Ispitivanje uticaja varijanti u genima TP53, XRCC1 i RAD51 i kliničkih faktora na efikasnost i ispoljenu toksičnost platinske hemioterapije u uznapredovalom nesitnoćelijskom karcinomu pluća
Evaluation of the effect of genetic variants in genes TP53, XRCC1 and RAD51 and clinical factors on the efficacy and toxicity of platinum-based chemotherapy in patients with advanced non-small cell lung cancer
Докторанд
Spasić, JelenaМентор
Nagorni-Obradović, LjudmilaЧланови комисије
Radosavljević, DavorinTatić, Svetislav
Vukičević-Adžić, Tatjana
Zarić, Bojan
Метаподаци
Приказ свих података о дисертацијиСажетак
Uvod: Cilj ovog istraživanja je bio ispitati da li se određeni klinički i genetski faktori mogu
koristiti kao minimalno invazivni prediktori prognoze i toksičnosti platinske hemioterapije kod
pacijenata sa odmaklim adenokarcinomom pluća.
Materijal i metode: U ovo istraživanje prospektivno-retrospektivnog karaktera uključen je
121 pacijent sa odmaklim adenokarcinomom pluća. Pacijenti su primali hemioterapiju
platinskim dubletom u prvoj liniji do progresije bolesti ili maksimalno 6 ciklusa. Efikasnost
terapije je procenjivana korišćenjem RECIST kriterijuma 1.1 a toksičnost pomoću CTCAE v.5.0.
Genotipizacija gena XRCC1, RAD51 i TP53 je vršena primenom RT-PCR.
Rezultati: Medijana vremena do progresije bolesti (PFS) je bila 5.6 meseci (95%CI 4.8 – 6.5), a
medijana ukupnog preživljavanja (OS) 10.0 meseci (95%CI 8.1 – 12.0). Statistički značajno
kraće preživljavanje je registrovano kod pacijenata lošeg performans statusa [ECOG PS2 vs. PS1
vs. PS0, 10.02 (9.28-10.76) vs. 5.55 (4.73-6.37) vs. 2....63 (3.91-4.31) meseci]. Nosioci Arg/Arg
genotipa XRCC1 gena imali su statistički značajno duži PFS i OS. Nije dokazan uticaj ispitanih
polimorfizama RAD51 i TP53 gena na dužinu PFS i OS. Nosioci 399Arg alela XRCC1 gena su bili
statistički značajno podložniji razvoju neuropatije i anemije (Pearson χ2 test, p=0.025 i p=0.004
respektivno). Nosioci 135G alela gena RAD51 su statistički značajno manje podložni razvoju
neuropatije. Mučnina i trombocitopenija, naročito visokog gradusa, su statistički značajno češće
registrovani kod nosilaca 72Pro alela gena TP53 (p-0.037 i p=0.051 respektivno).
Zaključak: Detektovana je statistički značajna povezanost polimorfizama Arg399Gln gena
XRCC1, G135C gena RAD51 i Arg72Pro gena TP53 sa efikasnošću i specifičnim toksičnostima
platinske hemioterapije kod pacijenata sa odmaklim adenokarcinomom pluća. Radi se o
minimalno-invazivnim i finansijski isplativim prognostičkim i prediktivnim parametrima koji
bi, kao takvi, mogli biti deo algoritama lečenja pacijenata sa odmaklim NSCLC.
Introduction: This investigation was conducted in order to determine whether certain clinical
and genetic factors can be used as minimally invasive predictors of efficacy and toxicity of
platinum-based chemotherapy in patients with advanced lung adenocarcinoma.
Materials and methods: A total of 121 advanced lung adenocarcinoma patients were enrolled
in this prospective and retrospective investigation. All patients were treated with platinum-
based chemotherapy doublet in first line until progression or up to 6 cycles. Response to
treatment was evaluated using RECIST1.1 and toxicity graded according to CTCAE v.5.0. RT-
PCR was used for XRCC1, TP53 and RAD51 genotyping.
Results: Median progression-free survival (PFS) was 5.6 months (95%CI 4.8 – 6.5), and median
overall survival (OS) 10.0 months (95%CI 8.1 – 12.0). Patients with poor ECOG PS had a
statistically shorter OS [ECOG PS2 vs. PS1 vs. PS0, 10.02 (9.28-10.76) vs. 5.55 (4.73-6.37) vs.
2.63 (3.91-4.31) months]. XRCC1 Arg399Gln Arg/A...rg carriers had a statistically longer PFS and
OS, while there was no influence of the investigated polymorphisms of RAD51 and TP53 on PFS
or OS. TP53 Arg72Pro Pro allele carriers were more prone to nausea (p=0.037) and
thrombocytopenia (p=0.051), especially high-grade. Anemia and neuropathy occurred more
frequently in XRCC1 Arg399Gln Arg allele carriers (Pearson χ2 test, p=0.025 and p=0.004
respectively). RAD51 G135C G allele carriers were statistically less prone to developing
neuropathy.
Conclusion: We detected a statistically significant association between gene polymorphisms
Arg399Gln of XRCC1 gene, G135C of RAD51 gene and Arg72Pro gena TP53 and the efficacy and
certain toxicities of platinum-based chemotherapy in advanced lung adenocarcinoma patients.
These parameters might prove useful for the construction of population-specific, time- and
cost-efficient prognostic and predictive algorithms in the treatment of advanced lung
adenocarcinoma.