Next Generation Sequencing of Reactive Stroma and Residual Breast Cancer Cells in Tumor Bed after Neoadjuvant Chemotherapy

Abstract

Primary systemic or neoadjuvant chemotherapy of breast cancer has become a standard therapy option in locally advanced or predefined intrinsic subtypes such as triple negative or Her2 positive breast cancer. Neoadjuvant chemotherapy can result in complete pathological response without residual tumor cells (tumor bed) or partial response and non-response with different amounts of reactive stroma and residual tumor cells. The interaction between therapy regimens and tumoral driver mutations have been extensively studied, although the reactive stroma of the tumor bed received less attention. In this study, we characterized the mutational status of residual breast cancer cells and reactive tumor stroma devoid of residual tumor cells in partial or non-responders using next generation sequencing. Twenty-one post-therapeutic breast surgical specimens after neoadjuvant chemotherapy underwent pathogenic driver-mutation screening using microdissected residual breast cancer cells and in reactive stroma adjacent to tumor bed areas. In reactive stroma, no mutations could be validated. In residual breast cancer cells, mutations were detected in sixteen of twenty-one cases (76%). In nine of these twenty-one cases (43%), pathogenic driver mutations (PIK3CA, PTEN, TP53, FN1, PLAG1) were identified. Pathogenic driver-mutations are exclusively restricted to residual carcinoma cells and are absent in reactive stroma independently from intrinsic breast cancer subtypes or tumor stage. These data suggest that the absence of pathogenic mutations in a tumor bed without residual tumor cells may have prognostic implications after neoadjuvant chemotherapy.

Neoadjuvant immunotherapy combined with chemotherapy in the treatment of stage III lung squamous cell carcinoma: a retrospective cohort study

“…The term “pathological complete response” (pCR) refers to the absence of any viable tumor cells upon examination of H&E slides following a comprehensive assessment of a surgically removed lung cancer specimen, which includes the evaluation of all sampled regional lymph nodes ( 21 ). The concept of pathological partial response (pPR) was established to describe a condition when the proportion of live tumor cells within the treated tumor bed is equal to or less than 50% ( 22 ). The term “pathological non-response” (pNR) was operationally defined as the presence of live tumor cells occupying more than 50% of the tumor bed ( 22 ).…”

“…The concept of pathological partial response (pPR) was established to describe a condition when the proportion of live tumor cells within the treated tumor bed is equal to or less than 50% ( 22 ). The term “pathological non-response” (pNR) was operationally defined as the presence of live tumor cells occupying more than 50% of the tumor bed ( 22 ).…”