The immune microenvironment of early stage oestrogen receptor positive, HER 2 negative breast cancer - impact on prognosis and prognostic signature performance
Tumour infiltrating lymphocytes (TILs) have been studied in numerous solid tumours as a surrogate marker of the immune system’s anti-tumour response. Increasing evidence suggests that TILs are both predictive of chemotherapy benefit and prognostic of improved survival in a number of cancer types.
The hormone positive, HER2 negative breast cancer subtype, is seen in approximately 70% of breast cancer diagnoses. However, the role of TILs in hormone positive/HER 2 negative breast cancer is unclear, partly due to a paucity of research in this tumour type which has traditionally been considered less immunogenic. While immune checkpoint inhibitors are now being used in triple negative breast cancer as standard of care, treatment for hormone positive breast cancer is still focused on cytotoxic chemotherapy and hormone blocking endocrine therapy.
In this research project, we explore the role of TILs in a cohort of early stage, hormone positive, HER2 negative breast cancer patients, with consideration of immune spatial phenotypes and TIL subpopulations using multiplex immunohistochemistry and digital image analysis.
Full face sections from 409 individual patients, with early stage hormone positive, HER2 negative breast cancer samples were stained with anti-CD45 antibody to identify immune cells. Digital image analysis of 409 slides showed that the majority of patients; 87% (n=367); had a low amount of immune cells, comprising less than 10% of total cells. Higher TILs numbers (>10%) were statistically more likely to have high Oncotype Dx recurrence scores. There was no statistically significant difference in disease free survival between the high and low TIL group on multivariate analysis (p = 0.713. HR 0.85, 95% CI 0.358-2.02).
Further digital image analysis was done to divide the cohort into three separate spatial phenotypes, Immune-Hot, Immune-Excluded and Immune-Cold. The Immune-Hot phenotype had a worse disease free survival (p =0.019, HR 3.1, 95% CI 1.36 –7.1). Multiplex immunohistochemistry was done to examine for immune subpopulations in particular, the presence of tertiary lymphoid structures (TLS). There was no statistically significant difference in relapse free survival between those with TLS immune infiltrate and those without (p=0.684, HR 1.2, 95% CI 0.46 –3.2).
Overall this study adds weight to the growing evidence that TILs may represent a negative prognostic marker in hormone positive, HER2 negative breast cancer, in contrast to other breast cancer subtypes.
History
First Supervisor
Prof. Darran O’ConnorSecond Supervisor
Prof. Catherine KellyComments
Submitted for the Award of Doctor of Medicine to RCSI University of Medicine and Health Sciences, 2024Published Citation
Lucas MW,. The immune microenvironmnet of early stage oestrogen receptor positive, HER 2 negative breast cancer - impact on prognosis and prognostic signature performance. [MD Thesis] Dublin: RCSI University of Medicine and Health Sciences; 2024Degree Name
- Doctor of Medicine (MD)
Date of award
2024-05-31Programme
- Doctor of Medicine (MD)