Disease monitoring of epidermal growth factor receptor (EGFR)‐mutated non‐small‐cell lung cancer patients treated with tyrosine kinase inhibitors via EGFR status in circulating tumor DNA

Abstract

Objective Circulating tumor DNA (ctDNA) monitoring proves to be a promising approach to assess response and predict survival in epidermal growth factor receptor (EGFR)‐mutated non‐small‐cell lung cancer (NSCLC) patients treated with tyrosine kinase inhibitors (TKIs). However, whether the dynamic changes in ctDNA EGFR mutation status have the same predictive value as ctDNA remains unknown. This study aims to explore the predictive value of dynamic changes in both ctDNA and ctDNA EGFR status. Methods A retrospective analysis was performed using 91 ctDNA samples from a cohort of 28 patients who were diagnosed with EGFR‐mutated NSCLC and treated with EGFR‐TKIs, including 14 patients treated with first‐/second‐generation TKIs and 14 treated with osimertinib. Blood samples at baseline (BL), within 4 weeks after TKI initiation (Week4), within 12 weeks before progression (pre‐PD), and at progression were collected. The relationship alternatives in ctDNA status, ctDNA EGFR status and response to EGFR‐TKIs as well as progression‐free survival (PFS) were analyzed. Results We categorized 20 BL‐ctDNA positive patients with available Week4‐ctDNA into two groups: ctDNA‐clearance (N = 7, 35%) and ctDNA‐non‐clearance (N = 13, 65%). The ctDNA‐clearance group had better PFS than the ctDNA‐non‐clearance group (ctDNA‐clearance vs. ctDNA‐non‐clearance, p = 0.091, hazard ratio [HR] = 0.42, 95% confidence interval [CI] = 0.15–1.19). According to Week4‐EGFR status, we observed that PFS was significantly longer in EGFR‐clearance patients than EGFR‐non‐clearance groups, (p = 0.011, HR = 0.23, 95% CI = 0.08–0.72). We then categorized patients into three subgroups according to Week4‐ctDNA and Week4‐EGFR status: non‐clearance (N = 9), only‐EGFR‐clearance (concomitant alterations non‐clearance) (N = 4), and all‐clearance (N = 7). The nonclearance group had a significantly worse PFS than the all‐clearance group (median PFS = 5.07 vs. 11.40 months, p = 0.029, HR = 3.45, 95% CI = 1.05–11.49). The only‐EGFR‐clearance group had a similar PFS to the all‐clearance group (p = 0.607), which was longer than that of the non‐clearance group (median PFS = 9.20 vs. 5.07 months, p = 0.060, HR = 0.25, 95% CI = 0.05–1.18). We found that the all‐clearance group had a similar objective response rate (ORR) to the only‐EGFR‐clearance group (p = 1.000) and a higher ORR than the non‐clearance group (p = 0.012). Conclusion Monitoring of EGFR clearance in ctDNA is promising and cost‐effective in assessing response and predicting survival in EGFR‐mutated NSCLC patients treated with EGFR‐TKIs, with similar predictive value to ctDNA surveillance.

Can Liquid Biopsy Based on ctDNA/cfDNA Replace Tissue Biopsy for the Precision Treatment of EGFR-Mutated NSCLC?

“…Table 1 presents data on the association between plasma ctDNA/cfDNA EGFR mutations and the efficacy and prognosis of targeted therapy in NSCLC patients [ 28 , 30 , 31 , 32 , 33 , 34 , 35 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 ]. The BENEFIT trial prospectively demonstrated the feasibility of using liquid biopsy to guide the efficacy of first-line EGFR-TKI therapy for the first time.…”

Liquid Biopsy in Clinical Oncology

“…Другим направлением ЖБ, нашедшим широкое применение в практической онкологии, является анализ цоДНК для мониторинга ответа опухоли на терапию и оценки риска рецидивов. Накоплено значительное количество данных о том, что падение уровня цоДНК в крови больных раком легкого на фоне применения противоопухолевых препаратов может расцениваться как благоприятный прогностический признак [45][46][47]. Аналогично длительный мониторинг концентрации и анализ мутаций цоДНК в плазме пациентов с раком прямой кишки на фоне лекарственной терапии позволяет выполнять эффективный контроль течения заболевания [48][49][50].…”

“…Однако на данный момент эта задача, хотя и необычайно многообещающая, все еще носит экспериментальный характер. Можно отметить, что в контексте более рутинной диагностики предварительный отбор ЦОК помогает улучшить детекцию предиктивных мутаций [45,110,117,118]. Кроме того, важно, что выделение ЦОК помогает упростить ЖБ в отношении выявления химерных транскриптов, методики детекции которых в реальной практике обычно основаны на анализе мРНК [119][120].…”

“…Установлено, что эффективная терапия опухолей сопровождается исчезновением ЦОК [45,113,123]. Многочисленные исследования в самых разных клинических ситуациях неизменно показывают, что обнаружение ЦОК само по себе обладает негативным прогностическим значением [124][125][126][127][128].…”

Enhancement of TKI sensitivity in lung adenocarcinoma through m6A-dependent translational repression of Wnt signaling by circ-FBXW7

“…The field of lung cancer treatment has undergone significant advancements, thanks to the identification of novel targets and continuous refinement of therapeutic approaches. Particularly noteworthy is the emergence of targeted therapies, such as tyrosine kinase inhibitors (TKIs), which have gained recognition for their ability to elicit improved responses with fewer side effects [ 1 – 3 ]. The development of third-generation TKIs has propelled them to the forefront of first-line therapy for patients with sensitive EGFR mutations, surpassing the efficacy of earlier generations [ 4 , 5 ].…”