Second-Harmonic Generation Imaging Reveals Changes in Breast Tumor Collagen Induced by Neoadjuvant Chemotherapy

Abstract

Breast cancer is the most common invasive cancer in women, with most deaths attributed to metastases. Neoadjuvant chemotherapy (NACT) may be prescribed prior to surgical removal of the tumor for subsets of breast cancer patients but can have diverse undesired and off-target effects, including the increased appearance of the ‘tumor microenvironment of metastasis’, image-based multicellular signatures that are prognostic of breast tumor metastasis. To assess whether NACT can induce changes in two other image-based prognostic/predictive signatures derived from tumor collagen, we quantified second-harmonic generation (SHG) directionality and fiber alignment in formalin-fixed, paraffin-embedded sections of core needle biopsies and primary tumor excisions from 22 human epidermal growth factor receptor 2-overexpressing (HER2+) and 22 triple-negative breast cancers. In both subtypes, we found that SHG directionality (i.e., the forward-to-backward scattering ratio, or F/B) is increased by NACT in the bulk of the tumor, but not the adjacent tumor-stroma interface. Overall collagen fiber alignment is increased by NACT in triple-negative but not HER2+ breast tumors. These results suggest that NACT impacts the collagenous extracellular matrix in a complex and subtype-specific manner, with some prognostic features being unchanged while others are altered in a manner suggestive of a more metastatic phenotype.

In vivo label-free optical signatures of chemotherapy response in human pancreatic ductal adenocarcinoma patient-derived xenografts

“…• High alignment in collagen is associated with worse survival in ex vivo human PDAC samples 50 . • More aligned collagen is associated with better response to therapy in ex vivo breast cancer 47 . • Collagen in the canine ex vivo mammary tumor has a higher alignment ratio than in the tumor margin 23 .…”

“… Image metric Metric implications Demonstrated relevance in cancer imaging SHG intensity SHG intensity increases with collagen content and can indicate changes in the collagen fiber internal structure. • SHG of collagen in ex vivo human breast cancer shows differences between tumor bulk and tumor-stroma interfaces and differences before and after neoadjuvant chemotherapy 47 . • PDAC shows significantly more SHG from collagen than normal pancreatic cancer 48 .…”

“…• SHG of collagen in ex vivo human breast cancer shows differences between tumor bulk and tumor-stroma interfaces and differences before and after neoadjuvant chemotherapy 47 .…”