Renato Tassi

The impact of sunitinib-induced hypothyroidism on progression-free survival of metastatic renal cancer patients: a prospective single-center study.

BACKGROUND Several studies have reported unexpected rates of hypothyroidism in patients treated with sunitinib. The biochemical basis of this impairment is unknown. A relationship between hypothyroidism and improved outcome has been suggested in some cancer patients. Here we describe the incidence of newly onset hypothyroidism and its relationship with progression-free survival in metastatic renal cell carcinoma patients undergoing sunitinib treatment at our institution. PATIENTS AND METHODS Between July 2007 and June 2009, 22 patients received a first line sunitinib for metastatic renal cell carcinoma. Thyroid function tests were prospectively evaluated as routine laboratory assessment in every patient, at baseline and on the first and last day of every ON and OFF sunitinib period. RESULTS The median duration of treatment was 39.5 weeks. During sunitinib therapy, 13 patients (59.1%) showed at least one elevated TSH level. No reductions of TSH below normal ranges were observed. L-thyroxine replacement therapy was required in 2 patients. Based on thyroid function, median progression-free survival was 8.55 months for hypothyroid compared with 7.03 months for euthyroid patients (P < 0.05). CONCLUSION Patients administered sunitinib have an high incidence of hypothyroidism. The improved outcome of hypothyroid patients suggests an important relationship between sunitinib and this uncommon side effect.

Biweekly sunitinib regimen reduces toxicity and retains efficacy in metastatic renal cell carcinoma: A single-center experience with 31 patients

Sunitinib is the standard care for first‐line treatment of metastatic renal cell carcinoma. The aim of this study was to determine whether a sunitinib regimen of 50 mg/day 2‐weeks on/1‐week off could maintain the same dose‐intensity as the standard 4‐weeks on/2‐weeks off schedule, and provide the same efficacy in terms of objective response, progression‐free survival and overall survival, while reducing drug‐related toxicity.

Sunitinib-induced hyperparathyroidism: a possible mechanism to altered bone homeostasis.

Sunitinib malate is an orally bioavailable tyrosine kinase inhibitor that is active against many tyrosine kinase receptors involving crucial pathways in both healthy tissues and malignant tissues. Because its use in clinical practice is quite recent, many of its possible side effects remain unknown. In this report, the authors describe the incidence of new‐onset hyperparathyroidism in a cohort of patients with metastatic renal cell carcinoma who received treatment with sunitinib.

HLA-G 3’UTR Polymorphisms Impact the Prognosis of Stage II-III CRC Patients in Fluoropyrimidine-Based Treatment

An important hallmark of CRC is the evasion of immune surveillance. HLA-G is a negative regulator of host’s immune response. Overexpression of HLA-G protein in primary tumour CRC tissues has already been associated to worse prognosis; however a definition of the role of immunogenetic host background is still lacking. Germline polymorphisms in the 3’UTR region of HLA-G influence the magnitude of the protein by modulating HLA-G mRNA stability. Soluble HLA-G has been associated to 3’UTR +2960 Ins/Ins and +3035 C/T (lower levels) and +3187 G/G (high levels) genotypes. HLA-G 3’UTR SNPs have never been explored in CRC outcome. The purpose of this study was to investigate if common HLA-G 3’UTR polymorphisms have an impact on DFS and OS of 253 stage II-III CRC patients, after primary surgery and ADJ-CT based on FL. The 3’UTR was sequenced and SNPs were analyzed for their association with survival by Kaplan-Meier and multivariate Cox models; results underwent internal validation using a resampling method (bootstrap analysis). In a multivariate analysis, we estimated an association with improved DFS in Ins allele (Ins/Del +Ins/Ins) carriers (HR 0.60, 95% CI 0.38–0.93, P = 0.023) and in patients with +3035 C/T genotype (HR 0.51, 95% CI 0.26–0.99, P = 0.045). The +3187 G/G mutated carriers (G/G vs A/A+A/G) were associated to a worst prognosis in both DFS (HR 2.46, 95% CI 1.19–5.05, P = 0.015) and OS (HR 2.71, 95% CI 1.16–6.63, P = 0.022). Our study shows a prognostic and independent role of 3 HLA-G 3’UTR SNPs, +2960 14-bp INDEL, +3035 C>T, and +3187 A>G.

Hyperlipidemia and hypothyroidism among metastatic renal cell carcinoma patients taking sunitinib malate. Related or unrelated adverse events

BACKGROUND In recent years, new-onset hypothyroidism was extensively reported in patients receiving sunitinib for malignancy. Effects of sunitinib on serum lipids are not described, however a hyperlipidemic state is commonly observed in hypothyroid patients. Here we report about the incidence and severity of hypercholesterolemia and hypertriglyceridemia in a cohort of patients receiving sunitinib for metastatic renal cell carcinoma. PATIENTS AND METHODS Thyroid function tests, serum triglycerides, and cholesterol were prospectively evaluated in 39 consecutive metastatic renal cell carcinoma patients, who were receiving sunitinib as a first-line treatment. Incidence of hyperlipidemia, thyroid function impairment, and their possible relationship were investigated. RESULTS Thyroid function tests, serum cholesterol, and triglycerides were assessed at baseline and before the beginning of each sunitinib cycle. During treatment, median triglyceride levels increased up to 271.3 mg/dL, and median cholesterol increased up to 234.7 mg/dL (+113% and +22%, respectively). A hyperlipidemic state developed in 27 patients (69.2%) within a mean time of 1.8 six-week cycles (range, 1-5 cycles) and persisted during treatment. Hypothyroidism was observed in 20 patients (51.2%) and usually developed within 2.3 cycles. Because hypothyroidism and hyperlipidemia developed at different time points of treatment and among different patients, our results failed to demonstrate a correlation between these adverse events. CONCLUSION New-onset hyperlipidemia was observed in an increased percentage of patients taking sunitinib. The mechanism of this side effect is still unclear. We recommend careful monitoring of serum lipid levels during sunitinib administration to recognize possible consequences, especially on cardiovascular health.

Progression-free survival (PFS) and overall survival (OS) in patients receiving three targeted therapies (TTs) for metastatic renal cell carcinoma (mRCC).

431 Background: In recent years, TTs have improved the prognosis of mRCC patients (pts). Despite a non-negligible number of pts received 3 TTs in clinical practice, no TTs have been evaluated as third-line. Aim of this study is to investigate the clinical outcome in pts who received 3 TTs. METHODS Pts with clear-cell mRCC who received 3 TTs were included. A questionnaire was sent to main Italian centers involved in the treatment of mRCC. Demographic data, history of RCC, type and length of first-, second- and third-line were collected; MSKCC risk class was calculated before starting the first-line. Sequences were evaluated by class (TKI-TKI-mTOR vs. TKI-mTOR-TKI) or by drug (Su-So-Ev vs. Su-Ev-So). Median PFS, OS and Time to Strategy Failure (TTSF: from start of first- to end of thrid-line) were estimated with the Kaplan-Meyer method with 95% CI and curves were compared with log-rank test. Cox model was used to explore predictors of TTSF and OS. The study had the ethical approval. RESULTS 2,065 pts were screened and 281 pts (13%) were treated with 3 TTs. No differences were found between TKI-TKI-mTOR and TKI-mTOR-TKI groups. The TTSF was 36.5 (30.5-42.6) mos vs. 29.3 (23.6-34.9) mos (p=0.059), and the OS was 50.7 (40.6-60.8) vs. 37.8 (34.2-41.5) mos (p=0.004), for TKI-TKI-mTOR and and TKI-mTOR-TKI, respectively. TTSF for Su-So-Ev was 32.1 vs. 30.4 mos for Su-Ev-So (p=0.006). The median OS was not reached in the group treated with Su-So-Ev compared to 35.6 (95%CI, 31.6-39.6) mos in the group treated with Su-Ev-So (p<0.001). The univariate and multivariable Cox analyses for TTSF and OS showed that the only predictive factor is the primary resistance to 1st line (HR: 3.15, 95%CI, 1.98-4.99; p<0.001). The Prognostic factors are the initial MSKCC group (HR: 2.07, 95% CI, 1.41 -3.05; p<0.001), the sequence of therapy (HR: 2.59, 95% CI, 1.59-4.22; p<0.001) and the primary resistance to first line (HR: 2.20, 95% CI, 1.16-4.11; p<0.001). CONCLUSIONS We report as the sequential treatment with two antiangiogenic inhibitors followed by an mTOR inhibitor could increase survival and the control disease in metastatic renal cell carcinoma.

The Inhibitory Effects of HYDAMTIQ, a Novel PARP Inhibitor, on Growth in Human Tumor Cell Lines With Defective DNA Damage Response Pathways.

The poly(ADP-ribose) polymerase (PARP) enzymes play a key role in the regulation of cellular processes (e.g., DNA damage repair, genomic stability). It has been shown that PARP inhibitors (PARPIs) are selectively cytotoxic against cells having dysfunctions in genes involved in DNA repair mechanisms (synthetic lethality). Drug-induced PARP inhibition potentiates the activity of anticancer drugs such as 5-fluorouracil in enhancing DNA damage, whose repair involves PARP-1 activity. The aim of this study was to evaluate the inhibitory effects of a novel PARPI, HYDAMTIQ, on growth in human tumor cell lines characterized by different features with regard to DNA damage response pathways (BRCA mutational status, microsatellite status, and ATM expression level) and degree of sensitivity/resistance to 5-fluorouracil. HYDAMTIQ showed a more potent inhibitory effect on cell growth in a BRCA2 mutant cell line (CAPAN-1) compared with wild-type cells (C2-6, C2-12, and C2-14 CAPAN-1 clones, and MCF-7). No statistically significant difference was observed after HYDAMTIQ exposure between cells having a different MS status or a different MRE11 mutational status. HYDAMTIQ induced greater antiproliferative effects in SW620 cells expressing a low level of ATM than in H630 cells expressing a high level of ATM. Finally, the combination of HYDAMTIQ and 5-fluorouracil exerted a synergistic effect on the inhibition of SW620 cell growth and an antagonistic effect on that of H630 cell growth. Our results show that the novel PARP inhibitor HYDAMTIQ potently inhibits the growth of human tumor cells with defective DNA damage response pathways and exerts synergistic cytotoxicity in combination with 5-fluorouracil. These data provide relevant examples of synthetic lethality and evidence for further development of this novel PARPI.

Role of genetic polymorphisms on R‐CHOP efficacy in diffuse large B ‐cell lymphoma patients: An interim analysis of a multicenter prospective pharmacogenetic study

USA; Center for Lymphoid Malignancies, Columbia University Medical Center, New York, NY, USA; Department of Medicine, British Columbia Cancer Center, Vancouver, BC, Canada; Division of Hematology / Oncology, University of Kansas Clinical Research Center, Westwood, KS, USA; Division of Oncology, Stanford University Medical Center, Stanford, CA, USA; Hematology and Hematopoietic Transplantation, City of Hope, Duarte, CA, USA

Emerging drugs in refractory colorectal cancer.

Colorectal cancer is the third leading cause of cancer-related deaths in the western world. Despite therapeutic advances, the prognosis of metastatic colorectal cancer patients remains poor due to intrinsic or acquired tumor drug resistance. The main mechanisms of tumor drug resistance are represented by genetic and epigenetic alterations. This leads to tumor refractoriness during treatment or disease progression following response to first-line therapy. Strategies to combat chemorefractory tumors involve the development of selective inhibitors of drug-resistant phenotypes, the epigenetic resensitization of drug-resistant cancer cells and new cytotoxic drugs devoid of cross resistance with first-line cytotoxics. The use of drug combination regimens may also increase treatment efficacy, and the exploitation of specific phenomena such as oncogenic and nononcogenic addiction or synthetic lethality represents another potential approach in combating tumor drug resistance. Clinical trials based on such strategies in mCRC patients whose tumors progressed following first-line chemotherapy are discussed herein.

Newly onset hyperlipidemia in metastatic renal cell carcinoma patients treated with sunitinib.

459 Background: To our knowledge effects of sunitinib on serum lipids metabolism are not described. Here we report about the occurrence of hypercholesterolemia and hypertriglyceridemia in patients receiving sunitinib for metastatic renal cell carcinoma (mRCC). METHODS Between July 2008 and September 2011, we prospectively evaluated serum triglycerides and cholesterol in 37 patients receiving sunitinib for mRCC according to classic 6-week schedule. On average they received sunitinib for 10.3 cycles. Serum lipids were measured before the beginning of treatment and at the end of each sunitinib ON period as routine laboratory evaluations. RESULTS At baseline median triglycerides was 163,83 mg/dl (± 76,6 mg/dl 95% CI) and median cholesterol was 201.6 mg/dl (± 35.5 mg/dl 95% CI). During sunitinib administration 25 patients (67.5 %) presented an elevation of serum lipids as compared to baseline. These abnormalities usually developed within 1.8 cycles (range 1-5 cycles). While on sunitinb median triglycerides was 333,6 mg/dl and median cholesterol was 243.5 mg/dl (+ 103% and + 21% respectively, compared to baseline). Patients who developed hypercholesterolemia presented an increase of both HDL and LDL cholesterol. CONCLUSIONS Hyperlipidemia develops in an elevate percentage of patients on sunitinib. The mechanism of this event remains unclear. Recently, an interaction between platelet derived growth factor receptor (PDGFR) and lipoprotein receptor (LR) family was described and this is supposed to be an important step towards the internalization of LR itself. Because sunitinib inhibits PDGFR, a lower plasma lipoproteins clearance could be expected, resulting in an increase of serum lipids. It is noteworthy that PDGFR inhibition was associated with delayed atherosclerotic plaque formation, having an anti-atherogenetic effect. Therefore treatment with sunitinib, even if associated to hypertension and hyperlipidemia, may not result in an increase of cardiovascular events.