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LBA3503 Background: Promising results have been obtained during the last decade using cytoreductive surgery (CRS) plus HIPEC for selected patients with colorectal PC who are amenable to complete macroscopic resection. This is the first trial to evaluate the specific role of HIPEC, after CRS, for the treatment of PC of colorectal origin. Methods: Prodige 7 is a randomized phase III, multicenter trial. Patients with histologically proven and isolated PC, peritoneal cancer index (PCI) ≤25 were eligible. Randomization (1:1) was stratified by center, complete macroscopic resection (R0/1 vs R2), and neoadjuvant systemic chemotherapy. Patients were treated with CRS plus HIPEC with oxaliplatin or CRS alone, in association with systemic chemotherapy. The primary endpoint was the overall survival (OS). Secondary endpoints were relapse-free survival (RFS) and toxicity. 264 patients were required to show a gain in median OS from 30 to 48 months (HR = 0.625) with a two-sided α = 0,046 and 80% power. Results: 265 patients from 17 centers were included between February 2008 and January 2014: 132 in Arm without HIPEC and 133 in Arm with HIPEC. The median age was 60 years (range: 30-74). Baseline characteristics were well balanced. The overall post-operative mortality rate was 1.5% and was not different between the two arms. The morbidity rates did not differ statistically at 30 days. At 60 days, the grade 3-5 morbidity rate was significantly higher with HIPEC (24.1% vs. 13.6%, p= 0.030). After a median follow up of 63.8 months (95% CI: 58.9-69.8), the median OS was 41.2 months (95% CI 35.1-49.7) in the non-HIPEC Arm and 41.7 months (95% CI: 36.2-52.8) in the HIPEC Arm, HR = 1.00 (95% CI: 0.73-1.37) p = 0.995. The median RFS was 11.1 months (95% CI: 9-12.7) in non-HIPEC Arm and 13.1 months (95% CI: 12.1-15.7) in HIPEC Arm, HR = 0.90 (95% CI: 0.69-1.90) (p = 0.486), whilst the 1-year RFS rates were 46.1% in non-HIPEC Arm and 59 % in the HIPEC Arm. Conclusions: The therapeutic curative management of PC from colorectal cancer by CRS shows satisfactory survival results. While the addition of HIPEC with oxaliplatin does not influence the OS. Clinical trial information: NCT00769405.

Our study showed no advantage of intensification of HIPEC by adding irinotecan, contrary to the results obtained with IV combination. Ox-alone HIPEC should continue as one of the standard HIPEC regimens for PC.

Sporadic or hereditary colorectal cancer (CRC) with microsatellite instability (MSI) is frequently characterized by inflammatory lymphocytic infiltration and tends to be associated with a better outcome than microsatellite stable (MSS) CRC, probably reflecting a more effective immune response. We investigated inflammatory mechanisms in 48 MSI CRCs and 62 MSS CRCs by analyzing: (1) the expression of 48 cytokines using Bio-Plex multiplex cytokine assays, and (2) the in situ immune response by immunohistochemical analysis with antibodies against CD3 (T lymphocytes), CD8 (cytotoxic T lymphocytes), CD45RO (memory T lymphocytes), T-bet (Th1 CD4 cells), and FoxP3 (regulatory T cells). MSI CRC exhibited significantly higher expression of CCL5 (RANTES), CXCL8 (IL-8), CXCL9 (MIG), IL-1β, CXCL10 (IP-10), IL-16, CXCL1 (GROα), and IL-1ra, and lower expression of MIF, compared with MSS CRC. Immunohistochemistry combined with image analysis indicated that the density of CD3+, CD8+, CD45RO+, and T-bet+ T lymphocytes was higher in MSI CRC than in MSS CRC, whereas the number of regulatory T cells (FoxP3+) was not statistically different between the groups. These results indicate that MSI CRC is associated with a specific cytokine expression profile that includes CCL5, CXCL10, and CXCL9, which are involved in the T helper type 1 (Th1) response and in the recruitment of memory CD45RO+ T cells. Our findings highlight the major role of adaptive immunity in MSI CRC and provide a possible explanation for the more favorable prognosis of this CRC subtype.

The purpose of this study was to investigate, in the context of a prospective node-positive-breast cancer trial HER2 containing-regimen (UNICANCER-PACS 04 trial), the predictive value of HER2, FCGRIIA, and FCGRIIIA gene polymorphisms for cardiac toxicity and efficacy of trastuzumab. We analyzed HER2-I655V, FCGR2A-H131R, and FCGR3A-V158F single nucleotide polymorphisms in patients in adjuvant setting treated by six courses of either fluorouracil 500 mg/m(2), epirubicin 100 mg/m(2) and cyclophosphamide 500 mg/m(2), or epirubicin 75 mg/m(2) and docetaxel 75 mg/m(2) every 3 weeks then randomly assigned, in case of HER2 overexpressing tumor, to either trastuzumab for 1 year or nothing. Left ventricular ejection fraction and clinical examination were monitored in each patient, seven times throughout the study to detect congestive heart failure or asymptomatic subclinical cardiac toxicity. All genotypes were analyzed in relation to cardiac toxicity, EFS, and OS. One hundred and thirty-two HER2-positive breast cancer patients were analyzed. The HER2-I655V genotype was significantly associated with cardiac toxicity (p = 0.025). The FCGR2A-131 H/H genotype was significantly correlated with a shorter EFS (p = 0.027). The FCGR3A-158 V/V genotype was not correlated with EFS nor OS. These results might be useful in making a treatment choice of HER2 blockers in adjuvant setting by with an increase in efficacy and decrease in toxicity.

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BackgroundOur retrospective, international study aimed at evaluating the activity and safety of eribulin mesylate (EM) in pretreated metastatic breast cancer (MBC) in a routine clinical setting.MethodsPatients treated with EM for a locally advanced or MBC between March 2011 and January 2014 were included in the study. Clinical and biological assessment of toxicity was performed at each visit. Tumour response was assessed every 3 cycles of treatment. A database was created to collect clinical, pathological and treatment data.ResultsTwo hundred and fifty-eight patients were included in the study. Median age was 59 years old. Tumours were Hormone Receptor (HR)-positive (73.3 %) HER2-positive (10.2 %), and triple negative (TN, 22.5 %). 86.4 % of the patients presented with visceral metastases, mainly in the liver (67.4 %). Median previous metastatic chemotherapies number was 4 [1–9]. Previous treatments included anthracyclines and/or taxanes (100 %) and capecitabine (90.7 %). Median number of EM cycles was 5 [1–19]. The relative dose intensity was 0.917. At the time of analysis (median follow-up of 13.9 months), 42.3 % of the patients were still alive. The objective response rate was 25.2 % (95 %CI: 20–31) with a 36.1 % clinical benefit rate (CBR). Median time to progression (TTP) and overall survival were 3.97 (95 %CI: 3.25–4.3) and 11.2 (95 %CI: 9.3–12.1) months, respectively. One- and 2-year survival rates were 45.5 and 8.5 %, respectively. In multivariate analysis, HER2 positivity (HR = 0.29), the presence of lung metastases (HR = 2.49) and primary taxanes resistance (HR = 2.36) were the only three independent CBR predictive factors, while HR positivity (HR = 0.67), the presence of lung metastases (HR = 1.52) and primary taxanes resistance (HR = 1.50) were the only three TTP independent prognostic factors. Treatment was globally well tolerated. Most common grade 3–4 toxicities were neutropenia (20.9 %), peripheral neuropathy (3.9 %), anaemia (1.6 %), liver dysfunction (0.8 %) and thrombocytopenia (0.4 %). Thirteen patients (5 %) developed febrile neutropenia.ConclusionEM is an effective new option in heavily pretreated MBC, with a favourable efficacy/safety ratio in a clinical practice setting. Our results comfort the use of this new molecule and pledge for the evaluation of EM-trastuzumab combination in this setting. Tumour biology, primary taxanes sensitivity and metastatic sites could represent useful predictive and prognostic factors.

Informed consent: Informed consent was obtained from all individual participants included in each of the studies (HERA, NSABP B-31 (NRG Oncology) and NCCTG N9831 (Alliance)).