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Background Breast Cancer (BC) patients who do not obtain pathologic complete response (pCR) after neoadjuvant chemotherapy (NACT) present higher rate of relapse and worse overall survival. Recent evidence suggests that chemotherapy (CT) efficacy relies on the capacity of chemotherapeutic agents to interact with the immune system. BC features a unique tumor microenvironment (TME) comprising of multiple immune cell types including Macrophages that share a double-edged relationship with cancer as they get polarised from M1 (anti-tumour) to M2 (Pro-tumour). Pro-tumour M2 macrophages are referred to as tumor-associated macrophages (TAMs) and are implicated extensively in angiogenesis, metastasis and therapy resistance. Establishing role of TAMs, facilitates the emergence of novel strategies that exploit them as theranostic targets/tools of interest for treating cancer. Utility of using Drugs like Zoledronic Acid, Trabectedin, Rebastinib in combination with 5-fu have shown promising anti-TAM activity and improved response to CT in clinical trials. In this study, we have characterized presence of M2-TAM and its correlation to NACT response in matched primary and residual tumours by examining expression of several biomarkers. Methods Treatment naïve primary and their matched residual tumour specimens from 45 women treated at a single center were accessed through IERB approved protocols. The study included locally advanced HR+HER2-ve and TNBC tumours treated with standard NACT regimes between 2018 to 2020. To determine the association of TAM population with response to NACT, expression levels of CD68 (pan macrophage marker) & CD163 (marker of М2 macrophages), were detected by immunohistochemistry (IHC) and represented as combined H score. We also performed gene expression of chemokines, inflammatory cytokines and interleukins involved in M1-M2 polarization by q-RT-PCR. Residual Cancer Burden Scoring was used to assess response and patients were divided into three groups (complete responders, partial responders and non-responders). Univariate and multi variate analysis were performed between gene expression groups and IHC groups with clinicopathological parameters. Findings from this study was validated on public data bases like TCGA, METABRIC and GEO. Results: 20% of all patients included in the study were complete responders. We arrived at a Macrophage Polarisation Score (MPS) by Gene expression and also a combined H score by IHC. MPS and H-score had a positive correlation (p=0.083) overall. Interestingly, Combined analysis of H-Score and MPS with response to treatment showed a greater and statistically significant correlation with residual tumours as compared to treatment naïve tumours (p=0.009). We also observed that high MPS and high combined H score in residual tumours were associated with increased tumour size and LVI (p=0.055 and p=0.03). Other clinicopathological parameters like receptor status, grade and stage at diagnosis were not significantly associated with H score or MPS. Taken together we found that 11% of patients who exhibited high TAM score by both H sascore and MPS fell into the non-responders category. We therefore report TAMs in residual tumours being more indicative for response to therapy compared to primary tumours. Conclusion Although primary tumours are useful for building predictive models to therapy response, we have demonstrated that there is utility in examining residual tumours as well for choice to adjuvant chemotherapy, since the tumour is constantly evolving through the NACT period. More work to arrive at a “TAM score” that could aid in choice of additional adjuvant treatment strategies is underway. We believe our work is helping us to move one step closer to Precision Medicine in a low and middle income country like India that has a higher burden of locally advanced disease. Our analysis also lends itself to becoming a clinical test since it is performed on an FFPE specimen Citation Format: Lohita Krishna, Aruna Korlimarla, B S Srinath, Anugnya Ranjolkar, Sudipta Nascar, Hari PS, Durga Devi, Nidhi l, Rekha V Kumar. Tumour associated macrophages in Breast Cancer - Are they critical players in response to Neo Adjuvant Chemotherapy? [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-21-10. |
