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Abstract In recent decades, using circulating tumor cell (CTC), circulating tumor DNA (ctDNA), circulating tumor RNA (ctRNA), exosomes and etc. as liquid biomarkers has received enormous attention in various tumors, including breast cancer (BC). To date, efforts in the area of liquid biopsy predominantly focus on the analysis of blood-based markers. It is worth noting that the identifications of markers from non-blood sources provide unique advantages beyond the blood and these alternative sources may be of great significance in offering supplementary information in certain settings. Here, we outline the latest advances in the analysis of non-blood biomarkers, predominantly including urine, saliva, cerebrospinal fluid, pleural fluid, stool and etc. The unique advantages of such testings, their current limitations and the appropriate use of non-blood assays and blood assays in different settings are further discussed. Finally, we propose to highlight the challenges of these alternative assays from basic to clinical implementation and explore the areas where more investigations are warranted to elucidate its potential utility.

HER2-positive breast cancer is a highly heterogeneous tumor, and about 30% of patients still suffer from recurrence and metastasis after trastuzumab targeted therapy. Predicting individual prognosis is of great significance for the further development of precise therapy. With the continuous development of computer technology, more and more attention has been paid to computer-aided diagnosis and prognosis prediction based on Hematoxylin and Eosin (H&E) pathological images, which are available for all breast cancer patients undergone surgical treatment. In this study, we first enrolled 127 HER2-positive breast cancer patients with known recurrence and metastasis status from Cancer Hospital of the Chinese Academy of Medical Sciences. We then proposed a novel multimodal deep learning method integrating whole slide H&E images (WSIs) and clinical information to accurately assess the risk of relapse and metastasis in patients with HER2-positive breast cancer. Specifically, we obtained the whole H&E staining images from the surgical specimens of breast cancer patients, and these images were adjusted to size 512 × 512 pixels. The deep convolutional neural network (CNN) was applied to these images to retrieve image features, which were combined with the clinical data. Based on the combined features. After that, a novel multimodal model was constructed for predicting the prognosis of each patient. The model achieved an area under curve (AUC) of 0.76 in the two-fold cross-validation (CV). To further evaluate the performance of our model, we downloaded the data of all 123 HER2-positive breast cancer patients with available H&E image and known recurrence and metastasis status in The Cancer Genome Atlas (TCGA), which was severed as an independent testing data. Despite the huge differences in race and experimental strategies, our model achieved an AUC of 0.72 in the TCGA samples. As a conclusion, H&E images, in conjunction with clinical information and advanced deep learning models, could be used to evaluate the risk of relapse and metastasis in patients with HER2-positive breast cancer.

BackgroundHER2-low expression breast cancer (BC) accounts for approximately 45%-55% of all BC cases. The purpose of this study was to investigate the prognostic difference between patients with HER2-low expression and HER2-zero BC.MethodsAn electronic search of Pubmed, Embase, Cochrane Library, and Web of Science databases was performed to screen studies that included prognostic comparisons between HER2-zero and HER2-low expression groups. A total of 14 studies involving 52106 patients were included.ResultsOur results indicated that HER2-low expression was associated with a significant benefit in OS among all patients with early BC (HR, 0.83; 95% CI, 0.78–0.88), patients with hormone-receptor positive BC (HR, 0.83; 95% CI, 0.77–0.89), and patients with TNBC (HR, 0.78; 95% CI, 0.70–0.87). HER2-low expression was associated with a significant benefit in DFS among all patients (HR, 0.81; 95% CI, 0.71–0.93), patients with hormone receptor-positive BC (HR, 0.81; 95% CI, 0.72–0.90), but no significant difference in DFS was found in patients with TNBC (HR, 0.87; 95% CI, 0.65–1.17). HER2-low expression was associated with a significant benefit in RFS among all patients (HR, 0.90; 95% CI, 0.85–0.95), patients with hormone receptor-positive BC (HR, 0.90; 95% CI, 0.84–0.96), but no significant difference in RFS was found in patients with TNBC (HR, 0.80; 95% CI, 0.55–1.16).ConclusionsAmong patients with early-stage BC, patients with HER2-low expression BC had better OS in the overall population, hormone receptor-positive and TNBC subgroups. Besides, favorable DFS and RFS were observed in both the overall population and hormone receptor-positive subgroup.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/, identifier (CRD 42022349458).

Objective: Anlotinib is a novel tyrosine kinase inhibitor blocking angiogenesis. This study was performed to assess the efficacy and safety of anlotinib in patients with metastatic breast cancer. Methods: Patients with HER2-negative breast cancer, who were pre-treated with anthracycline or taxanes in a neoadjuvant, adjuvant, or metastatic setting, and had treatment failure after at least one prior chemotherapy regimen in the metastatic setting were enrolled. Anlotinib was administered at 12 mg daily for 14 days in a 21-day cycle until disease progression or unacceptable toxicity occurred. Simultaneously, 5–10 mL of venous blood was collected to perform circulating tumor DNA (ctDNA) testing every 2 treatment cycles. The primary endpoint was the objective response rate (ORR). Secondary endpoints included the disease control rate (DCR), progression-free survival (PFS), overall survival, safety, and biomarkers. Results: Twenty-six eligible patients were enrolled, with a median age of 56 (30–75) years. The median follow-up time was 10.5 months. The ORR was 15.4%, the DCR was 80.8%, and the median PFS was 5.22 months (95% confidence interval 2.86–6.24). Fourteen (53.8%) patients survived for more than 10 months. The changes in the detectable ctDNA variant allele frequency were consistent with the tumor response. The most common treatment-related adverse events were hypertension (57.7%), thyroid-stimulating hormone elevation (34.6%), and hand-foot syndrome (23.1%). Conclusion: Anlotinib showed objective efficacy with tolerable toxicity in heavily pre-treated, metastatic HER2-negative breast cancer. The dynamic changes in the ctDNA variant allele fraction may be predictive of the tumor response.

Based on the whole life cycle process of the economic exploitation of natural gas hydrate, this paper proposes the basic problem of stabilizing the wellbore for the basic conditions that must be met to ensure the integrity of the wellbore for exploitation: revealing the complex mechanism of fluid–solid–heat coupling in the process of the physical exchange of equilibrium among gas, water, and multiphase sand flows in the wellbore, hydrate reservoir, and wellbore, defining the interface conditions to ensure wellbore stability during the entire life cycle of hydrate production and proposing a scientific evaluation system of interface parameters for wellbore integrity.