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Background: Cyclin‐dependent kinase (CDK) 4/6 inhibitor plus endocrine therapy (ET) become standard‐of‐care for patients with hormone receptor‐positive, human epidermal growth factor receptor‐2 negative (HR+/HER2−) metastatic breast cancer (MBC). However, the optimal therapeutic paradigm after progression on CDK4/6 inhibitor remains unclear. This study aimed to evaluate the efficacy and safety of abemaciclib with switching ET versus chemotherapy after progression on prior palbociclib‐based ET in Chinese patients with HR+/HER2− MBC. Methods: From 414 consecutive patients with HR+/HER2− MBC who had been treated with palbociclib plus ET from September 2018 to May 2022 in Peking University Cancer Hospital, we identified 80 patients who received abemaciclib plus switching ET or chemotherapy after progression on palbociclib, matched for age, original stage at diagnosis, disease‐free interval, and tumor burden at 1:1 ratio. The primary endpoint was progression‐free survival (PFS) compared using the Kaplan–Meier method. A Cox proportional hazard model was performed to identify clinical factors associated with PFS in the abemaciclib group. Results: The median PFS was 6.0 months (95% confidence interval [CI]: 3.94–8.06) in abemaciclib group and 4.0 months (95% CI, 2.52–5.49) in chemotherapy group (p = 0.667). And, there was no difference in median PFS between the sequential and nonsequential arm (6.0 vs. 6.0 months) in the abemaciclib group though fewer lines of prior systemic therapy and longer PFS from prior palbociclib in the sequential arm. However, patients with prior palbociclib as the first‐line therapy had a significantly longer median PFS versus prior palbociclib as ≥2nd‐line therapy (11.0 vs. 5.0 months, p = 0.043). Based on multivariable analysis, ER+/PR+ was an independent factor associated with longer PFS. There was no significant difference in overall survival between the abemaciclib and chemotherapy groups (p = 0.069). Conclusion: Our findings indicate that abemaciclib plus switching ET might be one of feasible treatment options for Chinese patients with HR+/HER2− MBC after progression on prior palbociclib‐based therapy in addition to chemotherapy. [ABSTRACT FROM AUTHOR]

CDK4/6 inhibitors have shown a synergistic effect with anti-HER2 therapy in hormone receptor (HR)-positive and HER2-positive breast cancer (BC). In this phase 2 study (NCT04293276), we aim to evaluate a dual-oral regimen of CDK4/6 inhibitor dalpiciclib combined with HER2 tyrosine kinase inhibitor pyrotinib as front-line treatment in women with HER2-positive advanced BC (n = 41) including those with HR-negative disease. The primary endpoint is the objective response rate, and secondary endpoints include progression-free survival (PFS), overall survival (OS), and safety. With a median follow-up of 25.9 months, 70% (28/40) of assessable patients have a confirmed objective response, meeting the primary endpoint. The median PFS is 11.0 months (95% CI = 7.3–19.3), and OS data are not mature. The most common grade 3 or 4 treatment-related adverse events (AEs) are decreased white blood cell count (68.3%), decreased neutrophil count (65.9%), and diarrhea (22.0%). Most AEs are manageable, and no treatment-related deaths occur. These findings suggest that this combination may have promising activity and manageable toxicity. Further investigation is needed. Dalpiciclib is a CDK4/6 inhibitor, recently approved for treatment in advanced breast cancer patients in China. Here, the authors report the results of a phase II trial investigating oral dalpiciclib (CDK4/6 inhibitor) and pyrotinib (pan-HER inhibitor) in patients with HER2-positive metastatic breast cancer. [ABSTRACT FROM AUTHOR]

Adding CDK4/6 inhibitor dalpiciclib to fulvestrant significantly prolonged progression-free survival in patients with hormone receptor-positive, HER2-negative advanced breast cancer progressing after endocrine therapy. We aimed to assess the efficacy and safety of dalpiciclib plus letrozole or anastrozole in patients with hormone receptor-positive, HER2-negative advanced breast cancer who had no previous systemic therapy in the advanced setting. DAWNA-2 is a randomised, double-blind, placebo-controlled, phase 3 trial done at 42 hospitals in China. Eligible patients were aged 18–75 years, of any menopausal status, had an ECOG performance status of 0–1, and had pathologically confirmed hormone receptor-positive, HER2-negative untreated advanced breast cancer. Patients were randomly assigned (2:1) to receive oral dalpiciclib (150 mg per day for 3 weeks, followed by 1 week off) or matching placebo. Both groups also received endocrine therapy: either 2·5 mg letrozole or 1 mg anastrozole orally once daily continuously. Randomisation was using an interactive web response system (block size of six) and stratified according to visceral metastasis, previous endocrine therapy in the adjuvant or neoadjuvant setting, and endocrine therapy partner. All investigators, patients, and the funders of the study were masked to group allocation. We present the results of the preplanned interim analyses for the primary endpoint of investigator-assessed progression-free survival, which was assessed in all randomly assigned patients who met the eligibility criteria by intention-to treat. Safety was analysed in all randomly assigned patients who received at least one dose of study treatment. The superiority boundary was calculated as a one-sided p value of 0·0076 or less. This trial is registered with ClinicalTrials.gov , NCT03966898 , and is ongoing but closed to recruitment. Between July 19, 2019, and Dec 25, 2020, 580 patients were screened and 456 were eligible and randomly assigned to the dalpiciclib group (n=303) or placebo group (n=153). At data cutoff (June 1, 2022), median follow-up was 21·6 months (IQR 18·3–25·9), and 103 (34%) of 303 patients in the dalpiciclib group and 83 (54%) of 153 patients in the placebo group had disease progression or died. Median progression-free survival was significantly longer in the dalpiciclib group than in the placebo group (30·6 months [95% CI 30·6–not reached] vs 18·2 months [16·5–22·5]; stratified hazard ratio 0·51 [95% CI 0·38–0·69]; one-sided log-rank p<0·0001). Adverse events of grade 3 or 4 were reported in 271 (90%) of 302 patients in the dalpiciclib group and 18 (12%) of 153 patients in the placebo group. The most common adverse events of grade 3 or 4 were neutropenia (259 [86%] in the dalpiciclib group vs none in the placebo group) and leukopenia (201 [67%] vs none). Serious adverse events were reported for 36 (12%) patients in the dalpiciclib group and ten (7%) patients in the placebo group. Two treatment-related deaths occurred, both in the dalpiciclib group (deaths from unknown causes). Our findings suggest that dalpiciclib plus letrozole or anastrozole could be a novel standard first-line treatment for patients with hormone receptor-positive, HER2-negative advanced breast cancer, and is an alternative option to the current treatment landscape. Jiangsu Hengrui Pharmaceuticals and Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences. For the Chinese translation of the abstract see Supplementary Materials section. [ABSTRACT FROM AUTHOR]

Background: Palbociclib was the only available cyclin‐dependent kinase 4/6 inhibitor in China until very recently, and its effect has not been systemically evaluated among Chinese patients. This study aims to assess the efficacy, safety and patient‐reported outcomes (PROs) of palbociclib plus endocrine therapy (ET) in real‐world China. Methods: An ambispective cohort study was conducted on patients with advanced HR+HER2− breast cancer who received palbociclib between July 2018, and November 2020 and were enrolled from 12 hospitals. Treatment patterns, survival outcomes, and safety events were documented, and PROs (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire‐Core 30 items [EORTC QLQ‐C30] and EuroQoL 5 dimensions [EQ‐5D]) were analyzed. The Kaplan–Meier method was used to visualize and estimate the median progression‐free survival (mPFS). Log‐rank tests, Cox regressions, t tests, and chi‐square tests were performed for comparison. Results: A total of 190 patients (median follow‐up of 18.0 months) were enrolled. Palbociclib was mostly combined with aromatase inhibitors (66.3%), fulvestrant (32.6%), and tamoxifen (1.1%). The mPFS values were 21.0, 14.0, and 7.0 months with palbociclib administered in first‐ (n = 83), second‐ (n = 41) and subsequent‐line settings (n = 66), respectively. Endocrine sensitivity was significantly associated with patient prognosis (mPFS: 23.0, 12.0, and 6.0 months for endocrine naïve, acquired, and primary resistant patients, respectively, p < 0.01). The outcome was worse for patients who failed to meet the inclusion criteria of PALOMA‐3 than for those who met the criteria (later‐line: 6.0 months vs. 9.0 months). The most common adverse events (AEs) were neutropenia (74.2%; grade 3/4: 30.0%), fatigue (48.4%), anemia (32.6%), and thrombocytopenia (22.1%). PRO data suggested that palbociclib plus ET significantly improved cognitive and emotional function, pain symptoms, and overall quality of life. Conclusions: Palbociclib is effective for front‐line use and for treating endocrine‐sensitive patients in real‐world China and is generally well tolerated. The prevalence of AEs in the Chinese population is different from that reported in the PALOMA‐2/3 trials. [ABSTRACT FROM AUTHOR]

Background: Palbociclib is the most widely used cyclin-dependent kinase 4/6 inhibitor in China, but its early application efficacy on Chinese metastatic breast cancer (MBC) patients was reported deficiently. Methods: Between February 2019 to December 2021, 95 female hormone receptor-positive (HR+)/human epidermal growth factor receptor-2 negative (HER2−) patients with MBC received palbociclib combined with AI or fulvestrant were retrospectively analyzed in our center. The primary outcome was progression-free survival (PFS). The objective response rate and clinical benefit rate (CBR) were evaluated. Results: The median follow-up period was 15 months (range from 2 to 37). Palbociclib performed superiorly when applicated in first-and-second line therapy than in later lines (P =.002). Palbociclib combined with AI or fulvestrant had a median PFS of 34 months (95% confidence interval [CI] = 6.87-61.13) and 12 months (95%CI = 7.76-16.24), respectively. Univariate subgroup analysis showed that the previous history of salvage chemotherapy (P =.015) and the presence of liver metastases (P <.001) significantly affected the efficacy of palbociclib. Despite the existence of liver metastases and primary endocrine resistance, which are two independent predictors of poor prognosis, early application of palbociclib in advanced stage can bring further benefits to these two groups of patients, rather than choosing salvage chemotherapy in the first place. Conclusion: Palbociclib combined with endocrine therapy has a favorable efficacy and acceptable toxicity in HR+/HER2− Chinese MBC patients. Better performance can be seen when palbociclib was applicated in the early stage. [ABSTRACT FROM AUTHOR]

In China, esophageal squamous cell carcinoma (ESCC), capable of direct invasion and early metastasis, exhibits high mortality. Identification of the molecular basis driving ESCC progression and development of new diagnostic biomarkers are urgently needed. Cyclin-dependent kinase inhibitor 3 (CDKN3) performs crucial roles in the modulation of tumor development. The present study aimed to explore the functions and underlying mechanism of CDKN3 in regulating ESCC cell proliferation and invasion. The expression levels of CDKN3 in ESCC cells were evaluated by reverse transcription-quantitative PCR. Cell counting kit-8 and colony forming assays were used to evaluate cell viability. Wound-healing assay was performed to explore cell migration. Transwell invasion analysis was conducted to investigate the invasive capacity of ESCC cells. Protein levels were detected by western blot assay. The results demonstrated that the expression of CDKN3 was significantly upregulated in ESCC tissues, as predicted using the UALCAN and Gene Expression Omnibus databases. PCR and western blot assays confirmed that CDKN3 was upregulated in ESCC cell lines. Functional assays revealed that CDKN3 knockdown with small interfering RNA decreased the ability of ESCC cells to proliferate, invade and migrate and suppressed G1/S transition. Further mechanistic analyses demonstrated that CDKN3 promoted cell proliferation and invasion by activating the AKT signaling pathway in ESCC cells. To the best of our knowledge, the present study is the first to identify the functions of CDKN3 in ESCC and provide evidence that CDKN3 regulates tumor progression by activating the AKT signaling pathway. Therefore, CDKN3 may serve as a potential effective therapeutic target for ESCC treatment. [ABSTRACT FROM AUTHOR]