Multi-omics portrait of ductal carcinoma in situ in young women.

BACKGROUND: Young patients with breast ductal carcinoma in situ (DCIS) often face a poorer prognosis. The genomic intricacies in young-onset DCIS, however, remain underexplored. METHODS: To address this gap, we undertook a comprehensive study encompassing exome, transcriptome, and vmethylome analyses. Our investigation included 20 DCIS samples (including 15 young-onset DCIS) and paired samples of normal breast tissue and blood. RESULTS: Through RNA sequencing, we identified two distinct DCIS subgroups: "immune hot" and "immune cold". The "immune hot" subgroup was characterized by increased infiltration of lymphocytes and macrophages, elevated expression of PDCD1 and CTLA4, and reduced GATA3 expression. This group also exhibited active immunerelated transcriptional regulators. Mutational analysis revealed alterations in TP53 (38%), GATA3 (25%), and TTN (19%), with two cases showing mutations in APC, ERBB2, and SMARCC1. Common genomic alterations, irrespective of immune status, included gains in copy numbers at 1q, 8q, 17q, and 20q, and losses at 11q, 17p, and 22q. Signature analysis highlighted the predominance of signatures 2 and 1, with "immune cold" samples showing a significant presence of signature 8. Our methylome study on 13 DCIS samples identified 328 hyperdifferentially methylated regions (DMRs) and 521 hypo-DMRs, with "immune cold" cases generally showing lower levels of methylation. CONCLUSION: In summary, the molecular characteristics of young-onset DCIS share similarities with invasive breast cancer (IBC), potentially indicating a poor prognosis. Understanding these characteristics, especially the immune microenvironment of DCIS, could be pivotal in identifying new therapeutic targets and preventive strategies for breast cancer.

Does the Dose of Standard Adjuvant Chemotherapy Affect the Triple-negative Breast Cancer Benefit from Extended Capecitabine Metronomic Therapy? An Exploratory Analysis of the SYSUCC-001 Trial.

Purpose: Results from studies of extended capecitabine after the standard adjuvant chemotherapy in early stage triple-negative breast cancer (TNBC) were inconsistent, and only low-dose capecitabine from the SYSUCC-001 trial improved disease-free survival (DFS). Adjustment of the conventional adjuvant chemotherapy doses affect the prognosis and may affect the efficacy of subsequent treatments. This study investigated whether the survival benefit of the SYSUCC-001 trial was affected by dose adjustment of the standard adjuvant chemotherapy or not. Patients and Methods: We reviewed the adjuvant chemotherapy regimens before the extended capecitabine in the SYSUCC-001 trial. Patients were classified into "consistent" (standard acceptable dose) and "inconsistent" (doses lower than acceptable dose) dose based on the minimum acceptable dose range in the landmark clinical trials. Cox proportional hazards model was used to investigate the impact of dose on the survival outcomes. Results: All 434 patients in SYSUCC-001 trial were enrolled in this study. Most of patients administered the anthracycline-taxane regimen accounted for 88.94%. Among patients in the "inconsistent" dose, 60.8% and 47% received lower doses of anthracycline and taxane separately. In the observation group, the "inconsistent" dose of anthracycline and taxane did not affect DFS compared with the "consistent" dose. Moreover, in the capecitabine group, the "inconsistent" anthracycline dose did not affect DFS compared with the "consistent" dose. However, patients with "consistent" taxane doses benefited significantly from extended capecitabine (P=0.014). The sufficient dose of adjuvant taxane had a positive effect of extended capecitabine (hazard ratio [HR] 2.04; 95% confidence interval [CI] 1.02 to 4.06). Conclusion: This study found the dose reduction of adjuvant taxane might negatively impact the efficacy of capecitabine. Therefore, the reduction of anthracycline dose over paclitaxel should be given priority during conventional adjuvant chemotherapy, if patients need dose reduction and plan for extended capecitabine.

Pyrotinib Combined with Vinorelbine in Patients with Previously Treated HER2-Positive Metastatic Breast Cancer: A Multicenter, Single-Arm, Prospective Study.

PURPOSE: This study aims to evaluate the efficacy and safety of a new combination treatment of vinorelbine and pyrotinib in human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) and provide higher level evidence for clinical practice. MATERIALS AND METHODS: This was a prospective, single-arm, phase 2 trial conducted at three institutions in China. Patients with HER2-positive MBC, who had previously been treated with trastuzumab plus a taxane or trastuzumab plus pertuzumab combined with a chemotherapeutic agent, were enrolled between March 2020 and December 2021. All patients received pyrotinib 400 mg orally once daily plus vinorelbine 25 mg/m2 intravenously or 60-80 mg/m2 orally on day 1 and day 8 of 21-day cycle. The primary endpoint was progression-free survival (PFS), and the secondary endpoints included the objective response rate (ORR), disease control rate (DCR), overall survival, and safety. RESULTS: A total of 39 patients were enrolled. All patients had been pretreated with trastuzumab and 23.1% (n=9) of them had accepted trastuzumab plus pertuzumab. The median follow-up time was 16.3 months (95% confidence interval [CI], 5.3 to 27.2), and the median PFS was 6.4 months (95% CI, 4.0 to 8.8). The ORR was 43.6% (95% CI, 27.8% to 60.4%) and the DCR was 84.6% (95% CI, 69.5% to 94.1%). The median PFS of patients with versus without prior pertuzumab treatment was 4.6 and 8.3 months (p=0.017). The most common grade 3/4 adverse events were diarrhea (28.2%), neutrophil count decreased (15.4%), white blood cell count decreased (7.7%), vomiting (5.1%), and anemia (2.6%). CONCLUSION: Pyrotinib plus vinorelbine showed promising efficacy and tolerable toxicity as second-line treatment in patients with HER2-positive MBC.

Construction of immune score and its prognostic value in invasive lobular carcinoma of the breast using computational pathology analysis.

BACKGROUND: Previous studies have shown that high level of TILs in invasive lobular carcinoma (ILC) is associated with poor prognosis, contrary to that in TNBC and HER2-positive breast cancer. METHODS: The densities of six immune cell markers and three immune checkpoints in the ILC microenvironment were detected by computational pathology analysis. Then, the LASSO cox regression model was used to construct an immune score (IS) and further evaluate its prognostic value. RESULTS: In our ILC cohort, the low density of CD4, CD8, CD20, CD56, CD68, FOXP3, PD-1, and PD-L1 had significantly longer disease-free survival (DFS) and overall survival (OS); however, the low density of CTLA-4 was associated with shorter DFS and OS. Based on this, an IS was constructed, and patients with low-IS had significantly prolonged DFS (p < 0.0001) and OS (p < 0.0001). Multivariate analysis revealed that IS was an independent prognostic indicator for DFS and OS. Further analysis showed that IS may increase the prognostic value of TNM stage. We further explored the prognostic role of CD68 and FOXP3 in the transcriptional level and the corresponding ISm in the METABRIC dataset, and found that low proportion of CD68 and FOXP3 and their ISm were associated with longer OS, and ISm was also an independent prognostic factor for OS. CONCLUSION: IS was a promising biomarker to distinguish the prognosis in ILC patients.

Genetic analysis of oligo-recurrence breast cancer: correlation with clinical outcomes.

BACKGROUND: We aimed to identify the relationship between the genomic characteristics and clinical outcomes of oligo-metastatic breast cancer. METHODS: Oligo-metastatic breast cancer diagnosed by pathology from January 2001 and August 2019 were reviewed and we matched the poly-metastatic patients based on the clinicopathological features of patients included. Clinicopathological values and data of genomic alterations were collected. Oligo-recurrence (oligo-R) was defined as a situation where disease progression occurred in less than 5 anatomical sites and other anatomic areas still suppressed by the ongoing therapy. RESULTS: A total of 26 breast cancer patients were enrolled in our study, including 14 patients with strict oligo-metastatic disease (oligo-R > 6 months) and 12 with simultaneous poly-metastatic disease. PIK3CA, TP53 and ERBB2 were the most common shared alterations identified in patients included. Based on the median time of oligo-R, we divided the patients with oligo-metastasis into longer oligo-R group (oligo-R > 31.04 months) and shorter oligo-R group (oligo-R ≤ 31.04 months). The analysis of PIK3CA mutation sites showed that H1047R mutation was closely associated with oligo-metastasis, rather than poly-metastasis. H1047R mutation also predicted a better prognosis (oligo-R > 31.04 months) in oligo-metastatic breast cancer. In addition, HER2 positive was more likely to be related to a good outcome in patients with oligo-metastasis. CONCLUSIONS: Through the genetic analysis of samples from oligo-metastasis, we found the prognostic values of PIK3CA H1047R and HER2 in oligo- and poly-metastasis. We improved the stratification of prognosis and provided new insights for biological behaviors of oligo-metastatic breast cancer.

The prognostic significance of skin involvement in breast cancer patients with chest wall recurrence.

PURPOSE: To assess the prognostic significance of skin involvement in breast cancer patients with chest wall recurrence (CWR). METHODS: We retrospectively analyzed the clinicopathological data of breast cancer patients with CWR who were diagnosed pathologically between January 2000 and April 2020. Disease-free survival (DFS) was the time from radical resection for CWR to disease recurrence. Progression-free survival (PFS) was defined as the time from the diagnosis of locally unresectable CWR to the first sign of disease progression. Persistent chest wall progression was defined as three consecutive chest wall progressions with no distant organ involvement. RESULTS: A total of 476 patients with CWR were included in this study. Skin involvement was confirmed in 345 patients. Skin involvement was significantly correlated with a high T stage (p = 0.003), more positive nodes at initial examination (p < 0.001) and lymphovascular invasion (p < 0.001). Kaplan-Meier analysis showed that skin involvement was a predictor of shorter DFS (p < 0.001), including both local disease progression (p < 0.001) and distant disease progression (p = 0.022). Multivariate analysis showed that skin involvement was an independent biomarker for DFS (p = 0.043). Patients with skin involvement were more likely to experience persistent chest wall progression (p = 0.040). After eliminating the potential deviation caused by an insufficient follow-up time, persistent chest wall progression was more likely to be associated with a high N stage (p = 0.002), negative progesterone receptor (PR; p = 0.001) and positive human epidermal growth factor receptor 2 (HER2; p = 0.046) of the primary site, and negative oestrogen receptor (ER; p = 0.027) and PR (p = 0.013) of the chest wall lesion and skin involvement (p = 0.020). CONCLUSION: Skin involvement was a predictor of poor disease control in patients with CWR and was closely related to persistent chest wall progression. We stratified the prognosis of individualized treatment for breast cancer patients with CWR to provide new insights into the biological behaviours of the disease.

Skin involvement is a predictor of poor local disease control in breast cancer patients with CWR and a factor contributing to persistent chest wall progression after CWR. We stratified the prognosis of individualized treatment for breast cancer patients with CWR.

Combined Wee1 and EGFR inhibition reveals synergistic antitumor effect in esophageal squamous cell carcinoma.

Epidermal growth factor receptor (EGFR) is one of the most common amplified and overexpressed oncogenes in esophageal squamous cell carcinoma (ESCC), while the clinical efficacy of EGFR-targeted therapy in ESCC is dismal. Here, we evaluated the efficacy of dual blockage using monoclonal antibody against EGFR (Nimotuzumab) and an Wee1 inhibitor (AZD1775) in ESCC. We found that the mRNA and protein expression of EGFR and Wee1 were positively correlated in ESCC. Nimotuzumab-AZD1775 co-treatment inhibited tumor growth in PDX models with different drug susceptibility. Transcriptome sequencing and mass spectrometry analysis indicated that higher sensitive models showed enrichment of the PI3K/Akt or MAPK signaling pathway in Nimotuzumab-AZD1775 group compared with control group. In vitro experiments showed that the combination further inhibit PI3K/Akt and MAPK pathways compared to their monotherapy as indicated by downregulation of pAKT, pS6, pMEK, pErk and p-p38 MAPK. Furthermore, AZD1775 potentiated Nimotuzumab's antitumor effect through inducing apoptosis. Meanwhile, the bioinformatics analysis suggests the POLR2A might be candidate molecule of EGFR/Wee1 downstream. In conclusion, our work uncovers that EGFR-mAb Nimotuzumab combined with Wee1 inhibitor AZD1775 elicited potentiated anticancer activity against ESCC cell line and PDXs partially through PI3K/Akt and MAPK pathways blockade. These preclinical data raise the promising that ESCC patients may benefit from dual target EGFR and Wee1.

What is the appropriate genetic testing criteria for breast cancer in the Chinese population?-Analysis of genetic and clinical features from a single cancer center database.

BACKGROUND: Genetic testing plays an important role in guiding screening, diagnosis, and precision treatment of breast cancer (BC). However, the appropriate genetic testing criteria remain controversial. The current study aims to facilitate the development of suitable strategies by analyzing the germline mutational profiles and clinicopathological features of large-scale Chinese BC patients. METHODS: BC patients who had undergone genetic testing at the Sun Yat-sen University Cancer Center (SYSUCC) from September 2014 to March 2022 were retrospectively reviewed. Different screening criteria were applied and compared in the population cohort. RESULTS: A total of 1035 BC patients were enrolled, 237 pathogenic or likely pathogenic variants (P/LPV) were identified in 235 patients, including 41 out of 203 (19.6%) patients tested only for BRCA1/2 genes, and 194 out of 832 (23.3%) received 21 genes panel testing. Among the 235 P/LPV carriers, 222 (94.5%) met the NCCN high-risk criteria, and 13 (5.5%) did not. While using Desai's criteria of testing, all females diagnosed with BC by 60 years and NCCN criteria for older patients, 234 (99.6%) met the high-risk standard, and only one did not. The 21 genes panel testing identified 4.9% of non-BRCA P/LPVs and a significantly high rate of variants of uncertain significance (VUSs) (33.9%). The most common non-BRCA P/LPVs were PALB2 (11, 1.3%), TP53 (10, 1.2%), PTEN (3, 0.4%), CHEK2 (3, 0.4%), ATM (3, 0.4%), BARD1 (3, 0.4%), and RAD51C (2, 0.2%). Compared with BRCA1/2 P/LPVs, non-BRCA P/LPVs showed a significantly low incidence of NCCN criteria listed family history, second primary cancer, and different molecular subtypes. CONCLUSIONS: Desai's criteria might be a more appropriate genetic testing strategy for Chinese BC patients. Panel testing could identify more non-BRCA P/LPVs than BRCA1/2 testing alone. Compared with BRCA1/2 P/LPVs, non-BRCA P/LPVs exhibited different personal and family histories of cancer and molecular subtype distributions. The optimal genetic testing strategy for BC still needs to be investigated with larger continuous population studies.

The prognostic value and immune microenvironment association of AR in HER2+ nonmetastatic breast cancer.

This study aimed to investigate the prognostic value of AR in HER2+ nonmetastatic breast invasive ductal carcinoma (IDC) and its relationship with the immune microenvironment. HER2+ nonmetastatic breast IDC patients diagnosed by pathology who underwent surgery at Sun Yat-sen University Cancer Center from 2016 to 2017 were included. AR+ and AR- breast IDC samples were matched 1:1 in age, T stage, and N stage for immune infiltration analysis. A total of 554 patients with HER2+ nonmetastatic breast cancer were included in this retrospective study, regardless of HR status. The cut-off value for AR was set at 10%. ER+ (p < 0.001) and PR+ (p < 0.001) were associated with positive AR expression. Kaplan-Meier survival curve analysis suggested that AR was closely correlated with overall survival (OS) (p = 0.001) but not disease-free survival (DFS) (p = 0.051). After eliminating the potential impact caused by HR, AR also predicted longer OS (p = 0.014) and was an independent predictive factor for OS of HER2+HR- nonmetastatic breast IDC patients, as revealed by multivariate analysis (p = 0.036). For AR+ and AR- matched HER2+HR- patients, TILs (p = 0.043) and PD-L1 (p = 0.027) levels were significantly lower in AR+ patients. The strongest negative correlation was observed between AR and PD-L1 (Pearson's r = -0.299, p = 0.001). AR+ status was markedly related to better OS in HER2+HR- nonmetastatic breast cancer patients, while a negative correlation was observed between AR and PD-L1/TILs. We provide new insights into the prognostic value of AR and its association with the immune microenvironment to optimize treatment strategies in HER2+ nonmetastatic breast IDCs.

Construction and validation of a macrophage polarization-related prognostic index to predict the overall survival in patients with early-stage triple-negative breast cancer.

Background: Triple-negative breast cancer (TNBC) is a highly heterogeneous disease and the current prognostic system cannot meet the clinical need. Interactions between immune responsiveness and tumor cells plays a key role in the progression of TNBC and macrophages are vital component of immune cells. A prognostic model based on macrophages may have great accuracy and clinical utility. Methods: For model development, we screened early stage (without metastasis) TNBC patients from The Cancer Genome Atlas (TCGA) database. We extracted messenger RNA (mRNA) expression data and clinical data including age, race, tumor size, lymph node status and tumor stage. The follow up time and vital status were also retrieved for overall survival calculation. Cell-type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT) was used to calculate the immune cell composition of each sample. Weighted gene co-expression network analysis (WGCNA) was used to identify M1-like macrophage-related genes. Combining least absolute shrinkage and selection operator (LASSO) with multivariate Cox regression, the M1-like macrophage polarization-related prognostic index (MRPI) was established. We obtained TNBC patients in Gene Expression Omnibus (GEO) database through PAM50 method and retrieved the mRNA expression data and survival data. The Harrell's concordance index (CI), the area under the receiver operating characteristic (ROC) curves (AUCs) and the calibration curve were used to evaluate the developed model. Results: We obtained 166 early TNBC cases and 113 normal tissue cases for model building, along with 76 samples from GSE58812 cohort for model validation. CIBERSORT analysis suggested obvious infiltration of macrophages, especially M1-like macrophages in early TNBC. Four genes were eventually identified for the construction of MPRI in the training set. The AUCs at 2 years, 3 years, and 5 years in the training cohort were 0.855, 0.881 and 0.893, respectively; and the AUCs at 2 years, 3 years, and 5 years in the validation cohort were 0.887, 0.792 and 0.722, respectively. Calibration curves indicated good predictive ability and high consistency of our model. Conclusions: MRPI is a promising biomarker for predicting the prognosis of early-stage TNBC, which may indicate personalized treatment and follow-up strategies and thus may improve the prognosis.

Significant response to margetuximab in Chinese HER2-positive metastatic breast cancer patient who progressed after second-line targeted therapy.

Activation of the antibody-dependent cellular cytotoxicity is one of the key mechanisms of anti-human epidermal growth factor receptor 2 (HER2) monoclonal antibody treatment. Margetuximab is a fragment C (Fc)-modified chimeric anti-HER2 immunoglobulin G1 monoclonal antibody that shares epitope specificity with trastuzumab. In this case, we reported that margetuximab plus chemotherapy was effective as later-line therapy in a postmenopausal Chinese woman with metastatic diseases, who was diagnosed with estrogen receptor -, progesterone receptor (PR)-, HER2+ invasive ductal carcinoma. This patient used paclitaxel-albumin plus trastuzumab and pertuzumab as the first-line therapy with progression-free survival (PFS) of 14 months, and pyrotinib in combined with vinorelbine as the second-line therapy with a PFS of 17 months. Then she received margetuximab plus capecitabine as the third-line treatment, the metastatic lesions in the liver were obviously shrunk, indicating clinical partial response and the PFS was 7 months. This case revealed that margetuximab plus chemotherapy may be an appropriate option for the patients who progressed after treating with anti-HER2 monoclonal antibodies and pyrotinib.

Current Situation of Diagnosis and Treatment of HER2-Positive Metastatic Breast Cancer Patients in China: A Nationwide Cross-Sectional Survey of Doctors.

BACKGROUND: The Advanced Breast Cancer Alliance conducted a nationwide investigation to understand the current situation of the diagnosis and treatment of human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) patients. METHODS: In 2019, electronic questionnaires including basic information about respondents, characteristics of patients, and the present status of diagnosis and treatment were sent to 495 doctors from 203 medical centers covering 28 provinces. RESULTS: The factors that influenced treatment plans included the disease process, the performance status, and the economic status of patients. Regimens and response to neoadjuvant/adjuvant chemotherapy were important factors in the decision of the first-line treatment. Overall, 54% of doctors retained trastuzumab and replaced chemotherapy drugs in second-line treatment regimens for patients with progression-free survival (PFS) ≥ 6 months in the first-line setting, while 52% of participants chose pyrotinib plus capecitabine for patients with PFS < 6 months. Economic factors played an important role in doctors' decision-making and the varying treatment options for respondents in first-tier, second-tier, and other cities. CONCLUSIONS: This large-scale survey regarding the diagnosis and treatment of HER2-positive MBC patients revealed that clinical decisions made by Chinese doctors followed the guidelines, but their choices were constrained by economic factors.

Systemic Therapy Combined with Locoregional Therapy Improved Survival in Oligometastatic Breast Cancer: A Single-Center Retrospective Cohort Study.

The optimal therapeutic options, adding locoregional therapy (LRT) to systemic therapy (ST) or not, for patients with oligometastatic breast cancer (OMBC) have not been fully elucidated. Hence, we designed a retrospective observational study which enrolled patients with measurable extracranial OMBC having less than 5 metastatic lesions not necessarily in the same organ. We retrospectively reviewed a total of 199 patients diagnosed with extracranial OMBC, including 28 receiving ST followed by LRT (ST to LRT group), 44 receiving LRT followed by ST (LRT to ST group), and 127 receiving ST alone (ST alone group). After a median follow-up of 28.7 months, patients receiving both ST and LRT had a significantly better prognosis than those receiving ST alone: the median progression-free survival (PFS) was 16.3, 14.0, and 9.3 months (P < 0.001) and the median overall survival (OS) was 39.8, 70.5, and 26.7 months (P < 0.001) in the ST to LRT, LRT to ST, and ST alone groups, respectively. Sequence of ST and LRT had no significant impact on survival among patients receiving both. Further exploratory analysis identified ST plus LRT as an independent predictor for longer PFS. In conclusion, we demonstrated that adding LRT to ST was associated with survival benefits for patients with OMBC, and further prospective studies were warranted.

Long-term survival after sentinel lymph node biopsy or axillary lymph node dissection in pN0 breast cancer patients: a population-based study.

PURPOSE: Findings from randomized clinical trials have shown that survival in patients with sentinel lymph node (SLN)-negative breast cancer is noninferior with SLN biopsy (SLNB) alone versus further axillary lymph node dissection (ALND). However, the long-term outcome of these two surgical approaches in pN0 breast cancer patients in real-world setting remains uncertain. METHODS: We included patients diagnosed with pathologically staged T1-2N0M0 breast cancer between 2000 and 2015 in surveillance, epidemiology, and end results 18-registry database. Patients were considered to have undergone SLNB alone if they had ≤ 5 examined lymph nodes (ELNs), and ALND if they had ≥ 10 ELNs. The outcomes included overall survival (OS) and breast cancer-specific survival. Propensity score analyses by weighting and matching and multivariable Cox regression analysis were performed to minimize treatment selection bias. RESULTS: We included 309,430 patients (253,501 SLNB and 55,929 ALND). In the weighted cohort, ALND was associated with significantly lower OS (hazard ratio [HR] 1.13; 95% confidence interval [CI] 1.10-1.16) and BCSS (HR 1.16; 95% CI 1.10-1.22) compared with SLNB alone. Both the propensity score-matching model and multivariable Cox model demonstrated a survival benefit for SLNB when compared with ALND. Subgroup analyses for key variables did not change these findings. CONCLUSION: We found statistically significant differences in OS and BCSS between SLNB and ALND, though the magnitude of these differences was small. Our findings further support that SLNB alone should be the standard of care for patients who do not have metastatic lymph nodes identified during breast cancer surgery.

The metabolic genomic atlas reveals potential drivers and clinically relevant insights into the etiology of esophageal squamous cell carcinoma.

Background: Esophageal squamous cell carcinoma (ESCC) is one of the most common cancers globally, with a poor prognosis and ambiguous therapy target. As a hallmark of cancer, metabolism reprogramming plays a critical role in the development of ESCC; however, the genomic alterations underlying this reconfiguration are still largely unknown. Methods: We have comprehensively studied the metabolic genomic variations in an integrated ESCC cohort of 490 patients and characterized the somatic alterations associated with various metabolic pathways. Results: The somatic mutations and copy number alterations (CNAs) occurred heterogeneously in all patients. Using CNA-based clustering, we stratified patients into three clusters and Cluster3 with more deletions marked for worse prognosis. Our findings revealed detailed genetic alterations in components of metabolic pathways and highlighted the role of metal ion channel transporters and non-neuronal/neuronal synapse systems in the development of ESCC. We found a subset of potential metabolic drivers and functionally validated RYR2, MGST3, and CYP8B1 involved in the ESCC-associated malignancy. Another key finding was that we identified 27 metabolic genes with genomic alterations that could serve as independent prognostic factors and figured out two genetic panels that could stratify patients into distinct prognostic groups. Conclusion: Collectively, our study provided a deep insight into the metabolic landscape in ESCC, extending our understanding of the metabolic reconfiguration underlying the genomic basis of ESCC. Furthermore, our findings revealed potential prognostic factors of ESCC, which are expected to contribute to the accurate determination of the prognosis in the clinic.

Breast cancer: an up-to-date review and future perspectives.

Breast cancer is the most common cancer worldwide. The occurrence of breast cancer is associated with many risk factors, including genetic and hereditary predisposition. Breast cancers are highly heterogeneous. Treatment strategies for breast cancer vary by molecular features, including activation of human epidermal growth factor receptor 2 (HER2), hormonal receptors (estrogen receptor [ER] and progesterone receptor [PR]), gene mutations (e.g., mutations of breast cancer 1/2 [BRCA1/2] and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [PIK3CA]) and markers of the immune microenvironment (e.g., tumor-infiltrating lymphocyte [TIL] and programmed death-ligand 1 [PD-L1]). Early-stage breast cancer is considered curable, for which local-regional therapies (surgery and radiotherapy) are the cornerstone, with systemic therapy given before or after surgery when necessary. Preoperative or neoadjuvant therapy, including targeted drugs or immune checkpoint inhibitors, has become the standard of care for most early-stage HER2-positive and triple-negative breast cancer, followed by risk-adapted post-surgical strategies. For ER-positive early breast cancer, endocrine therapy for 5-10 years is essential. Advanced breast cancer with distant metastases is currently considered incurable. Systemic therapies in this setting include endocrine therapy with targeted agents, such as CDK4/6 inhibitors and phosphoinositide 3-kinase (PI3K) inhibitors for hormone receptor-positive disease, anti-HER2 targeted therapy for HER2-positive disease, poly(ADP-ribose) polymerase inhibitors for BRCA1/2 mutation carriers and immunotherapy currently for part of triple-negative disease. Innovation technologies of precision medicine may guide individualized treatment escalation or de-escalation in the future. In this review, we summarized the latest scientific information and discussed the future perspectives on breast cancer.

BRAF V600E Mutation in Triple-Negative Breast Cancer: A Case Report and Literature Review.

BACKGROUND: The B-Raf proto-oncogene (BRAFV600E) gene mutation has been identified in a variety of malignancies, but no evidence of the efficacy of vemurafenib treatment in BRAFV600E mutant breast cancer (BC) has been reported. CASE PRESENTATION: We reported a 60-year-old woman with confirmed triple-negative BC with BRAFV600E mutation. Progression-free survival (PFS) for first-line chemotherapy was 7 months. The patient received vemurafenib and albumin-bound paclitaxel as second-line therapy, exhibiting regression of some pulmonary metastatic lesions with concomitant progression of other lesions, and achieved 4.4 months of PFS. Genetic testing of the progressed pulmonary lesion revealed the BRAFV600E mutation, and acquired new mutations and AR amplification. The patient ultimately died of multiple organ failure and achieved 12 months of overall survival. CONCLUSIONS: The BRAFV600E mutation may be a potential prognostic factor and therapeutic target for BC.

Trastuzumab Plus Endocrine Therapy or Chemotherapy as First-line Treatment for Patients with Hormone Receptor-Positive and HER2-Positive Metastatic Breast Cancer (SYSUCC-002).

PURPOSE: There is no research evidence demonstrate which is the better partner strategy, endocrine therapy or chemotherapy, to combine with anti-HER2 therapy as the first-line management of hormone receptor (HR)-positive (HR+) and HER2-positive (HER2+) metastatic breast cancer (MBC). We wished to ascertain if trastuzumab plus endocrine therapy is noninferior to trastuzumab plus chemotherapy. PATIENTS AND METHODS: We conducted an open-label, noninferiority, phase III, randomized, controlled trial (NCT01950182) at nine hospitals in China. Participants, stratified by previous adjuvant endocrine therapy and disease status (recurrent disease vs. de novo metastasis), were assigned randomly (1:1) to receive trastuzumab plus endocrine therapy (per investigator's choice of oestrogen-receptor modulators or aromatase inhibitor, with/without concurrent ovarian suppression) or chemotherapy (per investigator's choice of taxanes, capecitabine, or vinorelbine). The primary endpoint was progression-free survival (PFS) with a noninferiority upper margin of 1.35 for the HR. The intention-to-treat population was used in primary and safety analyses. RESULTS: A total of 392 patients were enrolled and assigned randomly to receive trastuzumab plus endocrine therapy (ET group, n = 196) or trastuzumab plus chemotherapy (CT group, n = 196). After a median follow-up of 30.2 months [interquartile range (IQR) 15.0-44.7], the median PFS was 19.2 months [95% confidence interval (CI), 16.7-21.7)] in the ET group and 14.8 months (12.8-16.8) in the CT group (hazard ratio, 0.88; 95% CI, 0.71-1.09; Pnoninferiority < 0.0001). A significantly higher prevalence of toxicity was observed in the CT group compared with the ET group. CONCLUSIONS: Trastuzumab plus endocrine therapy was noninferior to trastuzumab plus chemotherapy in patients with HR+HER2+ MBC.

Distribution Characteristics and Prognostic Value of Immune Infiltration in Oligometastatic Breast Cancer.

BACKGROUND: To assess the distribution characteristics and the prognostic value of immune infiltration in female oligometastatic breast cancer patients. METHODS: We retrospectively analyzed the clinicopathological data of oligometastatic breast cancer (OMBC) patients diagnosed between June 2000 and January 2020. Immune markers were quantified by immunohistochemistry on FFPE tissues in paired normal breast tissues, primary breast cancers and oligometastatic lesions. Survival analyses were performed using the Kaplan-Meier curves and Cox-proportional hazards model. RESULTS: A total of 95 female OMBC patients visited Sun Yat-sen University Cancer Center between June 2000 and January 2020, and 33 of them had matched normal breast tissues, primary cancers and oligometastatic lesions and were reviewed in immune infiltration analysis. CD8 of primary tumors had a higher expression than that in matched normal tissues. The expressions of CD8 and FOXP3 were higher in the primary sites than that in the oligometastatic lesions. CD3, CD4 and CD8 were significantly lower in the intratumoral regions than that in the peritumoral regions both in primary and oligometastatic lesions. Notably, the high percentage of CD3 in the intratumoral oligometastatic lesions predicted the longer PFS and OS, and higher CD4 in the same lesions also predicted a better OS. There was obviously positive correlation between CD4/CD3 and Ki-67 in primary cancers and negative correlation between CD4/CD3 and ER in oligometastatic sites. CONCLUSION: We explored immune distribution and evolution in time and space in OMBC to provide new understandings for biological behaviors of this disease and further divided patients in different prognosis.

Identification of a risk prediction model for clinical prognosis in HER2 positive breast cancer patients.

Background New biomarkers are needed to identify different clinical outcomes for HER2+ breast cancer (BC). Methods Differential genes of HER2+ BC were screened based on TCGA database. We used WGCNA to identify the genes related to the survival. Genetic Algorithm was used to structure risk prediction model. The prognostic model was validated in GSE data. Results We constructed a risk prediction model of 6 genes to identify prognosis of HER2+ BC, including CLEC9A, PLD4, PIM1, PTK2B, AKNAD1 and C15orf27. Kaplan-Meier curve showed that the model effectively distinguished the survival of HER2+ BC patients. The multivariate Cox regression suggested that the risk model was an independent predictor for HER2+ BC. Analysis related to immune showed that significant differences in immune infiltration between high- and low-risk groups classified by the prognostic model. Conclusions Our study identified a risk prediction model of 6 genes that could distinguish the prognosis of HER2+ BC.