Among patients with advanced breast cancer and a germline BRCA1/2 mutation, single-agent talazoparib provided a significant benefit over standard chemotherapy with respect to progression-free survival. Patient-reported outcomes were superior with talazoparib. (Funded by Medivation [Pfizer]; EMBRACA ClinicalTrials.gov number, NCT01945775 .).
There is a clinical need to predict sensitivity of metastatic hormone receptor-positive and HER2-negative (HR+/HER2−) breast cancer to endocrine therapy, and targeted RNA sequencing (RNAseq) offers diagnostic potential to measure both transcriptional activity and functional mutation. We developed the SET ER/PR index to measure gene expression microarray probe sets that were correlated with hormone receptors ( ESR1 and PGR ) and robust to preanalytical and analytical influences. We tested SET ER/PR index in biopsies of metastastic HR+/HER2− breast cancer against the treatment outcomes in 140 patients. Then we customized the SET ER/PR assay to measure 18 informative, 10 reference transcripts, and sequence the ligand-binding domain (LBD) of ESR1 using droplet-based targeted RNAseq, and tested that in residual RNA from 53 patients. Higher SET ER/PR index in metastatic samples predicted longer PFS and OS when patients received endocrine therapy as next treatment, even after adjustment for clinical-pathologic risk factors (PFS: HR 0.534, 95% CI 0.299 to 0.955, p = 0.035; OS: HR 0.315, 95% CI 0.157 to 0.631, p = 0.001). Mutated ESR1 LBD was detected in 8/53 (15%) of metastases, involving 1−98% of ESR1 transcripts (all had high SET ER/PR index). A signature based on probe sets with good preanalytical and analytical performance facilitated our customization of an accurate targeted RNAseq assay to measure both phenotype and genotype of ER-related transcription. Elevated SET ER/PR was associated with prolonged sensitivity to endocrine therapy in patients with metastatic HR+/HER2− breast cancer, especially in the absence of mutated ESR1 transcript.
Early phase trials targeting the T-cell inhibitory molecule PD-L1 have shown clinical efficacy in cancer. This study was undertaken to determine whether PD-L1 is overexpressed in triple-negative breast cancer (TNBC) and to investigate the loss of the phosphatase and tensin homolog (PTEN) as a mechanism of PD-L1 regulation. The Cancer Genome Atlas (TCGA) RNA sequencing data showed significantly greater expression of the PD-L1 gene in TNBC (n=120) compared to non-TNBC (n=716) (P<0.001). Breast tumor tissue microarrays were evaluated for PD-L1 expression which was present in 19% (20 of 105) TNBC specimens. PD-L1+ tumors had greater CD8+ T-cell infiltrate than PD-L1− tumors (688 cells/mm versus 263 cells/mm; P<0.0001). To determine the effect of PTEN loss on PD-L1 expression, stable cell lines were generated using PTEN shRNA. PTEN knockdown led to significantly higher cell-surface PD-L1 expression and PD-L1 transcripts, suggesting transcriptional regulation. Moreover, PI3K pathway inhibition using the AKT inhibitor MK-2206 or rapamycin resulted in decreased PD-L1 expression, further linking PTEN and PI3K signaling to PD-L1 regulation. Co-culture experiments were performed to determine the functional effect of altered PD-L1 expression. Increased PD-L1 cell surface expression by tumor cells induced by PTEN loss led to decreased T cell proliferation and increased apoptosis. PD-L1 is expressed in 20% of TNBC, suggesting PD-L1 as a therapeutic target in TNBC. Since PTEN loss is one mechanism regulating PD-L1 expression, agents targeting the PI3K pathway may increase the antitumor adaptive immune responses.
Purpose To explore whether a crosstalk exists between PARP inhibition and PD-L1/ PD-1 immune checkpoint axis, and determine if blockade of PD-L1/ PD-1 potentiates PARP inhibitor (PARPi) in tumor suppression. Experimental Design Breast cancer cell lines, xenograft tumors and syngeneic tumors treated with PARPi were assessed for PD-L1 expression by immunoblotting, immunohistochemistry and FACS analyses. The phospho-kinase antibody array screen was used to explore the underlying mechanism of PARPi-induced PD-L1 upregulation. The therapeutic efficacy of PARPi alone, PD-L1 blockade alone, or their combination was tested in syngeneic tumor model. The tumor-infiltrating lymphocytes and tumor cells isolated from syngeneic tumors were analyzed by CytoF and FACS to evaluate the activity of anti-tumor immunity in the tumor microenvironment. Results PARPis upregulated PD-L1 expression in breast cancer cell lines and animal models. Mechanistically, PARPi inactivated GSK3β, which in turn enhanced PARPi-mediated PD-L1 upregulation. PARPi attenuated anticancer immunity via upregulation of PD-L1, and blockade of PD-L1 re-sensitized PARPi-treated cancer cells to T cell killing. The combination of PARPi and anti-PD-L1 therapy compared with each agent alone significantly increased the therapeutic efficacy in vivo. Conclusion Our study demonstrates a crosstalk between PARPi and tumor-associated immunosuppression, and provides evidence to support the combination of PARPi and PD-L1 or PD-1 immune checkpoint blockade as a potential therapeutic approach to treat breast cancer.
Approximately 7% of women with breast cancer are diagnosed before the age of 40 years, and this disease accounts for more than 40% of all cancer in women in this age group. Survival rates are worse when compared to those in older women, and multivariate analysis has shown younger age to be an independent predictor of adverse outcome. Inherited syndromes, specifically BRCA1 and BRCA2, must be considered when developing treatment algorithms for younger women. Chemotherapy, endocrine, and local therapies have the potential to significantly impact both the physiologic health -including future fertility, premature menopause, and bone health-and the psychological health of young women as they face a diagnosis of breast cancer.Although a diagnosis of breast cancer is distressing at any age, this occurrence in young women is fraught with several unique challenges. This article reviews the distinct epidemiology, etiology, clinicopathologic characteristics, biology, treatment strategies, outcomes, and psychosocial challenges of breast cancer before 40 years of age. Also included in this review are issues of familial breast cancer, fertility, premature menopause, breast cancer during pregnancy, and bone health. The US Surveillance, Epidemiology and End Results (SEER) database was the source of data for the tables and graphs presented here. 1 EpidemiologyThe American Cancer Society (ACS) estimates that 182,460 women in the United States were diagnosed with breast cancer in 2008 and that 40,480 women died of the disease during the year. 2 The incidence of breast cancer appears to have a sigmoid function in women less than 55 years of age (Figure 1, lower panel), with 6.6% of all cases diagnosed before age 40, 2.4% diagnosed before age 35, and 1% diagnosed before age 30 (Figure 2, inset). The individual average risk of a woman developing breast cancer was 1 in 173 by the age of 40 and approximately 1 in 1,500 by the age of 30 (Table 1). Of all cancers diagnosed among women, more than 40% is breast cancer by the age of 40, 20% by the age of 30, and slightly more than 2% by 20 years of age (Figure 1, upper panel).
The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic focus primarily on assessment of pathogenic or likely pathogenic variants associated with increased risk of breast, ovarian, and pancreatic cancer and recommended approaches to genetic testing/counseling and management strategies in individuals with these pathogenic or likely pathogenic variants. This manuscript focuses on cancer risk and risk management for BRCA-related breast/ovarian cancer syndrome and Li-Fraumeni syndrome. Carriers of a BRCA1/2 pathogenic or likely pathogenic variant have an excessive risk for both breast and ovarian cancer that warrants consideration of more intensive screening and preventive strategies. There is also evidence that risks of prostate cancer and pancreatic cancer are elevated in these carriers. Li-Fraumeni syndrome is a highly penetrant cancer syndrome associated with a high lifetime risk for cancer, including soft tissue sarcomas, osteosarcomas, premenopausal breast cancer, colon cancer, gastric cancer, adrenocortical carcinoma, and brain tumors.
The NCCN Clinical Practice Guidelines in Oncology for Genetic/Familial High-Risk Assessment: Breast and Ovarian provide recommendations for genetic testing and counseling for hereditary cancer syndromes and risk management recommendations for patients who are diagnosed with a syndrome. Guidelines focus on syndromes associated with an increased risk of breast and/or ovarian cancer. The NCCN Genetic/Familial High-Risk Assessment: Breast and Ovarian panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. The NCCN Guidelines Insights summarize the panel's discussion and most recent recommendations regarding risk management for carriers of moderately penetrant genetic mutations associated with breast and/or ovarian cancer.
Metformin has been reported to possess antitumor activity and maintain high cytotoxic T lymphocyte (CTL) immune surveillance. However, the functions and detailed mechanisms of metformin's role in cancer immunity are not fully understood. Here, we show that metformin increases CTL activity by reducing the stability and membrane localization of programmed death ligand-1 (PD-L1). Furthermore, we discover that AMP-activated protein kinase (AMPK) activated by metformin directly phosphorylates S195 of PD-L1. S195 phosphorylation induces abnormal PD-L1 glycosylation, resulting in its ER accumulation and ER-associated protein degradation (ERAD). Consistently, tumor tissues from metformin-treated breast cancer patients exhibit reduced PD-L1 levels with AMPK activation. Blocking the inhibitory signal of PD-L1 by metformin enhances CTL activity against cancer cells. Our findings identify a new regulatory mechanism of PD-L1 expression through the ERAD pathway and suggest that the metformin-CTLA4 blockade combination has the potential to increase the efficacy of immunotherapy.
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