Alì Greta, Poma Anello Marcello, Di Stefano Iosè, Zirafa Carmelina Cristina, Lenzini Alessandra, Martinelli Giulia, Romano Gaetano, Chella Antonio, Baldini Editta, Melfi Franca, Fontanini Gabriella
Unit of Pathological Anatomy, University Hospital of Pisa, Pisa, Italy.
Department of Surgical, Medical, Molecular Pathology and Critical Area, University of Pisa, Pisa, Italy.
Front Oncol. 2023 Feb 9;13:1115156. doi: 10.3389/fonc.2023.1115156. eCollection 2023.
Non-small cell lung cancer (NSCLC) is the leading cause of cancer incidence and mortality worldwide. Neoadjuvant chemo-immunotherapy has led to clinical benefits in resectable NSCLC in comparison to chemo-therapy alone. Major pathological response (MPR) and pathological complete response (pCR) have been used as surrogates of neoadjuvant therapy response and clinical outcomes. However, the factors affecting the pathological response are still controversial. Therefore, in this study we retrospectively examined MPR and pCR in two different cohorts of NSCLC patients, 14 treated by chemotherapy and 12 by chemo-immunotherapy in the neoadjuvant setting.
In resected tumor specimens, different histological characteristics were evaluated: necrosis, fibrosis, inflammation, presence of organizing pneumonia, granuloma, cholesterol cleft, and reactive epithelial alterations. In addition, we evaluated how MPR impacts on event-free survival (EFS) and overall survival (OS). In a small group of patients treated by chemo-immunotherapy, a gene expression analysis of the Hippo pathway was performed both in preoperative biopsies and matched post-surgical specimens.
We observed a better pathological response in the chemo-immunotherapy treated cohort: 6/12 patients (50.0%) achieved a MPR ≤10% and 1/12 (8.3%) achieved pCR both on primary tumor and on lymph nodes. On the contrary, no patient treated with chemotherapy alone achieved pCR or MPR ≤10%. A higher amount of stroma in the neoplastic bed was observed in patients treated with immuno-chemotherapy. Moreover, patients achieving better MPR (including pCR) had significantly improved overall survival (OS) and event-free survival (EFS). After neoadjuvant chemo-immunotherapy, residual tumors showed a remarkable upregulation of genes consistent with the activation of YAP/TAZ. Also, alternative checkpoint, such as CTLA-4, were enhanced.
Our findings showed that neoadjuvant chemo-immunotherapy treatment improves MPR and pCR thus resulting in better EFS and OS. Moreover, a combined treatment could induce different morphological and molecular changes in comparison to chemotherapy alone, thus giving new insights in the assessment of pathological response.
非小细胞肺癌（NSCLC）是全球癌症发病率和死亡率的主要原因。与单纯化疗相比，新辅助化疗免疫疗法已在可切除的NSCLC中带来临床益处。主要病理反应（MPR）和病理完全缓解（pCR）已被用作新辅助治疗反应和临床结果的替代指标。然而，影响病理反应的因素仍存在争议。因此，在本研究中，我们回顾性研究了两组不同的NSCLC患者的MPR和pCR，一组14例接受化疗，另一组12例在新辅助治疗中接受化疗免疫疗法。
在切除的肿瘤标本中，评估了不同的组织学特征：坏死、纤维化、炎症、机化性肺炎、肉芽肿、胆固醇裂隙和反应性上皮改变的存在。此外，我们评估了MPR如何影响无事件生存期（EFS）和总生存期（OS）。在一小群接受化疗免疫疗法治疗的患者中，对术前活检和匹配的术后标本进行了Hippo通路的基因表达分析。
我们观察到接受化疗免疫疗法治疗的队列有更好的病理反应：12例患者中有6例（50.0%）达到MPR≤10%，12例中有1例（8.3%）在原发性肿瘤和淋巴结上均达到pCR。相反，单纯接受化疗的患者没有达到pCR或MPR≤10%。接受免疫化疗的患者在肿瘤床中观察到更高量的基质。此外，达到更好MPR（包括pCR）的患者的总生存期（OS）和无事件生存期（EFS）显著改善。新辅助化疗免疫疗法后，残留肿瘤显示与YAP/TAZ激活一致的基因显著上调。此外，替代检查点，如CTLA-4，也增强了。
我们的研究结果表明，新辅助化疗免疫疗法治疗可改善MPR和pCR，从而带来更好的EFS和OS。此外，与单纯化疗相比，联合治疗可能会诱导不同形态和分子变化，从而为病理反应的评估提供新的见解。
