Exploring the clinical outcomes and safety profile of inetetamab treatment in metastatic breast cancer patients: A multicenter assessment of a Chinese-origin recombinant Anti-HER2 monoclonal antibody.

BACKGROUND: Inetetamab is a novel recombinant humanized anti-HER2 monoclonal antibody. This study aimed to evaluate the efficacy and safety of inetetamab and predictive factors for response in HER2-positive metastatic breast cancer (MBC) patients. METHODS: A cohort of HER2-positive MBC patients who received inetetamab-based therapy between June 2020 and August 2021 was evaluated. The primary endpoint was progression-free survival (PFS), and the secondary endpoints included objective response rate (ORR) and disease control rate (DCR). Adverse events (AEs) were graded according to the National Cancer Institute Common Toxicity Criteria. RESULTS: A total of 141 patients were included in the final analysis. The median PFS of the entire cohort was 7.1 months. The median number of treatment lines administered was three. The ORR was 36.9 %, and the DCR was 80.9 %. The most frequently employed treatment strategy was inetetamab + chemotherapy (49/141, 34.8 %), followed by inetetamab + HER2-tyrosine kinase inhibitors (HER2-TKIs) + chemotherapy, inetetamab + pertuzumab + chemotherapy, inetetamab + endocrine treatment and inetetamab + HER2-TKIs. Cox multivariate analysis revealed that PFS was associated with liver metastasis (hazard ratio [HR] 2.112, 95 % confidence interval [CI] 1.334-3.343, p = 0.001), previous HER2-TKI treatment (HR 2.019, 95 % CI 1.133-3.597, p = 0.017) and estrogen receptor positivity (HR 0.587, 95 % CI 0.370-0.934, p = 0.024). The toxicity was tolerable, with neutropenia being the most common treatment-related grade 3/4 AE (14.9 %). CONCLUSION: Inetetamab demonstrates effectiveness with a manageable safety profile, offering a promising therapeutic option for HER2-positive breast cancer patients who have shown resistance to prior anti-HER2 treatments.

Pyrotinib in combination with letrozole for hormone receptor-positive, human epidermal growth factor receptor 2-positive metastatic breast cancer (PLEHERM): a multicenter, single-arm, phase II trial.

BACKGROUND: Human epidermal growth factor receptor 2 (HER2) targeted therapy combined with endocrine therapy has been recommended as an alternative treatment strategy for patients with hormone receptor (HR)-positive, HER2-positive metastatic breast cancer (MBC). This study aimed to evaluate the role of pyrotinib, an oral pan-HER irreversible tyrosine kinase inhibitor, in combination with letrozole for patients with HR-positive, HER2-positive MBC. METHODS: In this multi-center, phase II trial, HR-positive and HER2-positive MBC patients who were not previously treated for metastasis disease were enrolled. Patients received daily oral pyrotinib 400 mg and letrozole 2.5 mg until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was the clinical benefit rate (CBR) assessed by an investigator according to the Response Evaluation Criteria in Solid Tumors version 1.1. RESULTS: From November 2019 to December 2021, 53 patients were enrolled and received pyrotinib plus letrozole. As of August 2022, the median follow-up duration was 11.6 months (95% confidence interval [CI], 8.7-14.0 months). The CBR was 71.7% (95% CI, 57.7-83.2%), and the objective response rate was 64.2% (95% CI, 49.8-76.9%). The median progression-free survival was 13.7 months (95% CI, 10.7-18.7 months). The most common treatment-related adverse event of grade 3 or higher was diarrhea (18.9%). No treatment-related deaths were reported, and one patient experienced treatment discontinuation due to adverse event. CONCLUSIONS: Our preliminary results suggested that pyrotinib plus letrozole is feasible for the first-line treatment of patients with HR-positive and HER2-positive MBC, with manageable toxicities. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04407988.

Impact of surgical management of primary tumors in stage IV breast cancer patients: a retrospective observational study based on SEER database.

OBJECTIVES: Although primary tumour surgery could prolong survival for patients with stage IV breast cancer, how to select candidates for primary tumour surgery is still a challenging problem for medical oncologists. DESIGN: This study is a retrospective database study. SETTING AND PARTICIPANTS: In this study, we aimed at evaluating the primary site surgery effect and select the beneficial subgroups. 13 618 patients with stage IV breast cancer, diagnosed between 2010 and 2015, were collected from SEER*Stat database. INTERVENTIONS: Based on the local surgery at primary tumour site, patients were categorised into three groups: primary tumour surgery performed group, recommended for primary tumour surgery but refused (RBR) group and surgery not recommended (NR) group. PRIMARY AND SECONDARY OUTCOME MEASURES: All-cause survival and breast cancer-specific survival (BCSS). RESULTS: Univariate Cox regression analyses showed that, compared with surgery group, patients in non-surgery (RBR and NR) groups tend to be older, T4, N0/NX, triple-negative and visceral metastatic. For both all-cause survival and BCSS, non-surgery, advanced T stage, triple-negative BC (TNBC) and visceral metastases were significant risk factors. Primary tumour surgery showed benefits for both all-cause survival (HR=0.44, 95% CI=0.39-0.49, p<0.0001) and BCSS (HR=0.43, 95% CI=0.38-0.49, p<0.0001). However, after propensity score matching, primary tumour surgery failed to demonstrate significant benefits for TNBC (HR=0.96, 95% CI=0.60-1.53, p=0.851) and patients with visceral metastases (HR=0.90, 95% CI=0.60-1.36, p=0.62). CONCLUSION: Surgery was associated with prolonged survival in stage IV breast cancers, but not in patients with TNBC and visceral metastases.

Pyrotinib plus capecitabine for patients with human epidermal growth factor receptor 2-positive breast cancer and brain metastases (PERMEATE): a multicentre, single-arm, two-cohort, phase 2 trial.

BACKGROUND: Patients with HER2-positive metastatic breast cancer have a high risk of developing brain metastases. Efficacious treatment options are scarce. We investigated the activity and safety of pyrotinib plus capecitabine in patients with HER2-positive metastatic breast cancer and brain metastases. METHODS: We did a multicentre, single-arm, two-cohort, phase 2 trial in eight tertiary hospitals in China. Patients aged 18 years or older who had radiotherapy-naive HER2-positive brain metastases (cohort A) or progressive disease after radiotherapy (cohort B), with an Eastern Cooperative Oncology Group performance status of 0-2, received pyrotinib 400 mg orally once daily, and capecitabine 1000 mg/m2 orally twice daily for 14 days, followed by 7 days off every 3 weeks until disease progression or unacceptable toxicity. The primary endpoint was confirmed intracranial objective response rate by investigator assessment according to the Response Evaluation Criteria In Solid Tumours (version 1.1). Activity and safety were analysed in patients with at least one dose of study drug. The study is ongoing, but recruitment is complete. The study is registered with ClinicalTrials.gov, NCT03691051. FINDINGS: Between Jan 29, 2019, and July 10, 2020, we enrolled 78 women: 51 (86%) of 59 patients in cohort A and 18 (95%) of 19 patients in cohort B had previous exposure to trastuzumab. Median follow-up duration was 15·7 months (IQR 9·7-19·0). The intracranial objective response rate was 74·6% (95% CI 61·6-85·0; 44 of 59 patients) in cohort A and 42·1% (20·3-66·5; eight of 19 patients) in cohort B. The most common grade 3 or worse treatment-emergent adverse event was diarrhoea (14 [24%] in cohort A and four [21%] in cohort B). Two (3%) patients in cohort A and three (16%) in cohort B had treatment-related serious adverse events. No treatment-related deaths occurred. INTERPRETATION: To our knowledge, this is the first prospective study showing the activity and safety of pyrotinib plus capecitabine in patients with HER2-positive breast cancer and brain metastases, especially in radiotherapy-naive population. This combination deserves further validation in a randomised, controlled trial. FUNDING: National Cancer Centre Climbing Foundation Key Project of China, Jiangsu Hengrui Pharmaceuticals. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

FGFR aberrations increase the risk of brain metastases and predict poor prognosis in metastatic breast cancer patients.

BACKGROUND: The survival status of patients with breast cancer and brain metastasis (BCBM) receiving current treatments is poor. METHOD: We designed a real-world study to investigate using patients' clinical and genetic aberrations to forecast the prognoses of BCBM patients. We recruited 146 BCBM patients and analyzed their clinical features to evaluate the overall survival (OS). For genetic testing, 30 BCBM and 165 non-brain-metastatic (BM) metastatic breast cancer (MBC) patients from Hunan Cancer Hospital, and 86 BCBM and 1416 non-BM MBC patients from the Geneplus database who received circulating tumor DNA testing, were compared and analyzed. RESULTS: Ki67 >14% and >3 metastatic brain tumors were significant risk factors associated with poor OS, while chemotherapy and brain radiotherapy were beneficial factors for better OS. Compared with non-BM MBC patients, BCBM patients had more fibroblast growth factor receptor (FGFR) aberrations. The combination of FGFR, TP53 and FLT1 aberrations plus immunohistochemistry HER2-positive were associated with an increased risk of brain metastasis (AUC = 77.13%). FGFR aberration alone was not only a predictive factor (AUC = 67.90%), but also a significant risk factor for poor progression-free survival (Logrank p = 0.029). FGFR1 aberration was more frequent than other FGFR family genes in BCBM patients, and FGFR1 aberration was significantly higher in BCBM patients than non-BM MBC patients. Most FGFR1-amplified MBC patients progressed within 3 months of the late-line (>2 lines) treatment. CONCLUSION: A group of genetic events, including FGFR, TP53 and FLT1 genetic aberrations, and HER2-positivity, forecasted the occurrence of BM in breast cancers. FGFR genetic aberration alone predicted poor prognosis.

In Vivo Detection of CTC and CTC Plakoglobin Status Helps Predict Prognosis in Patients with Metastatic Breast Cancer.

This study aims to detect the prognostic value of circulating tumour cell (CTC) in patients with metastatic breast cancer. In this study, 38 patients with metastatic breast cancer were enrolled. The in vivo CellCollector® method was used to detect the number of CTC in patients. Single CTC and CTC clusters were counted, and the expression of plakoglobin was also analysed. At baseline, 73.7% (28/38) of the patients were positive for ≥ 1 CTC (range, 1-14 cells). No CTC-like events were observed in the control group. Among the CTC-positive patients, 21.4% (6/28) of patients had CTC clusters, and 42.9% (12/28) of patients had plakoglobin-positive CTC. After chemotherapy, 48.6% (17/35) of the patients were positive for ≥ 1 CTC (range, 1-3 cells), of which 3 patients had CTC clusters, and 35.3% (6/17) had plakoglobin-positive CTC. Additionally, we found that the number of CTC clusters in plakoglobin-positive patients was much greater than that in plakoglobin-negative patients, and the number of CTC was associated with the number of sites of metastases. We also found that patients with ≥ 3 CTC at baseline had shorter progression-free survival (PFS) and overall survival (OS), and pre-chemotherapy CTC detection was associated with PFS (P = 0.0001) and OS (P = 0.0091). CTC plakoglobin expression was associated with PFS (P = 0.02) but not OS (P = 0.22). CTC collected by the in vivo CellCollector method in Chinese patients with metastatic breast cancer have prognostic significance. CTC plakoglobin expression may be associated with CTC clusters, and more in-depth studies are needed.

Inducing or Preventing Subsequent Malignancies for Breast Cancer Survivors? Double-edged Sword of Estrogen Receptor and Progesterone Receptor.

INTRODUCTION: Hormone receptor and human epidermal growth factor receptor 2 (HER2) status is important for breast cancer (BC) treatment. Previous studies have shown that the long-term treatment outcomes of BC are significantly impaired by the development of subsequent malignancies. Therefore, in the present study, we evaluated the effect of hormone receptor/HER2 status on subsequent malignancies in breast cancer survivors. METHODS AND MATERIALS: The Surveillance, Epidemiology, and End Results*Stat database (8.3.4) was used as the data source. We identified 535,941 female survivors with first primary BC through the database from 1973 to 2013. Of these patients, 23,964 had developed subsequent contralateral BC, 8398 had developed subsequent uterine or ovarian cancer, and 7435 patients had developed subsequent colorectal cancer. RESULTS: Estrogen receptor (ER) positivity and progesterone receptor (PR) positivity were significant protective factors against subsequent BC and ovarian cancer. However, ER+ BC and PR+ BC were significant risk factors for subsequent colorectal cancer. In addition, HER2+ status demonstrated a marginally significant risk effect for subsequent thyroid cancer. Triple-negative (ER-/PR-/HER2-) status showed elevated risk of subsequent breast, ovarian, and uterine cancer. CONCLUSION: ER+/PR+ patients were less likely develop secondary breast and ovarian malignancies, possibly owing to advancements in anti-ER/PR treatment. However, ER+/PR+ patients were more likely to develop colorectal cancer, suggesting a potential screening necessity for these patients.

Identifying Circulating Tumor DNA Mutation Profiles in Metastatic Breast Cancer Patients with Multiline Resistance.

PURPOSE: In cancer patients, tumor gene mutations contribute to drug resistance and treatment failure. In patients with metastatic breast cancer (MBC), these mutations increase after multiline treatment, thereby decreasing treatment efficiency. The aim of this study was to evaluate gene mutation patterns in MBC patients to predict drug resistance and disease progression. METHOD: A total of 68 MBC patients who had received multiline treatment were recruited. Circulating tumor DNA (ctDNA) mutations were evaluated and compared among hormone receptor (HR)/human epidermal growth factor receptor 2 (HER2) subgroups. RESULTS: The baseline gene mutation pattern (at the time of recruitment) varied among HR/HER2 subtypes. BRCA1 and MED12 were frequently mutated in triple negative breast cancer (TNBC) patients, PIK3CA and FAT1 mutations were frequent in HR+ patients, and PIK3CA and ERBB2 mutations were frequent in HER2+ patients. Gene mutation patterns also varied in patients who progressed within either 3 months or 3-6 months of chemotherapy treatment. For example, in HR+ patients who progressed within 3 months of treatment, the frequency of TERT mutations significantly increased. Other related mutations included FAT1 and NOTCH4. In HR+ patients who progressed within 3-6 months, PIK3CA, TP53, MLL3, ERBB2, NOTCH2, and ERS1 were the candidate mutations. This suggests that different mechanisms underlie disease progression at different times after treatment initiation. In the COX model, the ctDNA TP53 + PIK3CA gene mutation pattern successfully predicted progression within 6 months. CONCLUSION: ctDNA gene mutation profiles differed among HR/HER2 subtypes of MBC patients. By identifying mutations associated with treatment resistance, we hope to improve therapy selection for MBC patients who received multiline treatment.

The association between non-Hodgkin lymphoma and methylation of p73.

To investigate the effects of methylation of the p73 gene on the pathogenesis of non-Hodgkin lymphoma (NHL), the methylation status of the p73 gene promoter and the expression of p73 mRNA were examined in NHLs by methylation-specific polymerase chain reaction (MSP) and reverse transcription-polymerase chain reaction, respectively; p73 protein was detected by Western blotting analysis. Furthermore, the expression of p73 mRNA in NHL cells treated with 5-Aza-2'-deoxycytidine was analyzed. MSP results revealed that the promoter of p73 was methylated in 87.5% of NHLs but was not methylated in reactive hyperplasia lymph node samples. The expression of p73 mRNA was not detected in 83.33% of NHLs but was detected in all of the reactive hyperplasia lymph node samples. The p73 protein was not detected in 91.67% of NHLs but was detected in all of the reactive hyperplasia lymph node samples. The expression of p73 mRNA was detected in NHL cells treated with 5-Aza-2'-deoxycytidine. The inactivation of p73, predominantly by methylation, may be involved in the pathogenesis of NHLs.