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Effects of EGFR driver mutations on pathologic regression in resectable locally advanced non-small cell lung cancer
Sarit Appel1, Jair Bar2,3, Akram Saad2
1Department of Radiation Oncology, Chaim Sheba Medical Center, Tel- Hashomer, Israel.
Objective:
We hypothesized that driver mutations in epidermal growth factor receptor (EGFR) are associated with decreased pathologic response to neoadjuvant chemoradiation (NA-ChRT) in locally advanced non-small cell lung cancer (LA-NSCLC).
Methods:
Patients with Stage IIB-IIIA NSCLC treated with NA-ChRT, completion surgery, and underwent molecular profile testing were identified in a lung cancer database. Pathologic response was quantified using: (i) major pathologic response (MPR), (ii) complete pathologic response (pCR), and (iii) mean residual viable tumor cells (MRTC). Two groups were formed based on the presence or absence of driver mutations. Clinical and pathological correlations between the groups were studied.
Results:
Forty-seven patients underwent tumor molecular profile testing, NA-ChRT, and completion surgery. Compared to the no-driver mutation group, the driver mutation group had lower MPR (23% vs 71%, p = 0.003), pCR (0% vs 26%, p = 0.02), and higher MRTC (43.4% vs 15.8%, p = 0.009). Univariate analysis showed an increased MPR rate for smokers, squamous cell histology, ChRT-surgery interval >65 days, and no-driver mutations. Multivariate analysis showed that only no-driver mutations (OR 0.39, p = 0.02) remained significant for MPR. PD-L1 status did not affect MPR. At 2 years, the driver mutation group had lower rates of local control (Hazard ration [HR] 0.67, p = 0.17) and disease-free survival (HR 0.5, p = 0.001). Overall survival was similar for both groups (HR = 1.04, p = 0.86).
Conclusion:
Following 60 Gray NA-ChRT, tumors with a driver mutation had lower MPR and pCR rates than tumors without a driver mutation. PD-L1 was not associated with tumor regression.
Advances In Knowledge:
Patients with resectable LA-NSCLC and an EGFR driver mutation treated with neoadjuvant-ChRT and completion surgery have reduced pathologic regression, lower local control rates, and shorter disease-free survival than patients without a driver mutation. Evaluation of molecular testing should be introduced in LA-NSCLC intended for prognostication and treatment decisions.
Insights
Driver mutations in EGFR are linked to poorer outcomes in locally advanced non-small cell lung cancer (LA-NSCLC) treated with neoadjuvant chemoradiation (NA-ChRT). Patients with these mutations showed reduced tumor response and shorter disease-free survival.
Area of Science:
- Oncology
- Molecular Biology
- Thoracic Surgery
Background:
- Locally advanced non-small cell lung cancer (LA-NSCLC) often requires multimodal treatment.
- Neoadjuvant chemoradiation (NA-ChRT) followed by surgery is a standard approach for resectable LA-NSCLC.
- The role of driver mutations in predicting response to NA-ChRT is an area of active investigation.
Purpose of the Study:
- To investigate the association between driver mutations, specifically in EGFR, and pathologic response to NA-ChRT in LA-NSCLC.
- To compare treatment outcomes between LA-NSCLC patients with and without driver mutations.
- To evaluate the prognostic value of molecular profiling in LA-NSCLC.
Main Methods:
- Retrospective analysis of Stage IIB-IIIA NSCLC patients who received NA-ChRT and completion surgery.
- Molecular profile testing was performed on tumor samples.
- Pathologic response assessed by major pathologic response (MPR), complete pathologic response (pCR), and mean residual viable tumor cells (MRTC).
- Comparison of clinical and pathological outcomes between groups with and without driver mutations.
Main Results:
- Patients with driver mutations (EGFR) exhibited significantly lower MPR (23% vs. 71%) and pCR (0% vs. 26%) rates compared to those without driver mutations.
- Higher mean residual viable tumor cells (MRTC) were observed in the driver mutation group (43.4% vs. 15.8%).
- Multivariate analysis identified the absence of driver mutations as a significant predictor of MPR (OR 0.39, p=0.02).
- The driver mutation group showed trends towards lower local control and significantly shorter disease-free survival (HR 0.5, p=0.001).
Conclusions:
- Driver mutations, particularly EGFR, are associated with diminished pathologic response to NA-ChRT in LA-NSCLC.
- Molecular profiling, including driver mutation status, should be integrated for prognostication and treatment decisions in LA-NSCLC.
- PD-L1 status did not demonstrate a significant association with tumor regression in this cohort.
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