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Acquired Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors
in Non-Small Cell Lung Cancer
Kuiper, J.L.
2016
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citation for published version (APA)
Kuiper, J. L. (2016). Acquired Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in
Non-Small Cell Lung Cancer.
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Transformation to a squamous cell carcinoma phenotype
of an EGFR -mutated NSCLC-patient after treatment with
an EGFR-tyrosine kinase inhibitor
J.L. Kuiper, M.I. Ronden, A. Becker, D.A.M. Heideman, P. van Hengel, B. Ylstra, E. Thunnissen, E.F. Smit
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Activating mutations in the epidermal growth factor receptor (EGFR) are detected in approximately 10% of Caucasian and up to 50% of Asian patients with non-small cell lung cancer (NSCLC) (1). EGFR-tyrosine kinase inhibitors (TKIs) constitute the preferred first-line treatment for these patients. Unfortunately, all patients eventually develop resistance to EGFR-TKI after a median of 13 months (2). Several different resistance-mechanisms have been demonstrated in biopsies of recurrent tumours after EGFR-TKI treatment. Among these are the T790M secondary resistance mutation on EGFR exon 20 and amplification of alternative pathways such as MET and HER2, but also morphological changes with epithelial-to-mesenchymal transition and transformation to a small cell lung cancer (SCLC) phenotype (2).
Here we report a case with transformation to a squamous cell carcinoma (SqCC) phenotype. To the best of our knowledge, this is the first report on transformation to SqCC after acquired TKI-resistance in EGFR-mutated NSCLC.
In August 2013, a 63-year old Caucasian non-smoking female was diagnosed with NSCLC (T2bN3M1b). A biopsy from the right lower lobe (RLL) revealed an adenocarcinoma (p63 immunohistochemistry (IHC)-negative, TTF-1 IHC-positive) (Figure 1A) and mutation analysis of EGFR (exons 18-21) showed an exon 21 mutation (c.2573T>G; p.L858R). She was treated with erlotinib until she developed progression in January 2014. Second-line chemotherapy (cisplatin/pemetrexed) was initiated, on which she progressed after two cycles. At this time, a rebiopsy from the same lesion in the RLL was performed and histopathological analysis revealed SqCC (p63 IHC-positive, TTF-1 IHC- and pas-d stain-negative) (Figure 1B). This time, a panel of genes was evaluated for mutations using TSACP-MiSeq-NGS (3), demonstrating the identical mutation in EGFR exon 21 (c.2573T>G; p.L858R) and a mutation in PIK3CA exon 20 (c.3140A>G;p.H1047R). No mutations in other genes of the oncopanel, such as KRAS, NRAS,
HRAS, BRAF, ALK, ERBB2, FGFR1, AKT, MEK or PTEN, were detected. She then started gefitinib
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tumour cells. This ‘selection-hypothesis’ may also apply to this case of ‘transformation’ to SqCC as the identical EGFR-mutation was detected both in the original biopsy and in the rebiopsy. It is known that EGFR-mutations in SqCC are rare and EGFR-TKI treatment is less effective in EGFR-mutated SqCC compared to EGFR-mutated adenocarcinoma (5).
PIK3CA mutations are associated with the SqCC histological subtype (6). Unfortunately,
the amount of remaining tumour tissue of the original biopsy was not sufficient for extensive mutation analysis, including PIK3CA. We therefore cannot exclude that this mutation was initially present. Nonetheless, this case emphasizes that tumour cell characteristics are dynamic and may change during (targeted) treatment (7). In order to tailor treatment to the individual NSCLC-patient, it is therefore necessary to perform molecular monitoring during the course of disease, such as rebiopsy of a growing lesion after targeted treatment, to remain optimally informed about the tumour characteristics.
Figure 1:
First biopsy stained with H&E (A), TTF1 (B, arrow: tumour nuclei +), PAS-D (C, tumour nuclei ±) and p63 (D, arrow: tumour nuclei -) favouring adenocarcinoma (i.e., TTF1 ++; mucin ±; p63 -).
Second (re)biopsy stained with H&E (E, G, small arrows: cytoplasmic bridges), TTF1 (F, tumour nuclei -) and p63 (H, tumour nuclei +) favouring squamous cell carcinoma (i.e., TTF1-; p63++).
Figure 1:
First biopsy stained with H&E (A), TTF1 (B, arrow: tumour nuclei +), PAS-D (C, tumour nuclei ±) and p63 (D, arrow: tumour nuclei -) favouring adenocarcinoma (i.e., TTF1 ++; mucin ±; p63 -).
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REFERENCE LIST
(1) Dearden S, Stevens J, Wu YL, Blowers D. Mutation incidence and coincidence in non small-cell lung cancer: meta-analyses by ethnicity and histology (mutMap). Ann Oncol 2013 Sep,24(9), 2371-2376.
(2) Yu HA, Arcila ME, Rekhtman N, et al. Analysis of Tumor Specimens at the Time of Acquired Resistance to EGFR-TKI Therapy in 155 Patients with EGFR-Mutant Lung Cancers. Clin Cancer Res 2013 Apr 15,19(8):2240-7.
(3) Sie D, Snijders PJ, Meijer GA, et al. Performance of amplicon-based next generation DNA sequencing for diagnostic gene mutation profiling in oncopathology. Cell Oncol (Dordr) 2014 Oct,37(5), 353-361.
(4) Gerlinger M, Rowan AJ, Horswell S, et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 2012 Mar 8,366(10), 883-892.
(5) Fiala O, Pesek M, Finek J, Benesova L, Bortlicek Z, Minarik M. Gene mutations in squamous cell NSCLC: insignificance of EGFR, KRAS and PIK3CA mutations in prediction of EGFR-TKI treatment efficacy. Anticancer Res 2013 Apr,33(4), 1705-1711.
(6) Li S, Li L, Zhu Y, et al. Coexistence of EGFR with KRAS, or BRAF, or PIK3CA somatic mutations in lung cancer: a comprehensive mutation profiling from 5125 Chinese cohorts. Br J Cancer 2014 May 27,110(11), 2812-2820.
