[Pathological assessment and prognosis of SMARCA4-deletion non-small cell lung cancer with neoadjuvant therapy]

Objective: To investigate the clinicopathological features, treatment-effect assessment and prognosis of SMARCA4-deletion non-small cell lung cancer (NSCLC) that was treated with neoadjuvant therapy. Methods: Eleven consecutive cases of SMARCA4-deletion NSCLC treated with neoadjuvant therapy in Guangdong Provincial People's Hospital, Guangzhou, China from January 2007 to October 2024 were collected. Their clinicopathological features, pathological assessment of treatment effect, and prognosis were retrospectively analyzed. Results: All the 11 patients were male. Their median age at diagnosis was 56 (49,64) years. Nine patients were smokers (9/11). Ten patients received neoadjuvant chemoimmunotherapy, and one received neoadjuvant targeted therapy. Eleven biopsy samples showed SMARCA4 complete loss, including 7 cases of invasive non-mucinous adenocarcinoma, 1 case of invasive mucinous adenocarcinoma, 1 case of non-keratinizing squamous cell carcinoma, and 2 cases of NSCLC, not otherwise specified. The histological response to neoadjuvant therapy in resected specimens varied, including tumor necrosis, foam cell aggregation, cholesterol clefts, immune cell infiltrates, reactive granulomas, and stromal fibrosis. Three cases of the primary lesion achieved major pathological response (MPR), and 2 cases achieved complete pathological response (CPR). The MPR rate of neoadjuvant chemoimmunotherapy was 3/10 while its CPR ratio was 2/10. Of the 9 resected specimens that did not achieve CPR, 5 showed a post-treatment histological type different from the pre-treatment one. Eight tumors showed complete SMARCA4 loss, while 1 showed heterogeneous expression. Of the 11 biopsy specimens examined using next generation sequencing, 9 cases showed class 1 SMARCA4 mutations (including 7 nonsense mutations and 2 acquired nonsense mutations), and 2 cases showed wild-type SMARCA4. Taking immunohistochemistry as the gold standard, the sensitivity of next generation sequencing for the detection of SMARCA4-deletion NSCLC was 9/11. After follow-up of 6.9 to 46.6 months, five patients experienced postoperative recurrence, and 6 patients were disease free. The disease-free survival ranged from 0.7 to 27.5 months (median, 7.6 months). Conclusions: The surgical specimens of SMARCA4-deletion NSCLC with neoadjuvant therapy show varying degrees of treatment response. The tumor components sensitive to chemoimmunotherapy and targeted therapy are mostly adenocarcinoma and squamous cell carcinoma, while large cell carcinoma, spindle cell carcinoma and giant cell carcinoma are relatively less sensitive to treatment. Assessment of MPR and CPR suggests that some NSCLC patients with SMARCA4-deletion can benefit from neoadjuvant therapy.