Temporal and spatial composition of the tumor microenvironment predicts response to immune checkpoint inhibition

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 28, 2025

Abstract Immune checkpoint inhibition (ICI) has fundamentally changed cancer treatment. However, only a minority of patients with metastatic triple negative breast (TNBC) benefit from ICI, and the determinants response remain largely unknown. To better understand factors influencing patient outcome, we assembled longitudinal cohort tissue multiple timepoints, including primary tumor, pre-treatment on-treatment tumor 117 treated ICI (nivolumab) in phase II TONIC trial. We used highly multiplexed imaging to quantify subcellular localization 37 proteins each tumor. extract meaningful information data, developed SpaceCat, computational pipeline that quantifies features data such as cell density, diversity, spatial structure, functional marker expression. applied SpaceCat 678 images 294 tumors, generating more than 800 distinct per Spatial were predictive like degree mixing between immune cells, diversity neighboring cells surrounding T infiltration at border. Non-spatial features, ratio subsets PD-L1 levels on myeloid also associated outcome. Surprisingly, did not identify robust predictors tumors. In contrast, tumors had numerous which predicted response. Some these cellular border, shared across but many single timepoint. trained multivariate models all dataset, finding could accurately predict outcome improved performance using validated our findings matched bulk RNA-seq most informative samples. Our study highlights importance profiling sequential biopsies evolution microenvironment, elucidating temporal dynamics underlying responses underscoring need for further research prognostic role its utility stratifying ICI.

Language: Английский

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Clinical implications of the intrinsic molecular subtypes in hormone receptor-positive and HER2-negative metastatic breast cancer

Cancer Treatment Reviews, Journal Year: 2022, Volume and Issue: 112, P. 102496 - 102496

Published: Dec. 9, 2022

Traditionally, the classification of breast cancer relies on expression immunohistochemical (IHC) biomarkers readily available in clinical practice. Using highly standardized and reproducible assays across patient cohorts, intrinsic molecular subtypes - also called "intrinsic subtypes" (IS) have been identified based 50 genes. Although IHC-based subgroups IS moderately correlate to each other, they are not superimposable. In fact, non-luminal biology has detected a substantial proportion (5–20%) hormone receptor-positive (HoR+) tumors, prognostic value, identifies reduced increased sensitivity endocrine therapy chemotherapy, respectively. During tumor progression, shift toward estrogen-independent more aggressive phenotype demonstrated. Intrinsic genomic instability cell plasticity, alone or combined with external constraints deriving from treatment selective pressure interplay microenvironment, may represent determinants such biological diversity between primary metastatic disease, during evolution. this review, we describe distribution behavior as disease progresses, focusing HoR+/HER2-negative advanced cancer. addition, provide an overview ongoing trials aiming validate predictive value towards their incorporation into routine care.

Language: Английский

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Comprehensive liquid biopsy analysis as a tool for the early detection of minimal residual disease in breast cancer

Scientific Reports, Journal Year: 2023, Volume and Issue: 13(1)

Published: Jan. 23, 2023

Abstract Liquid biopsy (LB) provides a unique minimally invasive tool to follow-up cancer patients over time, detect minimal residual disease (MRD), study metastasis-biology and mechanisms of therapy-resistance. Molecular characterization CTCs offers additionally the potential understand resistance therapy implement individualized targeted treatments which can be modified during evolution period patient. In this study, we present long-term operable breast based on comprehensive liquid analysis. We performed analysis in peripheral blood 13 with early-stage at several time points for ten years, consisting of: (a) CTC enumeration using CellSearch system, (b) phenotypic Immunofluorescence, (c) gene expression analysis, EpCAM (+) CK-19, CD24,CD44, ALDH1, TWIST1 , (d) PIK3CA ESR1 mutations corresponding plasma ctDNA (e) DNA methylation CTCs. 10/13 (77%) were found negative LB markers PB whole period, these did not relapse follow-up. However, 3/13(18%) that positive least one marker relapsed within period. The molecular characteristics highly different even same patient points, always increased before clinical relapse. Our results indicate reveal presence MRD 4 years appearance clinically detectable metastatic demonstrating important information therapeutic management patients.

Language: Английский

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Design of SERENA-6, a phase III switching trial of camizestrant in ESR1 -mutant breast cancer during first-line treatment

Future Oncology, Journal Year: 2023, Volume and Issue: 19(8), P. 559 - 573

Published: March 1, 2023

ESR1 mutation (ESR1m) is a frequent cause of acquired resistance to aromatase inhibitor (AI) plus cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i), which first-line therapy for hormone-receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC). Camizestrant next-generation oral selective estrogen degrader (SERD) that in phase II study significantly improved progression-free survival (PFS) over fulvestrant (also SERD) ER+/HER2- ABC. SERENA-6 (NCT04964934) randomized, double-blind, III evaluating the efficacy safety switching from an AI camizestrant, while maintaining same CDK4/6i, upon detection ESR1m circulating tumor DNA before clinical disease progression on HR+/HER2- The aim treat clones extend duration control ER-driven growth, delaying need chemotherapy. primary end point PFS; secondary points include chemotherapy-free survival, time second event (PFS2), overall patient-reported outcomes safety.

Language: Английский

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Cyclin-Dependent Kinase 4/6 Inhibitors for Treatment of Hormone Receptor–Positive, ERBB2-Negative Breast Cancer

JAMA Oncology, Journal Year: 2023, Volume and Issue: 9(9), P. 1273 - 1273

Published: June 29, 2023

Combination therapy with cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i: palbociclib, ribociclib, abemaciclib) endocrine (ET) has been a major advance for the treatment of hormone receptor-positive (HR+), ERBB2 (formerly HER2)-negative (ERBB2-) advanced or metastatic breast cancer.

Language: Английский

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Obesity-associated changes in molecular biology of primary breast cancer

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: July 21, 2023

Obesity is associated with an increased risk of developing breast cancer (BC) and worse prognosis in BC patients, yet its impact on biology remains understudied humans. This study investigates how the untreated primary differs according to patients' body mass index (BMI) using data from >2,000 patients. We identify several genomic alterations that are differentially prevalent overweight or obese patients compared lean report evidence supporting ageing accelerating effect obesity at genetic level. show BMI-associated differences bulk transcriptomic profile subtle, while single cell profiling allows detection more pronounced changes different compartments. These analyses further reveal elevated unresolved inflammation tumor microenvironment obesity, distinct characteristics contingent estrogen receptor status. Collectively, our imply inflammaging-like phenotype. conclude patient adiposity may play a significant role heterogeneity should be considered for treatment tailoring.

Language: Английский

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Emerging systemic therapy options beyond CDK4/6 inhibitors for hormone receptor-positive HER2-negative advanced breast cancer

npj Breast Cancer, Journal Year: 2023, Volume and Issue: 9(1)

Published: Sept. 8, 2023

Abstract Endocrine therapy (ET) with cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) is currently the standard first-line treatment for most patients hormone receptor (HR) positive, human epidermal growth factor (HER2) negative advanced breast cancer. However, resistance to ET and CDK4/6i inevitably ensues. The optimal post-progression regimens their sequencing continue evolve in rapidly changing landscape. In this review, we summarize mechanisms of CDK4/6i, which can be broadly classified as alterations affecting cell cycle mediators activation alternative signaling pathways. Recent clinical trials have been directed at targets pathways implicated, including estrogen androgen receptors, PI3K/AKT/mTOR MAPK pathways, tyrosine receptors such FGFR HER2, homologous recombination repair pathway, other components death. We describe findings from these using small molecule inhibitors, antibody–drug conjugates immunotherapy, providing insights into how novel strategies may circumvent resistance, discuss some not translated benefit. challenges posed by tumor heterogeneity, adaptive rewiring dose-limiting toxicities underscore need elucidate latest biology each patient, develop treatments improved therapeutic index era precision medicine.

Language: Английский

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Open-label, phase II, multicenter study of lasofoxifene plus abemaciclib for treating women with metastatic ER+/HER2− breast cancer and an ESR1 mutation after disease progression on prior therapies: ELAINE 2

Annals of Oncology, Journal Year: 2023, Volume and Issue: 34(12), P. 1131 - 1140

Published: Dec. 1, 2023

Acquired ESR1 mutations in estrogen receptor-positive (ER+) metastatic breast cancer (mBC) drive treatment resistance and tumor progression; new strategies are needed. Lasofoxifene, a next-generation, oral, endocrine therapy tissue-specific ER antagonist, provided preclinical antitumor activity, alone or combined with cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) ESR1-mutated mBC.In the open-label, phase II, ELAINE 2 trial (NCT04432454), women ESR1-mutated, ER+/human epidermal growth factor receptor 2-negative (HER2-) mBC who progressed on prior therapies (including CDK4/6i) received lasofoxifene 5 mg/day abemaciclib 150 mg b.i.d until disease progression/toxicity. The primary endpoint was safety/tolerability. Secondary endpoints included progression-free survival (PFS), clinical benefit rate (CBR), objective response (ORR).Twenty-nine (median age 60 years) participated; all but one were previously treated CDK4/6i duration years). lasofoxifene-abemaciclib combination well tolerated primarily grade 1/2 treatment-emergent adverse events (TEAEs), most commonly diarrhea, nausea, fatigue, vomiting. One patient (with no discontinued due to diarrhea. No deaths occurred during study. Median PFS 56.0 weeks [95% confidence interval (CI) 31.9 weeks-not estimable; ∼13 months]; rates at 6, 12, 18 months 76.1%, 56.1%, 38.8%, respectively. CBR 24 65.5% (95% CI 47.3% 80.1%). In patients measurable lesions, ORR 55.6% 33.7% 75.4%). ESR1-mutant circulating DNA (ctDNA) allele fraction decreased from baseline week 4 21/26 (80.8%) patients.Lasofoxifene plus had an acceptable safety profile, tolerated, exhibited meaningful activity ER+/HER2- after progression CDK4/6i. Observed decreases ctDNA concordant suggest target engagement. If findings confirmed initiated, III, 3 trial, these data could be practice-changing help address critical unmet need.

Language: Английский

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Filling the Gap after CDK4/6 Inhibitors: Novel Endocrine and Biologic Treatment Options for Metastatic Hormone Receptor Positive Breast Cancer

Cancers, Journal Year: 2023, Volume and Issue: 15(7), P. 2015 - 2015

Published: March 28, 2023

The rise of cyclin-dependent kinase (CDK)4/6 inhibitors has rapidly reshaped treatment algorithms for hormone receptor (HR)-positive metastatic breast cancer, with endocrine (ET) plus a CDK4/6-inhibitor currently representing the standard care in first line setting. However, selection those patients experiencing progression while on ET + CDK4/6-inhibitors remains challenging due to suboptimal activity or significant toxicities available options. There is also paucity data regarding efficacy older regimens, such as everolimus exemestane, post-CDK4/6 inhibition. In this setting high unmet need, several clinical trials novel drugs have recently reported encouraging results: addition AKT-inhibitor capivasertib fulvestrant demonstrated improvement progression-free survival (PFS); oral selective estrogen degrader (SERD) elacestrant prolonged PFS compared traditional phase 3 trial, particularly among detectable ESR1 mutations; finally, PARP are options pathogenic BRCA1/2 germline mutations. Overall, plethora and biologic finally filling gap between first-line later chemotherapy. review article, we recapitulate these their potential role future algorithms.

Language: Английский

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Precision therapeutics and emerging strategies for HR-positive metastatic breast cancer

Nature Reviews Clinical Oncology, Journal Year: 2024, Volume and Issue: 21(10), P. 743 - 761

Published: Aug. 23, 2024

Language: Английский

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