Analisi farmacogenetiche esplorative in pazienti affetti da carcinoma colorettale metastatico trattati con chemioterapia in associazione a bevacizumab

In questo elaborato sono presentati i dati relative alla ricerche svolte dal Dr. Fotios Loupakis nel corso dei tre anni di Dottorato in “Tecnologie per la Salute: valutazione e gestione delle innovazioni nel settore biomedicale”. L’ambito degli studi è quello che ha caratterizzato l’impegno scientifico del Dr. Loupakis anche durante la Scuola di Specializzazione in Oncologia, ovvero la maggiore definizione di aspetti molecolari caratterizzanti il tumore colorettale con particolare riguardo all’identificazione di fattori predittivi di efficacia dei trattamenti nel setting metastatico. Il trattamento del tumore colorettale metastatico ha subito profondi cambiamenti nell’ultimo decennio ed in particolare, l’introduzione nella pratica clinica di farmaci biologici a target molecolare, ha segnato in maniera decisiva l’approccio terapeutico a questa neoplasia. L’impiego del farmaco antiangiogenico bevacizumab ha migliorato in maniera significativa l’outcome dei pazienti seppur non esistano ad oggi criteri di selezione molecolare che possano identificare soggetti con maggiori probabilità di beneficiare realmente del trattamento stesso. Una delle sfide più importanti dell’attuale ricerca traslazionale in oncologia nel presente e nel prossimo futuro è proprio quella di poter offrire alla clinica raffinati elementi di caratterizzazione biomolecolare che consentano di definire in maniera ottimale prognosi e probobabilità di risposta agli specifici trattamenti

Circulating microRNAs in metastatic colorectal cancer (mCRC) patients (pts) treated with regorafenib

Introduction: Regorafenib is indicated for the treatment of mCRC patients who have failed all other therapies. Nevertheless a substantial percentage of patients experiences rapid disease progression (PD) and serious adverse events may occur. For these reasons, clinical and/or molecular markers able to improve the cost/benefit ratio are urgently needed. Circulating microRNAs (c-miRNAs) have been recognized as possible prognostic and diagnostic markers in mCRC. The aim of this study was to describe the early changes in plasma levels of 10 selected c-miRNAs during the treatment with regorafenib and to investigate their correlation with clinical outcome.Methods: Plasma samples of patients treated with regorafenib at our Institution were collected at baseline (D1) and after 15 days of treatment (D15). Plasma levels of c-miR-17, c-miR-21, c-miR-29, c-miR-34, c-miR-92, c-miR-126, c-miR-141, c-miR-221, c-miR-601, c-miR-760 were analysed by means of real-time PCR. Paired levels at D1 and D15 were compared by means of Wilcoxon test for each c-miRNA. C-miRNAs showing significant changes were further analysed in order to identify possible correlations with outcome.Results: Thirty-four patients were included in the present study. Main characteristics were the following: M/F = 50%/50%; median age = 65 (range 48-78 years); ECOG-PS 0/1-2 = 71%/29%; time from diagnosis of metastases </ ? 18 months 15%/85%. Median PFS and OS were 2.4 and 6.5 months, respectively. One (3%) patient achieved a response and 16 (47%) had disease stabilization (disease control rate: 50%). As compared to D1, the following c-miRNAs increased at D15: c-miR-601 (p = 0.01), c-miR-141 (p = 0.04) and c-miR-21 (p = 0.06). Despite a median increase in the overall population, 12 (35%) out of 34 patients showed reduced level of c-miR-21 at D15. Nine out of 12 (75%) patients with reduced levels of c-miR-21 achieved disease control, as compared to 8 out of 23 (35%) patients with increased levels (Fisher \u27s Exact Test, p = 0.035). Median PFS of patients with increased and decreased level of levels of c-miR-21 were 2.1 and 3.9 months, respectively (HR = 1.89 95%CI 0.92-4.14 p = 0.08). Data on OS are not yet mature. Early modifications of c-miR-21 levels showed a sensitivity of 82% in predicting benefit from regorafenib.Conclusion: The early modulation of c-miR-21 levels may predict benefit from regorafenib in terms of disease control. These results need validation in independent series

Final results of DESTINY-CRC01 investigating trastuzumab deruxtecan in patients with HER2-expressing metastatic colorectal cancer

Colorectal cancer; Metastasis; Targeted therapiesCáncer colorrectal; Metástasis; Terapias dirigidasCàncer de colorectal; Metàstasi; Teràpies dirigidesDESTINY-CRC01 (NCT03384940) was a multicenter, open-label, phase 2 trial assessing the efficacy and safety of trastuzumab deruxtecan (T-DXd) in patients with HER2-expressing metastatic colorectal cancer (mCRC) that progressed after ≥2 prior regimens; results of the primary analysis are published. Patients received T-DXd 6.4 mg/kg every 3 weeks and were assigned to either: cohort A (HER2-positive, immunohistochemistry [IHC] 3+ or IHC 2+/in situ hybridization [ISH]+), cohort B (IHC 2+/ISH−), or cohort C (IHC 1+). Primary endpoint was objective response rate (ORR) by independent central review in cohort A. Secondary endpoints included ORR (cohorts B and C), duration of response, disease control rate, progression-free survival, overall survival, pharmacokinetics, and safety of T-DXd. 86 patients were enrolled (53 in cohort A, 15 in cohort B, and 18 in cohort C). Results of the primary analysis are published, reporting an ORR of 45.3% in cohort A. Here, we report the final results. No responses occurred in cohorts B or C. Median progression-free survival, overall survival, and duration of response were 6.9, 15.5, and 7.0 months, respectively. Overall serum exposure (cycle 1) of T-DXd, total anti-HER2 antibody, and DXd were similar regardless of HER2 status. Most common grade ≥3 treatment-emergent adverse events were decreased neutrophil count and anemia. Adjudicated drug-related interstitial lung disease/pneumonitis occurred in 8 patients (9.3%). These findings support the continued exploration of T-DXd in HER2-positive mCRC.This study was sponsored by Daiichi Sankyo and funded by both Daiichi Sankyo and AstraZeneca. The sponsor was involved in data collection, analysis, interpretation, and preparation of the manuscript. We thank the patients who participated in this study, as well as their families and caregivers. We also thank the staff and investigators at all the study sites. We thank Masato Fukae, PhD, and Emi Kamiyama, PhD, for the analysis of the pharmacokinetic parameters, both of whom are employed by Daiichi Sankyo. Under the guidance of the authors, assistance in medical writing and editorial support was provided by Cindy M. Rigby, PhD, and Marianna B. Johnson, PhD, of ApotheCom, and was funded by Daiichi Sankyo

KRAS and BRAF genotyping of synchronous colorectal carcinomas.

Abstract. v‑Ki‑ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) genotyping is required prior to anti‑epidermal growth factor receptor monoclonal antibody therapy administered in cases of metastatic colorectal carcinoma (CRC). Thus, KRAS mutation screening is required for patient management. The present study reported the experience of KRAS/v‑raf murine sarcoma viral oncogene homolog B1 (BRAF) mutational screening on synchronous CRC pairs from 26 patients, which were defined as index lesions (ILs) and concurrent lesions (CLs) on the basis of tumor grade and dimension and their respective lymph node and distant metastases. Overall, KRAS mutations were present in 38.4% of patients, whereas BRAF mutations were present at a frequency of 11.5%. The genotyping of paired synchronous carcinomas indicated that 11 patients (42.3%) exhibited discordant KRAS mutational statuses in terms of the presence of a mutation in only one lesion of the pair or of two different mutations harbored by each lesion. BRAF mutations were present in the synchronous tumors of two cases, whereas in two other cases, only the IL or CL harbored mutant BRAF. Overall, the mutational statuses of distant and lymph node metastases confirm the genetic heterogeneity of synchronous primary tumors. These results highlighted the fact that adequate sampling and comprehensive testing, when feasible, is likely to optimize the decision‑making process for treatment approaches, even in the relatively rare event of multiple synchronous lesions

Magnitude of benefit of the addition of bevacizumab to first-line chemotherapy for metastatic colorectal cancer: meta-analysis of randomized clinical trials

<p>Abstract</p> <p>Background</p> <p>Although the addition of bevacizumab to 1^stline chemotherapy provides a significant survival benefit for advanced colorectal cancer, the magnitudes of both advantages and toxicities have not been extensively investigated.</p> <p>Methods</p> <p>A literature-based meta-analysis was conducted; Hazard Ratios were extracted from randomized trials for primary end-points (Progression Free Survival, PFS, Overall Survival OS). The log of event-based risk ratio were derived for secondary endpoints (objective/partial response rate, ORR/PR; severe hypertension, bleeding and proteinuria). Absolute differences and the number needed to treat/harm (NNT/NNH) were calculated. A meta-regression analysis with clinical predictors and a sensitivity analysis according to the trial phase-design were conducted as well.</p> <p>Results</p> <p>Five trials (2,728 pts) were selected. The addition of bevacizumab to 1^stline chemotherapy significantly increased both PFS (although with significant heterogeneity) and OS over exclusive chemotherapy by 17.1% and 8.6% (NNT 6 and 12), regardless of the study setting (non significant interaction between phase II and III). The chance to improve PR was significantly increased by 6.5% (NNT 15), with a trend for ORR. The risk of hypertension was significantly increased by 6.2% (NNH 16). According to the meta-regression analysis, female gender and rectal primary site were significant predictors for PFS benefit.</p> <p>Conclusions</p> <p>Notwithstanding all the concerns related to costs and the significant HTN risk, the significant outcome improvement provided by bevacizumab in first-line treatment for unselected advanced colorectal cancer patients, should be considered when choosing the appropriate up-front therapy.</p

Circulating microRNAs in metastatic colorectal cancer (mCRC) patients (pts) treated with regorafenib

Abstract not availabl

Glucose metabolism enzymes gene expression analysis and selective metabolic advantage in the clinical progression of colorectal cancer (CRC)

No abstract availabl