Major advancements in metastatic breast cancer treatment: when expanding options means prolonging survival

ESMO Open, Journal Year: 2022, Volume and Issue: 7(2), P. 100409 - 100409

Published: Feb. 25, 2022

•The treatment landscape of MBC has progressively widened in the last years.•Several therapeutic strategies proved to be capable prolonging survival patients with MBC.•We comprehensively reviewed practice-changing data on according BC subtype. In years we have witnessed tremendous advancements metastatic breast cancer (MBC), leading a progressive prolongation progression-free and, some cases, also overall survival. This led substantial increase advanced disease treatability. present review and critically describe most significant progresses scenario particular, studies reporting hormone receptor-positive/human epidermal growth factor receptor 2 (HER2)-negative, HER2-positive triple-negative BC, hint BRCA-related tumors emerging HER2-low-positive category.

Language: Английский

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Efficacy, safety, and biomarker analysis of nivolumab in combination with abemaciclib plus endocrine therapy in patients with HR-positive HER2-negative metastatic breast cancer: a phase II study (WJOG11418B NEWFLAME trial)

Journal for ImmunoTherapy of Cancer, Journal Year: 2023, Volume and Issue: 11(9), P. e007126 - e007126

Published: Sept. 1, 2023

Background Hormone receptor (HR)-positive breast cancer is a disease for which no immune checkpoint inhibitors have shown promise as effective therapies. Cyclin-dependent kinase 4 and 6 (CDK4/6) synergistically increased the effectiveness of antiprogrammed cell death protein-1 (anti-PD-1)/programmed death-ligand 1 (PD-L1) antibodies in preclinical studies. Methods This non-randomized, multicohort, phase II study evaluated efficacy safety anti-PD-1 antibody nivolumab 240 mg administered every 2 weeks combination with CDK4/6 inhibitor abemaciclib 150 twice daily either fulvestrant (FUL) or letrozole (LET) first-line second-line treatment HR-positive HER2-negative metastatic cancer. The primary end point was objective response rate (ORR), secondary points were toxicity, progression-free survival, overall survival. Blood, tissue, fecal samples collected at multiple correlative studies to evaluate immunity biomarkers. Results From June 2019 early termination due concerns on July 2020, 17 patients enrolled (FUL: n=12, LET: n=5). One patient prior history FUL cohort excluded. ORRs 54.5% (6/11) 40.0% (2/5) LET cohorts, respectively. Treatment-emergent (TE) adverse events (AEs) grade ≥3 occurred 11 (92%) 5 (100%) most common TEAEs neutropenia (7 (58.3%) 3 (60.0%) respectively), followed by alanine aminotransferase elevation (5 (41.6%) (80.0%)). treatment-related from interstitial lung cohort. Ten developed liver-related AEs. Liver biopsy specimens showed hepatitis characterized focal necrosis predominant CD8+ lymphocyte infiltration. Marked tumor factor-related cytokines interleukin-11, decrease peripheral regulatory T cells (Tregs), observed hepatotoxicity. These findings suggest that toxicities immune-related AEs likely caused proinflammatory cytokine production suppression Treg proliferation addition therapy. Conclusions Although active, it severe prolonged Trial registration number JapicCTI-194782, jRCT2080224706, UMIN000036970.

Language: Английский

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CDK4/6 inhibitor resistance in estrogen receptor positive breast cancer, a 2023 perspective

Frontiers in Cell and Developmental Biology, Journal Year: 2023, Volume and Issue: 11

Published: March 22, 2023

CDK4/6 inhibitors have become game-changers in the treatment of estrogen receptor-positive (ER+) breast cancer, and combination with endocrine therapy are standard care first-line for ER+/HER2-negative advanced cancer. Although prolong survival these patients, resistance is inevitable there currently no clear next-line treatment. There an urgent unmet need to dissect mechanisms which drive intrinsic acquired guide subsequent therapeutic decisions. We will review insights gained from preclinical studies clinical cohorts into diverse inhibitor action resistance, highlight potential strategies context resistance.

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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Abemaciclib Is Effective in Palbociclib-Resistant Hormone Receptor–Positive Metastatic Breast Cancers

Cancer Research, Journal Year: 2023, Volume and Issue: 83(19), P. 3264 - 3283

Published: June 29, 2023

Cyclin-dependent kinases 4/6 inhibitor (CDK4/6i) plus endocrine therapy (ET) is standard of care for patients with hormone receptor (HR)-positive, HER2-negative metastatic breast cancer (MBC). However, resistance to CDK4/6is ET remains a clinical problem limited therapeutic options following disease progression. Different might have distinct mechanisms resistance, and therefore using them sequentially or targeting their differentially altered pathways could delay To understand leading the palbociclib abemaciclib, we generated multiple in vitro models palbociclib-resistant (PR) abemaciclib-resistant (AR) cell lines as well vivo patient-derived xenografts (PDX) ex PDX-derived organoids (PDxO) from who progressed on CDK4/6i. PR AR cells exhibited transcriptomic proteomic profiles that sensitized different classes inhibitors; upregulated G2-M responded while mediators oxidative phosphorylation pathway (OXPHOS) OXPHOS inhibitors. PDX organoid derived remained responsive abemaciclib. Resistance maintaining sensitivity abemaciclib was associated pathway-specific transcriptional activity but not any individual genetic alterations. Finally, data cohort 52 indicated HR-positive/HER2-negative MBC palbociclib-containing regimens can exhibit meaningful overall benefit abemaciclib-based when administered after palbociclib. These findings provide rationale trials evaluating treatment progression prior

Language: Английский

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Real-world time trends in overall survival, treatments and patient characteristics in HR+/HER2− metastatic breast cancer: an observational study of the SONABRE Registry

The Lancet Regional Health - Europe, Journal Year: 2023, Volume and Issue: 26, P. 100573 - 100573

Published: Jan. 6, 2023

This study aims to evaluate whether changes in therapeutic strategies have improved survival of patients diagnosed with hormone receptor positive (HR+), HER2 negative (HER2-) advanced breast cancer (ABC) real-world.

Language: Английский

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Systemic Treatment of Patients With Metastatic Breast Cancer: ASCO Resource–Stratified Guideline

JCO Global Oncology, Journal Year: 2024, Volume and Issue: 10

Published: Jan. 10, 2024

PURPOSE To guide clinicians and policymakers in three global resource-constrained settings on treating patients with metastatic breast cancer (MBC) when Maximal setting–guideline recommended treatment is unavailable. METHODS A multidisciplinary, multinational panel reviewed existing ASCO guidelines conducted modified ADAPTE formal consensus processes. RESULTS Four published resource-agnostic were adapted for settings; informing two rounds of consensus; recommendations received ≥75% agreement. RECOMMENDATIONS Clinicians should recommend according to menopausal status, pathological biomarker features quality results are available. In first-line, hormone receptor (HR)–positive MBC, a non-steroidal aromatase inhibitor CDK 4/6 combination unavailable, use hormonal therapy alone. For life-threatening disease, single-agent chemotherapy or surgery local control. premenopausal patients, ovarian suppression ablation plus Basic settings. human epidermal growth factor 2 (HER2)–positive if trastuzumab, pertuzumab, trastuzumab chemotherapy; chemotherapy. HER2-positive, HR-positive standard first-line therapy, endocrine contraindications. triple-negative MBC unknown PD-L1 PD-L1–positive immunotherapy germline BRCA1/ mutation–positive poly(ADP-ribose) polymerase (HR-positive MBC) (HR-negative MBC). second-line, Enhanced setting depend prior treatment; Limited, tamoxifen HER2-positive deruxtecan emtansine; capecitabine lapatinib; and/or (hormonal alone Additional information available at www.asco.org/resource-stratified-guidelines . It ASCO's view that healthcare providers system decision-makers be guided by the highest stratum resources The guideline intended complement but not replace guidelines.

Language: Английский

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Comparative overall survival of CDK4/6 inhibitors in combination with endocrine therapy in advanced breast cancer

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: Feb. 7, 2024

Individual trials of abemaciclib, palbociclib, and ribociclib show a similar impact on progression-free survival yet differing statistical significance for overall (OS). A robust comparative evaluation OS, safety, tolerability the three drugs is warranted. systematic literature search identified phase 3 randomized clinical reporting OS CDK4/6 inhibitors (CDK4/6i) in combination with endocrine therapy ER-positive/HER2-negative advanced breast cancer. Trial-level data common serious adverse events (AE) were extracted each drug. In absence direct comparisons, network meta-analysis was performed to evaluate pairwise efficacy, CDK4/6i. Seven studies comprising 4415 patients met inclusion criteria. Median follow-up 73.3 months (range: 48.7-97.2 months). There no statistically significant differences between any Compared abemaciclib both showed significantly higher GI toxicity (grade 1-2 vomiting OR 1.87 [95% CI 1.37-2.56] 2.27 1.59-3.23] respectively). associated more grade 3-4 diarrhea 118.06 7.28-1915.32]. contrast, palbociclib neutropenia than but lower risk infections. Abemaciclib had less transaminitis ribociclib. Treatment discontinuation death due AE difference CDK4/6i despite levels individual trials. Real-world analyses may help identify if there meaningful inter-drug efficacy. Significant are observed safety outcomes.

Language: Английский

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Systemic Treatment of Patients With Metastatic Breast Cancer: ASCO Resource–Stratified Guideline Q and A

JCO Global Oncology, Journal Year: 2024, Volume and Issue: 10

Published: Jan. 10, 2024

The Systemic Treatment of Patients with Metastatic Breast Cancer: @ASCO Resource-Stratified Guideline Q and A presents takeways, rationale, key recommendations based on #JCOGO full guideline for patients by menopausal marker status.

Language: Английский

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Phase I/Ib Trial of Inavolisib Plus Palbociclib and Endocrine Therapy for PIK3CA-Mutated, Hormone Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative Advanced or Metastatic Breast Cancer

Journal of Clinical Oncology, Journal Year: 2024, Volume and Issue: 42(33), P. 3947 - 3956

Published: Sept. 5, 2024

PURPOSE To investigate the safety, tolerability, pharmacokinetics (PK), and preliminary antitumor activity of inavolisib, a potent selective small-molecule inhibitor p110α that promotes degradation mutated p110α, in combination with palbociclib endocrine therapy (ET), phase I/Ib study patients PIK3CA -mutated, hormone receptor–positive/human epidermal growth factor receptor 2–negative locally advanced/metastatic breast cancer (ClinicalTrials.gov identifier: NCT03006172 ). METHODS Women ≥18 years age received palbociclib, letrozole (Inavo + Palbo Letro arm) or fulvestrant Fulv until unacceptable toxicity disease progression. The primary objective was to evaluate safety tolerability. RESULTS Fifty-three were included, 33 Inavo arm 20 arm. Median duration inavolisib treatment 15.7 20.8 months (cutoff: March 27, 2023), respectively. Treatment-related adverse events (TRAEs) occurred all patients; most frequent stomatitis, hyperglycemia, diarrhea; grade ≥3 any TRAE rates 87.9% 85.0%; 6.1% 10.0% discontinued due TRAEs arms, No PK drug–drug interactions (DDIs) observed among treatments when administered. Confirmed response 52.0% 40.0% measurable disease, median progression-free survival 23.3 35.0 Available paired pre- on-treatment tumor tissue circulating DNA analyses confirmed effects on pharmacodynamic pathophysiologic biomarkers response. CONCLUSION Inavolisib plus ET demonstrated manageable profile, lack DDIs, promising activity.

Language: Английский

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