Resistance to neoadjuvant chemotherapy in triple-negative breast cancer mediated by a reversible drug-tolerant state

Abstract

Eradicating triple negative breast cancer (TNBC) resistant to neoadjuvant chemotherapy (NACT) is a critical unmet clinical need. In this study, patient-derived xenograft (PDX) models of treatment-naïve TNBC and serial biopsies from TNBC patients undergoing NACT were used to elucidate mechanisms of chemoresistance in the neoadjuvant setting. Barcode-mediated clonal tracking and genomic sequencing of PDX tumors revealed that residual tumors remaining after treatment with standard front-line chemotherapies, doxorubicin (Adriamycin) combined with cyclophosphamide (AC), maintained the subclonal architecture of untreated tumors yet their transcriptomes, proteomes, and histologic features were distinct from those of untreated tumors. Once treatment was halted, residual tumors gave rise to AC-sensitive tumors with similar transcriptomes, proteomes, and histological features to those of untreated tumors. Taken together, these results demonstrated that tumors can adopt a reversible drug-tolerant state that does not involve clonal selection as an AC resistance mechanism. Serial biopsies obtained from patients with TNBC undergoing NACT revealed similar histologic changes as well as maintenance of stable subclonal architecture, demonstrating that AC-treated PDXs capture molecular features characteristic of human TNBC chemoresistance. Finally, pharmacologic inhibition of oxidative phosphorylation using an inhibitor currently in phase I clinical development delayed residual tumor regrowth. Thus, AC resistance in treatment-naïve TNBC can be mediated by non-selective mechanisms that confer a reversible chemotherapy-tolerant state with targetable vulnerabilities.

Molecular profiles of BRCA1‐associated ovarian cancer treated by platinum‐based therapy: Analysis of primary, residual and relapsed tumors

“…These mechanisms may include activation of drug efflux mechanisms, global expression reprogramming of cancer cells, exhaustion of antitumor immunity, etc. [32][33][34] In conclusion, our study demonstrated plasticity of somatic BRCA1 status during the natural history of BRCA1-driven OC. This plasticity appears to play a central role in determining primary cancer development, response to systemic therapy and subsequent relapse.…”

Dietary Compound Isoliquiritigenin, an Antioxidant from Licorice, Suppresses Triple-Negative Breast Tumor Growth via Apoptotic Death Program Activation in Cell and Xenograft Animal Models

“…Triple-negative breast cancer cells have been reported to exhibit genetic and phenotypical shifts in subpopulations, leading to resistance to the available standard drugs [29,30]. However, the functional differences made by genomically heterogeneous triple-negative breast cancer cells to chemoresistance remain poorly understood [31]. Natural ingredients from plants are widely explored to identify their availability for application in patients with breast cancer as an adjuvant approach [32].…”

<p>Pretreatment Systemic Inflammation Response Index in Patients with Breast Cancer Treated with Neoadjuvant Chemotherapy as a Useful Prognostic Indicator</p>

“…8 According to the NACT for breast cancer, the breast-conserving surgery rate is increasing, and the tumor stage is decreasing. 9 Many NACT regimens have been applied to the treatment for breast cancer; however, there are no internationally generally accepted NACT regimens for patients with advanced breast carcinoma. 10 Therefore, it is necessary to look for accurate and sensitive tumor indicators of breast cancer to improve the survival outcome and provide the better prognosis factor for breast cancer.…”