Receptor-negative Breast Cancer Research Articles

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.

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.

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.

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.

The Analysis of Plasma Proteomics for Luminal A Breast Cancer.

Breast cancer is the prevailing malignancy among women, exhibiting a discernible escalation in incidence within our nation; hormone receptor-positive (HR+) human epidermal growth factor receptor 2-negative (HER2-) breast cancer is the most common subtype. In this study, we aimed to search for a non-invasive, specific, blood-based biomarker for the early detection of luminal A breast cancer through proteomic studies. To explore new potential plasma biomarkers, we applied data-independent acquisition (DIA), a technique combining liquid chromatography and tandem mass spectrometry, to quantify breast cancer-associated plasma protein abundance from a small number of plasma samples in 10 patients with luminal A breast cancer, 10 patients with benign breast tumors, and 10 healthy controls. The proteomes of 30 participants in all cohorts were analyzed using the DIA method, and a total of 517 proteins and 3584 peptides were quantified. We found that there were significant differences in plasma protein expression profiles between breast cancer patients and non-breast cancer patients, and breast cancer was mainly related to lipid metabolism pathways. Finally, the optimal protein combinations for the diagnosis of breast cancer were PON3, IGLV3-10, and IGHV3-73 through multi-model analysis, which had a high prediction accuracy for breast cancer (AUC = 0.92), and the model could also distinguish breast cancer from HC (AUC = 0.92) and breast cancer from benign breast tumor (AUC = 0.91). The study revealed proteomic signatures of patients with luminal A breast cancer, identified multiple differential proteins, and identified three plasma proteins as potential diagnostic biomarkers for breast cancer. It provides a reference for the screening of biomarkers for breast cancer.

Lichenoid dermatitis induced by abemaciclib in a patient with HR+/HER2- breast cancer

Cyclin-dependent kinase (CDK) 4/6 inhibitors, such as palbociclib, ribociclib, and abemaciclib, are widely used in combination with endocrine therapy for the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer. Despite their efficacy, these drugs are associated with a range of adverse events, including dermatologic toxicities. This case report presents a rare instance of lichenoid dermatitis in a 48-year-old woman following treatment with abemaciclib. The patient developed erythematous, edematous plaques and papules on her hands and forearms, which resolved after discontinuation of the drug and treatment with topical corticosteroids. This report highlights the need for awareness of cutaneous side effects associated with CDK4/6 inhibitors, particularly abemaciclib.

MAP3K1 mutations confer tumor immune heterogeneity in hormone receptor-positive HER2-negative breast cancer.

Hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer, the most common type of breast cancer, is facing challenges such as endocrine therapy resistance and distant relapse. Immunotherapy has shown progress in treating triple-negative breast cancer, but immunological research on HR+/HER2- breast cancer is still in its early stages. Here, we performed a multi-omics analysis of a large cohort of HR+/HER2- breast cancer patients (n = 351) and revealed that HR+/HER2- breast cancer possessed a highly heterogeneous tumor immune microenvironment. Notably, the immunological heterogeneity of HR+/HER2- breast cancer was related to MAP3K1 mutation and we validated experimentally that MAP3K1 mutation could attenuate CD8+ T cell-mediated antitumor immunity. Mechanistically, MAP3K1 mutation suppressed MHC-I-mediated tumor antigen presentation through promoting the degradation of antigen peptide transporter 1/2 (TAP1/2) mRNAs, thereby driving tumor immune escape. In preclinical models, the postbiotics tyramine could reverse the MAP3K1 mutation-induced MHC-I reduction, thereby augmenting the efficacy of immunotherapy. Collectively, our study identified the vital biomarker driving the immunological heterogeneity of HR+/HER2- breast cancer and elucidated the underlying molecular mechanisms, which provided the promise of tyramine as a novel therapeutic strategy to enhance the efficacy of immunotherapy.

Real-world outcomes of everolimus-based treatment in a Taiwanese cohort with metastatic HR+/HER2- breast cancer.

Everolimus was the first orally targeted therapy for certain cancers. It was introduced before CDK4/6 inhibitors and is widely used to treat advanced hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer. This study presents comprehensive findings including updated data and long-term survival analyses focusing on patients with HR+/HER2- metastatic breast cancer who received everolimus-based treatment. The objectives were to assess the impact of everolimus on overall survival (OS) and progression-free survival (PFS) by treatment line, and to evaluate its role in therapeutic strategies in a real-world setting. We included 299 women aged over 20 years with histologically confirmed HR+/HER2- breast cancer who received everolimus-based treatment from multiple medical centers in Taiwan. Survival curves were generated using the Kaplan-Meier method, with the log-rank test for comparisons. Univariate and multivariate analyses were performed using a Cox proportional hazards regression model. Adverse effects were graded according to the Common Terminology Criteria for Adverse Events version 5.0. The median PFS was 5.6 months, and the median OS was 60.1 months. Patients receiving everolimus treatment in three or more lines and those who underwent chemotherapy prior to everolimus-based treatment had a significantly shorter PFS but longer OS. Patients with liver and central nervous system metastases had significantly shorter PFS and OS. The disease control rate was 51.5%, and the overall response rate was 8.0%. These findings support current guidelines and advocate for the inclusion of everolimus in treatment plans for patients with metastatic HR+/HER2- breast cancer, particularly in late-line treatment, with careful consideration of the benefit-risk profile for each patient.

The role of adjuvant endocrine treatment in ER+, PR−, HER2− early breast cancer: a retrospective study of real-world data

Purpose: Estrogen receptor-positive (ER+), progesterone receptor-negative (PR-) and human epidermal growth factor receptor 2-negative (HER2−) breast cancer (BC) often developed resistance to endocrine treatment (ET). We aimed to explore (1) the different clinicopathological features between ER+/PR+/HER2- and ER+/PR-/HER2- BC, and (2) whether ER+/PR-/HER2- early BC patients could benefit from adjuvant ET. Methods: All patients treated for ER+/HER2- early BC who underwent surgery between 2010 and 2021 from a BC database in China were retrospectively examined. The cases followed up for less than six months were excluded. Results: The records of ER+/PR+/HER2- (n = 10843) and ER+/PR-/HER2- BC (n = 1193) cases were reviewed, with median follow-up times of 35.8 and 47.0 months, respectively. Compared with ER+/PR+/HER2- cases, ER+/PR-/HER2- BC occurred more in postmenopausal women (73.1% vs. 52.9%, p = 0.000) and were more likely to be T > 2 cm (40.6% vs. 37.6%, p = 0.048) and Ki67 > 20%+ (48.1% vs. 36.9%, p = 0.000). However, ER+/PR-/HER2- cases had fewer nodal involvement (32.9% vs. 36.9%, p = 0.000). Approximately 82.2% (981/1193) of ER+/PR-/HER2- patients received ET, while approximately 17.8% (212/1193) did not. Compared to patients did not receive adjuvant ET, the ET group had similar disease-free survival (DFS) (HR = 1.33, 95% confidence interval (CI): 0.68–2.59, p = 0.444) and overall survival (OS) (HR = 1.17, 95%CI: 0.37–3.68, p = 0.799). 65.7% of recurrent ER+/PR-/HER2- patients experienced distant relapse (65.7% vs. 48.2% (for ER+/PR + cases), p = 0.011). By comparison, recurrent ER+/PR+/HER2- patients were more likely to experience only local relapse (31.6% vs. 14.9% (for ER+/PR- cases), p = 0.007). Conclusions: ER+/PR-/HER2- BC was a special subtype with aggressive clinicopathological features and more tend to have distant metastasis rather than nodal involvement or local relapse. ER+/PR-/HER2- early BC did not seem to benefit from adjuvant ET.

High chromosomal instability is associated with higher 10-year risks of recurrence for hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer patients: clinical evidence from a large-scale, multiple-site, retrospective study.

Long-term survival varies among hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) breast cancer patients and is seriously impaired by metastasis. Chromosomal instability (CIN) was one of the key drivers of breast cancer metastasis. Here we evaluate CIN and 10-year invasive disease-free survival (iDFS) and overall survival (OS) in HR+/HER2-- breast cancer. In this large-scale, multiple-site, retrospective study, 354 HR+/HER2- breast cancer patients were recruited. Of these, 204 patients were used for internal training, 70 for external validation, and 80 for cross-validation. All medical records were carefully reviewed to obtain the disease recurrence information. Formalin-fixed paraffin-embedded tissue samples were collected, followed by low-pass whole-genome sequencing with a median genome coverage of 1.86X using minimal 1 ng DNA input. CIN was then assessed using a customized bioinformatics workflow. Three or more instances of CIN per sample was defined as high CIN and the frequency was 42.2% (86/204) in the internal cohort. High CIN correlated significantly with increased lymph node metastasis, vascular invasion, progesterone receptor negative status, HER2 low, worse pathological type, and performed as an independent prognostic factor for HR+/- breast cancer. Patients with high CIN had shorter iDFS and OS than those with low CIN [10-year iDFS 11.1% versus 82.2%, hazard ratio (HR) = 11.12, p < 0.01; 10-year OS 45.7% versus 94.3%, HR = 14.17, p < 0.01]. These findings were validated in two external cohorts with 70 breast cancer patients. Moreover, high CIN could predict the prognosis more accurately than Adjuvant! Online score (10-year iDFS 11.1% versus 48.6%, HR = 2.71, p < 0.01). Cross-validation analysis found that high consistency (83.8%) was observed between CIN and MammaPrint score, while only 45% between CIN and Adjuvant! Online score. In conclusion, high CIN is an independent prognostic indicator for HR+/HER2- breast cancer with shorter iDFS and OS and holds promise for predicting recurrence and metastasis.

Predictive Value of Immune Activity Changes in Breast Cancer Patients Treated With Dose-dense Neoadjuvant Chemotherapy: A Retrospective Study.

Dose-dense chemotherapy is recommended for patients with breast cancer who have a high recurrence risk. However, whether dose-dense neoadjuvant chemotherapy (ddNAC) improves patient prognoses compared to the normal-dose regimen remains controversial. In this study, we evaluated the predictive value of immune activities on short-term outcomes for patients treated with ddNAC. We classified 82 patients with human epidermal growth factor receptor 2-negative breast cancer treated with NAC into a normal dose group (62 patients) and ddNAC group (20 patients) and examined the differences in clinicopathological features. The ddNAC group was further divided according to patient responses to NAC and the predictive factors for pathological complete response (pCR) were evaluated. There were no differences in the clinicopathological features before NAC between the normal dose and ddNAC groups. Although the pCR rates tended to be higher in the ddNAC group compared than those in the normal dose group (35.0% vs. 25.8%), there was not significant difference (p=0.264). Among all patients treated with ddNAC, the absolute lymphocyte count decreased and the neutrophil-to-lymphocyte ratio increased during dose-dense doxorubicin plus cyclophosphamide treatment. There was no significant correlation between the pCR and any of the clinicopathological parameters tested including systemic peripheral markers and tumor-infiltrating lymphocyte levels. ddNAC affected the levels of systemic peripheral immune markers. However, monitoring these markers may not be useful for predicting responses to ddNAC.

Palbociclib plus aromatase inhibitors in patients with metastatic breast cancer and cardiovascular diseases: real-world effectiveness.

Patients with cardiovascular disease (CVD) comorbidities are often excluded from participating in breast cancer clinical trials. Consequently, data to inform treatment decisions for patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic breast cancer (mBC) and CVD are limited. We compared the effectiveness of first-line palbociclib plus an aromatase inhibitor (AI) vs an AI alone and evaluated palbociclib treatment patterns in patients with HR+/HER2- mBC and CVD in routine clinical practice. Data from the Flatiron Health Analytic Database were captured for patients with HR+/HER2- mBC and CVD who initiated first-line treatment with palbociclib plus an AI or an AI alone between February 2015 and March 2020 (data cutoff: September 30, 2020). Overall survival (OS), real-world progression-free survival (PFS), and treatment patterns were evaluated. Of the 469 patients with identifiable CVD, 160 received palbociclib plus an AI, and 309 received an AI alone. After stabilized inverse probability treatment weighting, both median OS (40.7 vs 26.5 months; hazard ratio [HR], 0.732 [95% CI, 0.537-0.997]; P = .048) and median real-world PFS (20.0 vs 12.5 months; HR, 0.679 [95% CI, 0.512-0.900]; P = .007) were significantly prolonged in patients treated with palbociclib plus an AI vs an AI alone. Among patients with a documented palbociclib starting dose, 78.5% started palbociclib at 125 mg/day, and 38.6% experienced dose adjustment. In this real-world analysis, first-line palbociclib plus an AI was associated with improved effectiveness compared with an AI alone in patients with HR+/HER2- mBC and CVD. NCT05361655 (ClinicalTrials.gov).