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Tailored therapy in patients treated with fluoropyrimidines: focus on the role of dihydropyrimidine dehydrogenase

Cancer Drug Resistance 2019年第3期2卷 787-802页

作者： Filippo Merloni Nicoletta Ranallo laura scortichini Riccardo Giampieri Rossana Berardi Scuola di Specializzazione in Oncologia Universita Politecnica delle MarcheAncona 60121Italy Clinica Oncologica UniversitàPolitecnica delle MarcheAOU Ospedali RiunitiAncona 60126Italy

Fluoropyrimidines are widely used in the treatment of solid tumors, mainly gastrointestinal, head and neck and breast cancer. Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme for catabolism of 5-FU and it is encoded by DPYD gene. To date, many known polymorphisms cause DPD deficiency and subsequent increase of 5-FU toxicity. In addition, reduced inactivation of 5-FU could lead to increased 5-FU intracellular concentration and augmented efficacy of this drugs. Therefore DPD expression, particularly intratumoral, has been investigated as predictive and prognostic marker in 5-FU treated patients. There also seems to be a tendency to support the correlation between DPD expression and response/survival in patients treated with fluoropyrimidine even if definitive conclusions cannot be drawn considering that some studies are conflicting. Therefore, the debate on intratumoral DPD expression as a potential predictor and prognostic marker in patients treated with fluoropyrimidines is still open. Four DPD-polymorphisms are the most relevant for their frequency in population and clinical relevance. Many studies demonstrate that treating a carrier of one of these polymorphisms with a full dose of fluoropyrimidine can expose patient to a severe, even life-threatening, toxicity. Severe toxicity is reduced if this kind of patients received a dose-adjustment after being genotyped. CPIC (Clinical Pharmacogenetics Implementation Consortium) is an International Consortium creating guidelines for facilitating use of pharmacogenetic tests for patient care and helps clinicians ensuring a safer drug delivery to the patient. Using predictive DPD deficiency tests in patients receiving 5FU-based chemotherapy, in particular for colorectal cancer, has proven to be a cost-effective strategy.

关键词： 5-fluorouracil fluoropyrimidines chemotherapy dihydropyrimidine dehydrogenase dihydropyrimidine dehydrogenase DPYD CPIC polymorphisms

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BRCA mutations and gastrointestinal cancers:When to expect the unexpected?

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World Journal of Clinical Oncology 2021年第7期12卷 565-580页

作者： Elena Maccaroni Riccardo Giampieri Edoardo Lenci laura scortichini Francesca Bianchi laura Belvederesi Cristiana Brugiati Silvia Pagliaretta Elisa Ambrosini Rossana Berardi Department of Medical Oncology Azienda Ospedaliero-Universitaria Ospedali Riuniti di AnconaAncona 60126Italy Department of Medical Oncology UniversitàPolitecnica delle MarcheAncona 60126Italy Dipartimento di Scienze Cliniche e Molecolari UniversitàPolitecnica delle MarcheAncona 60126Italy

BRCA1/2 pathogenic variants are widely known as major risk factors mainly for breast and ovarian cancer,while their role in gastrointestinal(GI)malignancies such as colorectal cancer(CRC),gastric cancer and oesophageal cancer(OeC)is still not well *** main objective of this review is to summarise the available evidence on this *** studies included in the review were selected from PubMed/GoogleScholar/ScienceDirect databases to identify published articles where BRCA1/2 pathogenic variants were assessed either as a risk factor or a prognostic/predictive factor in these *** review suggests that BRCA1/2 might have a role as a risk factor for colorectal,gastric and OeC,albeit with differences among these diseases:In particular BRCA1 seems to be much more frequently mutated in CRC whereas BRCA2 appears to be much more closely associated with gastric and ***-onset cancer seems to be also associated with BRCA1/2 mutations and a few studies suggest a positive prognostic role of these *** assessment of a potentially predictive role of these mutations is hampered by the fact that most patients with these diseases have been treated with platinum compounds,where it is expected that a higher probability of response should be seen.A few clinical trials focused on poly(ADPribose)polymerase inhibitors use in GI cancers are currently ongoing.

关键词： BRCA Colorectal cancer Gastric cancer Esophageal cancer Prognosis Poly(ADP-ribose)polymerase inhibitors

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