Factor Receptor 2-negative Breast Cancer Research Articles

Activity-Regulated Cytoskeleton-Associated Protein Gene Expression Is Associated With High Infiltration of Stromal Cells and Immune Cells, but With Less Cancer Cell Proliferation and Better Overall Survival in Estrogen Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Breast Cancers.

Peritumoral lidocaine infiltration prior to excision is associated with better survival in breast cancer (BC), which led us to hypothesize that innervation to the tumor affects its biology and patient survival. Activity-regulated cytoskeleton-associated protein (ARC) gene expression is known to be regulated by neuronal activity. Therefore, we studied the clinical relevance of ARC gene expression as a surrogate of neuronal activity in BC. Sweden Cancerome Analysis Network - Breast (SCAN-B (GSE96058), n = 3,273) cohort and The Cancer Genome Atlas (TCGA, n = 1,069) were analyzed. High ARC expression was significantly associated with smaller tumor size, without lymph node metastasis, and less stage IV disease in one cohort, but not validated by the other. Estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) and luminal A expressed significantly higher ARC compared to the other subtypes in both cohorts (P < 0.005). High ARC BC was significantly associated with lower Nottingham histological grade and lower Ki67 gene expression consistently in ER+/HER2- but not triple negative breast cancer (TNBC) in both cohorts (P < 0.001). Cell proliferation-related gene sets in the Hallmark collection (E2F targets, G2M checkpoint, and mitotic spindle) were significantly enriched to low ARC BC in ER+/HER2- but not TNBC in TCGA. The stromal cells (fibroblasts, vascular endothelial cells, and adipocytes) were all significantly infiltrated in high ARC ER+/HER2-, but not in TNBC, except for neurons. Homologous recombination deficiency, intratumor heterogeneity, fraction altered, silent or non-silent mutation rate were all significantly lower in high ARC ER+/HER2- but not TNBC. Although there was no difference in single nucleotide variant or indel neoantigens, tumor infiltrating lymphocytes, and cytolytic activity by ARC expression regardless of subtype, multiple immune cells were significantly infiltrated in high ARC ER+/HER2-, including CD8, CD4 memory cells, helper type II T cells, regulatory T cells, M2 macrophages, and B cells (all P < 0.03 in both cohorts), but not in TNBC. Disease-specific and overall survival were significantly improved in high ARC ER+/HER2- consistently in both cohorts (all P < 0.05), but this was not the case in TNBC. ARC gene expression was associated with less cancer cell proliferation, high infiltration of stromal cells and immune cells, and better survival in the ER+/HER2- but not TNBC subtype.

Molecular characterization of HER2-negative breast cancers reveals a distinct patient subgroup with 17q12 deletion and heterozygous loss of ERBB2.

The approval of trastuzumab deruxtecan has prompted the subgrouping of human epidermal growth factor receptor 2-negative (HER2-) breast cancers (BCs) to HER2 0 and HER2 low on the basis of immunohistochemistry, although the biological significance of these subgroups remains uncertain. This study is aimed to better understand the molecular and genetic differences among HER2- tumors stratified by quantitative levels of HER2. We analyzed the transcriptomic and genomic data from the Molecular Taxonomy of BC International Consortium (discovery cohort) and The Cancer Genome Atlas (independent validation cohort). HER2- BCs, including hormone receptor positive and triple negative, were divided into three subgroups based on ERBB2 messenger RNA (mRNA) levels: minimal, moderate and enhanced. We observed significant differences in mutational and transcriptional profiles across the subgroups. Tumors with enhanced ERBB2 mRNA expression had a higher prevalence of PIK3CA mutations and increased estrogen receptor signaling, while tumors with minimal ERBB2 mRNA expression displayed higher expression of proliferation and immune-related genes. We identified a distinct subgroup of BCs characterized by a large deletion of chromosome 17q12 (17q12del) with heterozygous loss of ERBB2, very low ERBB2 mRNA and HER2 protein expression. This subgroup was also enriched for heterozygous losses of TP53 and other tumor suppressor genes. Analysis of two large real-world cohorts of patients with HER2- metastatic BC (Dana-Farber Cancer Institute cohort n= 1063 and Memorial Sloan Kettering MetTropism cohort n= 1018) showed that patients with 17q12del and heterozygous loss of ERBB2 had poorer overall survival (OS). We identified a biologically and clinically distinct subgroup of BCs characterized by a 17q12del with a heterozygous loss of ERBB2 and low ERBB2 mRNA and HER2 protein expression. In two large real-world cohorts of patients with HER2- metastatic BC, this subgroup was associated with poor OS, highlighting its clinical significance.

Palbociclib Is Safe for Breast Cancer Patients With Mild Hepatic Impairment: A Multicenter Retrospective Study Using Real-World Data.

The liver is crucial for metabolizing the anticancer drug palbociclib, but limited information is available on the impact of hepatic impairment on its toxicity and efficacy, with no real-world data available. This study aims to evaluate how hepatic impairment affects hematological toxicity and progression-free survival (PFS) of palbociclib in advanced hormone receptor-positive/human epidermal growth factor receptor 2-negative breast cancer, using the National Cancer Institute scoring system, in a large real-world dataset. This multicenter retrospective observational study included female patients treated with palbociclib between August 2017 and February 2024. Regression analysis was used to compare the risk of developing grade 3/4 hematological toxicity and PFS between patients with normal and mild impaired liver function. In total, 478 female patients were included. Patients with mild hepatic impairment (n = 205) did not have an increased risk of developing grade 3/4 neutropenia compared with patients with normal hepatic function (n = 273) (hazard ratio (HR) = 1.11; 95% CI 0.83-1.47). In addition, the PFS was not significantly different between both groups (HR = 1.15; 95% CI 0.93-1.42). In real-world settings, patients with mild hepatic impairment do not have a higher risk of developing palbociclib-induced neutropenia or disease progression than patients with normal hepatic function. These findings can guide clinicians when treating breast cancer patients with mild hepatic impairment.

Pembrolizumab and chemotherapy in high-risk, early-stage, ER+/HER2- breast cancer: a randomized phase 3 trial.

Addition of pembrolizumab to neoadjuvant chemotherapy followed by adjuvant pembrolizumab improved outcomes in patients with high-risk, early-stage, triple-negative breast cancer. However, whether the addition of neoadjuvant pembrolizumab to chemotherapy would improve outcomes in high-risk, early-stage, estrogen receptor-positive/human epidermal growth factor receptor 2-negative (ER+/HER2-) breast cancer remains unclear. We conducted a double-blind, placebo-controlled phase 3 study (KEYNOTE-756) in which patients with previously untreated ER+/HER2- grade 3 high-risk invasive breast cancer (T1c-2 (≥2 cm), cN1-2 or T3-4, cN0-2) were randomly assigned (1:1) to neoadjuvant pembrolizumab 200 mg or placebo Q3W given with paclitaxel QW for 12 weeks, followed by four cycles of doxorubicin or epirubicin plus cyclophosphamide Q2W or Q3W. After surgery (with/without adjuvant radiation therapy), patients received adjuvant pembrolizumab or placebo for nine cycles plus adjuvant endocrine therapy. Dual primary endpoints were pathological complete response and event-free survival in the intention-to-treat population. In total, 635 patients were assigned to the pembrolizumab-chemotherapy arm and 643 to the placebo-chemotherapy arm. At the study's prespecified first interim analysis, the pathological complete response rate was 24.3% (95% confidence interval (CI), 21.0-27.8%) in the pembrolizumab-chemotherapy arm and 15.6% (95% CI, 12.8-18.6%) in the placebo-chemotherapy arm (estimated treatment difference, 8.5 percentage points; 95% CI, 4.2-12.8; P = 0.00005). Event-free survival was not mature in this analysis. During the neoadjuvant phase, treatment-related adverse events of grade ≥3 were reported in 52.5% and 46.4% of patients in the pembrolizumab-chemotherapy and placebo-chemotherapy arms, respectively. In summary, the addition of pembrolizumab to neoadjuvant chemotherapy significantly improved the pathological complete response rate in patients with high-risk, early-stage ER+/HER2- breast cancer. Safety was consistent with the known profiles of each study treatment. Follow-up continues for event-free survival. ClinicalTrials.gov identifier: NCT03725059 .

Neoadjuvant nivolumab and chemotherapy in early estrogen receptor-positive breast cancer: a randomized phase 3 trial.

Patients with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) primary breast cancer (BC) have low pathological complete response (pCR) rates with neoadjuvant chemotherapy. A subset of ER+/HER2- BC contains dense lymphocytic infiltration. We hypothesized that addition of an anti-programmed death 1 agent may increase pCR rates in this BC subtype. We conducted a randomized, multicenter, double-blind phase 3 trial to investigate the benefit of adding nivolumab to neoadjuvant chemotherapy in patients with newly diagnosed, high-risk, grade 3 or 2 (ER 1 to ≤10%) ER+/HER2- primary BC. In total, 510 patients were randomized to receive anthracycline and taxane-based chemotherapy with either intravenous nivolumab or placebo. The primary endpoint of pCR was significantly higher in the nivolumab arm compared with placebo (24.5% versus 13.8%; P = 0.0021), with greater benefit observed in patients with programmed death ligand 1-positive tumors (VENTANA SP142 ≥1%: 44.3% versus 20.2% respectively). There were no new safety signals identified. Of the five deaths that occurred in the nivolumab arm, two were related to study drug toxicity; no deaths occurred in the placebo arm. Adding nivolumab to neoadjuvant chemotherapy significantly increased pCR rates in high-risk, early-stage ER+/HER2- BC, particularly among patients with higher stromal tumor-infiltrating lymphocyte levels or programmed death ligand 1 expression, suggesting a new treatment paradigm that emphasizes the role of immunotherapy and T cell immunosurveillance in luminal disease. Clinical trials.gov identifier: NCT04109066.

Intense FAP Expression of Ovarian Metastatic Breast Cancer Detected by [68Ga]RTX-1363 PET/CT.

PET/CT targeting fibroblast activation protein α (FAP) in cancer-associated fibroblasts shows promise in theranostics. Here, we report the case of a 31-year-old woman with hormone receptor-positive/human epidermal growth factor receptor 2-negative breast cancer who presented with rising CA15-3 for further diagnostic workup. Whereas [18F]FDG PET/CT was unremarkable, novel [68Ga]RTX-1363 PET/CT revealed intense tracer accumulation in thoracoabdominal lymph nodes and both ovaries. Follow-up imaging confirmed tumor progression, and diagnostic laparoscopy verified metastatic disease in the ovaries with high FAP expression in the tumor stroma. This case underscores the superior sensitivity of [68Ga]RTX-1363 PET/CT over [18F]FDG PET/CT, enhancing breast cancer diagnostic and therapeutic strategies.

Evaluating the Effectiveness of Cyclin-Dependent Kinase 4/6 Inhibitors in Early- and Very Early-Onset Metastatic Breast Cancer: A Multicenter Study.

Background and Objectives: Early-onset breast cancer (EOBC), particularly in patients under 40, presents with distinct biological characteristics and worse survival outcomes compared to late-onset cases. Despite intensive treatments, EOBC patients, especially those with hormone receptor-positive, HER2-negative (HR+/HER2-) subtypes, show poorer prognosis. CDK4/6 inhibitors, combined with endocrine therapy (ET) have become the standard for HR+/HER2- metastatic breast cancer, yet younger patients are underrepresented in clinical trials. This study aims to evaluate the efficacy of ribociclib and palbociclib with ET in HR+/HER2- metastatic breast cancer, addressing the critical gap in understanding treatment outcomes in younger patient populations. Materials and Methods: This multicenter, retrospective study evaluated the efficacy and safety of cyclin-dependent kinase 4 and 6 (CDK 4/6) inhibitors, ribociclib, and palbociclib, in combination with endocrine therapy in patients with hormone receptor-positive and human epidermal growth factor receptor 2-negative metastatic breast cancer. Results: A total of 198 patients treated between 2019 and 2023 were analyzed for progression-free survival, overall survival, and prognostic factors. Very early-onset breast cancer, which is diagnosed before the age of 35, was identified as an independent prognostic factor for poor progression-free survival. Additional factors associated with poorer outcomes included liver metastasis, progesterone receptor negativity, high tumor grade, and the concurrent use of fulvestrant with CDK4/6 inhibitors. Both ribociclib and palbociclib demonstrated similar efficacy, and dose reductions due to treatment-related adverse events did not compromise therapeutic outcomes. Conclusions: This study is the first to focus specifically on the treatment of early-onset breast cancer with CDK4/6 inhibitors, providing critical insights into the unique challenges faced by this patient population. The findings underscore the urgent need for personalized treatment strategies, routine genetic testing, and dedicated clinical trials designed to address the specific needs of these high-risk subgroups. By advancing our understanding of the clinical and molecular landscape of early-onset breast cancer and very early-onset breast cancer, this study lays the groundwork for improving outcomes in these underserved patients through tailored therapeutic approaches.

Multimodal integration using a machine learning approach facilitates risk stratification in HR+/HER2- breast cancer.

Hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer is the most common type of breast cancer, with continuous recurrence remaining an important clinical issue. Current relapse predictive models in HR+/HER2- breast cancer patients still have limitations. The integration of multidimensional data represents a promising alternative for predicting relapse. In this study, we leverage our multi-omics cohort comprising 579 HR+/HER2- breast cancer patients (200 patients with complete data across 7 modalities) and develop a machine-learning-based model, namely CIMPTGV, which integrates clinical information, immunohistochemistry, metabolomics, pathomics, transcriptomics, genomics, and copy number variations to predict recurrence risk of HR+/HER2- breast cancer. This model achieves concordance indices (C-indices) of 0.871 and 0.869 in the train and test sets, respectively. The risk population predicted by the CIMPTGV model encompasses those identified by single-modality models. Feature analysis reveals that synergistic and complementary effects exist in different modalities. Simultaneously, we develop a simplified model with a mean area under the curve (AUC) of 0.840, presenting a useful approach for clinical applications.

Second-Line Treatment Options for Patients with Metastatic Triple-Negative Breast Cancer: A Review of the Clinical Evidence.

Metastatic triple-negative breast cancer has a poor prognosis and poses significant therapeutic challenges. Until recently, limited therapeutic options have been available for patients with advanced disease after failure of first-line chemotherapy. The aim of this review is to assess the current evidence supporting second-line treatment options in patients with metastatic triple-negative breast cancer. Evidence was reviewed from controlled clinical trials in which eribulin, vinorelbine, capecitabine, gemcitabine, gemcitabine plus carboplatin, fam-trastuzumab-deruxtecan, sacituzumab govitecan, olaparib, and talazoparib were used in the second-line treatment for metastatic breast cancer, either as study drugs or as comparators. The benefit of treatment was evaluated using the European Society for Medical Oncology-Magnitude of Clinical Benefit Scale. Based on the evidence review, sacituzumab govitecan was identified as the preferred second-line treatment option for patients with metastatic triple-negative breast cancer, supported by clinical evidence and consensus across international clinical guidelines. Olaparib and talazoparib are of use in patients with human epidermal growth factor receptor 2-negative metastatic breast cancer and germline BRCA1/2 mutations. Exploratory data for fam-trastuzumab-deruxtecan suggest a survival benefit in human epidermal growth factor receptor 2-low, hormone-receptor-negative patients, but further solid evidence is required. Other chemotherapies with lower European Society for Medical Oncology-Magnitude of Clinical Benefit Scale scores may continue to be useful in highly selected patients.

Fulvestrant Versus Anastrozole in Endocrine Therapy-Naïve Women With Hormone Receptor-Positive Advanced Breast Cancer: Final Overall Survival in the Phase III FALCON Trial.

The randomized phase III FALCON trial demonstrated significant improvement in progression-free survival (PFS) with fulvestrant versus anastrozole in postmenopausal women with endocrine therapy-naïve, hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer. Herein, the prespecified final overall survival (OS) analysis is reported. After the primary PFS analysis, data were collected on survival, serious adverse events, and health-related quality of life. The final OS analysis was triggered at ≥65% maturity and ≥8 years since the last patient was enrolled. Analyses were descriptive with nominal P values (one-sided α threshold .01845). At the data cutoff (July 11, 2022), 314 (68.0%) of 462 patients had died (fulvestrant, 157/230 [68.3%], anastrozole, 157/232 [67.7%]). The final OS analysis of FALCON demonstrated no significant difference between fulvestrant and anastrozole (medians, 44.8 and 42.7 months, respectively; hazard ratio [HR], 0.97 [95% CI, 0.77 to 1.21]; P = .7579). Among patients with nonvisceral disease (n = 208), a trend showed a 15% reduction in the relative risk of death with fulvestrant versus anastrozole (median OS, 65.2 v 47.8 months; HR, 0.85 [95% CI, 0.60 to 1.20]). Data from FALCON are consistent with published evidence of long-term clinical benefit with fulvestrant and other endocrine therapies in the subset of patients with nonvisceral disease.

Comparative overall survival of CDK4/6 inhibitors plus an aromatase inhibitor in HR+/HER2- metastatic breast cancer in the US real-world setting.

Randomized controlled trials have shown inconsistent overall survival (OS) benefit among the three cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) as first-line (1L) treatment of patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC). Several real-world studies compared CDK4/6i effectiveness, with inconsistent findings. This study compared overall survival (OS) of patients with HR+/HER2- mBC receiving 1L palbociclib, ribociclib, or abemaciclib, in combination with an aromatase inhibitor (AI), in US clinical practice. This retrospective study used real-world data from the Flatiron Health electronic health record-derived deidentified longitudinal database. Patients with HR+/HER2- mBC aged ≥18 years at mBC diagnosis started 1L CDK4/6i therapy (index treatment) between February 2015 and November 2023, with a potential ≥6-month follow-up. OS was defined as months from start of index treatment to death. Stabilized inverse probability of treatment weighting (sIPTW; primary analysis) was used to balance baseline patient characteristics. Multivariable Cox proportional hazards model was carried out as a sensitivity analysis. Of 9146 eligible patients, 6831, 1279, and 1036 received palbociclib plus AI, ribociclib plus AI, or abemaciclib plus AI, respectively. After sIPTW, baseline characteristics were balanced between treatment groups. After sIPTW, no significant OS differences were found between treatment groups [ribociclib versus palbociclib: adjusted hazard ratio (aHR) 0.98, 95% confidence interval (CI) 0.87-1.10, P= 0.7531; abemaciclib versus palbociclib: aHR 0.95, 95% CI 0.84-1.08, P= 0.4292; abemaciclib versus ribociclib: aHR 0.97, 95% CI 0.82-1.14, P= 0.6956]. Sensitivity analysis including a subanalysis of patients who started index treatment in 2017 or later also showed no significant OS differences between treatment groups. This large real-world study suggested that there were no significant OS differences between 1L ribociclib, abemaciclib, and palbociclib in combination with an AI for patients with HR+/HER2- mBC. These findings together with other factors such as safety and quality of life are helpful in the selection of CDK4/6i combination therapy for patients with HR+/HER2- mBC.

Non-Luminal Disease Score for Everolimus in Patients withHormone Receptor‑positive and Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: A Multicenter and Retrospective Study.

This study aims to explore the role of the non-luminal disease score (NOLUS) for everolimus in patients with hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer (ABC). NOLUS has previously been established as an algorithm: NOLUS (0-100) = - 0.45 × ER(%) - 0.28 × PR(%) + 0.27 × Ki67(%) + 73. Information of cancer patients was retrospectively collected from three cancer centers in China. Totally, 198HR+/HER2- ABC patients with complete records in expression rates (%) of ER, PR and Ki67 were enrolled in the study. The expression rates (%) of ER, PR, and Ki67 were 38.8 ± 27.9 versus 80.9 ± 14.2 (p < 0.001), 13.9 ± 14.3 versus 50.2 ± 30.4 (p < 0.001), and 37.8 ± 23.6 versus 28.7 ± 19.9 (p = 0.04), respectively, for NOLUS-positive patients and NOLUS-negative patients. For the overall population, the median PFS was 5.8 months versus 5.1 months in NOLUS-positive and NOLUS-negative patients (p = 0.16, HR = 0.75, 95% CI = 0.50, 1.12). The median 1L-, 2L, and 3L-PFS was 13.9 months versus 11.8 months (p = 0.22, HR = 1.63, 95% CI = 0.74, 3.62), 6.7 months versus 3.6 months (p = 0.08, HR = 0.34, 95% CI = 0.10, 1.18), and 4.6 months versus 4.0 months (p = 0.81, HR = 1.07, 95% CI = 0.63, 1.79) respectively, for NOLUS-positive patients and NOLUS-negative patients. NOLUS-positive patients have a lower percentage of ER and PR, but a higher percentage of Ki67 index. The correlation between thebenefits of everolimus and NOLUS failed to develop significance, suggesting that NOLUS may not be applicable in predicting everolimus efficacy in patients with HR+/HER2- ABC. Further research is expected.

Research Progress on CDK4/6 Inhibitors Combined with Endocrine Therapy for Advanced Breast Cancer

The introduction of CDK4/6 inhibitors has revolutionized the treatment paradigm for hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer. These inhibitors, when combined with endocrine therapy, have shown significant improvements in both progression-free survival (PFS) and overall survival (OS). However, the development of resistance presents substantial challenges that limit their long-term effectiveness. This article provides a review of the mechanisms of action, clinical efficacy, and safety of CDK4/6 inhibitors, as well as treatment after disease progression on a CDK4/6 inhibitor, offering valuable references.

Cell-free tumor DNA analysis in advanced or metastatic breast cancer patients: mutation frequencies, testing intention, and clinical impact.

Circulating cell-free tumor DNA (ctDNA) provides a non-invasive approach for assessing somatic alterations. The German PRAEGNANT registry study aims to explore molecular biomarkers and investigate their integration into clinical practice. In this context, ctDNA testing was included to understand the motivations of clinicians to initiate testing, to identify somatic alterations, and to assess the clinical impact of the results obtained. Patients with advanced/metastatic breast cancer were prospectively enrolled in the Prospective Academic Translational Research Network for the Optimization of Oncological Health Care Quality in the Adjuvant and Advanced/Metastatic Setting (PRAEGNANT study; NCT02338167). The FDA-approved and CE-marked GUARDANT360 CDx test was used to assess somatic alterations. A ctDNA-analysis report was provided to the treating physician along with a questionnaire about the intent for testing and the clinical implications of test results. ctDNA from 49 patients was analyzed prospectively: 37 (76%) had at least one somatic alteration in the analyzed geneset; 14 patients (29%) harbored alterations in TP53, 12 (24%) in PIK3CA, and 6 (12%) in ESR1. Somatic mutations in BRCA1 or BRCA2 were detected in 3 (6%) and 4 (8%) patients, respectively, and 59% of patients had hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer. Questionnaires regarding test intentions and clinical impact were completed for 48 (98%) patients. These showed that ctDNA testing influenced treatment decisions for 35% of patients. The high prevalence of somatic alterations in TP53, PIK3CA, ESR1, and BRCA1/2 genes, identified by ctDNA genotyping, highlights their potential as biomarkers for targeted therapies. Detection of specific mutations affected treatment decisions, such as eligibility for alpelisib, and might further facilitate treatment with e.g. elacestrant or capiversatib in future treatment lines.

Targeting autophagy plus high-dose CDK4/6 inhibitors in advanced HR+HER2- breast cancer: A phase 1b/2 trial.

The unmet needs of managing patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer who progress after cyclin-dependent kinase (CDK)4/6 inhibitor (CDK4/6i) treatment remain unclarified. This was a phase 1b/2, single-arm, open-label study that enrolled 29 patients with HR+/HER2- breast cancer who experienced first-line palbociclib treatment failure. The primary endpoint was the incidence of dose-limiting toxicity (DLT). The secondary endpoints were the objective response rate (ORR) and progression-free survival (PFS). The clinical trial registration number is ClinicalTrials.gov: NCT05953350. The phase 1b study demonstrated no DLT in patients treated with hydroxychloroquine (HCQ; 600mg, bis in die [bid]) plus increasing doses of palbociclib (100, 150, or 200mg, quaque die [qd]). The plasma pharmacokinetics of palbociclib were not significantly affected by HCQ. The recommended phase 2 dose (RP2D) was HCQ (600mg, bid) plus palbociclib (200mg, qd). The dose-expansion cohort demonstrated that HCQ plus palbociclib (200mg, qd) treatment was tolerable. Grade 3 treatment-emergent adverse events (TEAEs) with an incidence higher than 15.0% included neutropenia (25.0%), leukopenia (25.0%), fatigue (20.0%), and back pain (15.0%). The ORR of all enrolled patients in our present trial was 41.4% (12/29). In the dose-expansion cohort, with the last enrolled patient having a follow-up duration of 32.3weeks, the median PFS was not reached. The clinical benefit rate (CBR) at 6months was 90.0% (95% confidence interval [CI]: 68.3%-98.8%). These findings were supported by preclinical data. Combined HCQ with high-dose CDK4/6i palbociclib (200mg, qd) showed tolerable toxicity and promising efficacy for patients with advanced HR+/HER2- breast cancer after CDK4/6i failure. This work was funded by the National Natural Science Foundation of China.

CDK4/6 inhibitor plus endocrine therapy for advanced breast cancer: results from a web-based survey in Japan.

Though efforts have been made toward standardizing access to quality cancer care in Japan, there are still geographical and institutional disparities in the level of cancer care availability. We investigated the utilization of cyclin-dependent kinase 4/6 inhibitors plus endocrine therapy (CDK4/6i+ET) as first-line (1 L) treatment for hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) in Japan. This cross-sectional survey included physicians who had treated ≥3 1 L patients with HR+/HER2- ABC in the past year. Of 41,695 physicians invited, 300 were included in the analysis. The mean percentage share of CDK4/6i+ET and ET monotherapy was 38.3% and 42.2%, respectively. Common challenges facing CDK4/6i+ET prescription were adverse reaction management, prohibitive cost, and a preference for ET monotherapy for treating elderly patients. Key solutions included reducing the burden of adverse reaction management, improving financial support, and preparing educational videos for medical staff. The study concluded that CDK4/6i+ET is not well established as a 1 L option in Japan as of 2022. More effective ways of creating awareness and supportive tools are needed for CDK4/6i+ET to be adopted as standard of care in Japan. UMIN000050760.

Abemaciclib Plus Fulvestrant in Advanced Breast Cancer After Progression on CDK4/6 Inhibition: Results From the Phase III postMONARCH Trial.

Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) combined with endocrine therapy (ET) are the standard first-line treatment for hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC); however, disease progression occurs in almost all patients and additional treatment options are needed. Herein, we report outcomes of the postMONARCH trial investigating a switch in ET with/without CDK4/6 inhibition with abemaciclib after disease progression on CDK4/6i. This double-blind, randomized phase III study enrolled patients with disease progression on previous CDK4/6i plus aromatase inhibitor as initial therapy for advanced disease or recurrence on/after adjuvant CDK4/6i + ET. Patients were randomly assigned (1:1) to abemaciclib + fulvestrant or placebo + fulvestrant. The primary end point was investigator-assessed progression-free survival (PFS). Secondary end points included PFS by blinded independent central review, objective response rate (ORR), and safety. This study randomly assigned 368 patients (abemaciclib + fulvestrant, n = 182 placebo + fulvestrant, n = 186). At the primary analysis (258 events), the hazard ratio (HR) was 0.73 (95% CI, 0.57 to 0.95; nominal P = .017), with median PFS 6.0 (95% CI, 5.6 to 8.6) versus 5.3 (95% CI, 3.7 to 5.6) months and 6-month PFS rates of 50% and 37% in the abemaciclib + fulvestrant and placebo + fulvestrant arms, respectively. These results were supported by BICR-assessed PFS (HR, 0.55 [95% CI, 0.39 to 0.77]; nominal P < .001). A consistent treatment effect was seen across major clinical and genomic subgroups, including with/without ESR1 or PIK3CA mutations. Among patients with measurable disease, investigator-assessed ORR was improved with abemaciclib + fulvestrant versus placebo + fulvestrant (17% v 7%; nominal P = .015). No new safety signals were observed, with findings consistent with the known safety profile of abemaciclib. Abemaciclib + fulvestrant significantly improved PFS after disease progression on previous CDK4/6i + ET in patients with HR+, HER2- ABC, offering an additional targeted therapy option for these patients.

Efficacy of Subsequent Treatments After Disease Progression on CDK4/6 Inhibitors in Patients With Hormone Receptor-Positive Advanced Breast Cancer.

Cyclin-dependent kinase 4/6 inhibitors (CDK4/6is) combined with endocrine therapy (ET) are the standard of care in hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer (aBC). Yet, disease progression remains common. In the absence of established postprogression sequencing guidelines, we conducted a pooled analysis of Kaplan-Meier (KM)-derived patient data to assess the efficacy of subsequent treatment options after disease progression on CDK4/6i therapy. We conducted a systematic review and meta-analysis searching PubMed, Embase, Cochrane, and conference proceedings for randomized trials and cohort studies published from 2016 to December, 2023. Studies assessing subsequent treatment postprogression on CDK4/6i in patients with HR+ HER2- aBC were included. We performed a pooled analysis of KM-derived individual patient data. Outcomes of interest were progression-free survival (PFS) and overall survival (OS). This study is registered in PROSPERO, CRD42023491090. Of 12,895 identified records, 18 studies comprising 4,899 patients were included. Maintaining treatment with a CDK4/6i plus ET post-CDK4/6i progression was associated with longer PFS (hazard ratio [HR], 0.61 [95% CI, 0.53 to 0.70]; P < .01) and prolonged OS (HR, 0.68 [95% CI, 0.60 to 0.77]; P < .01) compared with ET monotherapy. The PFS benefit was seen in both continuing the previous CDK4/6i (HR, 0.67 [95% CI, 0.56 to 0.79]; P < .01) and switching to a different CDK4/6i (HR, 0.68 [95% CI, 0.54 to 0.85]; P < .01). Subsequent therapy with everolimus plus ET achieved similar PFS (HR, 1.10 [95% CI, 0.90 to 1.35]; P = .35) and significantly shorter OS (HR, 1.52; [95% CI, 1.21 to 1.90], P < .01) as compared with ET monotherapy. This extensive data pool suggests significant benefit of CDK4/6i regimens after disease progression as compared with ET monotherapy. Our data also support current guideline recommendations of ET-based therapies over chemotherapy for treatment sequencing.

Alternative Palbociclib Dosing Schedules for Hormone Receptor-Positive and HER2-Negative Metastatic Breast Cancer

Introduction: The cyclin-dependent kinase 4 and 6 inhibitor palbociclib is associated with a high incidence of neutropenia. Treatment continuation using the standard dosing schedule (3 consecutive weeks of oral administration followed by 1-week off-treatment: 3/1 schedule) can be difficult, and other dosing schedules have been previously adopted. We aimed to investigate whether alternative dosing schedules can be used effectively to continue palbociclib. Methods: This study included all patients who received palbociclib for hormone receptor-positive and human epidermal growth factor receptor 2-negative metastatic breast cancer (HR+/HER2-MBC) at Ogaki Municipal Hospital between January 2018 and November 2023. Reasons for treatment discontinuation, changes in treatment administration, treatment duration, relative dose intensity (RDI), overall response rate (ORR), clinical benefit rate (CBR), and adverse events were retrospectively investigated using electronic medical records. Results: On November 30, 2023 (a data censor date), patients who discontinued or continued palbociclib on the 3/1 schedule were classified into the 3/1 schedule group (n = 20), and those who started a 3/1 schedule (partly on a 2/2 schedule) and then switched to the 3/2 schedule (3 consecutive weeks of oral administration followed by 2-week off-treatment) or the 2/2 schedule (2 consecutive weeks of oral administration followed by 2-week off-treatment) were classified into the 3/2 (n = 10) or 2/2 schedule groups (n = 18), respectively. For the 3/1, 3/2, and 2/2 schedule groups, respectively, the median treatment duration was 255.5, 1,253.0, and 923.0 days (p = 0.0013), the median RDI (%) was 71.0%, 69.2%, and 40.8% (p < 0.001), and the ORR was 15.0%, 80.0%, and 50.0% (p = 0.002), while the CBR was 55.0%, 100%, and 72.2% (p = 0.028). Conclusion: Dosing schedules other than the standard 3/1 schedule can be used to continue palbociclib with HR+/HER2-MBC while ensuring therapeutic efficacy. Alternative dosing schedules look promising and need further research (preferably, prospective studies) with a larger sample size and longer follow-up to validate treatment efficacy.

Evaluation of cyclin-dependent kinase 4/6 inhibitor-induced serum creatinine elevations in patients with hormone receptor positive breast cancer.

Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) have improved the efficacy of endocrine therapy in hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer (BC) and are now used in both early-stage and metastatic disease. Recent case reports suggest that pseudo-serum creatinine (Scr) elevations are likely a class effect of CDK4/6i. This single-center retrospective analysis included patients aged ≥18 years who received at least one dose of palbociclib, ribociclib, or abemaciclib for the treatment of HR+/HER2- BC in the early or advanced setting. The primary objective was the incidence of pseudo-Scr elevation for each of the three agents. CDK4/6i-induced pseudo-Scr elevation was suspected when the Scr elevation could not be fully attributed to other causes. Secondary endpoints included the grade, onset, duration, and clinical consequences of pseudo-Scr elevation. 143 patients were included. Pseudo-Scr elevation was suspected in patients treated with palbociclib, ribociclib, or abemaciclib, with incidences of 16% (8/50), 14% (6/43), and 20% (10/50), respectively. Rates did not significantly differ between agents (p = 0.727). Among patients with CDK4/6i-induced pseudo-Scr elevation, all events were grade 1 (8.3%) or 2 (91.7%). The median onset from treatment initiation to first Scr elevation was 33.5, 42, and 21.5 days, for palbociclib, ribociclib, or abemaciclib, respectively. Pseudo-Scr elevation appears to be a class effect of CDK4/6i, with similar rates of Scr elevation observed across the three agents currently FDA approved.