compared with patients with patients with bone/soft tissues metastases (median 11.1 mos vs 6.4 mos, p=0.0746). The levels of estrogen receptor expression (>or< 50%) did not impact PFS, overall and by treatment arm. At the time of this writing, a total of 61 death events have been recorded. No difference in OS was observed between the two arms (median 33.9 mos for EVE+AI vs 33.5 mos for AI, HR 0.97, 95% CI 0.59-1.61).Conclusions Maintenance EVE+AI did not significantly impact on the outcome of metastatic breast cancer patients deemed suitable for first line chemotherapy. Citation Format: Valentina Guarneri, Saverio Cinieri, Maria Vittoria Dieci, Carmelo Bengala, Gabriella Mariani, Giancarlo Bisagni, Antonio Frassoldati, Claudio Zamagni, Laura Orlando, Carlo Alberto Giorgi, Gian Luca De Salvo, PierFranco Conte. Maintenance therapy with everolimus plus aromatase inhibitors vs aromatase inhibitors as after first-line chemotherapy in HR+/HER2- metastatic breast cancer: Updated analyses of the phase III randomized MAIN-A 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 PS12-22.

Summary Background The triplet FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) plus bevacizumab showed improved outcomes for patients with metastatic colorectal cancer, compared with FOLFIRI (fluorouracil, leucovorin, and irinotecan) plus bevacizumab. However, the actual benefit of the upfront exposure to the three cytotoxic drugs compared with a preplanned sequential strategy of doublets was not clear, and neither was the feasibility or efficacy of therapies after disease progression. We aimed to compare a preplanned strategy of upfront FOLFOXIRI followed by the reintroduction of the same regimen after disease progression versus a sequence of mFOLFOX6 (fluorouracil, leucovorin, and oxaliplatin) and FOLFIRI doublets, in combination with bevacizumab. Methods TRIBE2 was an open-label, phase 3, randomised study of patients aged 18–75 years with an Eastern Cooperative Oncology Group (ECOG) performance status of 2, with unresectable, previously untreated metastatic colorectal cancer, recruited from 58 Italian oncology units. Patients were stratified according to centre, ECOG performance status, primary tumour location, and previous adjuvant chemotherapy. A randomisation system incorporating a minimisation algorithm was used to randomly assign patients (1:1) via a masked web-based allocation procedure to two different treatment strategies. In the control group, patients received first-line mFOLFOX6 (85 mg/m2 of intravenous oxaliplatin concurrently with 200 mg/m2 of leucovorin over 120 min; 400 mg/m2 intravenous bolus of fluorouracil; 2400 mg/m2 continuous infusion of fluorouracil for 48 h) plus bevacizumab (5 mg/kg intravenously over 30 min) followed by FOLFIRI (180 mg/m2 of intravenous irinotecan over 120 min concurrently with 200 mg/m2 of leucovorin; 400 mg/m2 intravenous bolus of fluorouracil; 2400 mg/m2 continuous infusion of fluorouracil for 48 h) plus bevacizumab after disease progression. In the experimental group, patients received FOLFOXIRI (165 mg/m2 of intravenous irinotecan over 60 min; 85 mg/m2 intravenous oxaliplatin concurrently with 200 mg/m2 of leucovorin over 120 min; 3200 mg/m2 continuous infusion of fluorouracil for 48 h) plus bevacizumab followed by the reintroduction of the same regimen after disease progression. Combination treatments were repeated every 14 days for up to eight cycles followed by fluorouracil and leucovorin (at the same dose administered at the last induction cycle) plus bevacizumab maintenance until disease progression, unacceptable adverse events, or consent withdrawal. Patients and investigators were not masked. The primary endpoint was progression-free survival 2, defined as the time from randomisation to disease progression on any treatment given after first disease progression, or death, analysed by intention to treat. Safety was assessed in patients who received at least one dose of their assigned treatment. Study recruitment is complete and follow-up is ongoing. This trial is registered with Clinicaltrials.gov , NCT02339116 . Findings Between Feb 26, 2015, and May 15, 2017, 679 patients were randomly assigned and received treatment (340 in the control group and 339 in the experimental group). At data cut-off (July 30, 2019) median follow-up was 35·9 months (IQR 30·1–41·4). Median progression-free survival 2 was 19·2 months (95% CI 17·3–21·4) in the experimental group and 16·4 months (15·1–17·5) in the control group (hazard ratio [HR] 0·74, 95% CI 0·63–0·88; p=0·0005). During the first-line treatment, the most frequent of all-cause grade 3–4 events were diarrhoea (57 [17%] vs 18 [5%]), neutropenia (168 [50%] vs 71 [21%]), and arterial hypertension (25 [7%] vs 35 [10%]) in the experimental group compared with the control group. Serious adverse events occurred in 84 (25%) patients in the experimental group and in 56 (17%) patients in the control group. Eight treatment-related deaths were reported in the experimental group (two intestinal occlusions, two intestinal perforations, two sepsis, one myocardial infarction, and one bleeding) and four in the control group (two occlusions, one perforation, and one pulmonary embolism). After first disease progression, no substantial differences in the incidence of grade 3 or 4 adverse events were reported between the control and experimental groups, with the exception of neurotoxicity, which was only reported in the experimental group (six [5%] of 132 patients). Serious adverse events after disease progression occurred in 20 (15%) patients in the experimental group and 25 (12%) in the control group. Three treatment-related deaths after first disease progression were reported in the experimental group (two intestinal occlusions and one sepsis) and four in the control group (one intestinal occlusion, one intestinal perforation, one cerebrovascular event, and one sepsis). Interpretation Upfront FOLFOXIRI plus bevacizumab followed by the reintroduction of the same regimen after disease progression seems to be a preferable therapeutic strategy to sequential administration of chemotherapy doublets, in combination with bevacizumab, for patients with metastatic colorectal cancer selected according to the study criteria. Funding The GONO Cooperative Group, the ARCO Foundation, and F Hoffmann–La Roche.

Background Although the efficacy of molecularly target agents in vitro, their use in routine setting is limited mainly to the use of anti‐HER2 and antiEGFR agents in vivo. Moreover, core biopsy of a single cancer site may not be representative of the whole expanding clones and cancer molecular profile at relapse may differ with respect to the primary tumor. Methods We assessed the status of a large panel of cancer driver genes by cell‐free DNA (cfDNA) analysis in a cohort of 68 patients with 13 different solid tumors at disease progression. Whenever possible, a second cfDNA analysis was performed after a mean of 2.5 months, in order to confirm the identified clone(s) and to check the correlation with clinical evolution. Results The approach was able to identify clones plausibly involved in the disease progression mechanism in about 65% of cases. A mean of 1.4 mutated genes (range 1‐3) for each tumor was found. Point mutations in TP53, PIK3CA, and KRAS and copy number variations in FGFR3 were the gene alterations more commonly observed, with a rate of 48%, 20%, 16%, and 20%, respectively. Two‐points‐Next‐Generation Sequencing (NGS) analysis demonstrated statistically significant correlation between allele frequency variation and clinical outcome (P = .026). Conclusions Irrespective of the primary tumor mutational burden, few mutated genes are present at disease progression. Clinical outcome is consistent with variation of allele frequency of specific clones indicating that cfDNA two‐point‐NGS analysis of cancer driver genes could be an efficacy tool for precision oncology., Core biopsy of a single cancer site may not be representative of the whole expanding clones and cancer molecular profile at relapse may differ with respect to the primary tumor. In this study, we performed a first and whenever possible, a second NGS liquid biopsy analysis after a mean of 2.5 months in advanced cancer patients. The approach was able to identify clones plausibly involved in the disease progression mechanism in about 65% of cases. Clinical outcome is consistent with variation of allele frequency of specific clones indicating that cfDNA two point‐NGS analysis of cancer driver genes could be an efficacy tool for precision oncology.

Key Points Question Do patients receiving abiraterone acetate with prednisone as first-line therapy for the treatment of metastatic castration-resistant prostate cancer with bone metastases benefit from the addition of bone resorption inhibitors? Findings In this cohort study of 745 patients receiving first-line abiraterone acetate with prednisone for the treatment of metastatic castration-resistant prostate cancer with bone metastases, the use of concomitant bone resorption inhibitors was associated with improvements in overall survival, particularly among those with a high volume of disease. Meaning These findings suggest that the addition of bone resorption inhibitors to abiraterone acetate with prednisone as first-line therapy could be beneficial for the treatment of patients with metastatic castration-resistant prostate cancer with bone metastases., Importance Bone resorption inhibitors (BRIs) are recommended by international guidelines to prevent skeletal-related events (SREs) among patients with metastatic castration-resistant prostate cancer (mCRPC) and bone metastases. Abiraterone acetate with prednisone is currently the most common first-line therapy for the treatment of patients with mCRPC; however, the clinical impact of the addition of BRIs to abiraterone acetate with prednisone in this disease setting is unknown. Objective To evaluate the association of the use of concomitant BRIs with overall survival (OS) and time to first SRE among patients with mCRPC and bone metastases receiving abiraterone acetate with prednisone as first-line therapy. Design, Setting, and Participants This retrospective cohort study collected data from 745 consecutive patients who began receiving abiraterone acetate with prednisone as first-line therapy for mCRPC with bone metastases between January 1, 2013, and December 31, 2016. Data were collected from 8 hospitals in Canada, Europe, and the US from June 15 to September 15, 2019. Exposures Patients were classified by receipt vs nonreceipt of concomitant BRIs and subclassified by volume of disease (high volume or low volume, using definitions from the Chemohormonal Therapy Vs Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer [CHAARTED] E3805 study) at the initiation of abiraterone acetate with prednisone therapy. Main Outcomes and Measures The primary end point was OS. The secondary end point was time to first SRE. The Kaplan-Meier method and Cox proportional hazards models were used. Results Of the 745 men (median age, 77.6 years [interquartile range, 68.1-83.6 years]; 699 White individuals [93.8%]) included in the analysis, 529 men (71.0%) received abiraterone acetate with prednisone alone (abiraterone acetate cohort), and 216 men (29.0%) received abiraterone acetate with prednisone plus BRIs (BRI cohort). A total of 420 men (56.4%) had high-volume disease, and 276 men (37.0%) had low-volume disease. The median follow-up was 23.5 months (95% CI, 19.8-24.9 months). Patients in the BRI cohort experienced significantly longer OS compared with those in the abiraterone acetate cohort (31.8 vs 23.0 months; hazard ratio [HR], 0.65; 95% CI, 0.54-0.79; P, This cohort study examines whether the addition of bone resorption inhibitors is associated with improvements in overall survival and skeletal-related events among patients with metastatic castration-resistant prostate cancer receiving abiraterone acetate with prednisone as first-line therapy.

Background Despite endocrine therapy being the mainstay of treatment for hormone receptor positive (HR+)/HER2− metastatic breast cancer, patients at risk of visceral crisis or doubt for endocrine sensitivity are still offered first-line chemotherapy. Maintenance hormonal therapy is generally offered at the discontinuation of chemotherapy. The MAINtenance Afinitor study is a randomised, phase III trial comparing maintenance everolimus combined with aromatase inhibitors (AIs) versus AI monotherapy in patients with disease control after first-line chemotherapy. Methods Patients with stable disease, partial response or complete response after first-line chemotherapy were randomised to everolimus plus AIs (exemestane or letrozole or anastrozole) or to AIs alone. Primary aim was progression-free survival (PFS). Secondary aims included response rate, safety and overall survival (OS). Results In total, 110 patients were randomised to everolimus + AIs (n = 52) or to AIs (n = 58). Median PFS was 11.0 months (95% confidence interval [CI] 8.1–13.8) in the everolimus + AI arm and 7.2 months (95% CI 4.7–10.9) in the AI monotherapy arm (hazard ratio [HR] 0.71, 95% CI 0.47–1.06). Objective response rate was 22.4% in everolimus + AI arm and 19.2% in AI monotherapy arm. A higher proportion of disease progression as best response was reported in the AI monotherapy arm (28.8% versus 14.3%). Median OS was 35.7 months (95% CI 26.0–47.8) in the combination arm versus 33.5 (95% CI 26.4–42.7) in the AI alone arm (HR 1.0, 95% CI 0.61–1.62). Conclusions EVE + AIs did not significantly impact on the outcome of metastatic breast cancer patients deemed suitable for first-line chemotherapy. Also taking into account treatment tolerability, maintenance endocrine therapy remains the standard. Trial registration EudraCT: 2013-004153-24.

Background: nab-Paclitaxel (nab-P)–containing regimens have demonstrated efficacy and safety in triple-negative breast cancer (TNBC). In the absence of a standard of care for metastatic (m) TNBC, tnAcity evaluated the efficacy and safety of 3 common chemotherapy combination regimens: nab-P + carboplatin (nab-P/C) or gemcitabine (nab-P/G) vs G/C as first-line treatment (Tx) for patients (pts) with mTNBC based on a ranking algorithm of efficacy and safety. Results of the phase 2 portion are reported here. Methods: Pts with pathologically confirmed mTNBC, no prior cytotoxic chemotherapy for metastatic disease, and no brain metastases were enrolled. Pts received (1:1:1) nab-P 125 mg/m2 + C AUC 2, nab-P 125 mg/m2 + G 1000 mg/m2, or G 1000 mg/m2 + C AUC 2, all given on d 1 and 8 every 3 weeks. The phase 2 primary endpoint was investigator-assessed progression-free survival (PFS); secondary endpoints included overall response rate (ORR), overall survival (OS), percentage of pts initiating cycle 6 receiving doublet therapy, and safety. Results: 191 pts were included in the phase 2 portion. Median age was 55, 53, and 59 years in the nab-P/C, nab-P/G, and G/C groups, respectively. Overall, 98% of pts had an ECOG PS of 0 - 1, 83% were white, and 48% were treated in North America. Most pts (81%) had relapsed disease. Median Tx duration was 25, 18, and 20 weeks, and 47%, 33%, and 52% of pts had ≥ 1 dose reduction for both agents in the nab-P/C, nab-P/G, and G/C groups, respectively. Key efficacy and safety results are summarized in the table. PFS was significantly longer with nab-P/C vs either nab-P/G or G/C (median, 7.4 vs 5.4 mo, P = 0.03 and 7.4 vs 6.0 mo, P = 0.02). Overall, 179 pts discontinued Tx; of these, 55% discontinued due to progression and 16% due to adverse events (AEs). Grade ≥ 3 AEs in ≥ 10% of pts were mainly hematologic. The rank sum of the algorithm for 5 key weighted efficacy and safety endpoints favored nab-P/C. Table 1 nab-P/Cnab-P/GG/CEfficacyn = 64n = 61n = 66PFS, median, mo7.4a5.4b6.0ORR, %71.937.743.9OS, median, mo16.411.913.7Pts initiating cycle 6 with a doublet, %64.155.750.0Safetyn = 64n = 60n= 64Myelosuppression-related events, %c53.141.767.2Pts discontinuing all Tx due to AE, %18.820.021.9Serious TEAEs, %29.736.737.5Grade ≥ 3 AEs, %Neutropenia40.633.348.4Anemia7.88.315.6Thrombocytopenia4.73.314.1Peripheral neuropathy4.75.01.6Deaths due to TEAE, n (%)1 (2)2 (3)2 (3)a P = 0.03 vs nab-P/G; P = 0.02 vs G/C; b P = 0.85 vs G/C; c Including grade ≥ 3 neutropenia, thrombocytopenia, anemia, bleeding, febrile neutropenia, or red blood cell/platelet transfusion. Conclusions: In this phase 2 study, nab-P/C demonstrated a statistically significant longer PFS and a better risk/benefit profile vs nab-P/G or G/C as first-line Tx in pts with mTNBC. These data demonstrate nab-P/C efficacy in mTNBC and address a relevant question around a nab-P/C chemotherapy backbone for this difficult-to-treat tumor type. Further studies are warranted in the context of immunotherapies and targeted agents. NCT01881230. Citation Format: Yardley D, Coleman R, Conte P, Cortes J, Brufsky A, Shtivelband M, Young R, Bengala C, Ali H, Eakel J, Schneeweiss A, de la Cruz Merino L, Wilks S, O'Shaugnessy J, Glück S, Li H, Beck R, Barton D, Harbeck N. nab-paclitaxel + carboplatin or gemcitabine vs gemcitabine/carboplatin as first-line treatment for patients with triple-negative metastatic breast cancer: Results from the randomized phase 2 portion of the tnAcity trial [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-15-03.

The aim of this retrospective study was to assess toxicity and efficacy of adjuvant high-dose chemotherapy (HDC) and autologous hematopoietic stem cell transplantation (AHSCT) in 583 high-risk breast cancer (BC) patients (>3 positive nodes) who were transplanted between 1995 and 2005 in Europe. All patients received surgery before transplant, and 55 patients (9.5%) received neoadjuvant treatment before surgery. Median age was 47.1 years, 57.3% of patients were premenopausal at treatment, 56.5% had endocrine-responsive tumors, 19.5% had a human epidermal growth factor receptor 2 (HER2)-negative tumor, and 72.4% had >= 10 positive lymph nodes at surgery. Seventy-nine percent received a single HDC procedure. Overall transplant-related mortality was 1.9%, at .9% between 2001 and 2005, whereas secondary tumor-related mortality was .9%. With a median follow-up of 120 months, overall survival and disease-free survival rates at 5 and 10 years in the whole population were 75% and 64% and 58% and 44%, respectively. Subgroup analysis demonstrated that rates of overall survival were significantly better in patients with endocrine-responsive tumors

30 Background: BM in patients (pts) with CRPC are associated with shorter overall survival (OS) and higher costs. BRI zoledronic acid and denosumab are frequently used to prevent skeletal-related events (SRE) in pts with CRPC and BM. AA is the most common 1st line therapy for men with metastatic CRPC. We aimed to assess the impact of BRI on OS and time to first SRE (ttSRE) of pts receiving 1st line treatment AA for CRPC with BM. Methods: A retrospective cohort of pts starting AA as 1st line therapy for CRPC with BM between 2013-2016 was identified through 8 hospitals’ IRB approved registries. Pts were classified by use of concomitant BRI and subgrouped by volume of disease (per E3805 definition) at AA start. Kaplan-Meier method and Cox models were used to assess OS and ttSRE with hazard ratio (HR) estimates (95% CI). Results: Of the 745 pts included (543 deaths), 529 (71.0%) had AA alone and 216 (29.0%) AA+BRI. Median follow-up was 23.5 months. Pts receiving concomitant BRI showed a significantly longer OS and a 35% reduced risk of death compared to AA alone (HR=0.65; 95% CI, 0.54-0.79; P5, PS 0 vs. ≥1, and PSA are independently associated with longer OS. Conclusions: The addition of BRI to 1st line AA for CRPC men with BM was associated with improved OS, particularly in HV, and worsened ttSRE, more evident in LV. These data suggest a potentially different impact of concomitant BRI on HV vs. LV, which could affect clinical decision making.[Table: see text]

Background Subcutaneous trastuzumab (H SC) is a valuable alternative to the intravenous formulation. This study assessed H SC safety and tolerability in human epidermal growth factor receptor 2 (HER2)+ early/locally advanced breast cancer (EBC/LABC). Methods SCHEARLY is a prospective, two-cohort, non-randomised, multicentre Italian trial included in the umbrella study UmbHER1, planning a 1-year treatment with H SC 600 mg in HER2+ EBC/LABC. Patients were sequentially assigned to cohort A (N = 121) and B (N = 119) to receive H SC via a handheld syringe and a single-use injection device, respectively. Adjuvant or neoadjuvant treatment included anthracycline-containing regimens followed by H SC plus taxanes and then alone for 18 cycles totally. Results Two hundred forty patients were enrolled (adjuvant therapy: 81.7%; neoadjuvant therapy: 18.3%), and 201 completed the treatment (early discontinuation was mainly due to intercurrent adverse events [AEs], 7.5%). Overall, the two cohorts displayed similar safety profiles. From H SC start, the rate of treatment-related AEs in the safety population (N = 228) was 3.9% for grade ≥3 AEs; 0.9% for serious AEs (one pleuropericarditis and one anaphylactic shock, both resolved) and 14.5% for cardiac AEs, the most common being the decreased left ventricular ejection fraction (7.9%; mean reduction from the screening to the follow-up visit was 2.9%). No cases of congestive heart failure occurred. The rate of systemic administration-related reactions and local injection site reactions was 68.0% and 21.9%, respectively, mostly of grade 1–2. Conclusions H SC 600 mg confirmed to be a safe and tolerable option as adjuvant/neoadjuvant therapy in patients with HER2+ EBC and LABC. ClinicalTrials.gov Identifier NCT01940497.

Introduction Nivolumab is the first checkpoint inhibitor approved for the treatment of nonsquamous NSCLC. We report results from the nivolumab Italian expanded access program focusing on never-smokers and patients with EGFR-mutant nonsqamous NSCLC. Methods Nivolumab (3 mg/kg intravenously every 2 weeks) was administered upon physicians' request to patients who had relapsed after one or more prior systemic treatments for stage IIIB/IV nonsquamous NSCLC. Efficacy and safety were evaluated in patients who received at least one dose of nivolumab. Results Of 1588 patients with nonsquamous NSCLC, 305 (19.2%) were never-smokers. EGFR status was available for 1395 patients. Of the 102 patients (6.4%) with EGFR mutation–positive tumors, 51 (50%) were never-smokers. The objective response rate was significantly higher in patients with wild-type EGFR than patients with EGFR-mutant tumors (19.6% versus 8.8% [p = 0.007]), in former and current smokers than in never-smokers (21.5% versus 9.2% [p = 0.0001]), and in never-smokers with wild-type EGFR than in never-smokers with mutant EGFR (11.0% versus 1.9% [p = 0.04]). There was no significant difference in objective response rate between smokers with wild-type EGFR and smokers with mutant EGFR (22.0% versus 20.6%). There was no statistically significant difference in median progression-free survival or in median overall survival. The median overall survival times were 11 months in patients with EGFR wild-type tumors versus 8.3 months in patients with EGFR-mutant tumors, 11.6 months in smokers versus 10.0 months in never-smokers, 11.0 months in never-smokers with EGFR wild-type tumors versus 5.6 months in never-smokers with EGFR-mutant tumors, and 14.1 months in smokers with EGFR-mutant tumors versus 11.3 months in smokers with EGFR wild-type tumors. Conclusions The data on the Italian expanded access program in populations with nonsquamous NSCLC suggest that subgroups of patients could benefit differently from nivolumab according to their EGFR mutational status and smoking habits. These results warrant further investigation.

Over the years, thanks to the addition of new generation systemic agents, as well as the use of more advanced and precise radiotherapy techniques, it was able to obtain a high curability rate for breast cancer. Anthracyclines play a key role in the treatment of breast disease, with a well-known benefit on disease-free survival of patients with positive nodal status. Trastuzumab have shown a significant outcome advantage after 1-year administration in case of HER2-positive disease. Unfortunately, significant increase in cardiotoxicity has been observed after anthracyclines and trastuzumab therapies. Even though the cardiology and oncology community strongly recommend a cardiotoxicity prevention strategy for this subset of patients, there is still no consensus on the optimal patient's approach. We aimed to review the published and ongoing researches on cardioprevention strategies and to present the SAFE trial (CT registry ID: NCT2236806; EudraCT number: 2015-000914-23). It is a randomized phase 3, four-arm, single-blind, placebo-controlled study that aims to evaluate the effect of bisoprolol, ramipril or both drugs, compared to placebo, on subclinical heart damage evaluated by speckle tracking cardiac ultrasound in non-metastatic breast cancer patients.

The efficacy of high-dose chemotherapy (HDC) and autologous hemopoietic progenitor cell transplantation (AHPCT) for breast cancer (BC) patients has been an area of intense controversy among the medical oncology community. The aim of this study was to assess toxicity and efficacy of this procedure in a large cohort of high-risk primary BC patients who underwent AHPCT in Italy. A total of 1183 patients receiving HDC for high-risk BC (HRBC) (>3 positive nodes) were identified in the Italian registry. The median age was 46 years, 62% of patients were premenopausal at treatment, 60.1% had endocrine-responsive tumors, and 20.7% had a human epidermal growth factor receptor 2 (HER2)–positive tumor. The median number of positive lymph nodes (LN) at surgery was 15, with 71.5% of patients having ≥ 10 positive nodes. Seventy-three percent received an alkylating agent-based HDC as a single procedure, whereas 27% received epirubicin or mitoxantrone-containing HDC, usually within a multitransplantation program. The source of stem cells was peripheral blood in the vast majority of patients. Transplantation-related mortality was .8%, whereas late cardiac and secondary tumor-related mortality were around 1%, overall. With a median follow-up of 79 months, median disease-free and overall survival (OS) in the entire population were 101 and 134 months, respectively. Subgroup analysis demonstrated that OS was significantly better in patients with endocrine-responsive tumors and in patients receiving multiple transplantation procedures. HER2 status did not affect survival probability. The size of the primary tumor and number of involved LN negatively affected OS. Adjuvant HDC with AHPCT has a low mortality rate and provides impressive long-term survival rates in patients with high-risk primary BC. Our results suggest that this treatment modality should be proposed in selected HRBC patients and further investigated in clinical trials.

e16087 Background: Several studies, the majority on melanoma and lung cancer, have addressed the value of gender with respect to immune check point inhibitors outcome as compared to standard therapy, showing conflicting results. Nevertheless, few focused on gender-related clinical outcome and toxicity in renal cell carcinoma (RCC) patients. Methods: This analysis evaluated the effect of gender on overall survival and adverse events (AEs) using Common Terminology Criteria for Adverse Events (CTCAE) v.4.0 in an expanded access programme of nivolumab 3 mg/kg once every 2 weeks in second-line and beyond metastatic RCC. Only patients assuming at least one dose of nivolumab were analyzed. Results: Of 389 patients analyzed, 25.2% were female. On study entry, no differences were found in women as compared to men in terms of age, on average 64 years, p = 0.91; overweight/obesity, 45 versus (vs) 49%, p = 0.47; LDH , mean U/L 391 vs 32, p = 0.17); and neutrophils/lymphocytes ratio> 3 (62 vs 63%, p = 0.87). Disease presentation was similar according to gender, although women tended to present less lung (66% vs 76%, p = 0.06) and bone metastases (42% vs 52%, p = 0.07). Notably, there was no differences in the IDMC prognostic model by gender (p = 0.94). Any drug related AEs (38 vs 30%, p 0.15), grade 3-4 (6% vs 6%) and median number of drug doses 12 (53% vs50%, p = 0.58 ) did not differ between gender. After adjusting for known prognostic variables, multivariate analysis showed that women had similar overall survival as compared to men (hazard ratio 0.81, 95% confidence interval 0.56-1.17, p = 0.26). Conclusions: Women demonstrate similar overall survival than men in metastatic RCC treated with secondal line and beyond nivolumab, with no differences observed in serious AEs and dose administered.

e16508 Background: BM in patients (pts) with CRPC correlate with higher mortality and costs. BRI zoledronic acid and denosumab are frequently used for the prevention of skeletal-related events (SRE) in pts with CRPC and BM. AA is the most common 1st line treatment for men with metastatic CRPC. We sought to evaluate the impact of BRI on time to first SRE (ttSRE) and OS of pts receiving 1st line therapy AA for CRPC with BM. Methods: We identified a cohort of men starting AA as 1st line therapy for CRPC with BM between 2013-2015 from 7 hospitals’ IRB approved registries. Pts were grouped by use of concomitant BRI and subgrouped by volume of disease (per E3805 definition) at AA start. The endpoints were OS, defined as time from AA start to death or last follow-up visit, and ttSRE. Results: Of the 338 pts included, 256 (76%) received AA alone and 82 (24%) AA+BRI. ECOG PS (PS) was ≥1 for 178 pts (52.7%). No statistically significant difference in ttSRE was found between the 2 cohorts [see Table]. Median follow-up for OS was 25.6 months. Pts receiving concomitant BRI showed a significantly longer OS and a 36% decreased risk of death compared to AA alone (HR = 0.64; 95% CI, 0.64 0.46-0.91; p = 0.012). Notably, OS in the AA alone group was shorter than commonly described. The OS benefit with BRI was greater for men with high volume disease (HV) (HR = 0.42; 95% CI, 0.25-0.71; p = 0.001). On MVA, BRI vs. no BRI, low volume of disease vs. HV, PS 0 vs. ≥1, baseline VAS pain ≤3 vs. > 5, and baseline PSA are independently associated with longer OS. Conclusions: Using a multicenter database, the addition of BRI to 1st line AA for CRPC men with BM and poor prognostic factors did not improve prevention of SRE. However, concomitant use of BRI and AA was associated with a significantly improved OS, particularly in HV. Further research to determine the driving factors is needed. [Table: see text]

Background Results from phase III clinical trial CheckMate 025 have established nivolumab as the standard of care for treatment of metastatic renal-cell carcinoma (mRCC) after VEGF inhibitor failure; however, elderly patients are under-represented in the registration trial and little is known about the activity of nivolumab in this subgroup. The purpose of the Expanded Access Program was to provide nivolumab to patients with mRCC who had progressed despite treatment with other agents that were considered standard of care. Methods Nivolumab 3 mg/kg was administered intravenously every 2 weeks to a maximum of 24 months or until progression or unacceptable toxicity. The current analysis included all patients from the EAP Italian cohort who had received ≥1 dose of nivolumab. Adverse events (AEs) were monitored using Common Terminology Criteria for Adverse Events v4.0. Results A total of 389 patients with advanced RCC were enrolled in the Italian cohort of the EAP and treated with nivolumab. Of these patients, 125 (32%) were at least 70 years of age and 70 (18%) were at least 75 years of age. Efficacy with nivolumab in the elderly patients was similar to that observed in the overall EAP population and in the CheckMate 025 trial. Safety was comparable between the elderly patients and the overall EAP population, and was consistent with what previously reported. Conclusion The final results suggest that elderly patients with pretreated metastatic RCC may benefit from therapy with nivolumab.

TPS4602Background: Despite recent advances in drug therapy, pts with mRCC have about a 10% 5-year survival rate. Several preclinical studies have documented an increase in peripheral antitumour imm...

e15158Background: The combination of external-beam radiotherapy (EBRT) and PD-1 inhibitors may enhance antitumor immune responses. The aim of this study was to assess the outcome of NSCLC pts who h...

Background: Advanced biliary tract carcinoma has a very poor prognosis, with chemotherapy being the mainstay of treatment. Sorafenib, a multikinase inhibitor of VEGFR-2/-3, PDGFR-β, B-Raf, and C-Raf, has shown to be active in preclinical models of cholangiocarcinoma. Methods: We conducted a phase II trial of single-agent sorafenib in patients with advanced biliary tract carcinoma. Sorafenib was administered at a dose of 400 mg twice a day. The primary end point was the disease control rate at 12 weeks. Results: A total of 46 patients were treated. In all, 26 (56%) had received chemotherapy earlier, and 36 patients completed at least 45 days of treatment. In intention-to-treat analysis, the objective response was 2% and the disease control rate at 12 weeks was 32.6%. Progression-free survival (PFS) was 2.3 months (range: 0–12 months), and the median overall survival was 4.4 months (range: 0–22 months). Performance status was significantly related to PFS: median PFS values for ECOG 0 and 1 were 5.7 and 2.1 months, respectively (P=0.0002). The most common toxicities were skin rash (35%) and fatigue (33%), requiring a dose reduction in 22% of patients. Conclusions: Sorafenib as a single agent has a low activity in cholangiocarcinoma. Patients having a good performance status have a better PFS. The toxicity profile is manageable.

Objective: to estimate the impact of lapatinib utilization within the Italian National Health Service (NHS) resources consumption. Lapatinib is an oral inhibitor of kinase protein, approved as dual therapy with capecitabine for the treatment of metastatic breast cancer patients with HER2 overexpression who experience disease progression despite trastuzumab treatment. Methods: the analysis is based on a model, which structure can be summarized as follows: a) national cancer registries-based estimate of the yearly number of HER2+ breast cancer patients who develop metastatic disease in Italy; b) literature-based identification of the rate of patients eligible to receive lapatinib; c) identification of the current therapeutic strategy-mix; d) costing of the alternatives, and e) calculation of budget impact. Direct NHS costs (drug acquisition and administration, and monitoring for 8 cycles of 21 days) are estimated based on current Italian prices and tariffs. Results: the annual number of patients eligible for lapatinib-based therapy can vary from 1,676 to 2,172, according to the expected extent of the trastuzumab use as adjuvant therapy. The current strategy-mix beyond progression is based on drugs used in the clinical practice, with a portion of patients continuing trastuzumab. Pharmaceutical cost of lapatinib results higher than the average cost of the current pattern of treatments. This cost increase would be partially offset by the reduction of laboratory tests and hospital personnel work for the oral administration of lapatinib, as compared to intravenous strategies. Furthermore, a risk sharing agreement has been adopted by NHS and manufacturer, according to which the NHS pays only for responding patients. As a consequence, lapatinib-based therapy would increase yearly NHS expenditure by about 3.8-4.9 millions of euro. Conclusions: lapatinib is the only treatment option specifically indicated for the management of HER2+, metastatic breast cancer in patients who received prior treatments including trastuzumab and is estimated to induce a low budget impact for the Italian NHS.

Purpose Although ovarian cancer is one of the most chemotherapy-sensitive solid tumors, cure after radical surgery and chemotherapy is uncommon. A randomized trial comparing high-dose sequential chemotherapy with peripheral blood stem cell (PBSC) support with platinum-based combination chemotherapy was conducted to investigate whether dose-intensification improves outcome. Patients and Methods One hundred forty-nine patients with untreated ovarian cancer were randomly assigned after debulking surgery to receive standard combination chemotherapy or sequential high-dose (HD) treatment with two cycles of cyclophosphamide and paclitaxel followed by three cycles of HD carboplatin and paclitaxel with PBSC support. HD melphalan was added to the final cycle. The median age was 50 years (range, 20 to 65 years) and International Federation of Gynecology and Obstetrics stage was IIb/IIc in 4%, III in 78%, and IV in 17%. Results Seventy-six percent of patients received all five cycles in the HD arm and the main toxicities were neuro-/ototoxicity, gastrointestinal toxicity, and infection and one death from hemorrhagic shock. After a median follow-up of 38 months, the progression-free survival was 20.5 months in the standard arm and 29.6 months in the HD arm (hazard ratio [HR], 0.84; 95% CI, 0.56 to 1.26; P, .40). Median overall survival (OS) was 62.8 months in the standard arm and 54.4 months in the HD arm (HR, 1.17; 95% CI, 0.71 to 1.94; P, .54). Conclusion This is the first randomized trial comparing sequential HD versus standard dose chemotherapy in first-line treatment of patients with advanced ovarian cancer. We observed no statistically significant difference in progression-free survival or OS and conclude that HD chemotherapy does not appear to be superior to conventional dose chemotherapy.

Background In the late 1990s, the use of high-dose chemotherapy (HDCT) and stem-cell rescue held promise for patients with advanced and poor prognosis germ-cell tumors (GCT). We started a randomized phase II trial to assess the efficacy of sequential HDCT compared with cisplatin, etoposide, and bleomycin (PEB). Patients and methods Patients were randomly assigned to receive four cycles of PEB every 3 weeks or two cycles of PEB followed by a high-dose sequence (HDS) comprising HD-cyclophosphamide (7.0 g/m2), 2 courses of cisplatin and HD-etoposide (2.4 g/m2) with stem-cell support, and a single course of HD-carboplatin [area under the curve (AUC) 27 mg/ml × min] with autologous stem-cell transplant. Postchemotherapy surgery was planned on responding residual disease in both arms. The primary end point was progression-free survival (PFS). The study was designed to detect a 30% improvement of 5-year PFS (from 40% to 70%), with 80% power and two-sided α at 5%. Results From December 1996 to March 2007, 85 patients were randomized: 43 in PEB and 42 in HDS arm. Median follow-up was 114.2 months [interquartile range (IQR): 87.7–165.8]. Complete or partial response with normal markers (PRm-) were obtained in 28 (65.1%) and 29 (69.1%) patients, respectively. Five-year PFS was 55.8% [95% confidence interval (CI) 42.8–72.8] and 54.8% (95% CI 41.6%–72.1%) in PEB and HDS arm, respectively (log-rank test P = 0.726). Five-year overall survival was 62.8% (95% CI 49.9–79.0) and 59.3% (95% CI 46.1–76.3). One toxic death (PEB arm) was recorded. Conclusions The study failed to meet the primary end point. Furthermore, survival estimates of conventional-dose chemotherapy higher than expected should be accounted for and will likely limit further improvements in the first-line setting. ClinicalTrials.gov NCT02161692.

An allogeneic antitumour effect has been reported for various cancers. We evaluated the experience of allogeneic haematopoietic stem cell transplantation (HSCT) for renal cell carcinoma (RCC) in 124 patients from 21 European centres.Reduced intensity conditioning and peripheral blood stem cells from an HLA-identical sibling (n = 106), a mismatched related (n = 5), or an unrelated (n = 13) donor were used. Immunosuppression was cyclosporine alone, or combined with methotrexate or mycophenolate mofetil. Donor lymphocyte infusions (DLI) were given to 42 patients. The median follow-up was 15 (range 3-41) months.All but three patients engrafted. The cumulative incidence of moderate to severe, grades II-IV acute GVHD was 40% and for chronic GVHD it was 33%. Transplant-related mortality was 16% at one year. Complete (n = 4) or partial (n = 24) responses, median 150 (range 42-600) days post-transplant, were associated with time from diagnosis to HSCT, mismatched donor and acute GVHD II-IV. Factors associated with survival included chronic GVHD (hazards ratio, HR 4.12, P0.001), DLI (HR 3.39, P0.001),3 metastatic sites (HR 2.61, P = 0.002) and a Karnofsky score70 (HR 2.33, P = 0.03). Patients (n = 17) with chronic GVHD and given DLI had a 2-year survival of 70%.Patients with metastatic RCC, less than three metastatic locations and a Karnofsky score70% can be considered for HSCT. Posttransplant DLI and limited chronic GVHD improved the patient survival.

The median survival of women with metastatic breast cancer (MBC) is 18-24 months, and fewer than 5% are alive and disease free at 5 years. We report toxicity and survival in a cohort of MBC patients receiving high-dose chemotherapy (HDC) with autologous hematopoietic SCT (AHSCT) in Italy between 1990 and 2005. Data set for survival analysis has been obtained for 415 patients. Clinical parameters including probability of transplant-related mortality (TRM), PFS and OS. With a median follow-up of 27 months (range 0-172), OS and PFS at 5 and 10 years in the whole population were 47/23 and 32/14%, respectively. A total 239 patients are alive with a median follow-up of 33 months (range 2-174). Survival was significantly more pronounced in patients harboring hormone receptor positive tumors (P=0.028), without visceral metastases (P=0.009) and in women with chemosensitive disease (P

Background Neutropenia and infections are the dose-limiting toxicities of the EID regimen and can cause dose reduction and/or delay in chemotherapy administration. The purpose of this study was to verify if EID + G-CSF is feasible with an acceptable toxicity in a day hospital setting and if G-CSF could allow an increase in the dose intensity of the EID regimen by shortening the intervals between the courses. Patients and methods 20 patients with inoperable primary, metastatic or residual disease after surgery or at high risk of recurrence after complete resection, histologically confirmed adult soft tissue sarcoma, entered the study. The dose and schedule of the chemotherapy agents were epidoxorubicin 30 mg/m2 days 1, 2, 3, dacarbazine 300 mg/m2 days 1, 2, 3, and ifosfamide 2500 mg/m2 with mesna uroprotection days 1, 2, 3. G-CSF, 300 micrograms/day subcutaneously, was administered from day 7 for a maximum of 14 days and discontinued when WBC was greater than 10 x 10(9)/L. Courses were repeated "as soon as possible," but never earlier than 10 days from the previous course and at least 48 hours after the last G-CSF injection. Results A total of 66 EID + G-CSF courses were administered. A G3 and G4 (WHO) neutropenia occurred in 66% of evaluables courses. Nonhematological toxicity was mild. The median number of G-CSF injections required during any interval between courses was 9 (range: 4-14 injections) and the median interval between courses was 21 days (range: 13-36 days). The median dose intensity at the third course of chemotherapy was 1.15 (range: 0.71-1.62). Conclusion This study shows that G-CSF allows a moderate increase in the delivered dose intensity of chemotherapy with an acceptable toxicity. Further studies are needed to investigate if this increase in DI may translate into an improved response rate.

Introduction: Standard chemotherapy represented by the R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) regimen is successful in about 60% of patients (pts) with diffuse large B-cell lymphoma (DLBCL). Pts who do not benefit from this treatment, due to the development of tumor drug resistance, have a very poor prognosis. Currently, knowledge on reasons of treatment related failures in DLBCL are scanty and predictive biomarker of response are largely unknown. We hypothesized that polymorphisms of gene involved in the pharmacokinetics and pharmacodynamics of drugs included in R-CHOP regimen may play a role in predicting the outcome in DLBCL pts.Thus, we designed a multicentre prospective pharmacogenetic trial aimed at identifying gene polymorphisms potentially predictive of drug efficacy/resistance in DLBCL pts treated with R-CHOP. An interim analysis on the first 80 enrolled ptswas planned and has been performed. Methods: The study included chemonaive DLBCL pts at various stages of disease candidate to an R-CHOP standard treatment. The Ethical Committee of each participating centre approved the pharmacogenetic protocol, and all pts signed a written informed consent. According to the aims of this interim analysis, the impact of single nucleotide polymorphisms (SNPs) on R-CHOP efficacy was evaluated by objective response (OR) rate at the end of treatment. The efficacy of R-CHOP was evaluated according to the Cheson criteria by performing standard hematochemical and instrumental (TC and FDFG-PET) tests and defining complete remission (CR), partial remission (PR), non response or progressive disease (PD). Genomic DNA wasextracted from peripheral blood of 80 pts. Twentysingle nucleotide polymorphisms (SNPs) from18candidate genes (ABCB1, ABCC1, ABCC2, ABCG2, CYBA, CYP2C9, FCGR2A, GSTP1, IL2, MLH1, NCF4, NQO1, NQO2, RAC2, TNF, TOP2A, TP53, TUBB)involved in pharmacokinetics and pharmacodynamics of R-CHOP (www.pharmgkb.org) have been analysed by a genotyping array based on Affimetrix methodology. Univariate analysis was performed to evaluate associations between polymorphisms and clinical/pathological characteristics or OR (Fisher exact test). Multivariate logistic regression analysis was performed to estimate adjusted odds ratios along with the corresponding 95% confidence intervals for the polymorphisms and OR. Results: Median age was 63 years. There were 37 men and 43 women. 47.5 % of pts were in stage I-II,52.5 % of pts in stage III-IV. 27.5% of ptshad bulky disease, 43.8 % of pts had involvement of extranodal site. 47.5% of pts had pathological LDH value. According to the revised IPI, 15 % pts were in the low risk group, 58.7 % in the intermediate risk group, and 26.3 % in the high risk group.Overall, 468 courses of R-CHOP had been administered (mean: 5.85 courses, range: 4-6). 81% of pts had CR to R-CHOP whereas the remaining showed PR (14%) or PD(5%). No statistically significant correlation was found between OR and clinical characteristics of pts.However, stage III-IV pts showed a worst OR than stage I-II pts (77% vs 87% of CR, respectively); pts with bulky disease had worst OR than non-bulky disease pts(73% vs 84.5% of CR, respectively); ptswith R-IPI 3-5 a worst OR than pts with R-IPI 0-2 (71.5% vs 85% of CR, respectively). Univariate and multivariateanalysis identified TOPOII rs13695as a predictor of OR (p=0.042). Pts with CT or TT genotypesshowed worst OR than CC wild-type homozygous pts (odds ratio 3.070, CI95% 1.113-13.457). Also, a statistical trend toward significance was observed for MLH1 rs1800734 polymorphism (p=0.062): ptswith homozygous genotype for the mutant allele showed a better OR than wild-type and heterozygous pt genotypes. Conclusions: No significant relationship between clinical/pathological characteristics and OR was observed. Our preliminary data show that SNPs affecting a gene involved in doxorubicin pharmacodynamics, i.e. the drug target TOPOII, as well asone of the major components of DNA mismatch repair, i.e. MLH1 gene,may predict response in DLBCL pts treated with R-CHOP. These preliminary results from the interim analysis are promising and warrant completion of pt accrual to reach the planned number of cases at the end of our study. Acknowledgments This work was supported by a grant from the Associazione Giacomo Onlus, Castiglioncello (LI), Italy to E.M. and Cassa di Risparmio di Firenze, Firenze, Italy to S.N. Disclosures No relevant conflicts of interest to declare.

Purpose: Dasatinib is a potent, oral SRC-family kinase inhibitor with preclinical antiproliferative, antimetastatic, and antiosteoclastic activity suggesting dasatinib sensitivity in triple-negative, or basal-like, breast cancer cell lines. This phase 2 trial assessed efficacy and safety of single-agent dasatinib in patients with advanced triple-negative breast cancer (TNBC). Experimental Design: Female patients with measurable, locally advanced or metastatic TNBC initially received dasatinib 100 mg twice daily (BID); to improve tolerability, the protocol was amended and subsequent patients received 70 mg BID. Primary endpoint was Response Evaluation Criteria in Solid Tumors–defined objective response rate (ORR); secondary endpoints included progression-free survival (PFS), disease control rate (DCR), safety, and limited pharmacokinetics. Results: Of the 44 treated patients, 43 were response evaluable. ORR was 4.7%: two patients had confirmed partial responses lasting 14 and 58 weeks, respectively. Of 11 patients with stable disease, two continued for more than 16 weeks, thus protocol-defined DCR was 9.3%. Median PFS was 8.3 weeks (95% CI: 7.3–15.3). Five patients discontinued before first tumor assessment. No grade 4 adverse events (AE) were reported; grade 3 AEs occurring in more than 5% of patients were fatigue (9.1%), diarrhea, pleural effusion, and dyspnea (all 6.8%). Laboratory abnormalities were uncommon. Dasatinib at 100 mg BID was not well tolerated; rates of treatment interruption, dose reduction, and serious AEs were lower with dasatinib 70 mg BID. Conclusions: Single-agent dasatinib has limited activity in unselected patients with TNBC. Dasatinib 70 mg BID was better tolerated than 100 mg BID. Future studies will investigate dasatinib in other breast cancer settings, including chemotherapy combinations. Clin Cancer Res; 17(21); 6905–13. ©2011 AACR.

Background: Epidermal growth factor receptor (EGFR), evaluated by immunohistochemistry, has been shown to have prognostic significance in patients with colorectal cancer. Gene copy number (GCN) of EGFR and KRAS status predict response and outcome in patients treated with anti-EGFR therapy, but their prognostic significance in colorectal cancer patients is still unclear. Methods: We have retrospectively reviewed the baseline EGFR GCN, KRAS status and clinical outcome of 146 locally advanced rectal cancer (LARC) patients treated with preoperative chemoradiotherapy. Pathological response evaluated by Dworak's tumour regression grade (TRG), disease-free survival (DFS) and overall survival (OS) were analysed. Results: Tumour regression grade 4 and TRG3–4 were achieved in 14.4 and 30.8% of the patients respectively. Twenty-nine (19.9%) and 33 patients (19.2%) had an EGFR/nuclei ratio >2.9 and CEP7 polisomy >50% respectively; 28 patients (19.2%) had a KRAS mutation. Neither EGFR GCN nor KRAS status was statistically correlated to TRG. 5-year DFS and OS were 63.3 and 71.5%, respectively, and no significant relation with EGFR GCN or KRAS status was found. Conclusion: Our data show that EGFR GCN and KRAS status are not prognostic factors in LARC treated with preoperative chemoradiation.

Triple-negative breast cancer (TNBC) has been recently recognized as an important subgroup of breast cancer with a distinct outcome and therapeutic approach compared with other breast cancer subgroups. Because TNBC is defined by the absence of a target (either hormone receptors or HER-2), conventional cytotoxic therapy is still the mainstay of treatment. This report focuses on the current state and recent advances in managing TNBC.

Background Cetuximab improves activity of chemotherapy in metastatic colorectal cancer (mCRC). Gene copy number (GCN) of epidermal growth factor receptor (EGFR) has been suggested to be a predictive factor of response to cetuximab in patients (pts) with mCRC; on the contrary, K-ras mutation has been associated with cetuximab resistance. Patients and methods We have conducted a phase II study with cetuximab administered weekly for 3 weeks as single agent and then with 5-fluorouracil and radiation therapy as neo-adjuvant treatment for locally advanced rectal cancer (LARC). EGFR immunohistochemistry expression, EGFR GCN and K-ras mutation were evaluated on diagnostic tumor biopsy. Dworak's tumor regression grade (TRG) was evaluated on surgical specimens. Results Forty pts have been treated; 39 pts are assessable. TRG 3 and 4 were achieved in nine (23.1%) and three pts (7.7%) respectively; TRG 3–4 rate was 55% and 5.3% in case of high and low GCN, respectively (P 0.0016). Pts with K-ras mutated tumors had lower rate of high TRG: 11% versus 36.7% (P 0.12). In pts with wild-type K-ras, TRG 3–4 rate was 58.8% versus 7.7% in case of high or low GCN, respectively (P 0.0012). Conclusions In pts with LARC, EGFR GCN is predictive of high TRG to cetuximab plus 5-FU radiotherapy. Moreover, our data suggest that a wild-type K-ras associated with a high EGFR GCN can predict sensitivity to cetuximab-based treatment.

Patients with metastatic breast cancer (MBC) represent a very heterogeneous population and several factors are important for therapeutic decision: patients' characteristics including age, comorbidities, performance status, tumor biological profile, site and extension of metastatic spread, previous adjuvant therapies, and disease-free interval. New cytotoxic agents, new endocrine agents, and targeted therapies are becoming the new mainstay of adjuvant treatment. The growing understanding of the biology of breast cancer cells has led to the identification of key molecular points that represent possible targets for target-specific agents. Trastuzumab, the monoclonal antibody against the HER2 receptor, represents the standard treatment of high-risk early-stage breast cancer overexpressing HER2. With increasing use of very active drugs in the adjuvant setting, there is a greater need for effective therapy at the time of relapse. In endocrine resistant disease, a treatment-free interval > 12 months after adjuvant chemotherapy has been shown to be an important factor for drug sensitivity. If the tumor has been exposed to an anthracycline and a taxane in adjuvant setting and the treatment-free interval is > 12 months, the rechallenge with the same agents might be an option. If the treatment-free interval is < 12 months, it is preferable to use a different agent. Capecitabine, gemcitabine, and vinorelbine have demonstrated substantial activity in MBC. Novel cytotoxic agents including epothilones and vinflunine are currently in clinical development for taxane-resistant disease. Lapatinib, a new target agent that simultaneously inhibits both HER2 and epidermal growth factor receptor tyrosine kinases has been shown to be active in trastuzumab-resistant MBC. Moreover, several new agents targeting HER2 are currently under clinical development. There are no data on rechallenge with trastuzumab in patients who had received this agent as adjuvant treatment and relapsed after a long treatment-free interval, and this issue is a new area of research.

Purpose: To evaluate expression of a panel of molecular markers, including p53, p21, MLH1, MSH2, MIB-1, thymidylate synthase, epidermal growth factor receptor (EGFR), and tissue vascular endothelial growth factor (VEGF), before and after treatment in patients treated with neoadjuvant chemoradiotherapy for locally advanced rectal cancer, to correlate the constitutive profile and dynamics of expression with pathologic response and outcome. Methods and Materials: Expression of biomarkers was evaluated by immunohistochemistry in tumor samples from 91 patients with clinical Stage II and III rectal cancer treated with preoperative pelvic radiotherapy (50 Gy) plus concurrent 5-fluorouracil by continuous intravenous infusion. Results: A pathologic complete remission was observed in 14 patients (15.4%). Patients with MLH1-positive tumors had a higher pathologic complete response rate (24.3% vs. 9.4%; p = 0.055). Low expression of constitutive p21, absence of EGFR expression after chemoradiotherapy, and high Dworak’s tumor regression grade (TRG) were significantly associated with improved disease-free survival and overall survival. A high MIB-1 value after chemoradiotherapy was significantly associated with worse overall survival. Multivariate analysis confirmed the prognostic value of constitutive p21 expression as well as EGFR expression and MIB-1 value after chemoradiotherapy among patients not achieving TRG 3–4. Conclusions: In our study, we observed the independent prognostic value of EGFR expression after chemoradiotherapy on disease-free survival. Moreover, our study suggests that a constitutive high p21 expression and a high MIB-1 value after neoadjuvant chemoradiotherapy treatment could predict worse outcome in locally advanced rectal cancer.

Metastatic breast cancer (MBC) remains an incurable disease. The aims of treatment include tumour shrinkage, symptom control, delay of disease progression and prolongation of survival while maintaining an acceptable quality of life. In the last decade, a decline in mortality has been observed. Combination chemotherapy generally provides some survival advantage over single-agent chemotherapy. Taxanes and antimetabolites are among the most effective agents, providing a balance between efficacy and tolerability. Increasing numbers of patients are receiving adjuvant anthracycline and taxane therapy. In these patients, treatment options include cytotoxic agents not used in adjuvant treatment, re-challenge with anthracycline and taxanes, or new targeted agents such as pertuzumab, lapatinib or bevacizumab. Biology of the disease at cell level plays a major role in treatment choice. Key points in the intracellular signal transduction pathways relevant for cell proliferation, apoptosis and the angiogenesis/metastasis process, represent possible targets for new target-specific agents. Tailored therapies are a step forward in improving patients' prognosis.

TPS1106 Background: Treatment of mTNBC is an unmet clinical need. First-line nab-P with gem or carbo/bevacizumab has demonstrated efficacy and safety in female patients (pts) with mTNBC. nab-P sign...

HER-2 overexpression is associated to a poor prognosis in high-risk and metastatic breast cancer (MBC) patients treated with high-dose chemotherapy (HDC). HER-2 status is also a predictive factor and when trastuzumab is administered in combination with or sequentially to chemotherapy, a significant disease-free and/or overall survival improvement has been observed in HER-2+ early and MBC. Unfortunately, in both settings, trastuzumab is associated with an increased risk of cardiac dysfunction (CD). We have reviewed the clinical charts of HER-2-overexpressing MBC patients treated with trastuzumab after HDC. Age, baseline left ventricular ejection fraction (LVEF), radiation therapy on cardiac area, exposure to anthracycline, single or multiple transplant, high-dose agents, trastuzumab treatment duration were recorded as potential risk factors. In total, 53 patients have been included in the analysis. Median LVEF at baseline was 60.5%; at the end of trastuzumab (data available for 28 patients only), it was 55% (P = 0.01). Five out of the 28 (17.9%) patients experienced CD. Two out of 53 (3.8%) patients developed a congestive heart failure. Ageor = 50 years and multiple transplant procedure were potential risk factors for CD. The overall incidence of CD observed in this population of HER-2+ MBC patients treated with trastuzumab after HDC is not superior to that reported with concomitant trastuzumab and anthracyclines. However, patients with ageor = 50 years or receiving multiple course of HDC should be considered at risk for CD.

3636 Background: Preoperative chemo-radiotherapy has been shown to improve local control in locally advanced rectal cancer. However the benefit in overall survival is still controversial. Moreover ...

This study aimed to define the maximum-tolerated dose (MTD) of fixed dose rate (FDR) of gemcitabine (2′-2′-difluorodeoxycitidine) infusion with circulating haemopoietic progenitor support and to evaluate the activity of the treatment. Secondary end points were pharmacokinetic of gemcitabine and difluorodeoxyuridina (dFdU) measured at first course and the activity and expression profile of cytidine deaminase (CdA) on circulating mononuclear cells. Patients with advanced pancreatic carcinoma received escalating dose of gemcitabine 10 mg m-2min-1 every 2 weeks with circulating haemopoietic progenitor support. First dose level was 3000 mg m-2 and the doses were increased by 500 mg m-2 until MTD. In all, 23 patients were enrolled. Toxicities were mild or moderate; the only patient treated at 7000 mg m-2 died because of toxicity; therefore; the MTD was established at 6500 mg m-2. The overall response rate was 22.2%. The AUC of gemcitabine showed a dose-dependent increase, while the AUC of dFdU reached a plateau at 4500 mg m-2. A significant relationship was found between the AUC of dFdU and CdA expression and activity (P < 0.05). Moreover, progression rate and survival were significantly related to CdA expression and activity levels. The activity of high-dose gemcitabine is not superior to that reported with less intensive FDR schedules. The predictive role of CdA expression and activity on outcome deserves further investigation.