Squamous cell transformation and EGFR T790M mutation as acquired resistance mechanisms in a patient with lung adenocarcinoma treated with a tyrosine kinase inhibitor: A case report

Abstract

The present case report describes the infrequent coexistence of squamous cell transformation and the epidermal growth factor receptor (EGFR) T790M mutation as resistance mechanisms to first line treatment with tyrosine kinase inhibitors. The patient was a 44-year-old female, diagnosed with a primitive advanced lung adenocarcinoma with bone metastases. The tumor was positive for the EGFR exon 19 deletion, therefore the patient was treated with afatinib (40 mg/day, orally) and radiotherapy for bone lesions. After 16 months, the patient developed resistance. Cytological examination of the pleural effusion confirmed an adenocarcinoma positive for the EGFR exon 19 deletion and the T790M mutation within exon 20, while a biopsy from the upper left bronchus revealed a keratinizing squamous cell carcinoma positive for the EGFR exon 19 deletion. In addition, the EGFR mutations were concomitantly detected in circulating cell-free tumour DNA. Due to the presence of the T790M mutation, the patient underwent osimertinib therapy (80 mg/day, orally), which resulted in a partial tumour regression at the 2-month follow-up, whereas the squamous lesions were treated with radiotherapy. The adenocarcinoma and squamous carcinoma components may share the same origin, according to the presence of the EGFR exon 19 deletion in both lesions. More accurate characterization of resistance mechanisms may lead to the development of improved treatment regimens.

Keywords: epidermal growth factor receptor; lung adenocarcinoma; resistance mechanisms; tyrosine kinase inhibitor.

Figure 1.

EGFR molecular analysis on ctDNA. Graphs from the quantitative polymerase chain reaction showing EGFR molecular analysis on ctDNA after (A) 9 and (B) 16 months of treatment with afatinib. Black curve: Control mix, including primers and probe for a non-polymorphic EGFR region. The amplification of the control region allows for the evaluation of ctDNA quality and quantity. Green curve: ex19del mix, including primers and probe for 21 types of EGFR deletions. Blue curve: T790M mix, including primers and probe for EGFR T790M mutation. EGFR, epidermal growth factor receptor; ctDNA, circulating cell-free tumour DNA.

Figure 2.

CT images and histological examinations of the patient. (A) CT image of patient at the time of diagnosis; (B and C) CT images of patient at the time of progression. (D) Pre-afatinib treatment of original adenocarcinoma in pleural effusion (hematoxylin and eosin, magnification, ×200); (E) TTF-1 positive stain. (F) Post-afatinib treatment adenocarcinoma in pleural effusion (hematoxylin and eosin). (G) TTF-1 positive stain. (H) Post-afatinib squamous cell transformation in core needle biopsy of the upper left bronchus (hematoxylin and eosin); (I) p40 positive stain. Scale bar, 100 µm. Magnification for histochemical staining images, ×200. CT, computed tomography; TTF-1, thyroid transcription factor-1.

Figure 3.

Diagram illustrating the longitudinal and clinical evaluation of the patient. Target dependent, lesions responding to afatinib treatment (epidermal growth factor receptor positive) (LLL and pleural effusion); target independent, lesions resistant to afatinib treatment [LUL (squamous cell carcinoma)]. LLL, left lower lobe; LUL, left upper lobe.