Targeted Therapy with an EGFR Tyrosine Kinase Inhibitor in Bronchioloalveolar Carcinoma of the Lung: A Literature Review and a Case Study of Clinically Prompt and Intensive Response to Erlotinib.

Česká verze

Authors: M. Svoboda ^1,2; P. Fabian ³; O. Slabý ^1,2; M. Staňková ⁴; R. Lakomý ^1,2; R. Němeček ¹; R. Vyzula ^1,2
Authors place of work: Klinika komplexní onkologické péče, Masarykův onkologický ústav, Brno ¹; Lékařská fakulta Masarykovy Univerzity, Brno ²; Oddělení patologie, Masarykův onkologický ústav, Brno ³; Institute of Applied Biotechnologies, a. s., Praha ⁴
Published in the journal: Klin Onkol 2010; 23(4): 224-230
Category: Přehledy

Summary

Introduction:
Bronchioloalveolar carcinoma (BAC) is an adenocarcinoma belonging to non-small cell lung carcinomas (NSCLC) that, in addition to its morphology and endobronchial spread, presents with certain specific clinical characteristics: greater incidence in women, non-smokers and younger patients, presence of malignant bronchorrhea and lower susceptibility to conventional cytostatic therapies in comparison to other subtypes of NSCLC. On the other hand, nonmucinous type of BAC may show better therapeutic response to targeted therapy with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) erlotinib or gefitinib, as it is 5 times more frequently a carrier of EGFR gene mutations compared to conventional lung adenocarcinomas.

Case description:
We present a case of a 41 years old man, non-smoker for the last 5 years, who was diagnosed with a pneumonic form of nonmucinous bronchioloalveolar carcinoma. Metastases to regional and distant lymph nodes and massive involvement of skeleton with infiltrations in the bone marrow were present at the diagnosis. During the first line palliative chemotherapy with combination regimen of carboplatin and paclitaxel, the disease progressed significantly and the patient’s condition deteriorated (performance status (PS) 3, severe dyspnoea at rest, malignant bronchorrhea). Subsequently, administration of erlotinib was initiated based on a series of case studies describing good response of BAC to treatment with EGFR TKI. An evident improvement of the patient’s condition was observed as early as 4 days of administration, together with regression of peripheral lymphadenopathy. Nearly complete disappearance of pulmonary infiltrates was observed after 30 days of therapy, with the patient becoming asymptomatic, PS 0. Molecular genetics confirmed the tumour phenotype to be highly responsive to EGFR TKI therapy. The tumour contained EGFR mutation in exon 19 (in-frame L747-753insS deletion) and wild-type K-ras. Disease relapse in the liver occurred 6 months later confirming disease progression. Further treatment remained ineffective despite brief stabilisations of liver enzyme progression following repeated administration of pemetrexed and gefitinib. The patient died 12 months after the diagnosis.

Conclusions:
Our case confirms the importance of targeted therapy when treating tumours of an appropriate phenotype. Such treatment may have prompt and intensive effect that may reverse the course of the disease even in patients with poor overall health status.

Key words:
lung cancer – bronchioloalveolar carcinoma – EGFR gene – K-ras gene – erlotinib – gefitinib – targeted therapy – prediction

Zdroje

1. Gandara DR, West H, Chansky K et al. Bronchioloalveolar carcinoma: a model for investigating the biology of epidermal growth factor receptor inhibition. Clin Cancer Res 2004; 10(12 Pt 2): 4205s– 4209s.

2. Yano S, Kanematsu T, Miki T et al. A report of two bronchioloalveolar carcinoma cases which were rapidly improved by treatment with the epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 („Iressa“). Cancer Sci 2003; 94(5): 453– 458.

3. Fong T, Morgensztern D, Govindan R. EGFR inhibitors as first‑line therapy in advanced non‑small cell lung cancer. J Thorac Oncol 2008; 3(3): 303– 310.

4. Kijima T, Suzuki M, Ueda K et al. Short‑term gefitinib treatment brought about a long‑term regression of bronchioloalveolar carcinoma without EGFR gene alterations: a case report. Oncol Res 2007; 16(10): 489– 495.

5. Miller VA, Riely GJ, Zakowski MF et al. Molecular characteristics of bronchioloalveolar carcinoma and adenocarcinoma, bronchioloalveolar carcinoma subtype, predict response to erlotinib. J Clin Oncol 2008; 26(9): 1472– 1478.

6. Marchetti A, Martella C, Felicioni L et al. EGFR mutations in non‑small‑cell lung cancer: analysis of a large series of cases and development of a rapid and sensitive method for diagnostic screening with potential implications on pharmacologic treatment. J Clin Oncol 2005; 23(4): 857– 865.

7. Shigematsu H, Lin L, Takahashi T et al. Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. J Natl Cancer Inst 2005; 97(5): 339– 346.

8. Travis WD. World Health Organization, International Agency for Research on Cancer, International Association for the Study of Lung Cancer, International Academy of Pathology. Pathology and Genetics of Tumours of the Lung, Pleura, Thymus and Heart. Lyon, Oxford: IARC Press, Oxford University Press 2004.

9. Henrikson RC, Kaye GI, Mazurkiewicz JE. Respiratory system. In: NMS Histology. 1st ed. Baltimore: Williams and Wilkins 1997: 311– 321.

10. Gazdar AF. Activating and resistance mutations of EGFR in non‑small‑cell lung cancer: role in clinical response to EGFR tyrosine kinase inhibitors. Oncogene 2009; 28 (Suppl 1): S24– S31.

11. Mok T, Wu YL, Thongprasert S et al. Phase III, randomised, open‑ label, first‑line study of gefitinib vs carboplatin/ paclitaxel in clinically selected patients with advanced non‑small‑cell lung cancer – IPASS. Ann Oncol 2008; 19 (Suppl 8): viii3.

12. Rolen KA, Fulton JP, Tamura DJ et al. Bronchioloalveolar carcinoma (BAC) of the lung is related to cigarette smoking: A case‑ control study from Rhode Island (RI). Proc Am Soc Clin Oncol 2003; 22: 674.

13. Ebright MI, Zakowski MF, Martin J et al. Clinical pattern and pathologic stage but not histologic features predict outcome for bronchioloalveolar carcinoma. Ann Thorac Surg 2002; 74(5): 1640– 1646.

14. Edge SB, Byrd DR, Compton CC. AJCC Cancer Staging Manual. 7th ed. New York: Springer‑ Verlag 2010.

15. Nakajima T, Terashima T, Nishida J et al. Treatment of bronchorrhea by corticosteroids in a case of bronchioloalveolar carcinoma producing CA19– 9. Intern Med 2002; 41(3): 225– 228.

16. Kancha RK, von Bubnoff N, Peschel C et al. Functional analysis of epidermal growth factor receptor (EGFR) mutations and potential implications for EGFR targeted therapy. Clin Cancer Res 2009; 15(2): 460– 467.

17. Kobayashi S, Boggon TJ, Dayaram T et al. EGFR mutation and resistance of non‑small‑cell lung cancer to gefitinib. N Engl J Med 2005; 352(8): 786– 792.