Molecular correlates of response to eribulin and pembrolizumab in hormone receptor-positive metastatic breast cancer

Keenan, Tanya E.; Guerriero, Jennifer L.; Barroso‐Sousa, Romualdo; Li, Tianyu; O'Meara, Tess A.; Giobbie‐Hurder, Anita; Tayob, Nabihah; Hu, Jiani; Severgnini, Mariano; Agudo, Judith; Vaz-Luís, Inês; Anderson, Leilani; Attaya, Victoria; Park, Jihye; Conway, Jake R.; He, Meng Xiao; Reardon, Brendan; Shannon, Erin; Wulf, Gerburg M.; Spring, Laura; Jeselsohn, Rinath; Krop, Ian E.; Lin, Nancy U.; Partridge, Ann; Winer, Eric P.; Mittendorf, Elizabeth A.; Liu, David; Allen, Eliezer M. Van; Tolaney, Sara M.

doi:10.1038/s41467-021-25769-z

Cited by 28 publications

(20 citation statements)

References 96 publications

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“…Furthermore, in a mixed lymphocyte reaction assay, sintilimab increased interleukin-2 and interferong in a dose-dependent manner, similar to nivolumab; however, sintilimab did not induce cytokine release (8). Gene expression analyses evaluating the association between clinical outcome with sintilimab and a specific immune cell signature revealed that a longer PFS and/or OS was attained in patients who had a higher MHC-II-associated gene expression (10), which has also been previously observed with pembrolizumab and nivolumab (21,22). This potentially implicates antigen presentation pathways, such as MHC-II pathway, in the mechanism of action and a crucial component to attain clinical benefit from sintilimab combination therapy (10).…”

Section: Mechanism Of Action and Class Effect Of Anti-pd-1/pd-l1 Inhi...supporting

confidence: 73%

The Applicability of the Results in the Asian Population of ORIENT-11 to a Western Population According to the ICH-E5 Framework

et al. 2022

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Sintilimab combined with pemetrexed and platinum met the primary endpoint of improving progression-free survival (PFS) as a first-line therapy for nonsquamous non-small cell lung cancer (NSCLC) in the phase 3 trial ORIENT-11 (NCT03607539). As seen in similar trials, the addition of sintilimab, a PD-1 inhibitor, to chemotherapy improved the PFS without significantly worsening the toxicity, with improvements in response rate and duration of response. In contrast to previous trials, the ORIENT-11 trial was conducted completely in China. Both intrinsic and extrinsic factors are important to consider when reviewing foreign clinical trial data, as they may influence the efficacy and the safety outcomes. Here we discuss the applicability of ORIENT-11 clinical results to a Western population.

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Section: Mechanism Of Action and Class Effect Of Anti-pd-1/pd-l1 Inhi...supporting

confidence: 73%

The Applicability of the Results in the Asian Population of ORIENT-11 to a Western Population According to the ICH-E5 Framework

et al. 2022

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“…An apparent dysfunction in ovarian steroidogenesis has been shown to be associated with polycystic ovarian syndrome and plays a crucial role in its prognosis [ 47 , 48 ]. Researchers found that approximately 70% of invasive breast cancers have some degree of independence from the estrogen hormone for cell proliferation and growth [ 49 ], and Keenan et al found that estrogen signaling was independently associated with resistance in hormone-positive breast cancer [ 50 , 51 ]. These studies suggest that the dysfunction pathways identified by our study are partly associated with the development and progression of tumors.…”

Section: Resultsmentioning

confidence: 99%

Tumor Microenvironment Characterization in Breast Cancer Identifies Prognostic Pathway Signatures

Qiu

Han

et al. 2022

Genes

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Breast cancer is one of the most common female malignancies worldwide. Due to its early metastases formation and a high degree of malignancy, the 10 year-survival rate of metastatic breast cancer does not exceed 30%. Thus, more precise biomarkers are urgently needed. In our study, we first estimated the tumor microenvironment (TME) infiltration using the xCell algorithm. Based on TME infiltration, the three main TME clusters were identified using consensus clustering. Our results showed that the three main TME clusters cause significant differences in survival rates and TME infiltration patterns (log-rank test, p = 0.006). Then, multiple machine learning algorithms were used to develop a nine-pathway-based TME-related risk model to predict the prognosis of breast cancer (BRCA) patients (the immune-related pathway-based risk score, defined as IPRS). Based on the IPRS, BRCA patients were divided into two subgroups, and patients in the IPRS-low group presented significantly better overall survival (OS) rates than the IPRS-high group (log-rank test, p < 0.0001). Correlation analysis revealed that the IPRS-low group was characterized by increases in immune-related scores (cytolytic activity (CYT), major histocompatibility complex (MHC), T cell-inflamed immune gene expression profile (GEP), ESTIMATE, immune, and stromal scores) while exhibiting decreases in tumor purity, suggesting IPRS-low patients may have a strong immune response. Additionally, the gene-set enrichment analysis (GSEA) result confirmed that the IPRS-low patients were significantly enriched in several immune-associated signaling pathways. Furthermore, multivariate Cox analysis revealed that the IPRS was an independent prognostic biomarker after adjustment by clinicopathologic characteristics. The prognostic value of the IPRS model was further validated in three external validation cohorts. Altogether, our findings demonstrated that the IPRS was a powerful predictor to screen out certain populations with better prognosis in breast cancer and may serve as a potential biomarker guiding clinical treatment decisions.

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“…In the TAPUR and NIMBUS studies, a subset of patients with MBC and high tTMB across subtypes were durable responders (31,53). However, in other non-biomarker selected populations, there has been no improvement in outcomes when adding ICI to chemotherapy (54). For this reason, evaluating the potential of incorporating ICI for HR+/HER2-negative patients with high bTMB, either as monotherapy or in combination, is needed.…”

Section: Discussionmentioning

confidence: 99%

Genomic Complexity Predicts Resistance to Endocrine Therapy and CDK4/6 Inhibition in Hormone Receptor–Positive (HR+)/HER2-Negative Metastatic Breast Cancer

Davis

Luo

Zheng³

et al. 2023

Clinical Cancer Research

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Purpose: Clinical biomarkers to identify patients unlikely to benefit from CDK4/6 inhibition (CDK4/6i) in combination with endocrine therapy (ET) are lacking. We implemented a comprehensive circulating tumor DNA (ctDNA) analysis to identify genomic features for predicting and monitoring treatment resistance. Experimental Design: ctDNA was isolated from 216 plasma samples collected from 51 patients with hormone receptor-positive (HR+)/HER2-negative (HER2-) metastatic breast cancer (MBC) on a phase II trial of palbociclib combined with letrozole or fulvestrant (NCT03007979). Boosted whole exome sequencing (WES) was performed at baseline and clinical progression to evaluate genomic alterations, mutational signatures, and blood tumor mutational burden (bTMB). Low-pass whole-genome sequencing was performed at baseline and serial timepoints to assess blood copy number burden (bCNB). Results: High bTMB and bCNB were associated with lack of clinical benefit and significantly shorter progression-free survival (PFS) compared to patients with low bTMB or low bCNB (all P<0.05). Dominant APOBEC signatures were detected at baseline exclusively in cases with high bTMB (5/13, 38.5%) vs. low bTMB (0/37, 0%) (P=0.0006). Alterations in ESR1 were enriched in samples with high bTMB (P=0.0005). There was a high correlation between bTMB determined by WES and bTMB determined using a 600-gene panel (R=0.98). During serial monitoring, an increase in bCNB scores preceded radiographic progression in 12/18 (66.7%) patients. Conclusions: Genomic complexity detected by non-invasive profiling of bTMB and bCNB predicted poor outcomes in patients treated with ET and CDK4/6i and identified early disease progression before imaging. Novel treatment strategies including immunotherapy-based combinations should be investigated in this population.

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Molecular correlates of response to eribulin and pembrolizumab in hormone receptor-positive metastatic breast cancer

Cited by 28 publications

References 96 publications

The Applicability of the Results in the Asian Population of ORIENT-11 to a Western Population According to the ICH-E5 Framework

The Applicability of the Results in the Asian Population of ORIENT-11 to a Western Population According to the ICH-E5 Framework

Tumor Microenvironment Characterization in Breast Cancer Identifies Prognostic Pathway Signatures

Genomic Complexity Predicts Resistance to Endocrine Therapy and CDK4/6 Inhibition in Hormone Receptor–Positive (HR+)/HER2-Negative Metastatic Breast Cancer

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