Biomarkers of neoadjuvant/adjuvant chemotherapy for breast cancer Takayuki Iwamoto, Yukiko Kajiwara, Yidan Zhu, Shigemichi Iha

Trastuzumab-emtansine (T-DM1) is a therapeutic agent molecularly targeting human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC), and it is especially effective for MBC with resistance to trastuzumab. Although several reports have described T-DM1 resistance, few have examined the mechanism underlying T-DM1 resistance after the development of acquired resistance to trastuzumab. We previously reported that YES1, a member of the Src family, plays an important role in acquired resistance to trastuzumab in HER2-amplified breast cancer cells. We newly established a trastuzumab/T-DM1-dual-resistant cell line and analyzed the resistance mechanisms in this cell line. At first, the T-DM1 effectively inhibited the YES1-amplified trastuzumab-resistant cell line, but resistance to T-DM1 gradually developed. YES1 amplification was further enhanced after acquired resistance to T-DM1 became apparent, and the knockdown of the YES1 or the administration of the Src inhibitor dasatinib restored sensitivity to T-DM1. Our results indicate that YES1 is also strongly associated with T-DM1 resistance after the development of acquired resistance to trastuzumab, and the continuous inhibition of YES1 is important for overcoming resistance to T-DM1.

Breast cancer is the leading cause of cancer-related morbidity and mortality among women worldwide, with bone being the most common site of all metastatic breast cancer. Bone metastases are often associated with pain and skeletal-related events (SREs), indicating poor prognosis and poor quality of life. Most current therapies for breast cancer bone metastasis primarily serve palliative purposes, focusing on pain management, mitigating the risk of bone-related complications, and inhibiting tumor progression. The emergence of nanodelivery systems offers novel insights and potential solutions for the diagnosis and treatment of breast cancer-related bone metastasis. This article reviews the recent advancements and innovative applications of nanodrug delivery systems in the context of breast cancer bone metastasis and explores future directions in nanotheranostics.

BackgroundPrevious studies of immune-related gene signatures (IGSs) in breast cancer have attempted to predict the response to chemotherapy or prognosis and were performed using different patient cohorts. The purpose of this study was to evaluate the predictive functions of various IGSs using the same patient cohort that included data for response to chemotherapy as well as the prognosis after surgery.MethodsWe applied five previously described IGS models in a public dataset of 508 breast cancer patients treated with neoadjuvant chemotherapy. The prognostic and predictive values of each model were evaluated, and their correlations were compared.ResultsWe observed a high proportion of expression concordance among the IGS models (r: 0.56-1). Higher gene expression scores of IGSs were detected in aggressive breast cancer subtypes (basal and HER2-enriched) (P < 0.001). Four of the five IGSs could predict chemotherapy responses and two could predict 5-year relapse-free survival in cases with hormone receptor-positive (HR+) tumors. However, the models showed no significant differences in their predictive abilities for hormone receptor-negative (HR-) tumors.ConclusionsIGSs are, to some extent, useful for predicting prognosis and chemotherapy response; moreover, they show substantial agreement for specific breast cancer subtypes. However, it is necessary to identify more compelling biomarkers for both prognosis and response to chemotherapy in HR- and HER2+ cases.