Claudia Maggi

Background Taxanes are a mainstay in the treatment of metastatic breast cancer (mBC). Combination chemotherapy, including platinum–taxens doublets, can improve tumor responses and progression-free survival (PFS), but is associated with more toxicities and an uncertain benefit in terms of overall survival (OS). Methods We performed a retrospective study on 274 consecutive patients with mBC treated at the Division of Medical Oncology of Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy, during the decade 2007–2016 with the combination of carboplatin AUC 2 plus paclitaxel 80 mg/m², both given on days 1 and 8 in every 21-day cycle. Results 264 patients were evaluable for treatment safety and activity. The objective response rate (ORR) was 44.7%. Median PFS and OS were 8.6 and 23.7 months, respectively. Triple-negative breast cancer (TNBC) patients had significantly lower PFS and OS times compared to other biology groups. At multivariable analysis, previous exposure to taxanes, HR-positive HER2-negative biology, a higher number of metastatic sites, and de novo metastatic disease at diagnosis were associated with reduced PFS, while receiving maintenance therapy correlated with improved PFS. Overall, the treatment was quite well tolerated, with 10.2% of patients discontinuing one or both drugs because of adverse events (AEs). G3–G4 neutropenia occurred in 16.8% of patients, while the incidence of febrile neutropenia was 2.3%. Conclusions Weekly carboplatin–paclitaxel regimen is active and well tolerated in mBC treatment. Prospective studies should be conducted to compare its efficacy and tolerability with standard single-agent paclitaxel or docetaxel treatment schedules, as well as with more recent combination regimens.

E12556 Background: Safety and activity of weekly carboplatin plus paclitaxel in patients (pts) with metastatic breast cancer (mBC) are poorly known. Nevertheless, taxane-based chemotherapy (ChT) is the milestone in mBC treatment. In this retrospective analysis, we report the safety and clinical activity of this combination in a consecutive series of pts treated at IRCCS Fondazione Istituto Nazionale dei Tumori in Milan in the last decade. Methods: We collecteddata on mBC patients treated between January 2007 and December 2016 with carboplatin AUC 2 plus paclitaxel 80 mg/m²on days 1 and 8, every three weeks. Selection criteria were: ECOG 0-1; evaluable and/or measurable mBC; known estrogen and progesterone receptors (ER/PgR) status and HER2 expression levels. 274 pts fulfilled the selection criteria, and 265 pts were evaluable for response and survival. Response was assessed according to RECIST criteria. Results: The median number of administered cycles was 6 (range 1-17). 66.4% and 88.3% of pts had received taxanes or antracyclines, respectively, as an adjuvant treatment or in the metastatic setting. 97% of HER2+ pts received trastuzumab concomitant with ChT. Among patients with ER/PgR-positive tumors, 42.8% received different endocrine treatments as maintenance therapy after achieving the best response with ChT or due inacceptable toxicity. Hematological and gastrointestinal toxicities were the most frequent adverse events (AEs), and were severe in 19% and 1.2% of pts, respectively. In particular, G3-G4 neutropenia and febrile neutropenia occurred in 16.8 % and 1.9 % of pts, respectively. 10.2% of pts discontinued the treatment because of toxicity. The objective response rate was 44.8% in the overall population, with median progression free survival (mPFS) of 8.6 months and median overall survival (mOS) of 23.7 months. Conclusions: Weekly carboplatin plus paclitaxel is a well-tolerated and active regimen across all different molecular subgroups of mBC. [Table: see text]

There is lack of evidence about systemic treatment of pseudomyxoma peritonei (PMP) relapsing after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. There is also lack of biomarkers able to predict outcomes beyond known clinical and pathological prognostic features. Fifteen patients with relapsed PMP and progressive disease within the last 6 months were included and received metronomic capecitabine (625 mg/mq/day b.i.d.) and bevacizumab (7.5 mg/Kg three-weekly) until progressive disease/unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Ion Torrent® next generation sequencing technology (Hot-spot Cancer Panel) was used to characterize molecular features. At a median follow up of 12 months, median PFS was 8.2 months and 1-year overall survival was 91 %. Partial responses were observed in 20 % of cases, but a significant reduction of tumor markers in up to 79 %. Treatment was very well tolerated without no new safety signals. All tumor samples except one had KRAS mutations. Patients with GNAS mutations had a significantly shorter median PFS as compared to GNAS wild-type ones (5.3 months vs. not reached; p < 0.007). The results were externally validated on our previous series of PMP patients. GNAS mutations were rare in a parallel cohort of 121 advanced colorectal cancers (2.5 %), but were associated with peculiar clinical-pathological features and aggressive course. Metronomic capecitabine and bevacizumab is an active and well tolerated option in patients with relapsed PMP. The negative prognostic effect of GNAS mutations in gastrointestinal cancers warrants further confirmatory studies and may prompt the development of effective targeted strategies.

The risk of developing renal cell carcinoma (RCC) increases with age, and given the constant gain in life expectancy of the general population, both localized RCC and metastatic RCC (mRCC) are more frequently observed in the elderly population. The elderly are a heterogeneous group of patients often characterized by the presence of comorbidities, different compliance to treatment and polypharmacy. Here we review the available data with the aim to analyze the safety and efficacy of new targeted therapies (TTs) in elderly mRCC patients. TTs seem to be effective in both older and younger patients, but elderly patients appear to show reduced tolerance to treatments compared to younger patients. Prospective trials are needed to better understand how to manage mRCC in elderly patients.

540 Background: Collecting duct carcinoma (CDC) of the kidney is a rare tumor, originating from renal medulla, characterized by younger age at diagnosis and poor prognosis. Since targeted therapies are currently not available for CDC, we aimed to identify the most deregulated pathways in this type of cancer to gain insights into new molecular targets. Methods: Total RNA was extracted from FFPE samples of primary CDC (n=9), clear cell carcinoma (CCC, n=7) and healthy normal (n=7) adjacent renal tissues (23 total samples). Gene expression profile was performed by GeneChip Human Transcriptome Array 2.0 (HTA 2.0 -Affymetrix). The One-Way between-subject ANOVA algorithm was used to calculate statistical significances of pairwise comparisons. Transcripts with a linear fold change (f.c.) of <-2/>2 (p-value

In a phase II study, we showed that temozolomide (TMZ) was tolerable and active in heavily pre-treated patients with advanced colorectal cancer (CRC) and MGMT methylation. A schedule of dose-dense TMZ may have enhanced activity due to the higher cumulative dose and induction of MGMT depletion, even in resistant tumors. Thirty-two patients with chemorefractory MGMT-methylated CRC were treated with TMZ at a daily dose of 75 mg/m² for 21 consecutive days every 4 weeks, for up to six cycles or until the occurrence of progressive disease/unacceptable toxicity. The primary endpoint was treatment activity in terms of objective response rate (ORR). MGMT protein expression was tested by immunohistochemistry (IHC) on two pooled cohorts: patients from the previous study of standard-dose TMZ and those from the current investigation. From November 2013 to December 2014, 32 patients were treated at Fondazione IRCCS Istituto Nazionale dei Tumori. We observed only three episodes of grade 3 asthenia and no significant myelotoxicity. The ORR was 16 % (all partial responses occurring in RAS-BRAF-mutated tumors). Median progression-free survival (PFS) and overall survival (OS) were 2.3 and 6.7 months, respectively. Patients with MGMT-low expression by IHC had a significantly higher ORR (p < 0.0001) and PFS (p = 0.001) compared to those with MGMT-high expression, while no difference was observed in OS.

Aims: Triplet chemotherapy with fluoropyrimidines, oxaliplatin and irinotecan is a standard therapy for metastatic colorectal cancer (CRC). Single nucleotide polymorphisms (SNPs) in DPYD and UGT1A1 influence fluoropyrimdines and irinotecan adverse events (AEs). Low frequency DPYD variants (c.1905 + 1G > A, c.1679 T > G, c.2846A > T) are validated but more frequent ones (c.496A > G, c.1129‐5923C > G and c.1896 T > C) are not. rs895819 T > C polymorphism in hsa‐mir‐27a is associated with reduced DPD activity. In this study, we evaluated the clinical usefulness of a pharmacogenetic panel for patients receiving triplet combinations.Methods: Germline DNA was available from 64 CRC patients enrolled between 2008 and 2013 in two phase II trials of capecitabine, oxaliplatin and irinotecan plus bevacizumab or cetuximab. SNPs were determined by Real‐Time PCR. We evaluated the functional variants in DPYD (rare: c.1905 + 1G > A, c.1679 T > G, c.2846A > T; most common: c.496A > G, c.1129‐5923C > G, c.1896 T > C), hsa‐mir‐27a (rs895819) and UGT1A1 (*28) genes to assess their association with grade 3–4 AEs.Results: None of the patients carried rare DPYD variants. We found DPYD c.496A > G, c.1129‐5923C > G, c.1896 T > C in heterozygosity in 19%, 5% and 8%, respectively, homozygous rs895819 in hsa‐mir‐27a in 9% and homozygous UGT1A1*28 in 8%. Grade 3–4 AEs were observed in 36% patients and were associated with DPYD c.496A > G (odds ratio (OR) 4.93, 95% CI 1.29, 18.87; P = 0.021) and homozygous rs895819 in hsa‐mir‐27a (OR 11.11, 95% CI 1.21, 102.09; P = 0.020). Carriers of DPYD c.1896 T > C and homozygous UGT1A1*28 showed an OR of 8.42 (95% CI 0.88, 80.56; P = 0.052). Multivariate analysis confirmed an independent value for DPYD c.496A > G and c.1896 T > C.Conclusions: Concomitant assessment of DPYD variants and the UGT1A1*28 allele is a promising strategy needing further validation for dose personalization.