Correlation of cytidine deaminase polymorphisms and activity with clinical outcome in gemcitabine-/platinum-treated advanced non-small-cell lung cancer patients

Tibaldi, Carmelo; Giovannetti, Elisa; Tiseo, Marcello; León, Leticia G.; D’Incecco, Armida; Loosekoot, N.; Bartolotti, Marco; Honeywell, Richard J.; Cappuzzo, Federico; Ardizzoni, Andrea; Peters, Godefridus J.

doi:10.1093/annonc/mdr280

Cited by 52 publications

(55 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…28 CDA deregulation is a risk factor for the occurrence of severe and life-threatening toxicities with gemcitabine, capecitabine, and azacytidine. 25,29 Case reports in children have already suggested a possible link between decreased CDA activity and severe toxicities upon Ara-C administration. 30 In this proof-of-concept study, for the first time we present additional evidence about the possible relationship between CDA PM status and severe toxicities in adult patients treated with Ara-C.…”

Section: Discussionmentioning

confidence: 99%

“…On the basis of previous studies in patients with solid tumors, mean CDA activity of 3.6 6 2.7 U/mg is considered a normal phenotype (ie, EM) in adults. 17 Additionally, genotypic investigations focused on the search for the canonical CDA*2 allelic variant (ie, CDA79A.C) 25 by high-resolution melting analysis as described previously. 19 Genotyping CDA was performed only in patients for whom written informed consent to undergo germinal pharmacogenetic investigation was obtained, following the French Agence de la Biomédecine-Haute Autorité de Santé guidelines.…”

Section: Cda Status Determinationmentioning

confidence: 99%

See 1 more Smart Citation

CDA as a predictive marker for life-threatening toxicities in patients with AML treated with cytarabine

et al. 2018

View full text Add to dashboard Cite

Key Points• Ara-C is the mainstay of treatment for patients with AML, and life-threatening toxicities are common.• We demonstrated that cytidine deaminase downregulation predicts severe/lethal toxicities with cytarabine.Cytarabine (Ara-C) is the backbone of acute myeloid leukemia (AML) chemotherapy. Little is known about possible risk factors predictive for the frequent (ie, up to 16%) life-threatening or lethal toxicities caused by Ara-C. Ara-C is detoxified in the liver by a single enzyme, cytidine deaminase (CDA), coded by a gene known to be highly polymorphic. In this proof-of-concept study, we particularly investigated the role of the CDA poor metabolizer (PM) phenotype in Ara-C toxicities. CDA phenotyping (measurement of CDA residual activity in serum) and genotyping (search for the CDA*2 allelic variant) were performed in 58 adult patients with AML treated with the standard 713 (Ara-C 1 anthracyclines)protocol. Statistically significantly lower CDA activity was observed in patients experiencing severe/lethal toxicities as compared with patients who did not (1.5 6 0.7 U/mg vs 3.95 6 3.1 U/mg; Student t test P , .001). Subsequent receiver operating characteristic analysis identified a threshold in CDA activity (ie, 2 U/mg) associated with PM syndrome and increased risk of developing severe toxicities. Five percent of patients experienced lethal toxicities, all displaying CDA PM status (1.3 6 0.5 U/mg). In terms of efficacy, a trend toward higher response rates and longer progression-free survival and overall survival were observed in patients with low CDA activity. Taken together, the results of this study strongly suggest that CDA is a predictive marker of life-threatening toxicities in patients with AML receiving induction therapy with standard Ara-C.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Cda Status Determinationmentioning

confidence: 99%

CDA as a predictive marker for life-threatening toxicities in patients with AML treated with cytarabine

et al. 2018

View full text Add to dashboard Cite

show abstract

“…Despite numerous important genomic alterations that characterize tumor DNA, the 'ordinary' polymorphisms still exist in the tumor genome. However, the risk of loss of heterozygosity may introduce a critical bias and alter the conclusions of a study dedicated, for instance, at the identification of the polymorphisms of a gene expressed in the liver and involved in drug activation or detoxification, such as cytidine deaminase for gemcitabine [19]. Conversely, it might be interesting to know the tumor as well as the germinal genotype of polymorphisms of DNA repair genes, because the DNA repair involved in resistance to alkylating drugs actually occurs within the cancer cells [20].…”

Section: Pharmacogenetics Of Nsclc: Which Patients and Specimens?mentioning

confidence: 99%

On the pharmacogenetics of non-small cell lung cancer treatment

Santarpía

Rolfo

Peters

et al. 2016

Expert Opinion on Drug Metabolism & Toxicology

View full text Add to dashboard Cite

Introduction. Despite many clinical efforts, non-small-cell lung cancer (NSCLC) has a dismal 5-year survival rate of 16%, and high incidence of recurrence. The success of biologically targeted agents, as well as the activity of well-established chemotherapeutic regimens, has been limited by inherited/ acquired resistance, and biomarkers to adapt the prescription of anticancer drugs to patients' features are urgently warranted. Areas covered. In oncology, pharmacogenetics should provide the way to select patients who may benefit from a specific therapy that best match the individual and tumor genetic profile, thus allowing maximum activity and minimal toxicity. The present review summarizes the main findings on NSCLC pharmacogenetics, critically reappraising the most important studies on polymorphisms correlated with outcome of pemetrexed and EGFR-inhibitors, and provides perspective on clinical application of genomic tests for treatment decision-making. Expert Opinion. A major challenge in NSCLC is the identification of subgroups of diseases/patients that will truly benefit from specific treatments. Ideally, convenient and minimally invasive tests to decipher biomarkers of chemosensitivity/resistance and toxicity should be developed alongside novel anticancer treatments. Integration with the latest generation of whole-genome analyses and liquid biopsies as well as prospective validation in large cohorts of patients will overcome the limitations of the traditional pharmacogenetic approaches. ARTICLE HISTORY

show abstract

“…In particular, when monitoring CDA activities as part of routine pretreatment screening over the last 2 years at Marseille University Hospital (Marseille, France), CDA activities recorded in 252 adults were 4.3 AE 3.4 U/mg proteins for women and 3.9 AE 3.5 U/mg proteins for men, with no significant difference between genders (P ¼ 0.278). Similarly, in our recent study conducted at VU University Medical Center (Amsterdam, the Netherlands) on 126 patients (2), no significant correlations were detected between CDA activity and gender (P ¼ 0.382).…”

mentioning

confidence: 66%

“…The impact of 79A > C CDA polymorphism remains debated (2), and the small sample size and low number of patients carrying the polymorphic variant are another caveat of this study.…”

mentioning

confidence: 90%

Gender, Cytidine Deaminase, and 5-Aza/Decitabine—Letter

Ciccolini¹,

Peters²,

Giovannetti³

2013

Clinical Cancer Research

View full text Add to dashboard Cite

We have read with interest the observational study by Mahfouz and colleagues (1), who examined the role of cytidine deaminase (CDA) on outcomes of patients treated with 5-azacytidine or decitabine. Surprisingly, gender emerged as the main determinant of CDA levels, and consequently, male patients displayed worse outcome as compared with females.These data do not match the results of all previous clinical studies on the role of CDA on outcome and toxicity of several nucleoside analogs. In particular, when monitoring CDA activities as part of routine pretreatment screening over the last 2 years at Marseille University Hospital (Marseille, France), CDA activities recorded in 252 adults were 4.3 AE 3.4 U/mg proteins for women and 3.9 AE 3.5 U/mg proteins for men, with no significant difference between genders (P ¼ 0.278). Similarly, in our recent study conducted at VU University Medical Center (Amsterdam, the Netherlands) on 126 patients (2), no significant correlations were detected between CDA activity and gender (P ¼ 0.382).Moreover, in our opinion, some key points should be discussed in more detail. As stated by the authors, CDA activity and polymorphisms have been studied for years in patients treated with gemcitabine, another nucleoside analog widely prescribed in a variety of settings (3). In addition, erratic CDA activities are a rising issue with cytarabine and capecitabine, because atypical metabolizers are at risk of life-threatening toxicities (4). However, Mahfouz and colleagues did not find a relationship between gender, and therefore CDA status, and outcome in cytarabine-treated patients.Besides, it is unclear why patients undergoing azacytidine and decitabine were grouped before analysis. The analysis of each group separately would have been useful to verify whether the role of CDA and gender holds true for azacytidine, decitabine, or both, whereas a cohort of patients who are not treated with these drugs is needed to distinguish their prognostic versus predictive values. Because CDA is supposed to play a role only with nucleoside analogs, its correlation with progression-free rather than overall survival would have been more relevant because no data are provided about subsequent treatments.The impact of 79A > C CDA polymorphism remains debated (2), and the small sample size and low number of patients carrying the polymorphic variant are another caveat of this study.Finally, Mahfouz and colleagues claim that due to the pharmacodynamics of azacytidine and decitabine, low circulating concentrations make ultra rapid metabolizers at risk of treatment failure the actual concern. However, no information is provided about poor metabolizers at risk of being overexposed. On the basis of our clinical expertise, poor metabolizers treated with 75 mg/m 2 azacytidine are at risk of life-threatening pancytopenia (5).Overall, though a gender-based adaptive dosing is interesting, we believe that extensive analyses of CDA, using both genotyping and phenotyping approaches, remain the most relevant strategy to improve t...

show abstract

Correlation of cytidine deaminase polymorphisms and activity with clinical outcome in gemcitabine-/platinum-treated advanced non-small-cell lung cancer patients

Cited by 52 publications

References 15 publications

CDA as a predictive marker for life-threatening toxicities in patients with AML treated with cytarabine

CDA as a predictive marker for life-threatening toxicities in patients with AML treated with cytarabine

On the pharmacogenetics of non-small cell lung cancer treatment

Gender, Cytidine Deaminase, and 5-Aza/Decitabine—Letter

Contact Info

Product

Resources

About