Patients with early-stage lung cancer can be cured with complete surgical resection with mediastinal lymph node dissection. Recurrence however, which occurs in 20-50% of these patients, can result in patient deaths with a 5-year overall survival rate of 58-73%. Adjuvant chemotherapy for patients with stage II-III lung cancer can be beneficial to prevent relapse. It is not recommended for stage IA patients, and for stage IB is dependent on risk factors such as visceral pleural invasion, poor differentiation, and size of the tumour without considering genetic mutations.
Mutational analysis of patients diagnosed with lung cancer to identify potential prognostic biomarkers would be an advantage for treatment stratification and outcome. To date, despite a number of biomarker studies being performed, recurrence biomarkers remain elusive and potential biomarkers such as KRAS, TP53 and EGFR7 have generated inconsistent results.
In this study the authors hypothesise that targeted sequencing with a panel of known cancer associated genes may detect the genetic alterations that cause recurrence. 230 patients with resected stage I–II lung adenocarcinoma were assessed, 64 (27.8%) of which had recurrence of the disease.
Patients with poorly differentiated tumours had a significantly shorter recurrence free survival (RFS) and stage at diagnosis was also associated with RFS. Patients with visceral-pleural invasion showed a significantly higher recurrence rate than patients without invasion (48.3% vs 20.5%, p\ 0.001).
The most common mutations were found in EGFR (52.2%). TP53 (18.3) and KRAS (14.3%) also demonstrated numerous alterations.
More frequent EGFR mutations were observed in patients with no recurrence, 58.4% Versus 35.9%.
A higher frequency of CTNNB1 mutations and fusion genes was noted in patients with recurrence, where 8/9 patients with mutations and 9/12 with fusions had recurrence.
Whilst 88.3% of patients had at least one pathogenic mutation, there was no significant association between the number of pathogenic mutations and RFS.
23 patients had driver mutations and demonstrated a similar short RFS to patients with multiple mutations.
Univariate analysis detected mutations in CTNNB1 as a poor prognostic marker for recurrence and multivariate analysis adjusted for age, sex, smoking history, stage and surgery morbidity confirmed the CTNNB1 mutations were significantly associated with RFS.
Fusions in the ALK, ROS1 and RET genes were also significantly associated with RFS, although in a separate group.
Mutations in EGFR was a good prognostic factor for recurrence and dual EGFR/TP53 mutations had a similar RFS, whilst double mutants with EGFR/CTNNB1 alterations demonstrated a significantly shorter RFS. KRAS/TP53 double mutations also had significantly shorter RFS.
Although CTNNB1 mutations were low, most patients with these mutations suffered recurrence and a missense mutation in exon 3 was present in all patients that had recurrence. One patient had this mutation without recurrence, however there was also a stop gain mutation in exon 4. Most patients with these mutations recurred with distal metastases.
Identification of prognostic biomarkers for recurrence of lung adenocarcinoma could be of huge benefit for treatment stratification and prediction of outcome. In this study the authors used targeted sequencing of early-stage lung adenocarcinomas with a panel of 170 cancer-related genes and 37 fusion genes. They identified mutations in CTNNB1 that was a prognostic indicator of recurrence. They also determined that fusions in ALK, ROS1 and RET genes was also a poor prognostic indicator and that recurrence from these fusions and the CTNNB1 genes occurred at distal metastatic sites. The authors conclude that targeted sequencing provides important information that can be used to predict recurrence risk and to select the optimal treatment strategy for each patient.
Kim, I.A., Hur, J.Y., Kim, H.J. et al. Targeted Next-Generation Sequencing Analysis for Recurrence in Early-Stage Lung Adenocarcinoma. Ann Surg Oncol (2020).