| Abstract | Uvod: ERCC1 je endonukleaza koja pripada NER sustavu zaduženom za popravak DNK
izrezivanjem nukleotida. Aktivna je u popravku platina-DNK adukata, nastalih djelovanjem
kemoterapije temeljene na platini (KTP) i jedan je od mogućih čimbenika uključenih u
rezistenciju na KTP. Ciljana terapija uznapredovalog adenokarcinoma pluća (AP) je suzila
primjenu KTP u prvoj liniji na oko 50% bolesnika koji nisu kandidati za tirozin kinazne
inhibitore ni imunoterapiju. Cilj retrogradne studije je utvrditi imunohistokemijski izražaj
ERCC1 u AP i ispitati povezanost s kliničko-patološkim pokazateljima, ukupnim
preživljenjem i odgovorom na KTP, odnosno prognostički i prediktivni značaj ERCC1 prije
ere ciljane terapije i imunoterapije u RH, kako bi dobili informacije važne u svakodnevnoj
kliničkoj praksi. Ujedno je ispitan prognostički značaj izražaja TTF-1 i Napsin A u AP.
Materijali i metode: U istraživanje je uključeno 253 ispitanika s AP dijagnosticiranim na
uzorcima bronhoskopske biopsije od 2013. - 2015. godine u KBC-u Split. Revidirani su
originalni histološki preparati i prikupljeni rezultati testiranja mutacije EGFR. Iz parafinskih
blokova tumorskog tkiva urađena je imunohistokemijska analiza ERCC1 u 129 ispitanika.
Izražaj ERCC1 je analiziran semikvantitativno i izračunat H-skor te njegov medijan određen
kao vrijednost za razdvajanje slabog (≤0,1) od jakog (>0,1) izražaja ERCC1. Histološki
podtip, imunohistokemijski izražaj TTF-1, Napsina A, ALK i ERCC1 te rtPCR metodom
određen EGFR status uspoređeni su s praćenim kliničko-patološkim pokazateljima i ukupnim
preživljenjem. Večina ispitanika je liječena samo KTP, a kod manje ispitanika je kombinirana
s operacijom ili radioterapijom. Podatci su statistički obrađeni i vrijednost p<0,05 izabrana
kao statistički značajna razlika.
Rezultati: Medijan životne dobi je bio 65 godina, u rasponu od 44 do 91 godine. Većina
bolesnika je bila muškog spola (63,6%), večinom pušači (86,5%) i sa stadijem bolesti IV
(69,5%). Solidni podtip je bio najčešći (51,8% ) i u usporedbi s ostalim podtipovima značajno
povezan s muškim spolom (p<0,05). TTF-1 je bio pozitivan u 83,2% i Napsin A u 76,8%
slučajeva; bili su koeksprimirani u 93% slučajeva. Negativan izražaj TTF-1 i Napsina A je bio
povezan s prisutnošću udaljenih metastaza (p=0,042, odnosno p=0,025), a negativan izražaj
Napsina A s većim tumorom (p=0,024 ). Jak izražaj ERCC1, nađen u 47,3% slučajeva, je bio
povezan s lošijim kliničkim statusom izraženim po ECOG-u (p=0,023), većim tumorom
(p=0,002), pozitivnim limfnim čvorovima (p=0,001), prisutnošću udaljenih metastaza
(p=0,005) i višim stadijem bolesti (p=0,021). Izražaj ERCC1 i klinički status izražen po
ECOG-u su bili nezavisni prognostički pokazatelji (p<0,001, odnosno p=0,008). Slab izražaj ERCC1 je bio povezan s duljim ukupnim preživljenjem ispitanika u stadijima bolesti I-II-III
koji su liječeni kombinacijom kemoterapije temeljene na platini s operacijom ili
radioterapijom i ispitanika u stadiju bolesti IV koji su liječeni samo kemoterapijom temeljenoj
na platini, u odnosu na ispitanike s jakim izražajem ERCC1 (p=0,001, odnosno p<0,001).
EGFR mutacija je utvrđena u 9,9% ispitanika, češće u žena (p=0,024), nepušača (p<0,001) i
starijih od 65 godina (p=0,041). ALK mutacija utvrđena je u 6,1% ispitanika, od kojih ni
jedan nije imao EGFR mutaciju.
Zaključak: Jak izražaj ERCC1 i negativan izražaj TTF-1 i Napsina A u AP su nepovoljni
prognostički pokazatelji. Izražaj ERCC1 ima prediktivnu vrijednost u ispitanika liječenih KTP
u svim stadijima bolesti, kako u stadiju IV u kojem je KTP bila jedina terapija, tako u
stadijima I-II-III gdje je KTP kombinirana s operacijom/radioterapijom. Analiza ERCC1 u AP
bi mogla pomoći u donošenju odluke o terapiji, s obzirom da slab izražaj ERCC1 upućuje na
vjerojatnost dobrog odgovora na KTP, a jak izražaj ERCC1 na slab odgovor i na taj način
izbječi toksičnost neučinkovite terapije. |
| Abstract (english) | Background: ERCC1 is an endonuclease that belongs to the NER system involved in the
DNA repair by nucleotide excision. It is activated in the repair of platinum-DNA adducts,
produced by the action of platinum-based chemotherapy (PBC) and is one of the possible
factors involved in PBC resistance. Targeted therapy for advanced lung adenocarcinoma
(LAC) has narrowed the use of first-line PBC to about 50% of patients who are not candidates
for tyrosine kinase inhibitors or immunotherapy. The aim of this retrograde study was to
determine the level of immunohistochemical expression of ERCC1 in LAC and to examine
the relationship with clinicopathologic variables, overall survival (OS) and response to PBC.
We want to analyse prognostic and predictive value of ERCC1 before the era of targeted
therapy and immunotherapy in Croatia, obtaining important information in everyday clinical
practice. The prognostic significance of TTF-1 and Napsin A expression in LAC was also
examined.
Material and methods: The study included 253 patients with LAC, patohistologicaly
diagnosed on bronchoscopic biopsy from 2013 to 2015 at the University Hospital Split,
Croatia. The original histological specimens were revised and results of EGFR testing were
collected. Immunohistochemical analysis of ERCC1 was performed from paraffin blocks of
tumor tissue in 129 patients. The expression of ERCC1 was analyzed semiquantitatively and
the H-score was calculated for each patient. Median of H-score was determined to separate
the weak (≤0.1) from the strong (> 0.1) ERCC1 expression. Histologic subtype,
immunohistochemical expression of TTF-1, Napsin A, ERCC1 and ALK, as well as rtPCR
determined EGFR status were compared with clinicopathologic variables and OS. All patients
were treated with PBC, alone in patients with stage disease IV and combined with surgery/
radiotherapy in patients with stage disease I-II-III. Data were statistically analysed and the
value of p <0.05 was chosen as a statistically significant difference.
Results: The median age was 65 years, range 44 - 91 years. The majority of patients were
male (63.6%), smokers (86.5%) and in stage disease IV (69.5%). The solid subtype was
dominant (51.8%), and compared to other subtypes, associated with male sex (p <0.05). TTF-
1 was positive in 83.2% and Napsin A in 76.8% of cases; they were coexpressed in 93% of cases. Negative expression of TTF-1 and Napsin A were associated with the presence of
distant metastases (p = 0.042 and p = 0.025, respectively), and negative expression of Napsin
A with a larger tumor (p = 0.024). Strong ERCC1 expression, found in 47.3% of cases, was
associated with poorer clinical status expressed according to ECOG (p = 0.023), larger tumor
(p = 0.002), positive lymph nodes (p = 0.001), the presence of distant metastases (p = 0.005)
and higher stage of the disease (p = 0.021). ERCC1 expression and clinical status, expressed
according to ECOG were independent prognostic factors (p <0.001 and p = 0.008,
respectively). Weak ERCC1 expression was associated with a longer overall survival of
patients with disease stage I-II-III treated with PBC combined with surgery or radiotherapy
and patients with stage IV disease treated with PBC as the only therapy, compared to patients
with strong ERCC1 expression (p = 0.001 and p <0.001, respectively). EGFR mutation was
found in 9.9% of subjects, more often in women (p = 0.024), non-smokers (p <0.001) and
older than 65 years (p = 0.041). The ALK mutation was found in 6.1% of patients, none of
whom had an EGFR mutation.
Conclusion: Strong ERCC1 expression and negative expression of TTF-1 and Napsin A in
LAC were unfavorable prognostic indicators. ERCC1 had a predictive value in patients
treated with PBC in all stages of the disease, both in stage IV with PBC as the only therapy,
and in stages I-II-III, with PBC combined with surgery or radiotherapy. Analysis of ERCC1
in LAC could help in making a therapeutic decision. Weak expression of ERCC1 indicates a
chance of a good response to PBC, and strong expression of ERCC1 indicates a poor response
to PBC, and toxicity of ineffective therapy should be avoided. |
