All HER2-negative breast cancer patients need gBRCA testing: cost-effectiveness and clinical benefits.

BACKGROUND: The OlympiA trial demonstrated the benefits of adjuvant usage of olaparib for high-risk patients with human epidermal growth factor receptor 2 (HER2)-negative breast cancer (BC) and germline BRCA (gBRCA) mutation. This provoked thoughts on the clinical criteria of gBRCA testing. This study aims to estimate the costs and benefits of gBRCA testing and adjuvant olaparib therapy for patients with triple-negative breast cancer (TNBC) and hormone-receptor (HR)-positive and HER2-negative BC in China and the United States of America (USA). METHODS: We used a Markov chain decision tree analytic model to compare three gBRCA screening policies in China and the USA: (1) no gBRCA testing; (2) selected gBRCA testing and (3) universal gBRCA testing for nonmetastatic TNBC and HR-positive HER2-negative BC patients. We modelled the benefit of systemic therapy and risk-reducing surgeries among patients identified with pathogenic or likely pathogenic variants (PVs) in BRCA1 and BRCA2. RESULTS: Changing from the selected gBRCA testing to the universal gBRCA testing in TNBC patients is cost-effective, with the incremental cost-effectiveness ratios (ICERs) being 10991.1 and 56518.2 USD/QALY in China and the USA, respectively. Expanding universal gBRCA testing to HR-positive HER2-negative BC and TNBC patients has ICERs of 2023.3 and 16611.1 USD/QALY in China and the USA, respectively. DISCUSSION: By performing gBRCA testing on all HER2-negative BC patients, adjuvant olaparib can be offered to high-risk patients with a PV in BRCA1 or BRCA2. These patients are also candidates for risk-reducing surgeries, an important aspect of their survivorship care, and these interventions can improve survival outcomes. With the willingness-to-pay thresholds being 31,500.0 and 100,000.0 USD per QALY gained in China and the USA, respectively, universal gBRCA testing is likely cost-effective for all HER2-negative BC patients. This simplified criterion of gBRCA testing for BC is recommended for adoption by current guidelines in China and the USA.

Metronomic chemotherapy in cancer treatment: new wine in an old bottle.

Over the past two decades, metronomic chemotherapy has gained considerable attention and has demonstrated remarkable success in the treatment of cancer. Through chronic administration and low-dose regimens, metronomic chemotherapy is associated with fewer adverse events but still effectively induces disease control. The identification of its antiangiogenic properties, direct impact on cancer cells, immunomodulatory effects on the tumour microenvironment, and metabolic reprogramming ability has established the intrinsic multitargeted nature of this therapeutic approach. Recently, the utilization of metronomic chemotherapy has evolved from salvage treatment for metastatic disease to adjuvant maintenance therapy for high-risk cancer patients, which has been prompted by the success of several substantial phase III trials. In this review, we delve into the mechanisms underlying the antitumour effects of metronomic chemotherapy and provide insights into potential combinations with other therapies for the treatment of various malignancies. Additionally, we discuss health-economic advantages and candidates for the utilization of this treatment option.

Contralateral axillary lymph node metastasis in breast cancer: An oligometastatic-like disease.

BACKGROUND: Contralateral axillary lymph node metastasis (CAM) is rare. It remains controversial whether CAM should be regarded as a regional or distant metastatic disease. Our study aims to investigate the accurate clinical orientation and management of CAM. METHODS: Two hundred and ninety-nine female patients diagnosed with breast cancer from 2000 to 2014 and confirmed to develop CAM, oligometastasis (OM) or locoregional recurrence (LRR) at Fudan University Shanghai Cancer Center (FUSCC) were included in this study. Baseline information and survival outcomes were analyzed and compared among the three groups. RESULTS: Patients with CAM exhibited similar overall survival (OS) and progression-free survival (PFS) to those with OM, but worse than those with LRR (HR: 0.47 [95 % CI: 0.27-0.85], p = 0.0097; HR:0.39 [95 % CI: 0.24-0.63], p < 0.0001, respectively). Considering the patients presented with CAM or OM as a whole, we found that local treatment combined with systemic treatment did not provide a superior survival benefit over systemic treatment alone. CONCLUSION: CAM was similar to an oligometastatic-like disease, and patients with these diseases may benefit from systemic treatment. Adding local treatment failed to significantly improve OS.

Prognostic factors and clinical outcomes of breast cancer patients with disease progression during neoadjuvant systemic therapy.

BACKGROUND: Disease progression during neoadjuvant systemic therapy for breast cancer indicates poor prognosis, while predictors of the clinical outcomes of these patients remain unclear. By comparing the clinical outcomes of patients with different patterns of salvage treatment strategies, we try to evaluate the factors predicting distant failure and explore the favourable treatment for them. METHODS: Patients with disease progression during neoadjuvant systemic therapy for stage I-III breast cancer diagnosed between January 1, 2008 and July 31, 2021 in Fudan University Shanghai Cancer Center were enrolled. Disease progression was defined as at least a 20% increase in the sum of diameters of target lesions or the appearance of new breast or nodal lesions. Kaplan-Meier, univariate and multivariate Cox proportional hazard regressions were utilized to compare survival outcomes between different salvage treatment strategies. RESULTS: Among 3775 patients treated with NST, 60 (1.6%) patients encountered disease progression. A significant difference between the outcomes of patients receiving direct surgery and other salvage modalities was found (p = 0.007). Triple-negative breast cancer (p = 0.010) and not receiving direct surgery (p = 0.016) were independently associated with distant disease-free survival on multivariate analysis. CONCLUSIONS: Predictors of distant failure in patients with disease progression include triple-negative breast cancer and not receiving direct surgery. Direct surgery seems to be more favourable than other treatments for patients with disease progression. For inoperable patients, neoadjuvant radiation can increase their operability but not improve their prognosis.

Targeting nucleotide metabolism: a promising approach to enhance cancer immunotherapy.

Targeting nucleotide metabolism can not only inhibit tumor initiation and progression but also exert serious side effects. With in-depth studies of nucleotide metabolism, our understanding of nucleotide metabolism in tumors has revealed their non-proliferative effects on immune escape, indicating the potential effectiveness of nucleotide antimetabolites for enhancing immunotherapy. A growing body of evidence now supports the concept that targeting nucleotide metabolism can increase the antitumor immune response by (1) activating host immune systems via maintaining the concentrations of several important metabolites, such as adenosine and ATP, (2) promoting immunogenicity caused by increased mutability and genomic instability by disrupting the purine and pyrimidine pool, and (3) releasing nucleoside analogs via microbes to regulate immunity. Therapeutic approaches targeting nucleotide metabolism combined with immunotherapy have achieved exciting success in preclinical animal models. Here, we review how dysregulated nucleotide metabolism can promote tumor growth and interact with the host immune system, and we provide future insights into targeting nucleotide metabolism for immunotherapeutic treatment of various malignancies.

In vivo multidimensional CRISPR screens identify Lgals2 as an immunotherapy target in triple-negative breast cancer.

Immune checkpoint inhibitors exhibit limited response rates in patients with triple-negative breast cancer (TNBC), suggesting that additional immune escape mechanisms may exist. Here, we performed two-step customized in vivo CRISPR screens targeting disease-related immune genes using different mouse models with multidimensional immune-deficiency characteristics. In vivo screens characterized gene functions in the different tumor microenvironments and recovered canonical immunotherapy targets such as Ido1. In addition, functional screening and transcriptomic analysis identified Lgals2 as a candidate regulator in TNBC involving immune escape. Mechanistic studies demonstrated that tumor cell-intrinsic Lgals2 induced the increased number of tumor-associated macrophages, as well as the M2-like polarization and proliferation of macrophages through the CSF1/CSF1R axis, which resulted in the immunosuppressive nature of the TNBC microenvironment. Blockade of LGALS2 using an inhibitory antibody successfully arrested tumor growth and reversed the immune suppression. Collectively, our results provide a theoretical basis for LGALS2 as a potential immunotherapy target in TNBC.

Prior Local or Systemic Treatment: A Predictive Model Could Guide Clinical Decision-Making for Locoregional Recurrent Breast Cancer.

INTRODUCTION: Locoregional recurrent breast cancer indicates poor prognosis. No solid prediction model is available to predict prognosis and guide clinical management. Prior local treatment or systemic treatment remains controversial. METHODS: Locoregional recurrent breast cancer patients operated in Fudan University Shanghai Cancer Center were enrolled as a training cohort. An external validation cohort included breast cancer patients after locoregional recurrence from Ruijin Hospital, Shanghai Jiaotong University. A nomogram predicting overall survival after locoregional recurrence was established using multivariable Cox regression analysis while internal and external validation were performed to evaluate its calibration and discrimination. RESULTS: Overall, 346 and 96 breast cancer patients were included in the training cohort and the validation cohort separately. A nomogram was developed, including age, neoadjuvant chemotherapy, breast surgery, pathology type, tumor size, lymph node status, hormonal receptor and Her-2 status, disease-free interval, and sites of locoregional recurrence. It had modest calibration and discrimination in the training cohort, internal validation and external validation (concordance index: 0.751, 0.734 and 0.722, respectively). The nomogram classified 266 and 80 patients into low and high-risk subgroups with distinctive prognosis. Local treatment after locoregional recurrence was associated with improved overall survival in low-risk group (P = 0.011), while systemic therapies correlated with better outcomes only in high-risk group (P < 0.001). CONCLUSION: A nomogram based on clinicopathological factors can predict prognosis and identify low and high-risk patients. Local treatment is a prior choice for low-risk patients whereas systemic treatment needs to be considered for high-risk patients, warranting further validation and exploration.

Facemask shortage and the novel coronavirus disease (COVID-19) outbreak: Reflections on public health measures.

BACKGROUND: A novel coronavirus disease (COVID-19) outbreak due to the severe respiratory syndrome coronavirus (SARS-CoV-2) infection occurred in China in late December 2019. Facemask wearing with proper hand hygiene is considered an effective measure to prevent SARS-CoV-2 transmission, but facemask wearing has become a social concern due to the global facemask shortage. China is the major facemask producer in the world, contributing to 50% of global production. However, a universal facemask wearing policy would put an enormous burden on the facemask supply. METHODS: We performed a policy review concerning facemasks using government websites and mathematical modelling shortage analyses based on data obtained from the National Health Commission (NHC), the Ministry of Industry and Information Technology (MIIT), the Centre for Disease Control and Prevention (CDC), and General Administration of Customs (GAC) of the People's Republic of China. Three scenarios with respect to wearing facemasks were considered: (1) a universal facemask wearing policy implementation in all regions of mainland China; (2) a universal facemask wearing policy implementation only in the epicentre (Hubei province, China); and (3) no implementation of a universal facemask wearing policy. FINDINGS: Regardless of different universal facemask wearing policy scenarios, facemask shortage would occur but eventually end during our prediction period (from 20 Jan 2020 to 30 Jun 2020). The duration of the facemask shortage described in the scenarios of a country-wide universal facemask wearing policy, a universal facemask wearing policy in the epicentre, and no universal facemask wearing policy were 132, seven, and four days, respectively. During the prediction period, the largest daily facemask shortages were predicted to be 589·5, 49·3, and 37·5 million in each of the three scenarios, respectively. In any scenario, an N95 mask shortage was predicted to occur on 24 January 2020 with a daily facemask shortage of 2·2 million. INTERPRETATION: Implementing a universal facemask wearing policy in the whole of China could lead to severe facemask shortage. Without effective public communication, a universal facemask wearing policy could result in societal panic and subsequently, increase the nationwide and worldwide demand for facemasks. These increased demands could cause a facemask shortage for healthcare workers and reduce the effectiveness of outbreak control in the affected regions, eventually leading to a pandemic. To fight novel infectious disease outbreaks, such as COVID-19, governments should monitor domestic facemask supplies and give priority to healthcare workers. The risk of asymptomatic transmission and facemask shortages should be carefully evaluated before introducing a universal facemask wearing policy in high-risk regions. Public health measures aimed at improving hand hygiene and effective public communication should be considered along with the facemask policy.