Expression of p63 as predictive and prognostic factor in advanced non-small-cell lung cancer
Abstract
Abstract
Background/Aim. Serbia belongs to the group of countries with a high lung cancer incidence and mortality rate. p63 gene plays an important role in development of lung cancer and immunohistochemical expression of p63 is considered to be a reliable marker for squamous histology. The results of some in vitro studies show a significant association of p63 expression and cisplatin chemoresistance. The aim of this study was to estimate the significance of p63 expression as predictive and prognostic factor in advanced non-small-cell lung cancer (NSCLC). Methods. Expression of p63 in 85 NSCLC (stages III, and IV) was investigated by the use of immunohistochemistry. Four weeks after the completion of 2 cycles of platinum-based doublet chemotherapy all the patients were evaluated based on the treatment response. Kaplan-Meier analysis with log-rank tests were used for overall survival (OS) and progression free survival (PFS) calcultations. Results. The expression of p63 was present in 49.4% of the patients out of whom 38.8% were with positive expression (p63+) and 10.6% of the patients were with weak expression (p63+-). Positive expression of p63 was seen in 93.9% of squamous cell carcinomas (SQCC), 5% of adenocarcinomas (AC), and in no patient with not otherwise specified (NOS) NSCLC. Weak expression of p63 was found in 12.5% of AC, 25% of NOS and only in 3% of SQCC. Analysis of the impact of the presence of p63 expression on the initial response to chemotherapy showed no statistical significance. The patients with weak p63 expression had a significantly shorter OS than the patients with no p63 expression (p = 0.049), and the tendency of shorter OS than the patients with p63 expression (p = 0.068). Conclusion. This study shows that p63 expression has no predictive significance for tumor response to initial chemotherapy regimen gemcitabine/cisplatin or paclitaxel/cisplatin observed in advanced NSCLC. Weak expression of p63 have a negative prognostic effect in stage III and IV NSCLC.
References
Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA: A Cancer J Clin 2015; 65(2):87-107. Available from :http://onlinelibrary. wiley.com/doi/10.3322/caac.21262/full
Institut za javno zdravlje Srbije “Dr Milan Jovanović Batut”. Incidencija I mortalitet od raka u centralnoj Srbiji: Izveštaj br.14. Miljuš D, Živković S, Božić Z, editors. Registar za rak u centralnojSrbiji. Beograd: Institut za javno zdravlje Srbije “Dr Milan Jovanović Batut”; 2014. Available from:http://www.batut.org.rs/download/publikacije /2012Incidencija IMortalitet Od Raka1.pdf
Vrdoljak E, Wojtukiewicz MZ, Pienkowski T, Bodoky G, Berzinec P, Finek J, et al. Cancer epidemiology in Central and South Eastern European countries. Croat Med J 2011;52(4):478-87.
Peters S, Adjei AA, Gridelli C, Reck M, Kerr K, Felip E. Metastatic non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology 2012; 23 (7): vii56–vii64.
Alberola V, Cortesi E, Juan O. Weekly paclitaxel in the treatment of metastatic and/or recurrent non-small cell lung cancer. Critical Reviews in Oncology/Hematology 2002; 44: S31-S41.
Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 2002; 346(2): 92-8.
NCCN Guidelines. Version 4.2016. Non-Small Cell Lung Cancer. April 2016.Available from: http://www.nccn.org/professionals/physician_gls/f_guidelines.asp
Travis WD, Brambilla E, Noguchi M, Nicholson AG, Geisinger K, Yatabe Y et al. Diagnosis of Lung Cancer in Small Biopsies and Cytology -Implications of the 2011 International Association for the Study of Lung Cancer/ American Thoracic Society/ European Respiratory Society Classification. Arch Pathol Lab Med 2013; 137:668-84.
Conde E, Angulo B, Redondo P, Toldos O, Garcia-Garcia E, Suarez-Gauthier A, et al. The use of p63 immunohistochemistry for the identification of squamous cell carcinoma of the lung. PLoS One 2010; 5(8): e 12209: 1-6.
Knout EC, Grag K, Arroyo JD, Correa Y, Sarkar D, Parkin RK et al. An integrative genomic approach identifies p73 and p63 as activatores of miR-200 microRNA family transcription. Nucl Acids Res 2012; 40 (2): 499-510.
Bishop PW. Immunohistochemistry in the diagnosis of pulmonary tumors. In:Hasleton P, Flieder D.B, editors. Spencer`s pathology of the lung. 6th ed. New York:Cambrige University Press; 2013.p. 1015-42.
Nobre AR, Albergaria A, Schmitt F. p40: A p63 Isoform Useful for Lung Cancer Diagnosis – A Review of the Physiological and Pathological Role of p63.Acta Cytologica 2013;57: 1–8.
G Melino. P63 is a suppressor of tumorigenesis and metastasis interacting with mutant p53.Cell Death Differ 2011 Sep; 18(9): 1487–99.
Sen T, Sen N, Brait M, Begum S, Chatterjee A, Hoque MO, et al. DeltaNp63alpha confers tumor cell resistance to cisplatin through the AKT1 transcriptional regulation.Cancer Res 2011 Feb 1;71(3):1167-76.
Soresen JB,Klee M, Palshof T,Hansen HH. Performance status assessment in cancer patients. An inter-observer variability study. Br J Cancer 1993;67(4):773-5.
Eisenhauer EA, Thetasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R et al. New response evaluation criteria in solid tumors: Revised RECIST guideline (version 1.1) . Eur J Cancer 2009;45:228-47.
Schottenfeld D, Searle JG. The etiology and epidemiology of lung cancer. In: Pass HI, Carbone DP, Minna JD, Johnson DH, Turrisi III AT, editors. Lung Cancer: Principles and Practice. 3rd ed. Philadelphia:Lippincott Williams & Wilkins;2005. p. 3-73.
Collins BT. Endobronchial ultrasound fine-needle aspiration biopsy of pulmonary non-small cell carcinoma with subclassification by immunohistochemistry panel.Cancer Cytopathol 2013;121(3):146-54.
Sigel CS, Moreira AL, Travis WD, Zakowski MF, Thornton RH, Riely GJ et al. Subtyping of non-small cell lung carcinoma: a comparison of small biopsy and cytology specimens. J Thorac Oncol 2011 Nov;6(11):1849-56.
Celik B, Khoor A, Bulut T, Nassar A. Rapid On-site Evaluation Has High Diagnostic Yield Differentiating Adenocarcinoma vs Squamous Cell Carcinoma of Non–Small Cell Lung Carcinoma, Not Otherwise Specified Subgroup. Pathol Oncol Res 2015; 21(1): 167–72.
Bir F, Aksoy Altınboga A, Satiroglu Tufan NL, Kaya S, Baser S, Yaren A. Potential utility of p63 expression in differential diagnosis of non-small-cell lung carcinoma and its effect on prognosis of the disease. Med Sci Monit 2014; 20: 219–26.
Yaman B, Nart D, Ekren PK, Çok G, Veral A.Expression of p63, TTF-1 and Maspin in Non-Small Cell Lung Carcinoma and Their Effect on the Prognosis and Differential Diagnosis. Turk Patoloji Derg 2015;31(3):163-74.
Carter GC, Barrett AM, Kaye JA, Liepa AM, Winfree KB, John WJ. A comprehensive review of nongenetic prognostic and predictive factors influencing the heterogeneity of outcomes in advanced non-small-cell lung cancer. Cancer Manag Res 2014; 6: 437–49.
Roberts JR, Pass HI. Lung cancer staging in non-small cell lung cancer including preoperative and intra-operative techniques In: Pass HI, Carbone DP, Minna JD, Johnson DH, Turrisi III AT, editors. Lung Cancer: Principles and Practice. 3rd ed. Philadelphia:Lippincott Williams & Wilkins;2005. p. 372-86.
Ma Y, Fan M, Dai L, Kang X, Liu Y, Sun Y, et al. Expression of p63 and CK5/6 in early-stage lung squamous cell carcinoma is not only an early diagnostic indicator but also
Barlési F, Pinot D, LeGoffic A, Doddoli C, Chetaille B,Torre JP et al. Positive thyroid transcription factor 1 staining strongly correlates with survival of patients with adenocarcinoma of the lung. Br J Cancer 2005; 93: 450–2.