Commentary: Tumor biology remains the star of the show.

Central MessageTumor biology remains among the most important factors in determining a patient's response to treatment in esophageal squamous cell carcinoma.See Article page 888. Tumor biology remains among the most important factors in determining a patient's response to treatment in esophageal squamous cell carcinoma. See Article page 888. The theatre has come a long way from the time of William Shakespeare and has become less formal and more casual in speech and format. Similarly, surgery has come a long way from the time of William Halsted, becoming less invasive and destructive. However, despite numerous advances, tumor biology remains among the most important prognostic factors across all cancers. Cheng and colleagues1Cheng D. Kong M. Sun J. Yang H. Chen Y. Fang W. et al.Prognostic value of recurrence pattern in locally advanced esophageal squamous cell carcinoma: results from the phase III trial NEOCRTEC5010.J Thorac Cardiovasc Surg. 2023; 165: 888-897Abstract Full Text Full Text PDF Scopus (3) Google Scholar examine recurrence patterns in 353 patients with locally advanced esophageal squamous cell carcinoma (ESCC) who were enrolled in the Neoadjuvant Chemoradiotherapy Followed by Surgery Versus Surgery Alone for Locally Advanced Squamous Cell Carcinoma of the Esophagus (NEOCRTEC5010) trial. Patients were randomized to either neoadjuvant chemoradiation followed by surgery (NCRT), or surgery alone. The results reflect something that most surgeons anecdotally understand to be true: Tumors that recur after appropriate therapy have more aggressive biology, resulting in a worse prognosis. This seems to be especially true in patients who have received NCRT before surgical resection then experience early recurrence. The authors' conclusion that NCRT prolongs survival but is associated with worse prognosis in patients with recurrence, especially early recurrence, needs to be appreciated in the appropriate context. A tumor that recurred early after an aggressive multimodal approach was also likely to have recurred if that patient had received surgery alone. Simply receiving NCRT cannot be viewed as an independent risk factor for worse prognosis and outcomes; instead, individuals with aggressive tumors that recur despite NCRT are associated with worse prognosis and outcomes! Innate tumor aggressiveness matters. The authors also report that patients with <20 lymph nodes sampled, those who had surgery alone, and those with a higher tumor regression grade more commonly recurred. However, the truth is, the stage has already been set by the tumor's biology. Several studies have shown that genetic derangements, including MYC-gain mutations, are more prevalent in recurrent ESCCs and those that demonstrate resistance to chemotherapy and radiation.2Hirata H. Niida A. Kakiuchi N. Uchi R. Sugimachi K. Masuda T. et al.The evolving genomic landscape of esophageal squamous cell carcinoma under chemoradiotherapy.Cancer Res. 2021; 81: 4926-4938Crossref PubMed Scopus (9) Google Scholar Others have examined radiomics signatures obtained from fluorodeoxyglucose–positron emission tomography scans, attempting to identify patients with ESCC at higher risk of nonresponse to neoadjuvant therapy.3Li Y. Beck M. Päßler T. A FDG-PET radiomics signature detects esophageal squamous cell carcinoma patients who do not benefit from chemoradiation.Nature. 2020; 10: 17671Google Scholar Proteomic biomarkers that are upregulated in ESCCs, such as prosaposin, plectin 1 and protein disulfide isomerase A 4 have also been reported.4Pawar H. Kashyap M. Sashasrabuddhe N.A. Renuse S. Harsha H.C. Kumar P. et al.Quantitative tissue proteomics of esophageal squamous cell carcinoma for novel biomarker discovery.Cancer Biol Ther. 2011; 12: 510-522Crossref PubMed Scopus (95) Google Scholar These studies all aim to better understand and risk-stratify individual patients' innate tumor aggressiveness. Understanding this will ultimately allow clinicians to better determine who will benefit from more vigilant surveillance or additional neoadjuvant or adjuvant therapies. More likely than not, a multiomic approach, incorporating genomic, radiomic, and proteomic markers will be most informative as we continue the quest to understand each tumor's biology. Cheng and colleagues1Cheng D. Kong M. Sun J. Yang H. Chen Y. Fang W. et al.Prognostic value of recurrence pattern in locally advanced esophageal squamous cell carcinoma: results from the phase III trial NEOCRTEC5010.J Thorac Cardiovasc Surg. 2023; 165: 888-897Abstract Full Text Full Text PDF Scopus (3) Google Scholar should be congratulated for providing us with a foundation for future investigation aimed at improving the outcomes of patients with locally advanced ESCC. Prognostic value of recurrence pattern in locally advanced esophageal squamous cell carcinoma: Results from the phase III trial NEOCRTEC5010The Journal of Thoracic and Cardiovascular SurgeryVol. 165Issue 3PreviewThe prognosis of patients with locally advanced esophageal squamous cell carcinoma with different recurrence backgrounds is highly heterogeneous. This study aims to explore the effects of recurrence patterns on prognosis. Full-Text PDF