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Papers by Federica Mazzuca

Journal of clinical oncology, Jun 1, 2024

Current Oncology, Jun 4, 2023

This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY

Annals of Oncology, Jul 1, 2020

European Journal of Cancer, Jul 1, 2020

Annals of Oncology, Jul 1, 2019

Cancer management and research, Dec 1, 2022

Annals of Oncology, Jul 1, 2020

Critical Reviews in Oncology/Hematology

Nature Medicine

Genomics has greatly improved how patients with cancer are being treated; however, clinical-grade... more Genomics has greatly improved how patients with cancer are being treated; however, clinical-grade genomic biomarkers for chemotherapies are currently lacking. Using whole-genome analysis of 37 patients with metastatic colorectal cancer (mCRC) treated with the chemotherapy trifluridine/tipiracil (FTD/TPI), we identified KRAS codon G12 (KRASG12) mutations as a potential biomarker of resistance. Next, we collected real-world data of 960 patients with mCRC receiving FTD/TPI and validated that KRASG12 mutations were significantly associated with poor survival, also in analyses restricted to the RAS/RAF mutant subgroup. We next analyzed the data of the global, double-blind, placebo-controlled, phase 3 RECOURSE trial (n = 800 patients) and found that KRASG12 mutations (n = 279) were predictive biomarkers for reduced overall survival (OS) benefit of FTD/TPI versus placebo (unadjusted interaction P = 0.0031, adjusted interaction P = 0.015). For patients with KRASG12 mutations in the RECOURSE...

Radiology and Oncology, Aug 14, 2022

Background. Electrochemotherapy (ECT) is a minimally invasive and safe treatment gaining positive... more Background. Electrochemotherapy (ECT) is a minimally invasive and safe treatment gaining positive and long-lasting antitumoral results that are receiving the attention of the scientific community. It is a local treatment that combines the use of electroporation and the administration of cytotoxic drugs to induce cell death in the target tissue. ECT is largely used for the treatment of cutaneous and subcutaneous lesions, and good results have been reported for the treatment of deep visceral tumors. The latest literature review is provided. Moreover, in line with its development for the treatment of visceral tumors in this article, we describe a novel approach of ECT: endoscopic treatment of colorectal cancer. Endoscopic ECT application was combined with systemic chemotherapy in the treatment of obstructing rectal cancer without prospective surgery. A good response after ECT was described: concentric involvement of the rectum was reduced, and no stenosing lesions were detected. Conclusions. Clinical studies have demonstrated that ECT is a very effective treatment for tumors of different histologic types and localizations. Endoscopic treatment for gastrointestinal cancer is an innovative application of ECT. The combination of systemic treatment and ECT was safe and highly effective in the treatment of colorectal cancer, especially when obstructive, giving the patient a significant gain in quality of life.

European Journal of Pharmacology, Nov 1, 2019

Melanoma onset and progression are associated with a high variety of activating mutations in the ... more Melanoma onset and progression are associated with a high variety of activating mutations in the MAPKpathway, most frequently involving BRAF (35-45%) and NRAS (15-25%) genes, but also c-KIT and PTEN. Targeted therapies with BRAF and MEK inhibitors showed promising results over the past years, but it is known that most responses are temporary, and almost all of patients develop a tumor relapse within one year. Different drug-resistance mechanisms underlie the progression of disease and activation of both MAPK and PI3K/AKT/ mTOR pathways. Therefore, in this article we reviewed the main studies about clinical effects of several target inhibitors, describing properly the most prominent mechanisms of both intrinsic and acquired resistance. Furthermore, suggestive strategies for overcoming drug resistance and the most recent alternative combination therapies to optimize the use of MAPK pathway inhibitors were also discussed.

Integrative Cancer Therapies, 2019

Background and Aims: Sarcopenia, the loss of both lean body and skeletal muscle mass, may interfe... more Background and Aims: Sarcopenia, the loss of both lean body and skeletal muscle mass, may interfere in cancer patients outcome. As investigated, whey proteins could prevent the onset of sarcopenia. We have conducted a study to evaluate the effects of whey protein in colorectal cancer patients, undergoing 5-fluorouracil-based chemotherapy. Methods: After written informed consent, patients were blind randomized 1:1 to whey protein (ProLYOtin; arm A) versus placebo (arm B). The patients were assessed both physically and nutritionally before chemotherapy and after 3 (T2) and 6 months (T3) by body impedance assessment, L3-computed tomography scan, Mini Nutritional Assessment (MNA), and Malnutrition Universal Screening Tool (MUST) tests. Results: Forty-seven patients were included in this preliminary analysis. Baseline characteristics were well balanced between the 2 arms. During chemotherapy, 33 patients were reevaluated: anthropometric parameters (lean body mass from 68.5% to 71.2% vs 68.7% to 66.3%, and sarcopenia from 84% to 54% and 83% to 77% from baseline to T2 evaluation in arms A and B, respectively), nutritional status (MNA >24 = 100% [A] vs 73.7% [B]), and toxicity (no adverse effects in 86% [A] vs 29% [B] and 94% [A] vs 29% [B] for hematological and gastrointestinal toxicities, respectively) resulted to be significantly different. At univariate analysis, a condition of malnutrition risk according to MUST (relative risk [RR] = 7.5, P = .02) or MNA (RR = 1.45, P = .02) and ProLYOtin intake (RR = 0.12, P = .01) were found to be significantly predictive of chemotherapy toxicity. Conclusions: At present, our study shows how whey protein could be an important therapeutic option to improve nutritional status, and particularly to prevent severe toxicity during chemotherapy.

Journal of Clinical Oncology, Feb 1, 2018

700 Background: The standard of care for locally advanced rectal cancer (RC) is neoadjuvant chemo... more 700 Background: The standard of care for locally advanced rectal cancer (RC) is neoadjuvant chemoradiotherapy (CRT) with 5FU aimed to tumor downstaging prior to radical resection but there is a wide spectrum of responses to it, from none to complete. The aim of this project is to validate top candidate genes previously identified by microarray studies as prognostic and predictive classifiers of locally advanced RC, using the NanoString nCounter Platform. Methods: Two cohorts of RC patients were identified according to tumor regression grade (TRG) of AJCC Staging Manual (7th) system: 1) good prognosis: patients that after neoadjuvant CRT obtained TRG0 (complete response); 2) poor prognosis: patients with TRG1 (moderate response), patients with TRG2 (minimum response rate) and patients with TRG3 (poor response). Pre-treatment biopsies tissues from ten TRG0 patients (ID TRG0bio) and thirteen TRG1-3 patients (ID TRG1-3bio) were macro-dissected from FFPE sections, RNA isolated and used for expression profiling of a 305 genes custom code set consisting of 12 normalizer genes, 101 prognostic genes (markers of stemness, invasiveness, proliferation, drug-resistance), 192 predictive genes (involved in response to 5-FU, to radiation therapy and in the response to CRT). All samples were normalized using the geometric mean of the housekeeper genes. P-values were calculated by student’s t-test and was consider significance if was less than 0.05. Gene-specific RNA expression profiles were compared using Spearman's correlation. The heat map was generated using MeV 4.9.0. Results: When we compared TRG0bio to TRG1-3bio tissues, among the 305 genes assayed, changes in expression levels of 18 genes (SSB, GAPDH, TXNDC9, DUT, PKM, STAT1,SLC28A3, DAG1, TYMS, FERMT1, ARNT,SLC6A6, SMAD3, SCRN1, POU5F1, GNG4, PDRG1, ATP5E) were statistically significant. Conclusions: Results suggest that TRG0 RC is characterized by distinct molecular events compared TRG1-3 disease. Next steps will be: to amplify sample size, to understand signaling pathways of top differentially expressed genes and to validate prospectively our gene signature.

Annals of Oncology, Sep 1, 2016

Background: Fluoropyrimidines are commonly used in metastatic breast cancer after anthracyclines ... more Background: Fluoropyrimidines are commonly used in metastatic breast cancer after anthracyclines and/or taxanes failure or in frail patients. The identification of a toxicity predictive biomarker could help to avoid severe toxicities and consequent dose reduction or treatment discontinuation. We analyzed the predictive role on toxicity of 5-FU-DR and polymorphisms in TSER, DPYD and MTHFR genes. Materials and methods: We collected blood samples of metastatic breast cancer patients before starting capecitabine-based treatment. 5-FU-DR was determined by measuring the decrease of a known dose of 5-FU incubated with peripheral blood mononuclear cells in a time unit. Patients were classified as: poor metabolizers (PM: 5-FU-DR ≤ 0.85 ng/ml/10 6 cells/min); normal metabolizers (NM: 0.85< 5-FU-DR > 2.2 ng/ml/10 6 cells/min); ultra-rapid metabolizers (UM: 5-FU-DR ≥ 2.2 ng/ ml/10 6 cells/min). Gene polymorphisms of MTHFR, DPYD and TSER were detected using DNA pyrosequensing. Toxicities were classified according to CTCAE v 3.0. SPSS2 software was used to perform statistical analysis. Gene polymorphisms and the 5-FU-DR were correlated with toxicities through Pearson's Chi Square test. Results: We analyzed 40 metastatic breast cancer patients treated with capecitabine alone or in combination regimens. 3 patients were PM, 35 were NM and 2 were UM. Grade 3-4 toxicities were observed in 20% of patients: 50% hematopoietic, 50% gastrointestinal, 12.5% hepatic and 12.5% hand-foot symdrome. PM and UM showed a higher incidence of G3-4 toxicities (p = 0.05) and PM required dose reduction due to

Annals of Oncology, Oct 1, 2016

Background: FOLFOX (5-FU, Oxaliplatin and Leucovorin) is the most effective treatment for CRC pat... more Background: FOLFOX (5-FU, Oxaliplatin and Leucovorin) is the most effective treatment for CRC patients in adjuvant setting. However, the toxicity can lead to reduction, delay or discontinuation of treatment. DPD is the key enzyme involved in 5-FU catabolism and 5-FU-DR is a phenotypic parameter, reflecting the entire metabolism of 5-FU. We investigated the association between 5-FU-DR and genetic polymorphisms of TSER, DPYD, MTHFR and with toxicity in CRC patients treated with adjuvant FOLFOX. Methods: We collected 126 blood samples before starting treatment. 5-FU-DR was determined by measuring the decrease of a fixed amount of 5-FU added to a solution of Peripheral Blood Mononuclear Cells after 2 hours of incubation. Patients were classified as: poor metabolizers (PM: 5-FU-DR ≤ 0.85 ng/ml/10 6 cells/min); normal metabolizers (NM: 0.85 < 5-FU-DR > 2.2 ng/ml/10 6 cells/min); ultra-rapid metabolizers (UM: 5-FU-DR ≥ 2.2 ng/ml/10 6 cells/min). DNA pyrosequensing was used to detect gene polymorphisms of MTHFR, DPYD and TSER. Toxicities were classified according to CTCAE v 4.0. Statistical analysis was performed with SPSS2 software. Pearson's Chi Square test was used to correlate gene polymorphisms and 5-FU-DR with toxicities. Results: We analyzed 126 resected CRC patients (91 M, 35 F; median age 65 y, range 36-81 y), receiving adjuvant FOLFOX. 7 patients were PM, 116 NM and 3 UM. Median 5-FU-DR was 1.495 ng/ml/10 6 cells/min (range 0.42-2.29). G3-4 toxicities were observed in 22.2% of the cases: 59.3% hematological, 29.6% gastrointestinal, 7.4% neurological and 3.7% others. A higher G3-4 toxicity incidence was observed in PM and UM than in NM group (71.4% and 33.3% respectively vs 19%; p = 0.05). PM and UM required more frequently dose reduction due to toxicity (71.4% and 66.6% vs 31%; p = 0.04). One case of DPYD heterozygous mutated was detected and it was associated with 5-FU-DR PM (p = 0.04) and G4 hematological toxicity (p = 0.06). No statistically significant associations between toxicities and TSER (p = 0.2), MTHFR C677T (p = 0.5) and MTHFR A1298C (p = 0.8) were observed. Conclusions: 5-FU-DR seems to predict toxicity in resected CRC patients treated with 5-FU. Larger and perspective studies are required to implement this results. Legal entity responsible for the study: N/A Funding: University of Rome "Sapienza" Disclosure: All authors have declared no conflicts of interest.

Anti-Cancer Drugs, Jun 1, 2017

The PI3K/AKT pathway plays an important role in the initiation and progression of cancer, and the... more The PI3K/AKT pathway plays an important role in the initiation and progression of cancer, and the drug development efforts targeting this pathway with therapeutic interventions have been advanced by academic and industrial groups. However, the clinical outcome is moderate. Combination of inhibition of PI3K/AKT and other targeted agents became a feasible approach. In this study we assessed the combined effect of ARQ 092, a pan-AKT inhibitor, and ARQ 087, a pan-FGFR inhibitor, in vitro and in vivo. In a panel of 45 cancer cell lines, on 24% (11 out of 45) the compounds showed synergistic effect, on 62% (28 out of 45) additive, and on 13% (6 out of 45) antagonistic. The highest percentage of synergism was found on endometrial and ovarian cancer cell lines. Mutational analysis revealed that PIK3CA/PIK3R1 mutations and aberrant activation of FGFR2 predicted synergism, whereas Ras mutations showed a reverse correlation. Pathway analysis revealed that a combination of ARQ 092 and ARQ 087 enhanced the inhibition of both the AKT and FGFR pathways in cell lines in which synergistic effects were found (AN3CA and IGROV-1). Cell cycle arrest and apoptotic response occurred only in AN3CA cell, and was not seen in IGROV-1 cells. Furthermore, enhanced antitumor activity was observed in mouse models with endometrial cancer cell line and patient-derived tumors when ARQ 092 and ARQ 087 were combined. These results from in-vitro and in-vivo studies provide a strong rationale in treating endometrial and other cancers with the activated PI3K/AKT and FGFR pathways.

Annals of Oncology, Sep 1, 2014

Aim: 5-FU based chemotherapy is the most common regimen used for patients affected by gastric can... more Aim: 5-FU based chemotherapy is the most common regimen used for patients affected by gastric cancer both in metastatic and in adjuvant setting.Identification of predictive markers of both response and toxicity to chemotherapy is a promising approach for drug selection. The present study analyzes the predictive role of 5-FU degradation rate (5-FU-DR) and genetic polymorphisms (MTHFR, TSER, DPYD) on predicting toxicity to chemotherapy and survival Methods: 94 patients affected by gastric cancer were enrolled. Genetic polymorphisms of MTHFR, TSER and DPYD and the 5-FU-DR were analyzed. 5-FU degradation rate

Journal of Clinical Oncology, Jun 1, 2022

Background: The Rome Trial is a randomized, prospective, multicenter, multi-basket, Phase II clin... more Background: The Rome Trial is a randomized, prospective, multicenter, multi-basket, Phase II clinical trial (EudraCT n � 2018-002190-21; NCT04591431). The aim is to evaluate the efficacy of Tailored Therapy (TT) vs Standard of Care (SoC) in patients (pts) with metastatic solid tumors who received at least one and no more than two lines of treatment. Pts with a molecular alteration were discussed in a Molecular Tumor Board (MTB), assigned to one or a combination of the 20 available treatments, and randomized to TT or SoC. Methods: Tissue (collected within 6 months) and blood samples from pts with refractory solid tumors were analyzed centrally with next generation sequencing (NGS, Foundatio-nOneCDx and FoundationOneLiquid). MTB discussed all screened pts with any actionable genomic alterations using common mutational database and ESCAT. Genomic data, MTB reports and treatment outcomes were collected. The 3 outcomes of the MTB were: A) assignment of a TT and randomization, B) screening failure (SF) C) SF for the trial but with relevant information from the genomic test. Outcome C was divided into 3 groups: 1) indication to receive a personalized standard treatment different from the planned one, 2) indication to access to another clinical trial/compassionate use/expanded access, 3) indication to perform a germline test (GT). Results: From Oct 2020 to Dec 2021, 497 pts were enrolled in 38 Italian accrual sites, 303 (61.0%) had relevant genomic alterations and were discussed to the MTB. Molecular profiling was determined both on tissue and liquid biopsy in 262/303 (86.5%) pts, while in 11 (3.5%) and 30 (10.0%) only on tissue or liquid, respectively. After applying clinical and molecular exclusion criteria and considering multiple actionable or resistance-conferring mutations (detected in 95 and 70 out of 303 patients): 135 pts (45%) were randomized (outcome A), 19 (30%) were SF (outcome B), and 78 (25%) SF but with an additional indication (outcome C). Of them, 14 patients (18%) were group 1 and 42 (54%) had indication to a target therapy outside from the trial (group 2). MTB suggested a GT to 60/303 pts (20%, group 3). To date, 8 out of 9 GT performed confirmed a germline mutation (4 BRCA1/2, 2 PALB2, 1 MUTHY, 1 ATM). Finally, 213 pts, 71% of those discussed to MTB and 43% of the entire screened population, were randomized or received at least one specific indication following the extended molecular assessment with NGS. Conclusions: We demonstrated the feasibility of screening a large numbers of pts from numerous accruing sites in a complex trial to test investigational therapies for moderately frequent molecular targets. Cooccurring resistance mutations were common and endorse to investigate combination targeted-therapy regimens. The Rome trial MTB, even when no actionable alterations were detected, provided a therapeutic and diagnostic indication with a potential impact on patient's outcomes. Clinical trial information: NCT04591431

Journal of clinical oncology, Jun 1, 2024

Current Oncology, Jun 4, 2023

This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY

Annals of Oncology, Jul 1, 2020

European Journal of Cancer, Jul 1, 2020

Annals of Oncology, Jul 1, 2019

Cancer management and research, Dec 1, 2022

Annals of Oncology, Jul 1, 2020

Critical Reviews in Oncology/Hematology

Nature Medicine

Genomics has greatly improved how patients with cancer are being treated; however, clinical-grade... more Genomics has greatly improved how patients with cancer are being treated; however, clinical-grade genomic biomarkers for chemotherapies are currently lacking. Using whole-genome analysis of 37 patients with metastatic colorectal cancer (mCRC) treated with the chemotherapy trifluridine/tipiracil (FTD/TPI), we identified KRAS codon G12 (KRASG12) mutations as a potential biomarker of resistance. Next, we collected real-world data of 960 patients with mCRC receiving FTD/TPI and validated that KRASG12 mutations were significantly associated with poor survival, also in analyses restricted to the RAS/RAF mutant subgroup. We next analyzed the data of the global, double-blind, placebo-controlled, phase 3 RECOURSE trial (n = 800 patients) and found that KRASG12 mutations (n = 279) were predictive biomarkers for reduced overall survival (OS) benefit of FTD/TPI versus placebo (unadjusted interaction P = 0.0031, adjusted interaction P = 0.015). For patients with KRASG12 mutations in the RECOURSE...

Radiology and Oncology, Aug 14, 2022

Background. Electrochemotherapy (ECT) is a minimally invasive and safe treatment gaining positive... more Background. Electrochemotherapy (ECT) is a minimally invasive and safe treatment gaining positive and long-lasting antitumoral results that are receiving the attention of the scientific community. It is a local treatment that combines the use of electroporation and the administration of cytotoxic drugs to induce cell death in the target tissue. ECT is largely used for the treatment of cutaneous and subcutaneous lesions, and good results have been reported for the treatment of deep visceral tumors. The latest literature review is provided. Moreover, in line with its development for the treatment of visceral tumors in this article, we describe a novel approach of ECT: endoscopic treatment of colorectal cancer. Endoscopic ECT application was combined with systemic chemotherapy in the treatment of obstructing rectal cancer without prospective surgery. A good response after ECT was described: concentric involvement of the rectum was reduced, and no stenosing lesions were detected. Conclusions. Clinical studies have demonstrated that ECT is a very effective treatment for tumors of different histologic types and localizations. Endoscopic treatment for gastrointestinal cancer is an innovative application of ECT. The combination of systemic treatment and ECT was safe and highly effective in the treatment of colorectal cancer, especially when obstructive, giving the patient a significant gain in quality of life.

European Journal of Pharmacology, Nov 1, 2019

Melanoma onset and progression are associated with a high variety of activating mutations in the ... more Melanoma onset and progression are associated with a high variety of activating mutations in the MAPKpathway, most frequently involving BRAF (35-45%) and NRAS (15-25%) genes, but also c-KIT and PTEN. Targeted therapies with BRAF and MEK inhibitors showed promising results over the past years, but it is known that most responses are temporary, and almost all of patients develop a tumor relapse within one year. Different drug-resistance mechanisms underlie the progression of disease and activation of both MAPK and PI3K/AKT/ mTOR pathways. Therefore, in this article we reviewed the main studies about clinical effects of several target inhibitors, describing properly the most prominent mechanisms of both intrinsic and acquired resistance. Furthermore, suggestive strategies for overcoming drug resistance and the most recent alternative combination therapies to optimize the use of MAPK pathway inhibitors were also discussed.

Integrative Cancer Therapies, 2019

Background and Aims: Sarcopenia, the loss of both lean body and skeletal muscle mass, may interfe... more Background and Aims: Sarcopenia, the loss of both lean body and skeletal muscle mass, may interfere in cancer patients outcome. As investigated, whey proteins could prevent the onset of sarcopenia. We have conducted a study to evaluate the effects of whey protein in colorectal cancer patients, undergoing 5-fluorouracil-based chemotherapy. Methods: After written informed consent, patients were blind randomized 1:1 to whey protein (ProLYOtin; arm A) versus placebo (arm B). The patients were assessed both physically and nutritionally before chemotherapy and after 3 (T2) and 6 months (T3) by body impedance assessment, L3-computed tomography scan, Mini Nutritional Assessment (MNA), and Malnutrition Universal Screening Tool (MUST) tests. Results: Forty-seven patients were included in this preliminary analysis. Baseline characteristics were well balanced between the 2 arms. During chemotherapy, 33 patients were reevaluated: anthropometric parameters (lean body mass from 68.5% to 71.2% vs 68.7% to 66.3%, and sarcopenia from 84% to 54% and 83% to 77% from baseline to T2 evaluation in arms A and B, respectively), nutritional status (MNA >24 = 100% [A] vs 73.7% [B]), and toxicity (no adverse effects in 86% [A] vs 29% [B] and 94% [A] vs 29% [B] for hematological and gastrointestinal toxicities, respectively) resulted to be significantly different. At univariate analysis, a condition of malnutrition risk according to MUST (relative risk [RR] = 7.5, P = .02) or MNA (RR = 1.45, P = .02) and ProLYOtin intake (RR = 0.12, P = .01) were found to be significantly predictive of chemotherapy toxicity. Conclusions: At present, our study shows how whey protein could be an important therapeutic option to improve nutritional status, and particularly to prevent severe toxicity during chemotherapy.

Journal of Clinical Oncology, Feb 1, 2018

700 Background: The standard of care for locally advanced rectal cancer (RC) is neoadjuvant chemo... more 700 Background: The standard of care for locally advanced rectal cancer (RC) is neoadjuvant chemoradiotherapy (CRT) with 5FU aimed to tumor downstaging prior to radical resection but there is a wide spectrum of responses to it, from none to complete. The aim of this project is to validate top candidate genes previously identified by microarray studies as prognostic and predictive classifiers of locally advanced RC, using the NanoString nCounter Platform. Methods: Two cohorts of RC patients were identified according to tumor regression grade (TRG) of AJCC Staging Manual (7th) system: 1) good prognosis: patients that after neoadjuvant CRT obtained TRG0 (complete response); 2) poor prognosis: patients with TRG1 (moderate response), patients with TRG2 (minimum response rate) and patients with TRG3 (poor response). Pre-treatment biopsies tissues from ten TRG0 patients (ID TRG0bio) and thirteen TRG1-3 patients (ID TRG1-3bio) were macro-dissected from FFPE sections, RNA isolated and used for expression profiling of a 305 genes custom code set consisting of 12 normalizer genes, 101 prognostic genes (markers of stemness, invasiveness, proliferation, drug-resistance), 192 predictive genes (involved in response to 5-FU, to radiation therapy and in the response to CRT). All samples were normalized using the geometric mean of the housekeeper genes. P-values were calculated by student’s t-test and was consider significance if was less than 0.05. Gene-specific RNA expression profiles were compared using Spearman&amp;amp;amp;amp;amp;#39;s correlation. The heat map was generated using MeV 4.9.0. Results: When we compared TRG0bio to TRG1-3bio tissues, among the 305 genes assayed, changes in expression levels of 18 genes (SSB, GAPDH, TXNDC9, DUT, PKM, STAT1,SLC28A3, DAG1, TYMS, FERMT1, ARNT,SLC6A6, SMAD3, SCRN1, POU5F1, GNG4, PDRG1, ATP5E) were statistically significant. Conclusions: Results suggest that TRG0 RC is characterized by distinct molecular events compared TRG1-3 disease. Next steps will be: to amplify sample size, to understand signaling pathways of top differentially expressed genes and to validate prospectively our gene signature.

Annals of Oncology, Sep 1, 2016

Background: Fluoropyrimidines are commonly used in metastatic breast cancer after anthracyclines ... more Background: Fluoropyrimidines are commonly used in metastatic breast cancer after anthracyclines and/or taxanes failure or in frail patients. The identification of a toxicity predictive biomarker could help to avoid severe toxicities and consequent dose reduction or treatment discontinuation. We analyzed the predictive role on toxicity of 5-FU-DR and polymorphisms in TSER, DPYD and MTHFR genes. Materials and methods: We collected blood samples of metastatic breast cancer patients before starting capecitabine-based treatment. 5-FU-DR was determined by measuring the decrease of a known dose of 5-FU incubated with peripheral blood mononuclear cells in a time unit. Patients were classified as: poor metabolizers (PM: 5-FU-DR ≤ 0.85 ng/ml/10 6 cells/min); normal metabolizers (NM: 0.85< 5-FU-DR > 2.2 ng/ml/10 6 cells/min); ultra-rapid metabolizers (UM: 5-FU-DR ≥ 2.2 ng/ ml/10 6 cells/min). Gene polymorphisms of MTHFR, DPYD and TSER were detected using DNA pyrosequensing. Toxicities were classified according to CTCAE v 3.0. SPSS2 software was used to perform statistical analysis. Gene polymorphisms and the 5-FU-DR were correlated with toxicities through Pearson's Chi Square test. Results: We analyzed 40 metastatic breast cancer patients treated with capecitabine alone or in combination regimens. 3 patients were PM, 35 were NM and 2 were UM. Grade 3-4 toxicities were observed in 20% of patients: 50% hematopoietic, 50% gastrointestinal, 12.5% hepatic and 12.5% hand-foot symdrome. PM and UM showed a higher incidence of G3-4 toxicities (p = 0.05) and PM required dose reduction due to

Annals of Oncology, Oct 1, 2016

Background: FOLFOX (5-FU, Oxaliplatin and Leucovorin) is the most effective treatment for CRC pat... more Background: FOLFOX (5-FU, Oxaliplatin and Leucovorin) is the most effective treatment for CRC patients in adjuvant setting. However, the toxicity can lead to reduction, delay or discontinuation of treatment. DPD is the key enzyme involved in 5-FU catabolism and 5-FU-DR is a phenotypic parameter, reflecting the entire metabolism of 5-FU. We investigated the association between 5-FU-DR and genetic polymorphisms of TSER, DPYD, MTHFR and with toxicity in CRC patients treated with adjuvant FOLFOX. Methods: We collected 126 blood samples before starting treatment. 5-FU-DR was determined by measuring the decrease of a fixed amount of 5-FU added to a solution of Peripheral Blood Mononuclear Cells after 2 hours of incubation. Patients were classified as: poor metabolizers (PM: 5-FU-DR ≤ 0.85 ng/ml/10 6 cells/min); normal metabolizers (NM: 0.85 < 5-FU-DR > 2.2 ng/ml/10 6 cells/min); ultra-rapid metabolizers (UM: 5-FU-DR ≥ 2.2 ng/ml/10 6 cells/min). DNA pyrosequensing was used to detect gene polymorphisms of MTHFR, DPYD and TSER. Toxicities were classified according to CTCAE v 4.0. Statistical analysis was performed with SPSS2 software. Pearson's Chi Square test was used to correlate gene polymorphisms and 5-FU-DR with toxicities. Results: We analyzed 126 resected CRC patients (91 M, 35 F; median age 65 y, range 36-81 y), receiving adjuvant FOLFOX. 7 patients were PM, 116 NM and 3 UM. Median 5-FU-DR was 1.495 ng/ml/10 6 cells/min (range 0.42-2.29). G3-4 toxicities were observed in 22.2% of the cases: 59.3% hematological, 29.6% gastrointestinal, 7.4% neurological and 3.7% others. A higher G3-4 toxicity incidence was observed in PM and UM than in NM group (71.4% and 33.3% respectively vs 19%; p = 0.05). PM and UM required more frequently dose reduction due to toxicity (71.4% and 66.6% vs 31%; p = 0.04). One case of DPYD heterozygous mutated was detected and it was associated with 5-FU-DR PM (p = 0.04) and G4 hematological toxicity (p = 0.06). No statistically significant associations between toxicities and TSER (p = 0.2), MTHFR C677T (p = 0.5) and MTHFR A1298C (p = 0.8) were observed. Conclusions: 5-FU-DR seems to predict toxicity in resected CRC patients treated with 5-FU. Larger and perspective studies are required to implement this results. Legal entity responsible for the study: N/A Funding: University of Rome "Sapienza" Disclosure: All authors have declared no conflicts of interest.

Anti-Cancer Drugs, Jun 1, 2017

The PI3K/AKT pathway plays an important role in the initiation and progression of cancer, and the... more The PI3K/AKT pathway plays an important role in the initiation and progression of cancer, and the drug development efforts targeting this pathway with therapeutic interventions have been advanced by academic and industrial groups. However, the clinical outcome is moderate. Combination of inhibition of PI3K/AKT and other targeted agents became a feasible approach. In this study we assessed the combined effect of ARQ 092, a pan-AKT inhibitor, and ARQ 087, a pan-FGFR inhibitor, in vitro and in vivo. In a panel of 45 cancer cell lines, on 24% (11 out of 45) the compounds showed synergistic effect, on 62% (28 out of 45) additive, and on 13% (6 out of 45) antagonistic. The highest percentage of synergism was found on endometrial and ovarian cancer cell lines. Mutational analysis revealed that PIK3CA/PIK3R1 mutations and aberrant activation of FGFR2 predicted synergism, whereas Ras mutations showed a reverse correlation. Pathway analysis revealed that a combination of ARQ 092 and ARQ 087 enhanced the inhibition of both the AKT and FGFR pathways in cell lines in which synergistic effects were found (AN3CA and IGROV-1). Cell cycle arrest and apoptotic response occurred only in AN3CA cell, and was not seen in IGROV-1 cells. Furthermore, enhanced antitumor activity was observed in mouse models with endometrial cancer cell line and patient-derived tumors when ARQ 092 and ARQ 087 were combined. These results from in-vitro and in-vivo studies provide a strong rationale in treating endometrial and other cancers with the activated PI3K/AKT and FGFR pathways.

Annals of Oncology, Sep 1, 2014

Aim: 5-FU based chemotherapy is the most common regimen used for patients affected by gastric can... more Aim: 5-FU based chemotherapy is the most common regimen used for patients affected by gastric cancer both in metastatic and in adjuvant setting.Identification of predictive markers of both response and toxicity to chemotherapy is a promising approach for drug selection. The present study analyzes the predictive role of 5-FU degradation rate (5-FU-DR) and genetic polymorphisms (MTHFR, TSER, DPYD) on predicting toxicity to chemotherapy and survival Methods: 94 patients affected by gastric cancer were enrolled. Genetic polymorphisms of MTHFR, TSER and DPYD and the 5-FU-DR were analyzed. 5-FU degradation rate

Journal of Clinical Oncology, Jun 1, 2022

Background: The Rome Trial is a randomized, prospective, multicenter, multi-basket, Phase II clin... more Background: The Rome Trial is a randomized, prospective, multicenter, multi-basket, Phase II clinical trial (EudraCT n � 2018-002190-21; NCT04591431). The aim is to evaluate the efficacy of Tailored Therapy (TT) vs Standard of Care (SoC) in patients (pts) with metastatic solid tumors who received at least one and no more than two lines of treatment. Pts with a molecular alteration were discussed in a Molecular Tumor Board (MTB), assigned to one or a combination of the 20 available treatments, and randomized to TT or SoC. Methods: Tissue (collected within 6 months) and blood samples from pts with refractory solid tumors were analyzed centrally with next generation sequencing (NGS, Foundatio-nOneCDx and FoundationOneLiquid). MTB discussed all screened pts with any actionable genomic alterations using common mutational database and ESCAT. Genomic data, MTB reports and treatment outcomes were collected. The 3 outcomes of the MTB were: A) assignment of a TT and randomization, B) screening failure (SF) C) SF for the trial but with relevant information from the genomic test. Outcome C was divided into 3 groups: 1) indication to receive a personalized standard treatment different from the planned one, 2) indication to access to another clinical trial/compassionate use/expanded access, 3) indication to perform a germline test (GT). Results: From Oct 2020 to Dec 2021, 497 pts were enrolled in 38 Italian accrual sites, 303 (61.0%) had relevant genomic alterations and were discussed to the MTB. Molecular profiling was determined both on tissue and liquid biopsy in 262/303 (86.5%) pts, while in 11 (3.5%) and 30 (10.0%) only on tissue or liquid, respectively. After applying clinical and molecular exclusion criteria and considering multiple actionable or resistance-conferring mutations (detected in 95 and 70 out of 303 patients): 135 pts (45%) were randomized (outcome A), 19 (30%) were SF (outcome B), and 78 (25%) SF but with an additional indication (outcome C). Of them, 14 patients (18%) were group 1 and 42 (54%) had indication to a target therapy outside from the trial (group 2). MTB suggested a GT to 60/303 pts (20%, group 3). To date, 8 out of 9 GT performed confirmed a germline mutation (4 BRCA1/2, 2 PALB2, 1 MUTHY, 1 ATM). Finally, 213 pts, 71% of those discussed to MTB and 43% of the entire screened population, were randomized or received at least one specific indication following the extended molecular assessment with NGS. Conclusions: We demonstrated the feasibility of screening a large numbers of pts from numerous accruing sites in a complex trial to test investigational therapies for moderately frequent molecular targets. Cooccurring resistance mutations were common and endorse to investigate combination targeted-therapy regimens. The Rome trial MTB, even when no actionable alterations were detected, provided a therapeutic and diagnostic indication with a potential impact on patient's outcomes. Clinical trial information: NCT04591431