Dalpiciclib and pyrotinib in women with HER2-positive advanced breast cancer: a single-arm phase II trial.

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.

Clinicopathological features and prognosis of breast cancer combined with symptomatic bone marrow metastases: A 10-year, single-center, real-world study of 67 cases.

PURPOSE: Bone marrow metastasis (BMM) is uncommon in breast cancer (BC), and early diagnosis is challenging. BMM lacks definitive treatment options and poses a great threat to the survival of patients. Herein, we investigated the clinical features, prognosis, and factors affecting the prognosis of BC patients with symptomatic BMM to help improve the understanding of this disease and provide effective diagnostic and treatment strategies. METHODS: Clinical data of 67 patients with BC and BMM were retrospectively analyzed for clinical characteristics, treatment, and prognosis of BMM. Univariate and multivariate analyses were performed to determine factors affecting overall survival following BMM (BMMOS). RESULTS: Among patients with BMM, 86.6% were diagnosed after bone metastasis (BM), while 13.4% were diagnosed simultaneously with BM. A total of 73.1%, 13.4%, and 13.4% of the patients had hormone receptor-positive/human epidermal growth factor 2-negative (HR+/HER2-) tumors, HER2+ tumors, and triple-negative tumors, respectively. The most common symptoms of BMM were the coexistence of anemia and thrombocytopenia (26.9%), anemia (19.4%), and pancytopenia (17.9%). The median BMMOS was 7.6 months (95% CI, 3.9-11.3). Univariate and multivariate analyses showed that BMMOS was associated with platelet count <75 × 109 /L at the time of BMM diagnosis. The BMMOS of patients who underwent endocrine therapy, combined chemotherapy, and mono-chemotherapy after BMM was 15.7, 9.7, and 8.6 months, respectively, whereas that of untreated patients was 2.9 months, and the difference among the results was statistically significant (χ2  = 20.102, p < 0.0001). Changes in patient hemogram and/or body temperature during treatment were consistent with the overall effect of the disease (p < 0.0001). CONCLUSION: BMM should be considered in BC patients with BM, an unexplained reduction in hemogram parameters, especially anemia and thrombocytopenia, and/or fever without chills. Active, effective, individualized treatment strategies can prolong BMMOS.

Diagnostic diversity and heterogeneity of tumors: a real-world study of metastasis re-biopsy in advanced breast cancer.

BACKGROUND: Re-biopsy of metastasis in advanced breast cancer (ABC) has become an international convention to assist the diagnosis and evaluation of tumor heterogeneity. This study aimed to detect diagnostic diversity and inconsistencies among estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression levels between primary and metastatic lesions. METHODS: We conducted a retrospective analysis of 1670 cases of ABC patients who had undergone at least one lesion re-biopsy from January 2010 to December 2018. The pathological diagnosis of biopsies, distribution of biopsy sites, and severe puncture complications at each site were collected. In addition, the inconsistency rates and related factors of ER, PR, and HER2 expression between primary and metastatic lesions were analyzed fully considering patients' demographic profiles and disease characteristics. RESULTS: In total, 1670 cases of breast cancer (BC) patients diagnosed by pathology underwent one to four biopsies of recurrences or metastases in different sites or at different stages during the rescue treatment, producing 2019 histopathological specimens which were analyzed in the study. Pathological diagnosis showed that eight patients had benign pathological diagnoses, 11 patients had second primary malignant tumors but without recurrences of breast cancer, and 17 patients had pathologically confirmed breast cancer recurrences combined with second primary cancer. In 1173 patients who presented ER, PR, and HER2 expressions in primary and metastatic lesions, the inconsistency rates of ER, PR, and HER2 were 17.5% (205/1173), 31.3% (367/1173), and 13.9% (163/1173), respectively. The multivariate analysis showed that the age at the onset of breast cancer or adjuvant endocrine therapy was an independent factor affecting changes in PR expression level. Except one liver puncture with local hemorrhage and two lung punctures with hemopneumothorax, no other severe puncture complications occurred in 1950 non-surgical rebiopsies. CONCLUSIONS: The pathological diagnosis of metastasis re-biopsy of ABC was diverse, and the ER, PR, and HER2 expression levels were inconsistent between primary and metastatic lesions. Therefore, more attention should be paid to perform biopsies of relapsed and metastatic breast cancers routinely in clinical practice.

First-in-human HER2-targeted Bispecific Antibody KN026 for the Treatment of Patients with HER2-positive Metastatic Breast Cancer: Results from a Phase I Study.

PURPOSE: KN026 is a novel bispecific antibody that simultaneously binds to two distinct HER2 epitopes. This first-in-human phase I study evaluated the safety/tolerability, pharmacokinetics, preliminary efficacy, and potential predictive biomarker activity of KN026 administered as monotherapy to patients with HER2-positive metastatic breast cancer (MBC). PATIENTS AND METHODS: Female patients with HER2-positive MBC who had progressed on prior anti HER2 therapies received intravenous KN026 monotherapy at 5 mg/kg (once weekly), 10 mg/kg (once weekly), 20 mg/kg (once every 2 weeks), or 30 mg/kg (once every 3 weeks). Dose escalation was guided by a "3+3" dose escalation rule followed by dose expansion. RESULTS: Sixty-three patients were enrolled. The most common treatment-related adverse events (TRAE) were pyrexia (23.8%), diarrhea (22.2%), aspartate aminotransferase increased (22.2%), alanine aminotransferase increased (22.2%). Only 4 patients reported grade 3 TRAEs. Results from exposure-response analysis supported the selection of the recommended phase II doses at 20 mg/kg once every 2 weeks or 30 mg/kg once every 3 weeks, which had objective response rates (ORR) of 28.1% and median progression-free survival (PFS) of 6.8 months (95% confidence interval: 4.2-8.3) in 57 patients. Translational research in 20 HER2-amplified patients further confirmed that co-amplification (vs. no co-amplification) of CDK12 was a promising biomarker in predicting better response to KN026 (ORR of 50% vs. 0% and median PFS of 8.2 vs. 2.7 months, P = 0.05 and 0.04, respectively). CONCLUSIONS: KN026, a HER2 bispecific antibody, was well tolerated and achieved comparable efficacy as trastuzumab and pertuzumab doublet even in the more heavily pretreated patients. Co-amplification of HER2/CDK12 may define patients who benefit more from KN026.

Distress Thermometer in breast cancer: systematic review and meta-analysis.

OBJECTIVE: This meta-analysis aimed to reach a summarised estimate of distress prevalence screened by Distress Thermometer (DT) among patients with breast cancer and compare different pooled prevalence estimated between different subgroups. METHODS: Two independent interviewers conducted a systematic search from PubMed, EMBASE, Ovid and Cochrane Library and checked related reviews and meta-analyses for eligible studies. The studies that identified distress of patients with breast cancer with DT were included. After extracting demographic characteristics and distress prevalence, the pooled analysis and the forest plot were completed by using STATA V.12.0 software. We conducted a subgroup analysis based on demographic and methodological characteristics of the studies. The publication bias was estimated by funnel plot. RESULTS: Seventeen studies describing 3870 patients with breast cancer were included in this meta-analysis. The distress prevalence of patients with breast cancer varied from 25.3% to 71.7% among these studies. The pooled distress prevalence was 50% (95% CI 49% to 52%) for the overall sample. The pooled distress prevalence rates in DT ≥7, DT ≥5 and DT ≥4 subgroups were 37% (95% CI 35% to 40%), 45% (95% CI 40% to 49%) and 62% (95% CI 60% to 65%), respectively. The distress prevalence had statistically significant differences between subgroups, which were differentiated by the initial time of distress identified, papers' publication time, patients' average age and country. There was no publication bias among the included studies. CONCLUSION: The distress prevalence was high among patients with breast cancer. Routine and timely screening of distress for patients with breast cancer is of great significance in oncology management.

Efficacy and safety of bevacizumab-containing therapy for refractory advanced breast cancer: a retrospective study.

BACKGROUND: Advanced breast cancer (ABC) is difficult to treat due to the primary and acquired resistance, which is the main cause of rescue treatment failure. Thus, developing a new rescue treatment strategy for clinicians is a challenge. This study retrospectively collected the medical information of patients with refractory ABC who were treated with bevacizumab at our department to analyze the efficacy and safety of bevacizumab-containing therapy as a new treatment method for refractory ABC. METHODS: The complete medical information of patients receiving bevacizumab treatment from November 2017 to November 2020 was collected, and patients' general medical history and disease characteristics were analyzed. The objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), time to failure (TTF), overall survival (OS), and safety were also analyzed using SPSS 20.0 statistical software. RESULTS: The data of 68 women with refractory ABC who received bevacizumab-containing therapy were collected. The last follow-up examinations were performed on March 31, 2021. The ORR was 41.2% and the DCR was 88.2%. The median PFS, TTF, and OS were 6.0 months [95% confidence interval (CI): 3.4-8.6 months], 4.0 months (95% CI: 3.2-4.8 months), and 26.6 months (95% CI: 10.2-43.0 months), respectively. Treatment was discontinued in 2 patients due to chemo-related adverse reactions. The main adverse events related to bevacizumab were hypertension (7.4%) and bleeding (2 cases, 2.9%), both of which were grade 1. No specific adverse events causing the discontinuation of bevacizumab treatment were observed in the other patients. CONCLUSIONS: Among patients with refractory ABC, bevacizumab-containing therapy is feasible and safe, and can be used as a new treatment strategy. However, the question of who can benefit the most from bevacizumab-containing therapy requires further exploration.

Clinical diagnosis and treatment of breast cancer with brain metastases and establishment of a prognostic model: a 10-year, single-center, real-world study of 559 cases.

BACKGROUND: This study involved a retrospective analysis of 559 metastatic breast cancer (MBC) patients with brain metastasis (BM). We aimed to establish the effectiveness of different preferred treatment methods and factors affecting overall survival following BM diagnosis (BMOS) and explore the feasibility of systemic treatment for MBC patients with BM. METHODS: Univariate and multivariate analyses were used to assess the efficacy of different preferred treatments and other factors associated with BMOS, and a nomogram was then established based on the results of the univariate analysis. RESULTS: Patients that initially received systemic drug therapy exhibited a clinical benefit rate (CBR) of 43.9% and an intracranial disease control rate (DCR) of 80.6%. The median time between BM diagnosis and the requirement for local intracranial treatment due to worsening disease status was 10.0 months for these patients (95% CI: 7.811-12.189 months). The median follow-up was 28.0 months, and the median BMOS was 16.0 months. Following BM diagnosis, the systemic drug treatment group had a better outcome than the local brain treatment group, with a respective median BMOS of 22.0 and 16.0 months (χ2=7.743, P=0.005). At the time of BM diagnosis, the median BMOS for patients without neurological symptoms diagnosed by regular screen was significantly longer than that of patients with neurological symptoms (18.0 vs. 13.0 months, respectively; χ2=11.371, P=0.001). Based on these analyses, a nomogram was constructed that incorporated disease-free survival (DFS), Karnofsky performance status (KPS), molecular subtype, number of extracranial metastases, BM location, number of BMs, neurological symptoms, and the preferred treatment approach, with a prediction probability (c-index) value of 0.76. CONCLUSIONS: Systemic drug treatment has a beneficial effect on brain lesions, and effective treatment delays the need for local intracranial treatment. Cranial magnetic resonance imaging (MRI) screening can detect asymptomatic BM in MBC patients (particularly those with HER2-positive or triple-negative disease), offering these patients an opportunity to undergo systemic drug therapy, thereby prolonging their survival. To our knowledge, this is a well-fitted nomogram including current treatment and medical examination strategies to predict BMOS probability that offers value as an adjunct for the prognostic evaluation of MBC-BM patients.

Clinical study of first-line endocrine therapy for type ER+/PR+ and ER+/PR- advanced breast cancer.

BACKGROUND: This study was designed to evaluate the relationship between estrogen receptor (ER) and progesterone receptor (PR) expression status and clinical outcomes in advanced breast cancer patients undergoing first-line endocrine therapy. METHODS: Data from 225 advanced breast cancer patients admitted to Henan Cancer Hospital from February 2010 to October 2019 were collected and compared using Chi-squared tests, with Cox regression models being used to identify relevant prognostic factors in these patients. RESULTS: PR+ and PR- patients had significantly different median progression-free survival (PFS) times of 25 months (95% CI: 13.50-36.50) and 7 months (95% CI: 4.03-9.97), respectively (P<0.001). Clinical benefit rates (CBR) were also significantly different between these 2 groups (80.9% and 55.6%, respectively; P<0.001). A subgroup analysis of PR+ and PR- patients that underwent aromatase inhibitor (AI) treatment revealed a median PFS of 25.0 months (95% CI: 14.28-35.72) and 7 months (95% CI: 4.18-9.82), respectively (P<0.001), and CBR values of 81.3% and 54.5%, respectively (P<0.001). In addition, for both the whole cohort and the AI subgroup, the total survival of patients with ER+/PR+ breast cancer was longer than that of patients with ER+/PR- breast cancer, and the difference was statistically significant (P<0.001). CONCLUSIONS: ER+/PR+ advanced breast cancer patients had a better prognosis than ER+/PR- advanced breast cancer patients undergoing first-line endocrine therapy. In addition, we found that PR status was an independent predictor of first-line endocrine therapy responses in hormone receptor-positive HER2 negative patients.

[Efficacies of aromatase inhibitors in the treatment of hormone dependent metastatic breast cancer in postmenopausal women: a report of 148 cases].

OBJECTIVE: To evaluate the clinical efficacies of aromatase inhibitors in the treatment of postmenopausal metastatic breast cancer. METHODS: A total of 148 postmenopausal women (including bilateral ovariectomy) with hormone dependent metastatic breast cancer receiving aromatase inhibitors (letrozole, anastrozole or exemestane) were analyzed retrospectively. Their clinical efficacies were evaluated. RESULTS: The median progression-free survival (PFS) was 6.5 months and the clinical benefit rate 63.5%. And the rates of PFS of patients on first-line and second-line or above treatments were 9.0 (95% CI: 6.95-11.05) and 3.0 months (95% CI: 1.8-10.1) respectively. The clinical benefit rates of two groups were 74.2% and 26.3% respectively. CONCLUSION: Aromatase inhibitors are both efficacious and well-tolerated for patients of postmenopausal metastatic breast cancer. It may be recommended as a first-line therapy for postmenopausal women with hormone dependent metastatic breast cancer.

Efficacy of capecitabine-based combination therapy and single-agent capecitabine maintenance therapy in patients with metastatic breast cancer.

OBJECTIVE: The purpose of this study was to observe the efficacy and toxicities of capecitabine-based chemotherapy and capecitabine monotherapy as maintenance therapy in the treatment of metastatic breast cancer (MBC). PATIENTS AND METHODS: A total of 98 MBC patients were treated with capecitabine combined with vinorelbine (NX). RESULTS: The median number of treatment was 6 cycles (1-7 cycles). There were two cases of complete remission (CR), 58 partial remission, 27 stable disease (SD), 11 progression disease. The overall response rate (ORR) (CR + PR) was 61.2%. The clinical benefit rate (CBR) was 75.5%. Fifty of effective patients received with capecitabine monotherapy as maintenance therapy. The ORR (CR + PR) was 4%. The CBR was 48%. The median progression-free survival (PFS) was 12 months. In maintenance therapy or not, the median post metastasis survival rate (MSR) was 63 and 28 months, respectively. In the combination therapy group, the major grade 3/4 toxicities included hand-foot syndrome (3.1%), skin pigmentation (2.0%), diarrhoea and abdominal distension (5.1%), stomatitis (1.0%), and leukopenia (20.4%). CONCLUSIONS: Capecitabine-based combination therapy and single-agent capecitabine maintenance therapy were well tolerated and effective to MBC.