Plasma branched-chain amino acids and risk of radiation-induced acute skin toxicity in women with breast cancer: Results from the ATHENA project

Sukshma Sharma¹Francesca Bracone¹Augusto Di Castelnuovo¹Emilia Ruggiero¹Amalia De Curtis¹Chiara Cerletti¹Giovanni De Gaetano¹Francesco Deodato^2,3Gabriella Macchia³Mariangela Boccardi³Savino Cilla³Alessio Giuseppe Morganti⁴Fulvio Mattivi⁵Andrea Anesi⁵Katia Petroni⁶Chiara Tonelli⁶Donati Maria Benedetta¹Licia Iacoviello^1,7*Marialaura Bonaccio¹

• ¹Mediterranean Neurological Institute Neuromed (IRCCS), Pozzilli, Italy
• ²Universita Cattolica del Sacro Cuore - Campus di Roma, Rome, Italy
• ³Responsible SpA, Campobasso, Italy
• ⁴Department of Experimental, Diagnostic and Speciality Medicine – DIMES, Alma Mater Studiorum Bologna University, Bologna, Italy, bologna, Italy
• ⁵Fondazione Edmund Mach Centro Ricerca e Innovazione, San Michele all'Adige, Italy
• ⁶Universita degli Studi di Milano, Milan, Italy
• ⁷Universita LUM Giuseppe Degennaro, Casamassima, Italy

Background/Objectives: Little is known regarding the influence of circulating plasma branched-chain amino acids (BCAAs) such as leucine, isoleucine, and valine on acute skin toxicity (AST) after breast cancer (BC) radiotherapy. Hence, this study examined the association between circulating plasma BCAAs and the risk of > grade 2 AST post-radiotherapy among BC patients. Methods: An observational study was conducted among 161 BC patients treated with radiotherapy within the ATHENA project in Italy. Plasma BCAAs were measured at 2-time points: at baseline (T0) and at the end of radiotherapy (T1) (after 3 or 5 weeks), and were ascertained using a validated method based on tandem mass spectrometry. AST was measured at T1 and defined according to the Radiation Therapy Oncology Group/European Organization for Research and Treatment Cancer (RTOG/EORTC) criteria. Analysis was conducted in two parts with separate study designs using multivariable-adjusted logistic regression models: 1) A cross-sectional analysis explored the association between plasma BCAAs at T1 and odds of AST post-radiotherapy; 2) A prospective analysis examined the association between plasma BCAAs at T0 and odds of AST post-radiotherapy. Results: AST post-radiotherapy was observed in 45 (28%) patients. In the cross-sectional analysis, at T1, plasma isoleucine (1-SD increment) was associated with 43% reduced odds of > grade 2 AST post-radiotherapy (OR=0.57;95% CI 0.36 to 0.91). A similar trend was observed in the prospective analysis at T0 (OR=0.65;95% CI 0.42 to 1.02). There was no evidence of an association between plasma leucine and valine with AST post-radiotherapy, either at T0 or T1. Plasma isoleucine was associated with lower odds of AST post-radiotherapy in BC patients. Conclusions: The findings highlight that plasma isoleucine is associated with a low risk of > grade 2 AST post-radiotherapy among BC patients. However, further studies such as isoleucine supplementation trials are needed to validate these findings.