Translational breast cancer research : a journal focusing on translational research in breast cancer最新文献

Background and objective: Cyclin dependent kinases 4 and 6 (CDK4/6) inhibitors are a class of drugs that are used in the first-line therapy of metastatic estrogen receptor (ER) positive/human epidermal growth factor receptor 2 (HER2) negative breast cancer and in the adjuvant therapy of the same cancers. Three drugs of the class, abemaciclib, palbociclib and ribociclib, are currently approved in partially overlapping indications. This review discusses biomarkers for prediction of efficacy of CDK4/6 inhibitors in breast cancer therapy and the potential for overcoming arising resistance.

Methods: A literature search was performed using the PubMed/Medline database and the proceedings of relevant congresses. Search was concluded on March 31, 2025.

Key content and findings: Combinations of CDK4/6 inhibitors with hormonal agents have improved survival outcomes of metastatic ER-positive/HER2-negative breast cancer patients, but resistance develops almost invariably. In addition, a minority of patients display primary resistance to the combinations. Significant efforts have been committed in determining the mechanisms of resistance with a view to both predicting which patients will become refractory to treatment and to developing new treatments and combinations to circumvent resistance. Alterations in the targeted protein node comprising CDK4/6, cyclin D and retinoblastoma, as well as alterations in upstream pathways that regulate the node and downstream effectors of transcription factor E2F, that execute the cell cycle regulation, have been affirmed as culprits in resistance development. A prominent downstream target of E2F that is repeatedly discussed in several studies is cyclin E.

Conclusions: Key resistance mechanisms interfering with CDK4/6 inhibitor efficacy have been identified but are not yet used clinically. Diverse resistance mechanisms observed in individual cases would require individualized approaches to re-sensitize cancer cells and patients to cell cycle inhibition.

Background: Endocrine therapy (ET) is the primary treatment for hormone receptor (HR)-positive breast cancer. Based on the 2023 expert consensus, the Chinese Consensus Group on Breast Cancer Endocrine Therapy updated this consensus by integrating clinical research data and practical experiences.

Methods: (I) Establishment of expert group: the expert group consists of experts from departments such as medical oncology, breast surgery, and pathology. (II) Literature search: mainly conducted in English databases (such as PubMed, Embase, and Cochrane Library) with a search cutoff date of Sep 30^th 2025. (III) Assessment of evidence quality and recommendation strength: evidence quality and recommendation opinions are graded based on the evidence category and recommendation level of the Chinese Society of Clinical Oncology (CSCO) guidelines.

Results: The 2026 consensus updated clinical research data on ET for both early and advanced breast cancer, defined the eligible population for neoadjuvant ET, and clarified the application of adjuvant cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) therapy in moderate and high-risk patients. For advanced breast cancer, the consensus optimized the treatment strategy of first-line ET plus CDK4/6i, and recommended preferred post-CDK4/6i regimens for patients with distinct clinic-pathological characteristics. It also provides clear recommendations on the indication, optimal timing, and methodology of genetic testing.

Conclusions: This consensus may provide clinical guidance for the standardized application of ET, thereby facilitating precise and individualized treatment for HR-positive breast cancer.

Background: Breast cancer (BC) remains the most common malignancy among women worldwide and a leading cause of cancer-related death, particularly in low- and middle-income countries. Social inequalities are known to influence access to diagnosis, treatment, and survival outcomes. However, evidence on these disparities in middle-income settings, such as Brazil, remains limited. Here, we investigated the association between sociodemographic factors and survival among women diagnosed with BC treated at all hospitals that comprise the Oncology Care Network of a state in southeastern Brazil.

Methods: We conducted a hospital-based retrospective cohort study using data from the Hospital Cancer Registries and the Mortality Information System of Espírito Santo, Brazil. The cohort included 12,096 women diagnosed with BC. Cases were categorized as death from BC, death from other causes, or survival at 5 years. Five-year survival was estimated using the Kaplan-Meier method and compared using the log-rank test. A Cox proportional hazards model for cause-specific mortality was applied for multivariate analysis.

Results: Among the cohort, 8,184 (67.66%) women survived until the end of follow-up, 2,947 (24.28%) died from BC, and 975 (8.06%) died from other causes. The overall cause-specific survival at 5 years was 82%. Multivariate analysis revealed that race was an independent risk factor for BC-specific mortality: Black women had a 60% higher risk of death compared with White women [hazard ratio (HR) =1.601; 95% confidence interval (CI): 1.303-1.967; P<0.001]. Similarly, marital status was associated with survival, as single women had a 31% higher risk of BC-specific death compared with married women (HR =1.314; 95% CI: 1.188-1.454; P<0.001).

Conclusions: Significant social inequalities in 5-year BC survival were observed, primarily influenced by age at diagnosis, race/skin color, marital status, and educational level. These findings highlight the urgent need for public health strategies to reduce disparities and improve equity in BC care in Brazil.

Background and objective: Breast cancer (BC) remains the most prevalent malignancy in women globally, with hormone receptor-positive (HR⁺)/human epidermal growth factor receptor 2-negative (HER2^-) tumors representing approximately 70% of cases. Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) have revolutionized treatment for this subtype, significantly improving progression-free survival (PFS) and overall survival (OS). However, emerging evidence suggests that patients with germline BRCA mutations (gBRCAm) may derive less benefit from CDK4/6i due to molecular alterations such as retinoblastoma 1 (RB1) gene loss and endocrine resistance mechanisms. This review critically evaluates the efficacy of CDK4/6i in gBRCAm HR⁺/HER2^- BC, explores underlying biological mechanisms of resistance, and aims to guide clinical decision-making for this distinct subgroup.

Methods: A narrative review was conducted using PubMed, Google Scholar, and abstracts from major oncology congresses [European Society for Medical Oncology (ESMO), American Society of Clinical Oncology (ASCO), and San Antonio Breast Cancer Symposium]. The search employed terms including "CDK inhibitors", "BRCA", and "breast cancer", with no restriction on publication date. References from identified studies were screened for additional relevant literature. Two authors independently selected studies, including phase III trials, subgroup analyses, and real-world evidence, with final inclusion determined by consensus.

Key content and findings: The review synthesizes data from retrospective studies and clinical trials, revealing consistent trends of shorter PFS and OS in gBRCAm patients treated with CDK4/6i compared to wild-type counterparts. Key mechanisms implicated include co-occurring RB1 alterations, PI3K/AKT hyperactivation, and disrupted cell-cycle regulation. The review also discusses therapeutic sequencing in gBRCAm patients, new treatment alternatives with their implications in this specific population, and highlights ongoing trials exploring combination strategies to overcome resistance.

Conclusions: This review underscores the need for prospective studies to clarify the prognostic and predictive role of gBRCAm in CDK4/6i-treated HR⁺/HER2^- BC. Current evidence supports routine BRCA testing to inform therapeutic sequencing, with poly(ADP-ribose) polymerase inhibitors (PARPis) prioritized in high-risk early-stage and metastatic settings. Future research should focus on biomarker-driven strategies, including combinations to optimize outcomes. These insights may refine clinical guidelines, advocate for personalized treatment algorithms, and stimulate research into resistance mechanisms, ultimately improving care for BRCA-mutated BC patients.

Background: Breast cancer (BC) has become the most prevalent malignancy worldwide in recent years. Human epidermal growth factor receptor 2 (HER2) low-expressing tumors account for approximately 60% of BCs in clinical practice, and HER2 low-expression is defined as immunohistochemistry (IHC) 1+ or 2+, along with negative fluorescence in situ hybridization (FISH). Although the efficacy of antibody-drug combinations (ADCs) for the treatment of metastatic HER2 low-expressing BC has been demonstrated, there is still a lack of data on the clinicopathologic characteristics, risk of recurrence, and adjuvant treatment outcomes of early-stage HER2-overexpressing BC compared with non-HER2-overexpressing BC. The objective of this study is to explore whether the clinically validated RecurIndex assay could provide additional prognostic stratification between HER2-low and HER2-zero early-stage BCs in a real-world, single-center cohort.

Methods: A retrospective analysis of data from 120 patients diagnosed with pT1-2N1M0 BC who had undergone RecurIndex testing. In order to enhance our comprehension of HER2-negative and HER2-positive tumors, we examined the clinicopathological characteristics, survival outcomes, and the RecurIndex risk model index for BCs categorized by HER2 status.

Results: In our study, there were significantly fewer hormone receptor-positive (HR⁺) patients in the HER2-zero group than in the HER2-low group. Other than that, other clinical characteristics were similar. Local recurrence (LR) and distal recurrence (DR) scores were statistically increased in the HER2-zero group (LR-score: HER2-zero vs. HER2-low group: median 41.3 vs. 39.2, P=0.03; DR-score: median 46.9 vs. 44.8, P=0.003). In the HR⁺ subgroup, the 9-year recurrence-free survival (RFS) was significantly higher in HER2-low BC than in HER2-zero BC [77.8% vs. 53.5%; hazard ratio =0.3026; 95% confidence interval (CI): 0.1039-0.8817; P=0.03]. HR⁺ DR low-risk BC patients without adjuvant chemotherapy had better 9-year RFS (100% vs. 99.7%, P=0.60) and overall survival (OS) (100% vs. 99.7%, P=0.60) than those who received chemotherapy.

Conclusions: Our results demonstrated that HER2-zero group have a higher recurrence risk and poor prognosis than HER2-low group. HER2-low HR⁺ RecurIndex-DR low risk patients may not benefit from adjuvant chemotherapy. RecurIndex may help explore prognostic stratification and may guide potential chemotherapy de-escalation in HER2-low early BC, laying groundwork for future ADC use.

Background: CDK4/6 inhibitors (CDK4/6i) combined with endocrine therapy (ET) have become the standard of care for hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR⁺/HER2^-) metastatic breast cancer (MBC). However, real-world data from China's central regions remain limited. This study aimed to evaluate the real-world treatment patterns and efficacy of CDK4/6i in HR⁺/HER2^- MBC patients across the Dongting Lake region in China.

Methods: This multicenter retrospective study included 590 HR⁺/HER2^- MBC patients treated with CDK4/6i between 2016 and 2025 in five tertiary cancer centers in the Dongting Lake area of Hunan province, China. Patient demographics, treatment patterns, progression-free survival (PFS), and prognostic factors were analyzed.

Results: Among 616 initially screened patients, 590 met eligibility criteria. Of these, 63.39% received CDK4/6i as first-line treatment and 25.59% as second-line. The most commonly used CDK4/6i were abemaciclib (33.39%), dalpiciclib (28.98%), palbociclib (25.76%), and ribociclib (10.85%). Median PFS was significantly longer in the first-line group than in the second-line group (32.3 vs. 17.6 months, P<0.001). While the objective response rate (ORR) was numerically higher in the first-line setting (49.52% vs. 42.31%), only the disease control rate (DCR) showed statistical significance (97.14% vs. 91.03%). Multivariate Cox analysis identified several independent predictors of shorter PFS: de novo stage IV disease (HR =1.50), Ki-67 ≥30% (HR =1.60), liver metastasis (HR =2.26), lung metastasis (HR =1.53), and use of CDK4/6i as second-line (HR =2.24), while disease-free interval ≥5 years was protective (HR =0.65, P=0.01).

Conclusions: CDK4/6i demonstrates favorable real-world efficacy in HR⁺/HER2^- MBC patients in central China, particularly in the first-line setting. Several clinical factors may aid in treatment selection and risk stratification.

Background: Breast cancer is the most common form of cancer among women, and PSEN1 dysfunction is a primary contributor to the pathogenesis of Alzheimer's disease. However, the involvement of PSEN1 in breast cancer remains unclear. This study was conducted to explore the function and related mechanisms of PSEN1 in breast cancer cells.

Methods: The correlation between two genes was determined utilizing the R2 platform, and the association between gene expression and prognosis was analyzed employing the Kaplan-Meier plotter. The expression of PSEN1 in breast cancer was assessed by in immunofluorescence. The Transwell assay was employed to detect the migration and invasion capabilities of cells. Colony formation and EdU staining were employed to evaluate the effects of PSEN1 on breast cancer cell proliferation.

Results: We observed a positive correlation between the expression of PSEN1 and the prognosis of breast cancer patients. After manipulated the expression of PSEN1 in breast cancer cell lines Sum159 and BT549, we found that PSEN1 could inhibit cell proliferation and growth in breast cancer through colony formation assays and EdU staining. Meanwhile, we revealed that interference with the cell cycle by PSEN1 was associated with cyclin-dependent kinases (CDKs) and cyclin-dependent kinase inhibitors (CKIs) in breast cancer samples. Furthermore, we observed that an increase in PSEN1 expression inhibited the invasive capabilities of breast cancer cells, while a decrease in PSEN1 expression enhanced invasion in both Sum159 and BT549 cell lines. Lastly, we discovered a negative correlation between PSEN1 and epithelial-to-mesenchymal transition (EMT) transcription factors as well as markers in breast cancer patients.

Conclusions: Our study demonstrates that PSEN1 inhibits the invasion and proliferation of breast cancer cells, suggesting that PSEN1 could potentially serve as a prognostic biomarker and a novel therapeutic target for patients with breast cancer.

Background: The MonarchE and NATALEE trials have established adjuvant CDK4/6 inhibitors (abemaciclib and ribociclib) as pivotal therapies for high-risk hormone receptor-positive (HR+) early breast cancer (EBC). However, real-world data regarding the populations eligible for these trials remains limited, especially in Asian cohorts, highlighting the need for data that bridges the gap between trial findings and clinical practice in diverse settings. We conducted this real-world study in a central Chinese population to identify patient characteristics potentially associated with clinical benefits from CDK4/6 inhibitors such as abemaciclib and ribociclib.

Methods: This retrospective study analyzed 1,947 patients with stage I-III HR+ invasive breast cancer (BC) treated at Xiangya Hospital, China, from 2015 to 2021. The clinicopathological profiles of patients meeting the eligibility criteria of the MonarchE and NATALEE trials were compared. Eligibility was defined according to trial-specific inclusion criteria: MonarchE required ≥4 positive lymph nodes (LNs) or 1-3 LNs with tumor size ≥5 cm or grade 3 histology (Cohort 1), or 1-3 LNs with Ki-67 ≥20% (Cohort 2). NATALEE included stage IIB-III and high-risk stage IIA (T2N0 with grade 3 or Ki-67 ≥20%).

Results: Among the cohort, 26.7% (n=519) met MonarchE criteria, with a higher proportion of grade 3 tumors (25.2%) and T3 disease (17.9%). The cohort was composed of 70.7% of Cohort 1 and 29.3% of Cohort 2. In Cohort 1, 36.5% of patients exhibited 1-3 node-positive disease with high-risk biological features. In contrast, 58.0% (n=1,130) were eligible for NATALEE, including 295 stage III, 417 stage IIB, and 312 node-negative (N0) patients with high-risk biological characteristics (26.0% grade 3; 85.3% Ki-67 ≥20%). NATALEE-eligible patients were older (median age 50 vs. 49 years) and showed greater heterogeneity in Ki-67 expression (44.9% had Ki-67 <20%). Notably, 45.8% of NATALEE-eligible patients overlapped with MonarchE criteria, and 27.6% of the NATALEE cohort consisted of N0 patients with aggressive biological features.

Conclusions: These findings challenge the traditional nodal-centric risk stratification model and highlight important disparities in the patient populations defined by trial eligibility criteria. The data suggest that nearly 60% of HR+ EBC patients may qualify for adjuvant ribociclib therapy under NATALEE criteria, indicating a broader therapeutic eligibility than previously recognized and emphasizing the need for a more inclusive, biology-driven approach to treatment selection in HR+ EBC.

Background: Male breast cancer (MBC) is a rare disease. Limited studies have investigated Chinese MBC patients or compared them with patients in other countries. This study aims to explore the features of Chinese MBC patients by comparing them with their American counterparts.

Methods: We retrospectively collected data of Chinese MBC patients from 36 centers in China and American MBC patients from the Surveillance, Epidemiology, and End Results database, all of which were diagnosed between 1988 and 2020. Overall survival (OS) comparisons were evaluated by the Kaplan-Meier method, log-rank test, and Cox regression analyses.

Results: In total, 1,119 Chinese MBC patients and 11,522 American patients were included. Comparatively, Chinese patients were younger (mean ± standard deviation: 60.9±12.7 in China vs. 66.6±12.8 years in the US, P<0.001) and present different stage distribution (P<0.001). Larger proportion of Chinese patients received mastectomy (89.1% vs. 67.3%, P<0.001) and chemotherapy (52.5% vs. 30.0%, P<0.001). They also demonstrated longer OS across all four adjustment models. Model 2, which adjusted for age, year of diagnosis, stage and surgery, achieved a balance between sample size and data completeness, and was considered the optimal model [Americans as reference, hazard ratio (HR) =0.65; 95% confidence interval (CI), 0.54-0.78; P<0.001].

Conclusions: The disparities in characteristics and treatment between Chinese and American MBC patients were demonstrated. Chinese patients tended to receive more aggressive surgery as well as chemotherapy and present with different OS even after adjustments.