A pan-tumor prospective translational, Irish study, investigating the association of gut microbiome (GM) diversity with pathological complete response (pCR) after neoadjuvant treatment in early stage breast, rectal, and esophageal cancers.
Authors: Cronin Christopher , Mc Laughlin Ronan Andrew , Devoy Ciaran , Moloney Carolyn , Fitzpatrick Orla , Mcmahon David , Conroy Michael R , O'Reilly David , Milewski Maciej , Egan Keith , Bennett Kathleen , Greally Megan , Murphy Adrian Gerard , Naidoo Jarushka , Morris Patrick G. , Breathnach Oscar S. , Grogan William , Toomey Sinead , Tangney Mark , Hennessy Bryan T. 
Published: June 2024

TPS3188 Background: The gut microbiome (GM) is thought to influence host immunity by modulating multiple immunologic pathways. Studies have suggested that dysbiosis of the GM confers a predisposition to certain malignancies and influences response to immune checkpoint inhibitors. However, little is known about how the GM diversity influences complete pathological response to neo-adjuvant therapy in gastrointestinal (GI) and breast tumors. We hypothesize that a more diverse GM constitution at baseline will lead to improved pathological response at the time of definitive surgery. Methods: This is a cross institutional multi-centre Irish translational study investigating the impact of the GM diversity on the efficacy of neo-adjuvant therapy in GI and breast cancers by assessing its association with pathological response. The study population includes pts with early-stage breast, rectal or esophageal cancers commencing neo-adjuvant therapy (including chemotherapy, immunotherapy and chemo-radiation) and planned for definitive surgery. Exclusion criteria include prior allogenic tissue/solid organ transplantation and prior receipt of anti-cancer therapy. The study assessments will include fecal sampling of the GM prior to neo-adjuvant therapy, upon completion and again six months post completion of therapy. Fecal samples will be analysed by 16S RNA sequencing. Pathological response will be examined at time of surgery and patients will be classified as responders (complete pathological response) or non-responders. The primary endpoint of the study is to examine the association between the GM diversity and pathological response. Exploratory analysis will include the assessment of the association between cf-DNA and the GM diversity as well as an assessment of the association between cf-DNA at baseline and pCR. 120 patients will be recruited over 18 months. Species richness (Alpha Diversity) will be analysed using the Shannon diversity index and Jaccard similarity index will be used to calculate beta diversity. Following planned study recruitment, classification and clustering analysis will be performed with Principal Component Analysis (PCA) and Random Forest analysis. To assess the primary endpoint the association between GM and complete pathological response will be examined using logistic regression analysis adjusting for potential confounding factors in the final statistical analysis. Adjusted odds ratios (OR) and 95% confidence intervals will be presented. This is expected to read out in early 2025. Recruitment is ongoing, with 14 pts recruited to date. We demonstrate that it is feasible to accrue to translational studies in Ireland and we have streamlined screening and recruitment pathways to improve our methodology and recruitment numbers.