Re-biopsy and liquid biopsy for patients with non-small cell lung cancer after EGFR-tyrosine kinase inhibitor failure

Abstract

Background: Re-biopsy is important for exploring resistance mechanisms, especially for non-small cell lung cancer (NSCLC) patients who develop resistance to EGFR-tyrosine kinase inhibitors (TKIs). Liquid biopsy using circulating tumor DNA has come into use for this purpose. This retrospective study investigated the status of re-biopsy and liquid biopsy in NSCLC patients with EGFR mutations and evaluated their effect on clinical strategies and prognosis.

Methods: Five hundred fifty-five NSCLC patients with resistance to EGFR-TKIs were included and divided into three groups: re-biopsy, liquid biopsy, and no re-biopsy. Amplification refractory mutation system (ARMS) PCR or super ARMS PCR was used to detect EGFR mutations.

Results: Three hundred eight (55.5%) patients underwent re-biopsy; 45.5% (140/308) were positive for T790M. The most common re-biopsy procedure was computed tomography-guided percutaneous core needle biopsy (60.1%), followed by effusion drainage (29.5%) and superficial lymph node biopsy (6.5%). One hundred eighteen (21.3%) patients underwent liquid biopsy; the T790M detection rate was 41.5% (49/118.) Of the 308 patients who underwent re-biopsy, 69 were examined for EGFR mutations with plasma. The concordance rate of T790M detection between tissue and plasma was 66.7%. A statistical difference in further treatment after EGFR-TKI failure was observed among all groups (P = 0.014). Patients in the biopsy groups were more likely to receive third-generation EGFR-TKIs. Multivariate analysis showed that re-biopsy had a significant impact on overall survival (P < 0.001).

Conclusion: Re-biopsy plays a pivotal role in the management of patients with NSCLC and resistance to EGFR-TKIs. Liquid biopsy may be an alternative if difficulties performing re-biopsy exist.

Keywords: EGFR-TKI resistance; liquid biopsy; non-small cell lung cancer; re-biopsy.

Figure 1

Flow chart of subject enrollment. PFS, progression‐free survival; PD, progressive disease; TKIs, tyrosine kinase inhibitors.

Figure 2

(a) The proportions of different sampling procedures in patients who underwent re‐biopsy, () CT‐guided PCNB, () Effusion drainage, () TBNA/EBUS‐TBNA, () SLNB and () other metastasis biopsy. The distribution of results in patients who were tested for EGFR mutation via (b) tissue (c) or plasma. () Consistent with baseline, () Mut plus T790M/T790M, () Wild type, and () others. “Others” in (b) include three patients with small‐cell lung cancer, two with baseline mutations and c‐MET, one with an exon 20 insert, one with translation from 19del to L858R, one with KRAS and one with ALK. “Others” in (c) include one patient with an exon 20 insert and one with baseline mutations (L858R), S768I, and T790M. CT, computed tomography; EBUS, endobronchial ultrasonography; mut plus T790M, patients harbored a baseline mutation and a T790M mutation when re‐tested; PCNB, percutaneous core needle biopsy; SLNB, superficial lymph node biopsy; TBNA, transbronchial needle aspiration; T790M, patients only harbored a T790M mutation and the baseline sensitive mutation disappeared.

Figure 3

Kaplan–Meier estimates of the duration of progression‐free survival (PFS) of further treatment in (a) patients who exhibited an objective response to EGFR‐tyrosine kinase inhibitors (TKIs), efficacy () PR, () SD and () PD, (b) patients who underwent re‐biopsy or not, if re‐biopsy () re‐biopsy, () liquid biopsy and () no biopsy and (c) patients divided into different groups according to whether T790M was positive and third‐generation TKIs (3‐TKIs) were administered, TBR () T790M +3‐TKI+, () T790M +3‐TKI−, () T790M −3‐TKI+ and () T790M −3‐TKI−. Kaplan–Meier estimates of the duration of overall survival (OS) of (d) patients who exhibited an objective response to EGFR‐TKIs, efficacy () PR, () SD, () PD, () PR‐censored, () SD‐censored and () PD‐censored and (e) patients who underwent re‐biopsy or not, if re‐biopsy () re‐biopsy, () liquid biopsy, () no rebiopsy, () re‐biopsy‐censored, () liquid biopsy‐censored and () no rebiopsy‐censored. HR, hazard ratio; mOS, median OS; mPFS, median PFS; mut plus T790M, patients harbored a baseline mutation and a T790M mutation when re‐tested; PD, progressive disease; PR, partial response; SD, stable disease; T790M, patients only harbored a T790M mutation and the baseline sensitive mutation disappeared.