2162 - Revealing Sex-Specific Treatment Outcomes and Molecular Signatures in Locally Advanced Rectal Cancer Patients Treated with Neoadjuvant Chemoradiotherapy: Implications for Personalized Therapy
Presenter(s)
N. Milan1, F. Navarria2, E. De Mattia1, L. Scarabel1, A. Giacomin1, R. Innocente2, M. Mascarin3, M. Gigante2, M. de Scordilli4, R. Cannizzaro5,6, V. Canzonieri7,8, C. Belluco9, A. Lauretta9, I. Molineris10, F. Ferrero10, M. Montico11, and E. Cecchin1; 1Experimental and Clinical Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, 33081, Pn, Italy, 2Department of Radiation Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, 33081, Pn, Italy, 3Department of Radiation Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy, 4Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, 33081, Pn, Italy, 5Oncological Gastroenterology Unit, Centro di Riferimento Oncologico Aviano (CRO) IRCCS, Aviano, 33081, Pn, Italy, 6Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, 34129, Italy, 7Pathology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy, 8Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy, 9Surgical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, 33081, Pn, Italy, 10Department of Life Sciences and Systems Biology, University of Torino, Torino, 10126, Italy, 11Clinical Trial Office, Scientific Direction, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, 33081, Pn, Italy
Purpose/Objective(s): Sex-related biological differences are increasingly recognized in oncology but remain largely under integrated into rectal cancer management. Recent evidence has suggested differential responses to neoadjuvant chemoradiotherapy (nCRT) between male and female patients with locally advanced rectal cancer (LARC). We investigated whether sex-specific tumor molecular features contribute to differential treatment response in patients with LARC
Materials/Methods:
A clinically homogeneous retrospective cohort of 99 patients, 41 women and 58 men, with LARC treated with fluoropyrimidine-based nCRT (RT dose 45-55Gy) was analyzed. Sex-specific differences in treatment response, clinical features, toxicity, and tumor mutational profiles were analyzed using targeted NGS on FFPE biopsy at diagnosis. Complete response (CR) was defined as clinical or pathological complete response. Treatment intensity was calculated as the percentage of the planned chemotherapy or radiotherapy dose delivered over the entire treatment course. Categorical variables were compared using Fisher’s exact test, and continuous variables using the Mann–Whitney test.Results:
Female patients exhibited significantly lower response rates compared with males (20% vs. 43%, p=0.0176), despite similar baseline clinical characteristics and treatment regimens. Molecular profiling revealed distinct sex-specific patterns: KRAS mutations were more frequent in women (51% vs. 29%, p=0.036), while NRAS alterations (10% vs. 0%, p=0.027) were observed exclusively in females, suggesting greater involvement of the RTK–RAS signaling pathway (68% vs. 43%, p=0.015). At the pathway level, RTK–RAS alterations were associated with a trend toward reduced sensitivity to neoadjuvant therapy, as complete response was achieved in 42% of wild-type patients compared with 25% of those harboring mutations (p=0.0859). Women also experienced treatment-related adverse events more frequently than men (90% vs. 72%, p = 0.0421), including a higher incidence of clinically relevant toxicities (12% vs. 2%, p = 0.0399). Despite the higher toxicity burden, females maintained comparable treatment intensity.Conclusion:
Sex-specific tumor biology, particularly RTK–RAS pathway dysregulation, may underlie differential responses to nCRT in LARC. In this rigorously selected and uniformly treated cohort, female patients experienced lower response and higher treatment-related toxicity rates compared with males, despite comparable therapeutic exposure. These findings suggest that intrinsic biological mechanisms, potentially involving dysregulation of the RTK–RAS pathway, may contribute to sex-specific treatment responses, and underscore the clinical importance of incorporating sex as a biological variable in assessing therapeutic efficacy and managing toxicity.