Sara Lucchesi

Prospective Validation of Candidate SNPs of VEGF/VEGFR Pathway in Metastatic Colorectal Cancer Patients Treated with First-Line FOLFIRI Plus Bevacizumab

Purpose The potential impact of different SNPs of VEGF/VEGFR pathway on the clinical outcome of mCRC patients receiving bev-containing regimens has been investigated in retrospective experiences with contrasting results. We previously reported the association of VEGFA rs833061 C/T variants with PFS in metastatic colorectal cancer patients treated with first-line FOLFIRI plus bevacizumab. The primary objective of this work was to prospectively validate that retrospective finding. A confirmatory analysis of other SNPs of VEGF/VEGFR pathway genes was included. Experimental design To detect a HR for PFS of 1.7 for VEGFA rs833061 T/T compared to C- variants in metastatic colorectal cancer patients treated with first-line FOLFIRI plus bevacizumab, setting two-sided α = 0.05 and β = 0.20, 199 events were required. VEGFA rs699946 A/G, rs699947 A/C, VEGFR1 rs9582036 A/C and rs7993418 A/G, VEGFR2 rs11133360 C/T, rs12505758 C/T and rs2305948 C/T and EPAS1 rs4145836 A/G were also tested. Germ-line DNA was extracted from peripheral blood. SNPs were analyzed by PCR and sequencing. Results Four-hundred-twenty-four pts were included. At the univariate analysis, no differences according to VEGFA rs833061 C/T variants were observed in PFS (p = 0.38) or OS (p = 0.95). Among analyzed SNPs, only VEGFR2 rs12505758 C- variants, compared to T/T, were associated to shorter PFS (HR: 1.36 [1.05–1.75], p = 0.015, dominant genetic model) and OS, with a trend toward significance (HR: 1.34 [0.95–1.88], p = 0.088). In the multivariate model, this association retained significance (HR: 1.405 [1.082–1.825], p = 0.012) in PFS, that was lost by applying multiple testing correction (p = 0.14). Conclusion This prospective experience failed to validate the hypothesized predictive impact of VEGFA rs833061 variants. Retrospective findings on different candidate SNPs were not confirmed. Only VEGFR2 rs12505758 variants, whose prognostic and not predictive impact was previously reported, correlated with PFS. Given the complexity of angiogenesis, it is rather unlike that a single germ-line SNP might be a good predictor of benefit from bevacizumab.

Genetic interaction of P2X7 receptor and VEGFR-2 polymorphisms identifies a favorable prognostic profile in prostate cancer patients.

VEGFR-2 and P2X7 receptor (P2X7R) have been described to stimulate the angiogenesis and inflammatory processes of prostate cancer. The present study has been performed to investigate the genetic interactions among VEGFR-2 and P2X7R SNPs and their correlation with overall survival (OS) in a population of metastatic prostate cancer patients. Analyses were performed on germline DNA obtained from blood samples and SNPs were investigated by real-time PCR technique. The survival dimensionality reduction (SDR) methodology was applied to investigate the genetic interaction between SNPs. One hundred patients were enrolled. The SDR software provided two genetic interaction profiles consisting of the combination between specific VEGFR-2 (rs2071559, rs11133360) and P2X7R (rs3751143, rs208294) genotypes. The median OS was 126 months (95% CI, 115.94–152.96) and 65.65 months (95% CI, 52.95–76.53) for the favorable and the unfavorable genetic profile, respectively (p < 0.0001). The genetic statistical interaction between VEGFR-2 (rs2071559, rs11133360) and P2X7R (rs3751143, rs208294) genotypes may identify a population of prostate cancer patients with a better prognosis.

Pharmacogenetic interaction analysis of VEGFR-2 and IL-8 polymorphisms in advanced breast cancer patients treated with paclitaxel and bevacizumab

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

Cardiac safety of adjuvant non-pegylated liposomal doxorubicin combined with cyclophosphamide and followed by paclitaxel in older breast cancer patients

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

303PCARDIAC SAFETY ASSESSMENT OF ADJUVANT NONPEGYLATED LIPOSOMAL DOXORUBICIN (NPLD) PLUS CYCLOPHOSPHAMIDE (C) FOLLOWED BY PACLITAXEL (P) IN ELDERLY BREAST CANCER (EBC) WOMEN

ABSTRACT Background: doxorubicin is effective in early breast cancer but concerns about higher incidence of cardiac toxicity in older patients (pts) (Swain SM, Cancer 2003) have contributed to limit its use in this setting. NPLD is active in advanced disease and has much less cardiotoxicity than doxorubicin. Methods: In order to explore the feasibility of adjuvant NPLD in terms of cardiac safety, we are conducting a phase II pilot study in high risk EBC pts older than 65 years with NPLD 60mg/sqm day 1 plus C 600mg/sqm day 1 q 21 for 3 cycles followed by P 80 mg/sqm weekly for 9 weeks. Hormonal therapy and radiotherapy post chemotherapy when indicated. Cardiac safety is evaluated by comparison between the basal left ventricular ejection fraction (LVEF) assessed with echocardiogram (ECHO) and LVEF at the end of NPLD + C, after P and every 6 months for 2 years. Cardiac events are defined as appearance of congestive heart failure and/or grade 3-4 LVEF decline, asymptomatic LVEF decline below 50% or an absolute drop > 15%. Results: Up to today 47 pts have been enrolled with a median follow up of 11.0+ months (range 2.3+ - 28.0 +) Main pts characteristics are: median age = 73 (range, 67-83), ECOG-PS 0/1 = 38/9, basal LVEF >50% in all pts and no relevant cardiac co-morbidities. Basal median LVEF is 60% (range, 55%-76%). 141 cycles of NPLD + C have been administered. After NPLD + C the median LVEF is unchanged with a value of 60% (range, 56%-74%), as well as median LVEF after weekly P, with a value of 60% (range, 50%-72%). 18 pts were evaluable for LVEF at 6 months after the end of chemotherapy: median LVEF is unchanged with a value of 60% (range, 50%-69%). No pts had cardiac events as above defined. One patient discontinued NPLD + C after the first cycle for an episode of asymptomatic arrhythmia and one patient had a 10% drop of LVEF above 50%. Toxicities ≥3 were not observed. Conclusions: These preliminary data suggest the feasibility of adjuvant NPLD + C followed by P in EBC pts older than 65 years of age. Disclosure: All authors have declared no conflicts of interest.