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. 2021 Nov 1;4(11):e2131892.
doi: 10.1001/jamanetworkopen.2021.31892.

Association of Clinicopathologic and Molecular Tumor Features With Recurrence in Resected Early-Stage Epidermal Growth Factor Receptor-Positive Non-Small Cell Lung Cancer

Stephanie P L Saw  1 , Siqin Zhou  2 , Jianbin Chen  3 , Gillianne Lai  1 , Mei-Kim Ang  1 , Kevin Chua  4 , Ravindran Kanesvaran  1 , Quan Sing Ng  1 , Amit Jain  1 , Wan Ling Tan  1 , Tanujaa Rajasekaran  1 , Darren W T Lim  1 , Aaron Tan  1 , Kam Weng Fong  4 , Angela Takano  5 , Xin Ming Cheng  5 , Kiat Hon Lim  5 , Tina Koh  6 , Boon-Hean Ong  6 , Eng Huat Tan  1 , Chee Keong Toh  7 , Anders J Skanderup  3 , Sze Huey Tan  2 , Daniel S W Tan  1   2   3   8
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Association of Clinicopathologic and Molecular Tumor Features With Recurrence in Resected Early-Stage Epidermal Growth Factor Receptor-Positive Non-Small Cell Lung Cancer

Stephanie P L Saw et al. JAMA Netw Open. .

Abstract

Importance: The recently published ADAURA study has posed a significant dilemma for clinicians in selecting patients for adjuvant osimertinib. Risk factors for recurrence in early-stage epidermal growth factor receptor (EGFR)-positive non-small cell lung cancer (NSCLC) also remain undefined.

Objective: To determine clinicopathologic characteristics and recurrence patterns of resected early-stage EGFR-positive NSCLC, using wildtype EGFR as a comparator cohort, and identify features associated with recurrence.

Design, setting, and participants: This is a cohort study including patients diagnosed with AJCC7 Stage IA to IIIA NSCLC between January 1, 2010, and June 30, 2018, who underwent curative surgical procedures at a specialist cancer center in Singapore. The cutoff for data analysis was October 15, 2020. Patient demographic characteristics, treatment history, and survival data were collated. In exploratory analysis, whole-exome sequencing was performed in a subset of 86 patients. Data were analyzed from September 3, 2020, to June 6, 2021.

Exposures: Adjuvant treatment was administered per investigator's discretion.

Main outcomes and measures: The main outcome was 2-year disease-free survival (DFS).

Results: A total of 723 patients were included (389 patients with EGFR-positive NSCLC; 334 patients with wildtype EGFR NSCLC). There were 366 women (50.6%) and 357 men (49.4%), and the median (range) age was 64 (22-88) years. A total of 299 patients (41.4%) had stage IA NSCLC, 155 patients (21.4%) had stage IB NSCLC, 141 patients (19.5%) had stage II NSCLC, and 125 patients (17.3%) had stage IIIA NSCLC. Compared with patients with wildtype EGFR NSCLC, patients with EGFR-positive NSCLC were more likely to be women (106 women [31.7%] vs 251 women [64.5%]) and never smokers (121 never smokers [36.2%] vs 317 never smokers [81.5%]). At median (range) follow up of 46 (0-123) months, 299 patients (41.4%) had cancer recurrence. There was no statistically significant difference in 2-year DFS for EGFR-positive and wildtype EGFR NSCLC (70.2% [95% CI, 65.3%-74.5%] vs 67.6% [95% CI, 62.2%-72.4%]; P = .70), although patients with EGFR-positive NSCLC had significantly better 5-year overall survival (77.7% [95% CI, 72.4%-82.1%] vs 66.6% [95% CI, 60.5%-72.0%]; P = .004). Among patients with EGFR-positive NSCLC, 2-year DFS was 81.0% (95% CI, 74.0%-86.3%) for stage IA, 78.4% (95% CI, 68.2%-85.6%) for stage IB, 57.1% (95% CI, 43.7%-68.4%) for stage II, and 46.6% (95% CI, 34.7%-57.7%) for stage IIIA. Overall, 5-year DFS among patients with stage IB through IIIA was 37.2% (95% CI, 30.1%-44.3%). Sites of disease at recurrence were similar between EGFR-positive and wildtype EGFR NSCLC, with locoregional (64 patients [16.5%] vs 56 patients [16.8%]), lung (41 patients [10.5%] vs 40 patients [12.0%]), and intracranial (37 patients [9.5%] vs 22 patients [6.6%]) metastases being the most common. A risk estimation model incorporating genomic data and an individual patient nomogram using clinicopathologic features for stage I EGFR-positive NSCLC was developed to improve risk stratification.

Conclusions and relevance: This cohort study found that recurrence rates were high in early-stage EGFR-positive NSCLC including stage IA, yet 37.2% of patients with stage IB through IIIA were cured without adjuvant osimertinib. Further studies are needed to elucidate individualized surveillance and adjuvant treatment strategies for early-stage EGFR-positive NSCLC.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Lai reported receiving personal fees from Amgen and grants from Merck, Astra Zeneca, Pfizer, Bristol Myers Squibb, and Roche outside the submitted work. Dr Chua reported receiving personal fees from AstraZeneca and PeerVoice outside the submitted work. Dr Kanesvaran reported receiving personal fees from Merck, Bristol Myers Squibb, and Novartis outside the submitted work. Dr Ng reported serving on advisory boards for Boehringer Ingelheim and Merck. Dr D.W.T. Lim reported receiving grants from Bristol Myers Squibb and Boehringer-Ingelheim and personal fees from Merck, Roche, Pfizer, Taiho, and Astra-Zeneca outside the submitted work. Dr A. Tan reported receiving personal fees from Amgen outside the submitted work. Dr Ong reported receiving personal fees from AstraZeneca, Johnson & Johnson, Medtronic, and Stryker and nonfinancial support from Johnson & Johnson, Medtronic, Stryker, and Broncus outside the submitted work. Dr D.S.W. Tan reported grants from AstraZeneca and Amgen and personal fees from Novartis, Boehringer Ingelheim, Bayer, GlaxoSmithKline, Janssen, Amgen, and C4 Therapeutics during the conduct of the study. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Outcomes of 2 Contemporaneous Cohorts of Resected Early-Stage Epidermal Growth Factor Receptor (EGFR)–Positive and Wildtype EGFR Non–Small Cell Lung Cancer
Crosses indicate censored patients. C, Dashed lines indicate 1-, 2-, 3-, 4-, and 5-year rates of recurrence.
Figure 2.
Figure 2.. Two- and 5-Year Disease-Free Survival by Stage for Epidermal Growth Factor Receptor (EGFR)–Positive Non–Small Cell Lung Cancer Cohort Demonstrating Long-term Survival for a Subset of Patients
Dashed lines indicate yearly cumulative rates of recurrence; crosses, censored patients.
See this image and copyright information in PMC

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