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PURPOSE: Triple-negative breast cancer (TNBC) is a heterogenous disease that carries the poorest prognosis of all breast cancers. Although novel TNBC therapies in development are frequently targeted towards tumors carrying a specific genomic, transcriptomic, or protein biomarker, how these biomarkers are correlated is poorly understood. EXPERIMENTAL DESIGN: To better understand the molecular features of TNBC and their correlation with one another, we performed multi-modal profiling on a cohort of 95 TNBCs. Our approach involved quantifying tumor-infiltrating lymphocytes through H&E staining, assessing the abundance of retinoblastoma (Rb), androgen receptor (AR), and PD-L1 proteins through immunohistochemistry, and carrying out transcriptomic profiling using the Nanostring BC360 platform, targeted DNA sequencing on a subset of cases, as well as evaluating associations with overall survival. RESULTS: Levels of RB1 mRNA and RB protein are better correlated with markers of Rb functionality than is RB1 mutational status. Luminal AR tumors clustered into two groups with transcriptomes that cluster with either basal or mesenchymal tumors. Tumors classified as PD-L1-positive by presence of immune or tumor cells showed similar biological characteristics. HER2-low TNBC showed no distinct biological phenotype when compared to HER2-zero. The majority of TNBCs classified as basal or HER2-enriched by PAM50, the latter showing significantly improved overall survival. CONCLUSIONS: Our study contributes new insights into biomarker utility for identifying suitable TNBC therapies and the intercorrelations between genomic, transcriptomic, protein, and cellular biomarkers. Additionally, our rich data resource can be used by other researchers to explore the interplay between DNA, RNA, and protein biomarkers in TNBC.
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PURPOSE: The antibody-drug conjugate (ADC) sacituzumab govitecan (SG) comprises the topoisomerase 1 (TOP1) inhibitor (TOP1i) SN-38, coupled to a monoclonal antibody targeting trophoblast cell surface antigen 2 (TROP-2). Poly(ADP-ribose) polymerase (PARP) inhibition may synergize with TOP1i and SG, but previous studies combining systemic PARP and TOP1 inhibitors failed due to dose-limiting myelosuppression. Here, we assess the proof-of-mechanism and clinical feasibility for SG and talazoparib (TZP) employing an innovative sequential dosing schedule. PATIENTS AND METHODS: In vitro models tested pharmacodynamic endpoints, and in a phase 1b clinical trial (NCT04039230), 30 patients with metastatic triple-negative breast cancer (mTNBC) received SG and TZP in a concurrent (N = 7) or sequential (N = 23) schedule. Outcome measures included safety, tolerability, preliminary efficacy, and establishment of a recommended phase 2 dose. RESULTS: We hypothesized that tumor-selective delivery of TOP1i via SG would reduce nontumor toxicity and create a temporal window, enabling sequential dosing of SG and PARP inhibition. In vitro, sequential SG followed by TZP delayed TOP1 cleavage complex clearance, increased DNA damage, and promoted apoptosis. In the clinical trial, sequential SG/TZP successfully met primary objectives and demonstrated median progression-free survival (PFS) of 7.6 months without dose-limiting toxicities (DLT), while concurrent dosing yielded 2.3 months PFS and multiple DLTs including severe myelosuppression. CONCLUSIONS: While SG dosed concurrently with TZP is not tolerated clinically due to an insufficient therapeutic window, sequential dosing of SG followed by TZP proved a viable strategy. These findings support further clinical development of the combination and suggest that ADC-based therapy may facilitate novel, mechanism-based dosing strategies.
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Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Camptotecina , Imunoconjugados , Inibidores de Poli(ADP-Ribose) Polimerases , Inibidores da Topoisomerase I , Humanos , Feminino , Imunoconjugados/administração & dosagem , Imunoconjugados/uso terapêutico , Imunoconjugados/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Pessoa de Meia-Idade , Anticorpos Monoclonais Humanizados/administração & dosagem , Camptotecina/análogos & derivados , Camptotecina/administração & dosagem , Camptotecina/uso terapêutico , Idoso , Inibidores da Topoisomerase I/administração & dosagem , Inibidores da Topoisomerase I/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Adulto , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Ftalazinas/administração & dosagem , Linhagem Celular Tumoral , DNA Topoisomerases Tipo I/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Antígenos de Neoplasias/imunologia , Moléculas de Adesão CelularRESUMO
PURPOSE: Cyclin-dependent kinase (CDK) 4/6 inhibitors (CDK4/6is) are an important component of treatment for hormone receptor-positive/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC), but it is not known if patients might derive benefit from continuation of CDK4/6i with endocrine therapy beyond initial tumor progression or if the addition of checkpoint inhibitor therapy has value in this setting. METHODS: The randomized multicenter phase II PACE trial enrolled patients with hormone receptor-positive/HER2- MBC whose disease had progressed on previous CDK4/6i and aromatase inhibitor (AI) therapy. Patients were randomly assigned 1:2:1 to receive fulvestrant (F), fulvestrant plus palbociclib (F + P), or fulvestrant plus palbociclib and avelumab (F + P + A). The primary end point was investigator-assessed progression-free survival (PFS) in patients treated with F versus F + P. RESULTS: Overall, 220 patients were randomly assigned between September 2017 and February 2022. The median age was 57 years (range, 25-83 years). Most patients were postmenopausal (80.9%), and 40% were originally diagnosed with de novo MBC. Palbociclib was the most common previous CDK4/6i (90.9%). The median PFS was 4.8 months on F and 4.6 months on F + P (hazard ratio [HR], 1.11 [90% CI, 0.79 to 1.55]; P = .62). The median PFS on F + P + A was 8.1 months (HR v F, 0.75 [90% CI, 0.50 to 1.12]; P = .23). The difference in PFS with F + P and F + P + A versus F was greater among patients with baseline ESR1 and PIK3CA alterations. CONCLUSION: The addition of palbociclib to fulvestrant did not improve PFS versus fulvestrant alone among patients with hormone receptor-positive/HER2- MBC whose disease had progressed on a previous CDK4/6i plus AI. The increased PFS seen with the addition of avelumab warrants further investigation in this patient population.
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Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Inibidores da Aromatase , Neoplasias da Mama , Quinase 4 Dependente de Ciclina , Quinase 6 Dependente de Ciclina , Fulvestranto , Piperazinas , Piridinas , Receptor ErbB-2 , Receptores de Estrogênio , Receptores de Progesterona , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias da Mama/mortalidade , Piridinas/uso terapêutico , Piperazinas/uso terapêutico , Inibidores da Aromatase/uso terapêutico , Pessoa de Meia-Idade , Fulvestranto/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Idoso , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Receptores de Estrogênio/metabolismo , Receptores de Estrogênio/análise , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Adulto , Receptor ErbB-2/metabolismo , Receptores de Progesterona/metabolismo , Anticorpos Monoclonais Humanizados/uso terapêutico , Idoso de 80 Anos ou mais , Progressão da Doença , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Intervalo Livre de ProgressãoRESUMO
PURPOSE: The time required for in-clinic drug administration can substantially affect breast cancer patients' quality of life. Subcutaneous (SC) drug administration, as opposed to intravenous (IV), may reduce this time commitment. This study sought to estimate the difference in time burden between IV and SC administration of trastuzumab and pertuzumab (HP). METHODS: We prospectively enrolled a subcohort of patients participating in the ADEPT trial (ClinicalTrials.gov identifier: NCT04569747, investigating adjuvant HP plus endocrine therapy for stage I human epidermal growth factor receptor 2-positive breast cancer) to this single-arm crossover time and motion substudy. Patients received two cycles of IV HP followed by two cycles of SC HP. During each cycle, time points in drug preparation and administration were captured. The primary end point was total patient time in the treatment chair. Additional end points included total patient treatment experience time and total pharmacy workflow time. A sample size of 22 patients was estimated to provide 90.7% power with two-sided alpha .05 to detect a difference of 70 minutes in the primary end point by treatment arm (IV v SC). RESULTS: Twenty-two patients were enrolled. The mean total patient time in the treatment chair was 61.8 minutes shorter with SC versus IV HP (22.5 v 84.3 minutes; P < .0001). The mean total patient treatment experience time (incorporating time spent waiting for treatment initiation and time spent in the treatment chair) was 81.8 minutes shorter for SC administration (96 v 177.8 minutes; P < .0001). The pharmacy workflow time was 78.2 minutes shorter for SC versus IV formulation (41 v 119.2 minutes; P < .0001). CONCLUSION: SC administration of HP shortened patient time burden by approximately 1 hour. SC drug administration can facilitate faster workflows for health care professionals and improve patients' breast cancer treatment experience.
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BACKGROUND: Preclinical and clinical data support potential synergy between anti-HER2 therapy plus immune checkpoint blockade. The safety and tolerability of trastuzumab emtansine (T-DM1) combined with pembrolizumab is unknown. METHODS: This was a single-arm phase Ib trial (registration date January 26, 2017) of T-DM1 plus pembrolizumab in metastatic, human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Eligible patients had HER2-positive, metastatic breast cancer previously treated with taxane, trastuzumab, and pertuzumab, and were T-DM1-naïve. A dose de-escalation design was used, with a dose-finding cohort followed by an expansion cohort at the recommended phase 2 dose (RP2D), with mandatory baseline biopsies. The primary endpoint was safety and tolerability. Secondary endpoints included objective response rate (ORR) and progression-free survival (PFS). Immune biomarkers were assessed using histology, protein/RNA expression, and whole exome sequencing. Associations between immune biomarkers and treatment response, and biomarker changes before and during treatment, were explored. RESULTS: 20 patients received protocol therapy. There were no dose-limiting toxicities. The RP2D was 3.6 mg/kg T-DM1 every 21 days plus 200 mg pembrolizumab every 21 days. 85% of patients experienced treatment-related adverse events (AEs) ≥grade 2, 20% of patients experienced grade 3 AEs, and no patients experienced grade >4 AEs. Four patients (20%) experienced pneumonitis (three grade 2 events; one grade 3 event). ORR was 20% (95% CI 5.7% to 43.7%), and median PFS was 9.6 months (95% CI 2.8 to 16.0 months). Programmed cell death ligand-1 and tumor infiltrating lymphocytes did not correlate with response in this small cohort. CONCLUSIONS: T-DM1 plus pembrolizumab was a safe and tolerable regimen. Ongoing trials will define if there is a role for checkpoint inhibition in the management of HER2-positive metastatic breast cancer. TRIAL REGISTRATION NUMBER: NCT03032107.
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Neoplasias da Mama , Ado-Trastuzumab Emtansina , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/patologia , Feminino , Humanos , Inibidores de Checkpoint Imunológico , Ligantes , RNA/uso terapêutico , Taxoides , Trastuzumab/efeitos adversosRESUMO
PURPOSE: In metastatic triple-negative breast cancer (mTNBC), consistent biomarkers of immune checkpoint inhibitor (ICI) therapy benefit remain elusive. We evaluated the immune, genomic, and transcriptomic landscape of mTNBC in patients treated with ICIs. METHODS: We identified 29 patients with mTNBC treated with pembrolizumab or atezolizumab, either alone (n = 9) or in combination with chemotherapy (n = 14) or targeted therapy (n = 6), who had tumor tissue and/or blood available before ICI therapy for whole-exome sequencing. RNA sequencing and CIBERSORTx-inferred immune population analyses were performed (n = 20). Immune cell populations and programmed death-ligand 1 expression were assessed using multiplexed immunofluorescence (n = 18). Clonal trajectories were evaluated via serial tumor/circulating tumor DNA whole-exome sequencing (n = 4). Association of biomarkers with progression-free survival and overall survival (OS) was assessed. RESULTS: Progression-free survival and OS were longer in patients with high programmed death-ligand 1 expression and tumor mutational burden. Patients with longer survival also had a higher relative inferred fraction of CD8+ T cells, activated CD4+ memory T cells, M1 macrophages, and follicular helper T cells and enrichment of inflammatory gene expression pathways. A mutational signature of defective repair of DNA damage by homologous recombination was enriched in patients with both shorter OS and primary resistance. Exploratory analysis of clonal evolution among four patients treated with programmed cell death protein 1 blockade and a tyrosine kinase inhibitor suggested that clonal stability post-treatment was associated with short time to progression. CONCLUSION: This study identified potential biomarkers of response to ICIs among patients with mTNBC: high tumor mutational burden; presence of CD8+, CD4 memory T cells, follicular helper T cells, and M1 macrophages; and inflammatory gene expression pathways. Pretreatment deficiencies in the homologous recombination DNA damage repair pathway and the absence of or minimal clonal evolution post-treatment may be associated with worse outcomes.
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Neoplasias de Mama Triplo Negativas , Biomarcadores Tumorais/genética , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Mutação , Intervalo Livre de Progressão , Neoplasias de Mama Triplo Negativas/tratamento farmacológicoRESUMO
Immune checkpoint inhibitors (ICIs) have minimal therapeutic effect in hormone receptor-positive (HR+ ) breast cancer. We present final overall survival (OS) results (n = 88) from a randomized phase 2 trial of eribulin ± pembrolizumab for patients with metastatic HR+ breast cancer, computationally dissect genomic and/or transcriptomic data from pre-treatment tumors (n = 52) for molecular associations with efficacy, and identify cytokine changes differentiating response and ICI-related toxicity (n = 58). Despite no improvement in OS with combination therapy (hazard ratio 0.95, 95% CI 0.59-1.55, p = 0.84), immune infiltration and antigen presentation distinguished responding tumors, while tumor heterogeneity and estrogen signaling independently associated with resistance. Moreover, patients with ICI-related toxicity had lower levels of immunoregulatory cytokines. Broadly, we establish a framework for ICI response in HR+ breast cancer that warrants diagnostic and therapeutic validation. ClinicalTrials.gov Registration: NCT03051659.