Publications by authors named "Francesca Romana Di Pietro"

14 Publications

  • Page 1 of 1

Clinicians' Attitude to Doublet Plus Anti-EGFR Versus Triplet Plus Bevacizumab as First-line Treatment in Left-Sided RAS and BRAF Wild-Type Metastatic Colorectal Cancer Patients: A Multicenter, "Real-Life", Case-Control Study.

Clin Colorectal Cancer 2021 Jul 18. Epub 2021 Jul 18.

Medical Oncology Unit, University Hospital of Parma, Parma, Italy.

Background: Doublets plus antiepidermal growth factor receptors monoclonal antibodies (EGFRi) are widely considered the preferable first-line regimen in patients with left-sided RAS/BRAF wild-type metastatic colorectal cancer (mCRC), resulting superior in terms of activity and efficacy compared to doublets plus bevacizumab. However, data comparing doublet plus EGFRi and triplet plus bevacizumab are lacking, and the relative benefit of an intensive regimen plus an antiangiogenic backbone in this population is debated.

Methods: This multicenter, retrospective study aimed at evaluating clinicians' attitude to triplet-bevacizumab and doublet-EGFRi as first-line regimen in patients with left-sided RAS/BRAF wild-type mCRC treated in clinical practice at 22 Oncology Units from March 2012 to October 2020. A random case-control matching was performed to compare activity (ORR), and effectiveness (PFS, OS, secondary resection rate of metastases with curative intent) between triplet-bevacizumab and doublet-EGFRi, on the basis of ECOG-PS, age, gender, and burden of disease.

Results: A total of 718 patients were consecutively treated with doublet-EGFRi (686, 95.5%) or triplet-bevacizumab (32, 4.5%). After case-control matching, median PFS was 13.6 (95% CI, 8.9-31.7) and 16.1 (95% CI, 12.1-36.8) months (P= .621), while median OS was 30.2 (95% CI, 14.4-69.5) and 38.1 (95% CI, 33.1-101.1) months (P= .0283) in the doublet-EGFRi and the triplet-bevacizumab cohort, respectively. The ORR was 65.6% and 90.6% (P= .016), while the secondary resection rate was 18.8% and 46.9% (P= .016), in the doublet-EGFRi and the triplet-bevacizumab cohort, respectively. Triplet-bevacizumab was associated with a higher incidence of G3/G4 neutropenia (25.0% vs. 12.5%, P= .041).

Conclusion: Although a doublet-EGFRi remains the recommended upfront regimen in patients with left-sided RAS and BRAF wild-type mCRC, our real life data suggest a triplet-bevacizumab might be at least equally active and effective in properly selected cases.
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July 2021

Merkel Cell Carcinoma.

Biomedicines 2021 Jun 23;9(7). Epub 2021 Jun 23.

Dermatology Department, IDI-IRCCS, 00167 Rome, Italy.

Merkel cell carcinoma (MCC) is a rare and extremely aggressive neuroendocrine carcinoma of the skin, with increasing incidence worldwide. This review intends to propose a comprehensive evaluation of MCC epidemiology, clinical features, pathogenetic mechanisms, diagnosis, and therapies. A section is dedicated to immunological aspects and another to the involvement of angiogenesis and angiogenic growth factors in MCC progression, proposing novel diagnostic and therapeutic approaches. Advanced MCC tumors have been treated with immune checkpoint inhibitors with effective results. Therefore, the state of art of this immunotherapy is also examined, reporting on the most recent clinical trials in the field. We conclude by underlining the achievements in the understanding of MCC pathology and indicating the present needs for effective diagnosis and therapeutic management of the disease.
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June 2021

The role of opioids in cancer response to immunotherapy.

J Transl Med 2021 03 23;19(1):119. Epub 2021 Mar 23.

Department of Clinical and Molecular Medicine, Sapienza University of Rome, 00185, Rome, Italy.

Background: The response to immunotherapy can be impaired by several factors including external intervention such as drug interactions with immune system. We aimed to examine the immunomodulatory action of opioids, since immune cells express opioid receptors able to negatively influence their activities.

Methods: This observational, multicenter, retrospective study, recruited patients with different metastatic solid tumors, who have received immunotherapy between September 2014 and September 2019. Immunotherapy was administered according to the standard schedule approved for each primary tumor and line of treatment. The concomitant intake of antibiotics, antifungals, corticosteroids and opioids were evaluated in all included patients. The relationship between tumor response to immunotherapy and the oncological outcomes were evaluated. A multivariate Cox-proportional hazard model was used to identify independent prognostic factors for survival.

Results: One hundred ninety-three patients were recruited. Overall, progression-free survival (PFS) and overall survival (OS) were significantly shorter in those patients taking opioids than in those who didn't (median PFS, 3 months vs. 19 months, HR 1.70, 95% CI 1.37-2.09, p < 0.0001; median OS, 4 months vs. 35 months, HR 1.60, 95% CI 1.26-2.02, p < 0.0001). In addition, PFS and OS were significantly impaired in those patients taking corticosteroids, antibiotics or antifungals, in those patients with an ECOG PS ≥ 1 and in patients with a high tumor burden. Using the multivariate analyses, opioids and ECOG PS were independent prognostic factors for PFS, whereas only ECOG PS resulted to be an independent prognostic factor for OS, with trend toward significance for opioids as well as tumor burden.

Discussion: Our study suggests that the concomitant administration of drugs as well as some clinical features could negatively predict the outcomes of cancer patients receiving immunotherapy. In particular, opioids use during immunotherapy is associated with early progression, potentially representing a predictive factor for PFS and negatively influencing OS as well.

Conclusions: A possible negative drug interaction able to impair the immune response to anti-PD-1/PD-L1 agents has been highlighted. Our findings suggest the need to further explore the impact of opioids on immune system modulation and their role in restoring the response to immunotherapy treatment, thereby improving patients' outcomes.
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March 2021

Cutaneous Squamous Cell Carcinoma: From Pathophysiology to Novel Therapeutic Approaches.

Biomedicines 2021 Feb 9;9(2). Epub 2021 Feb 9.

IDI-IRCCS, Dermatological Research Hospital, via di Monti di Creta 104, 00167 Rome, Italy.

Cutaneous squamous cell carcinoma (cSCC), a non-melanoma skin cancer, is a keratinocyte carcinoma representing one of the most common cancers with an increasing incidence. cSCC could be in situ (e.g., Bowen's disease) or an invasive form. A significant cSCC risk factor is advanced age, together with cumulative sun exposure, fair skin, prolonged immunosuppression, and previous skin cancer diagnoses. Although most cSCCs can be treated by surgery, a fraction of them recur and metastasize, leading to death. cSCC could arise de novo or be the result of a progression of the actinic keratosis, an in situ carcinoma. The multistage process of cSCC development and progression is characterized by mutations in the genes involved in epidermal homeostasis and by several alterations, such as epigenetic modifications, viral infections, or microenvironmental changes. Thus, cSCC development is a gradual process with several histological- and pathological-defined stages. Dermoscopy and reflectance confocal microscopy enhanced the diagnostic accuracy of cSCC. Surgical excision is the first-line treatment for invasive cSCC. Moreover, radiotherapy may be considered as a primary treatment in patients not candidates for surgery. Extensive studies of cSCC pathogenic mechanisms identified several pharmaceutical targets and allowed the development of new systemic therapies, including immunotherapy with immune checkpoint inhibitors, such as Cemiplimab, and epidermal growth factor receptor inhibitors for metastatic and locally advanced cSCC. Furthermore, the implementation of prevention measures has been useful in patient management.
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February 2021

[The integrated care pathway for non melanoma skin cancer: the Istituto Dermopatico dell'Immacolata - IRCCS experience in Rome.]

Recenti Prog Med 2020 Dec;111(12):749-760

Unità di Clinica Epidemiologica, Istituto Dermopatico dell'Immacolata - IRCCS, Roma.

The incidence of non-melanoma skin cancers (NMSC) is increasing worldwide and these skin cancers have become an important health issue. An integrated care pathway (ICP) is a multidisciplinary outline of anticipated care, placed in an appropriate timeframe, to help a patient with a specific condition. The aim of this paper is to define the ICP for patients affected by NMSC referring to the Istituto Dermopatico dell'Immacolata - IRCCS of Rome and Villa Paola, Italy. This ICP is multidisciplinary and included various specialists like dermatologist, oncologist, general surgeon, plastic surgeon, anatomopathologist, molecular biologist and epidemiologist. This ICP is based on the most recent acquisitions in the literature, referring in particular to the national (EADO and SIDEMAST) and international guidelines (EDF and NCCN). We firstly valued the current practice for patients affected by NMSC referring to our Institute to define the multidisciplinary process map. This process delineated the activities and the responsibilities performed during delivery of care to the patients and the potential problem areas or opportunities for improvements. Subsequently, we defined the final ICP process. This ICP of NMSC represents an innovative strategy to provide high quality healthcare. This allows to ensure all the necessary procedures for the patient, optimizing the "continuum" of care and the use of health services, and improving the organization of the Institute regarding an important health issue.
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December 2020

Soluble Immune Checkpoints, Gut Metabolites and Performance Status as Parameters of Response to Nivolumab Treatment in NSCLC Patients.

J Pers Med 2020 11 4;10(4). Epub 2020 Nov 4.

Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy.

Patients with non-small cell lung cancer (NSCLC) have been shown to benefit from the introduction of anti-PD1 treatment. However, not all patients experience tumor regression and durable response. The identification of a string of markers that are direct or indirect indicators of the immune system fitness is needed to choose optimal therapeutic schedules in the management of NSCLC patients. We analyzed 34 immuno-related molecules (14 soluble immune checkpoints, 17 cytokines/chemokines, 3 adhesion molecules) released in the serum of 22 NSCLC patients under Nivolumab treatment and the gut metabolomic profile at baseline. These parameters were correlated with performance status (PS) and/or response to treatment. Nivolumab affected the release of soluble immune checkpoints (sICs). Patients with a better clinical outcome and with an optimal PS (PS = 0) showed a decreased level of PD1 and maintained low levels of several sICs at first clinical evaluation. Low levels of PDL1, PDL2, Tim3, CD137 and BTLA4 were also correlated with a long response to treatment. Moreover, responding patients showed a high proportion of eubiosis-associated gut metabolites. In this exploratory study, we propose a combination of immunological and clinical parameters (sICs, PS and gut metabolites) for the identification of patients more suitable for Nivolumab treatment. This string of parameters validated in a network analysis on a larger cohort of patients could help oncologists to improve their decision-making in an NSCLC setting.
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November 2020

Basal Cell Carcinoma: From Pathophysiology to Novel Therapeutic Approaches.

Biomedicines 2020 Oct 23;8(11). Epub 2020 Oct 23.

Istituto Dermopatico dell'Immacolata-IRCCS, via dei Monti di Creta 104, 00167 Rome, Italy.

Basal cell carcinoma (BCC) is the most common human cancer worldwide, and is a subtype of nonmelanoma skin cancer, characterized by a constantly increasing incidence due to an aging population and widespread sun exposure. Although the mortality from BCC is negligible, this tumor can be associated with significant morbidity and cost. This review presents a literature overview of BCC from pathophysiology to novel therapeutic approaches. Several histopathological BCC subtypes with different prognostic values have been described. Dermoscopy and, more recently, reflectance confocal microscopy have largely improved BCC diagnosis. Although surgery is the first-line treatment for localized BCC, other nonsurgical local treatment options are available. BCC pathogenesis depends on the interaction between environmental and genetic characteristics of the patient. Specifically, an aberrant activation of Hedgehog signaling pathway is implicated in its pathogenesis. Notably, Hedgehog signaling inhibitors, such as vismodegib and sonidegib, are successfully used as targeted treatment for advanced or metastatic BCC. Furthermore, the implementation of prevention measures has demonstrated to be useful in the patient management.
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October 2020

Late immune-related adverse events in long-term responders to PD-1/PD-L1 checkpoint inhibitors: A multicentre study.

Eur J Cancer 2020 07 23;134:19-28. Epub 2020 May 23.

Department of Medical, Oral and Biotechnological Sciences, University G. D'Annunzio, Chieti-Pescara, Italy.

Background: Data on spectrum and grade of immune-related adverse events (irAEs) in long-term responders to immune checkpoint inhibitors (ICIs) are lacking.

Methods: We performed a retrospective multicenter study to characterized irAEs occurring after a 12-months minimum treatment period with PD-(L)1 ICIs in patients with advanced cancer. IrAEs were categorized into 'early' (≤12 months) and 'late' (>12 months).

Results: From September 2013 to October 2019, 436 consecutive patients were evaluated. Two hundred twenty-three experienced any grade early-irAEs (51.1%), whereas 132 experienced any grade late-irAEs (30.3%) (p < 0.0001). Among the latter, 29 (22%) experienced a recurrence of an early-irAEs, whereas 103 (78%) experienced de novo late-irAEs involving different system/organ. Among patients with late-irAEs, 21 experienced GIII/GIV irAEs (4.8%). Median time to onset of early-irAEs was 3.4 months (95% confidence interval [CI]: 2.8-4.2), whereas the median time to onset of late-irAEs was 16.6 months (95% CI: 15.8-17.6). Cumulative time-adjusted risk of disease progression according to both the early-irAEs (hazard ratio [HR] = 0.63 [95% CI: 0.30-1.29], p = 0.204) and late-irAEs occurrence revealed no statistically significant differences (HR = 0.75 [95% CI: 0.37-1.56], p = 0.452). In addition, the time-adjusted cumulative risk of death in accordance with both early-irAEs (HR = 0.79 [95% CI: 0.34-1.86], p = 0.598) and late-irAEs (HR = 0.92 [95% CI: 0.49-1.74], p = 0.811) did not show statistically significant differences.

Conclusion: Although less frequent than early-irAEs, late-irAEs are quite common in long responders to PD-(L)1 ICIs and are different in terms of spectrum and grade. Time-adjusted analysis revealed that the cumulative risk of disease progression and death were not significantly reduced in patients who experienced late-irAEs.
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July 2020

The treatment paradigm of right-sided metastatic colon cancer: harboring BRAF mutation makes the difference.

Int J Colorectal Dis 2020 Aug 7;35(8):1513-1527. Epub 2020 May 7.

Department of Clinical and Molecular Medicine, Oncology Unit, Sant' Andrea Hospital, University "La Sapienza", Rome, Italy.

Purpose: BRAF mutations represent the main negative prognostic factor for metastatic colorectal cancer and a supposed negative predictive factor of response to standard chemotherapy. We have explored survival difference in right-sided colon cancer (RCC) patients according to BRAF mutations, with the aim to identify any predictive factors of response to targeted-based therapy.

Methods: A retrospective study of RCC patients, with BRAF known mutation status, treated with chemotherapy (CT) from October 2008 to June 2019 in 5 Italian centers, was conducted.

Results: We identified 207 advanced RCC patients: 20.3% BRAF mutant and 79.7% BRAF wild type (wt). BRAF-mutant cancers were more likely to be pT4 (50.0% v 25.7%, p = 0.016), undifferentiated (71.4% v 44.0%, p = 0.004), KRAS wt (90.5% v 38.2%, p < 0.001), and MSI-H (41.7% v 16.2%, p = 0.019) tumors, with synchronous (52.4% v 31.5%, p = 0.018) and peritoneal metastases (38.1% v 22.4%, p = 0.003). Median overall survival (OS) was 16 v 27 months in BRAF mutant and BRAF wt (P = 0.020). In first-line setting, BRAF-mutant showed a 2ys OS of 80% in clinical trials, 32% in anti-VEGF, 14% in epidermial growth factor receptor (EGFR), and 0% in chemotherapy alone regimens (P = 0.009). BRAF-mutant patients demonstrated worse survival, regardless of targeted therapy administered. However, survival difference was statistically significant in the anti-EGFR-treated subgroup (16 v 28 months, P = 0.005 in BRAF mutant v BRAF wt, respectively).

Conclusions: Our study demonstrated that BRAF status makes the difference in treatment's outcome. Therefore, the anti-EGFR should not be excluded in all advanced RCC but considered on a case-by-case basis.
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August 2020

The Agnostic Role of Site of Metastasis in Predicting Outcomes in Cancer Patients Treated with Immunotherapy.

Vaccines (Basel) 2020 Apr 28;8(2). Epub 2020 Apr 28.

Department of Clinical and molecular oncology, University of Rome "Sapienza", 00185 Rome, Italy.

Immune checkpoint inhibitors have revolutionized treatment and outcome of melanoma and many other solid malignancies including non-small cell lung cancer (NSCLC) and renal cell carcinoma (RCC). Unfortunately, only a minority of patients have a long-term benefit, while the remaining demonstrate primary or acquired resistance. Recently, it has been demonstrated that the prevalence of programmed death-ligand 1 (PD-L1) and tumor-infiltrating lymphocytes (TILs) varies based on the anatomical site of metastases. In particular, liver seems to have more immunosuppressive microenvironment while both the presence of lymph nodal disease and lung metastases seem to have the highest prevalence of PD-L1 and TILs. The aim of the present study is to investigate the possible role of site of metastases as a predictive factor for response or resistance to immunotherapy in several types of cancer. In this multicenter retrospective study, we enrolled patients with metastatic NSCLC, melanoma, RCC, urothelial, merkel carcinoma, and colon cancer who received immunotherapy from April 2015 to August 2019. Major clinicopathological parameters were retrieved and correlated with patients' survival outcomes in order to assess their prognostic value and build a useful tool to assist in the decision-making process. A total of 291 patients were included in this study. One hundred eighty-seven (64%) patients were male and 104 (36%) female. The tumor histology was squamous NSCLC in 56 (19%) patients, non-squamous NSCLC in 99 (34%) patients, melanoma in 101 (35%) patients, RCC in 28 (10%) patients, and other tumors in the remaining 7 (2%) patients. The number of metastatic sites was 1 in 103 patients (35%), 2 in 104 patients (36%) and 3 in 84 patients (29%). Out of 183 valuable patients, the entity of response was complete response (CR), partial response (PR), stable disease (SD), and progression disease (PD) in 15, 53, 31, and 79 patients, respectively. Using an univariate analysis (UVA), tumor burden ( = 0.0004), the presence of liver ( = 0.0009), bone ( = 0.0016), brain metastases ( < 0.0001), the other metastatic sites ( = 0.0375), the number of metastatic sites ( = 0.0039), the histology ( = 0.0034), the upfront use of immunotherapy ( = 0.0032), and Eastern Cooperative Oncology Group (ECOG) Perfomance status (PS) ≥ 1 ( < 0.0001) were significantly associated with poor overall survival (OS). Using a multivariate analysis (MVA) the presence of liver ( = 0.0105) and brain ( = 0.0026) metastases, the NSCLC diagnosis ( < 0.0001) and the ECOG PS ( < 0.0001) resulted as significant prognostic factors of survival. Regarding the progression free survival (PFS), using a UVA of the tumor burden ( = 0.0004), bone ( = 0.0098) and brain ( = 0.0038) metastases, the presence of other metastatic sites ( = 0.0063), the number of metastatic sites ( = 0.0007), the histology ( = 0.0007), the use of immunotherapy as first line ( = 0.0031), and the ECOG PS ≥ 1 ( ≤ 0.0001) were associated with a lower PFS rate. Using an MVA, the presence of brain ( = 0.0088) and liver metastases ( = 0.024) and the ECOG PS ( < 0.0001) resulted as predictors of poor PFS. Our study suggests that the site of metastases could have a role as prognostic and predictive factor in patients treated with immunotherapy. Indeed, regardless of the histology, the presence of liver and brain metastases was associated with a shorter PFS and OS, but these results must be confirmed in further studies. In this context, a deep characterization of microenvironment could be crucial to prepare patients through novel strategies with combination or sequential immunotherapy in order to improve treatment response.
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April 2020

A nomogram to predict survival in non-small cell lung cancer patients treated with nivolumab.

J Transl Med 2019 03 27;17(1):99. Epub 2019 Mar 27.

Department of Clinical and Molecular Medicine, Sant'Andrea Hospital, Sapienza University of Rome, Rome, Italy.

Background: The advent of immune checkpoint inhibitors (ICIs) has considerably expanded the armamentarium against non-small cell lung cancer (NSCLC) contributing to reshaping treatment paradigms in the advanced disease setting. While promising tissue- and plasma-based biomarkers are under investigation, no reliable predictive factor is currently available to aid in treatment selection.

Methods: Patients with stage IIIB-IV NSCLC receiving nivolumab at Sant'Andrea Hospital and Regina Elena National Cancer Institute from June 2016 to July 2017 were enrolled onto this study. Major clinicopathological parameters were retrieved and correlated with patients' survival outcomes in order to assess their prognostic value and build a useful tool to assist in the decision making process.

Results: A total of 102 patients were included in this study. The median age was 69 years (range 44-85 years), 69 (68%) were male and 52% had ECOG PS 0. Loco-regional/distant lymph nodes were the most commonly involved site of metastasis (71%), followed by lung parenchyma (67%) and bone (26%). Overall survival (OS) in the whole patients' population was 83.6%, 63.2% and 46.9% at 3, 6 and 12 months, respectively; while progression-free survival (PFS) was 66.5%, 44.4% and 26.4% at 3, 6 and 12 months, respectively. At univariate analysis, age ≥ 69 years (P = 0.057), ECOG PS (P < 0.001), the presence of liver (P < 0.001), lung (P = 0.017) metastases, lymph nodes only involvement (P = 0.0145) were significantly associated with OS and ECOG PS (P < 0.001) and liver metastases (P < 0.001), retained statistical significance at multivariate analysis. A prognostic nomogram based on three variables (liver and lung metastases and ECOG PS) was built to assign survival probability at 3, 6, and 12 months after nivolumab treatment commencement.

Conclusion: We developed a nomogram based on easily available and inexpensive clinical factors showing a good performance in predicting individual OS probability among NSCLC patients treated with nivolumab. This prognostic device could be valuable to clinicians in more accurately driving treatment decision in daily practice as well as enrollment onto clinical trials.
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March 2019

The Incidence of Alcoholism in Patients with Advanced Cancer Receiving Active Treatment in Two Tertiary Care Centers in Italy.

Alcohol Alcohol 2019 Jan;54(1):47-50

Medical Oncology Unit, University of L'Aquila, L'Aquila, Italy.

Introduction: Substance abuse is frequently under-diagnosed among cancer patients. Alcoholism is a problem afflicting about 18% of the general population. This percentage is higher in hospitalized patients. Previous studies conducted on advanced cancer patients admitted in palliative care units have highlighted this problem only for a small percentage of cases. The objective of the study was to evaluate the incidence of alcoholism in patients with advanced cancer admitted to two Italian Oncology Units for active cancer treatment, using a recognized and validated assessment tool.

Short Summary: To evaluate the incidence of alcoholism in cancer patients and its impact on symptoms, the CAGE questionnaire was completed by 117 patients in active anticancer treatment. The percentage of CAGE-positive patients was higher than previously detected in palliative settings and was associated to male sex and lower ESAS score.

Methods: All eligible patients were enrolled consecutively during a 12-month recruitment period. Clinical and demographic data were collected. Each enrolled patient completed the Cut down, Annoyed, Guilty, Eye-opener (CAGE) questionnaire.

Results: Hundred and seventeen consecutive patients were surveyed in the 12-month period. The mean age was 63.3 (SD 12.0) years and 66 were males. The mean Karnofsky level was 68.3 (SD 16.0). Twelve patients were CAGE positive (10.3%). Males (P = 0.05) and patients with low Edmonton Symptom Assessment System score (P = 0.03) proved to be CAGE positive.

Conclusions: Alcoholism is widespread and under-diagnosed among patients undergoing active cancer treatment. Compared with other experience in palliative settings among European population, percentage of CAGE-positive patients was double. CAGE-positive patients were more likely to be male, with lower ESAS score. It is possible to hypothesize an effect of alcohol consumption on patients' perception of symptoms. This data has never been reported in the literature and will certainly need confirmation studies.
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January 2019

Pharmacogenetic Approach to Toxicity in Breast Cancer Patients Treated with Taxanes.

Anticancer Res 2017 05;37(5):2633-2639

Department of Clinical and Molecular Medicine, "Sapienza" University of Rome, Rome, Italy.

Background: Taxanes are widely used to treat breast cancer patients. Taxanes are metabolized in human liver by the cytochrome CYP3A and are substrate of ATP-binding cassette multidrug transporters ABCB1. Single-nucleotide polymorphisms (SNPs) in genes involved in taxanes' metabolism could affect the inter-individual variability in reported toxicities.

Materials And Methods: In this retrospective study, 152 women, affected by breast cancer and receiving a taxane-based chemotherapy, were enrolled. A peripheral blood sample was taken for genotyping the following polymorphisms: CYP3A4* 1B (A>G), CYP3A5 *3 (G>A) and ABCB1 (C1236T; C3435T).

Results: We observed an association between ABCB1 3435 T/T and lower grade of toxicities (p=0.05). No other association were found for CYP 3A4 *1B, 3A5*3 and ABCB1 C1236T.

Conclusion: ABCB1 3435 T/T seems to be associated to lower rate of toxicity in patients receiving taxanes. Further prospective and larger studies should be performed to clarify the role of this polymorphism.
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May 2017

Evaluation of 5-fluorouracil degradation rate and Pharmacogenetic profiling to predict toxicity following adjuvant Capecitabine.

Eur J Clin Pharmacol 2017 Feb 18;73(2):157-164. Epub 2016 Nov 18.

Clinical and Molecular Medicine Department, Sapienza University of Rome - Sant'Andrea Hospital, Via di Grottarossa 1035, 00189, Rome, Italy.

Background: On account of the lack of predictive biomarkers of toxicity, we investigated whether polymorphisms of genes involved in fluoropyrimidine metabolism and 5-fluorouracil (5-FU) degradation rate were associated with outcomes of adjuvant capecitabine in patients with early stage gastrointestinal cancers.

Methods: Genotyping of DPYD GIVS14A, MTHFR C677T and A1298C SNPs were performed by pyro-sequencing technology. PCR analysis was used for genotyping TYMS-TSER. We also evaluated the 5-FU degradation rate, which determines the amount of drug consumed by PBMC in a time unit. Association of these variables with clinical outcome was evaluated using multivariate logistic regression analysis.

Results: One hundred forty-two patients with early stage colon (39%), rectal (28%), stomach (20%) and pancreatic (13%) cancer, treated with adjuvant capecitabine, were included in this retrospective analysis. Seventy and 20% of the patients suffered from at least one G1-4 and G3-4 adverse events, respectively. According to the 5-FU degradation rate, three and 13 patients were assigned as poor (<0.86 ng/mL/10 cells/min) and ultra-rapid (>2.1 ng/mL/10 cells/min) metabolizers, respectively. At a multivariate logistic regression analysis, an altered 5-FU degradation rate (values <0.86 or >2.10 ng/mL/10 cells/min) was associated with grade 3-4 adverse events (OR = 2.09, 95% CI: 1.14-3.82, P = 0.01). No correlation was reported between toxicity and gene polymorphisms except for hand-foot syndrome that was more frequent in the MTHFR 1298CC homozygous variant genotype (OR = 2.03, 95% CI 1.04-3.96, P = 0.03).

Conclusions: 5-FU degradation rate may be regarded as possible predictive biomarker of capecitabine toxicity in early stage gastrointestinal cancer.
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February 2017