Perioperative corticosteroids for reducing postoperative complications following esophagectomy: an updated systematic review and meta-analysis.

BACKGROUND: This updated systematic review and meta-analysis aims to evaluate the efficacy and safety of perioperative corticosteroid administration versus placebo for esophageal cancer patients following scheduled esophagectomy. METHODS: We searched databases through June 30, 2023. We included articles on randomized controlled trials (RCTs) comparing perioperative corticosteroid administration with placebo in esophageal cancer patients with esophagectomy. The outcomes were the death rate during hospitalization, length of hospital stay, and short-term complications. Risk ratios (RRs) and corresponding 95% confidence interval (CIs) for each estimated effect size were applied for dichotomous outcomes, and the mean difference (MD) and corresponding 95% CIs for each estimated effect size were applied for continuous outcomes. We used GRADE to evaluate the quality of each of the outcome and the level of recommendations. RESULTS: Nine RCTs with 508 participants were included in this study. Severe outcomes, including the length of hospital stay, leakage, mortality during the hospitalization period in the corticosteroid group was comparable to that in the control group, but positive effects of corticosteroid administration were observed on the length of intensive care unit stay (MD -3.1, 95% CI - 5.43 to - 0.77), cardiovascular disorders (RR 0.44, 95% CI 0.21-0.94) and other general complications (RR 0.49, 95% CI 0.29-0.85). CONCLUSIONS: Peri-operative intravenous corticosteroid administration may reduce cardiovascular disorders, other general complications and the length of ICU stay without carrying severe outcomes. More high quality RCTs are warranted to further investigate the effects of corticosteroids on postoperative mortality and complications for esophageal cancer patients with esophagectomy. SYSTEMATIC REVIEW REGISTRATION: Cochrane, registration number: 196.

Genomic alteration profile and PD-L1 expression among different breast cancer subtypes in Chinese population and their correlations.

BACKGROUD: There were limitations existing in programmed cell-death ligand 1 (PD-L1) as predictive biomarkers for breast cancer (BC), hence exploring the correlation between PD-L1 levels and other biomarkers in BC may become a very useful therapeutic clinical tool. METHODS: A total of 301 Chinese patients with different BC subtypes including 47 HR+/HER2+, 185 HR+/HER2-, 38 HR-/HER2+, and 31 triple-negative breast cancer (TNBC) were enrolled in our study. Next-generation sequencing based Yuansu450 gene panel was used for genomic alteration identification and PD-L1 expression was tested using immunohistochemistry. RESULTS: The most prevalent BC-related mutations were TP53 mutations, followed by mutations in PIK3CA, ERBB2, CDK12, and GATA3 in our Chinese cohort. We found that mutations DDR2 and MYCL were only mutated in HR-/HER2+ subtype, whereas H3-3A and NRAS mutations were only occurred in HR-/HER2- subtype. The percentage of patients with PD-L1-positive expression was higher in patients with HR-/HER2- mainly due to the percentage of PD-L1-high level. Mutational frequencies of TP53, MYC, FAT4, PBRM1, PREX2 were observed to have significant differences among patients with different BC subtypes based on PD-L1 levels. Moreover, a positive correlation was observed between TMB and PD-L1 level in HR+/HER2- subtype, and showed that the proportion of patients with high PD-L1 expression was higher than that of patients with low PD-L1 expression in the HR+/HER2- and HR+/HER2+ cohorts with high Ki67 expression. CONCLUSIONS: The genomic alterations based on PD-L1 and other biomarkers of different cohorts may provide more possibilities for the treatment of BC with different subtypes.

Single-cell profile of tumor and immune cells in primary breast cancer, sentinel lymph node, and metastatic lymph node.

PURPOSE: Little is known about the host-tumor interaction in the lymph-node basin at a single cell level. This study examines single cell sequences in breast cancer nodal metastases of a patient with triple-negative breast cancer. METHODS: The primary breast tumor, sentinel lymph node, an adjacent lymph node with metastatic involvement and a clinically normal-appearing lymph node were collected during surgery. Single-cell sequencing was performed on all four specimens. RESULTS: 14,016 cells were clustered into 6 cell subpopulations. Cancer cells demonstrated the molecular characteristics of TNBC basal B subtype and highly expressed genes in the MAPK signaling cascade. Tumor-associated macrophages regulated antigen processing and presentation and other immune-related pathways to promote tumor invasion. CD8 + and CD4 + T lymphocytes concentrated more in sentinel lymph node and mainly stratified into two transcriptional states. The immune-cell amount variation among primary tumor, sentinel and normal lymph nodes showed a similar tendency between the sc-RNA-seq profile of TNBC samples and a previous reported bulk RNA-seq profile of a breast cancer cohort, including all four breast cancer subtype samples. DISCUSSION: Single-cell sequencing analysis suggested that the sentinel lymph node was the initial meeting site of tumor infiltration and immune response, where partial T lymphocytes perform anti-tumor activity, while other T cells exhibit an exhausted state. We proposed a molecular explanation to the well-established clinical principle that the 5-year and 10-year survival outcomes were noninferior between SLND and ALND.

Characteristics of MYC Amplification and Their Association with Clinicopathological and Molecular Factors in Patients with Breast Cancer.

MYC amplification is detected in ∼15% of breast tumors and is associated with poor prognosis by mediating acquired resistance to anticancer therapies. This study aimed to determine the prevalence of MYC amplifications in Chinese women with breast cancer (BRCA) and investigate the correlation between MYC amplification and clinicopathological and molecular characteristics and its clinical implications. We analyzed MYC alterations in tissue specimens from 410 women diagnosed with BRCA in our hospital from June 1, 2017 to September 27, 2018. We compared our results with publicly available data from The Cancer Genome Atlas (TCGA) BRCA cohort (n = 1079). MYC amplification was identified in 12.4% (51/410) of our cohort, with mean copy number (CN) of 4.42 (range: 2.84-11.27). In TCGA cohort, MYC amplification was identified in 21.2% (229/1079) and was associated with age, estrogen receptor status, progesterone receptor status, human epidermal growth factor receptor 2 (HER2) status, and molecular subtype, whereas in our cohort, MYC amplification was associated with smaller tumor size (T1-2, p = 0.023) and higher Ki-67 levels (≥20%; p = 0.031). Analysis of molecular profiles revealed that MYC-amplified breast tumors had significantly more concurrent CN variations compared with MYC nonamplified BRCA in both Guangdong Provincial People's Hospital (GDPH) and TCGA cohorts (p < 0.001). Pathway mapping analysis demonstrated that MYC-amplified tumors had more mutations involved in 15 different but interrelated pathways critical in DNA repair, cell cycle, and cell proliferation. Patients in TCGA cohort with MYC-amplified hormone receptor (HR)-positive/HER2-positive BRCA (p = 0.038) and MYC nonamplified triple-negative BRCA (p = 0.027) had significantly shorter overall survival. In conclusion, this study contributes to a better understanding that MYC-amplified breast tumors had distinct clinicopathological and molecular features compared with MYC nonamplified breast tumors. Further research with a larger sample size is necessary to further elucidate the clinical and survival implications of MYC amplifications.

Distinct clinical and somatic mutational features of breast tumors with high-, low-, or non-expressing human epidermal growth factor receptor 2 status.

BACKGROUND: HER2-low breast cancers were reported to have distinct clinicopathological characteristics from HER2-zero; however, the difference in their genetic features remains unclear. This study investigated the clinical and molecular features of breast tumors according to HER2 status. METHODS: We analyzed the clinicopathological and genomic data of 523 Chinese women with breast cancer. Genomic data was generated by targeted next-generation sequencing (NGS) of breast tumor samples using a commercial 520 gene panel. The cohort was stratified according to HER2 status as HER2-zero (n = 90), HER2-low (n = 231), and HER2-positive (n = 202) according to their immunohistochemistry and fluorescence in situ hybridization results. RESULTS: HER2-low breast tumors were enriched with hormone receptor-positive tumors, and who had lower Ki67 expression levels. Genes were differentially mutated across HER2 subgroups. HER2-low tumors had significantly more mutations involved in PI3K-Akt signaling than HER2-positive (p < 0.001) and HER2-zero breast tumors (p < 0.01). HER2-zero tumors had more mutations in checkpoint factors (p < 0.01), Fanconi anemia (p < 0.05), and p53 signaling and cell cycle pathway (p < 0.05) compared to HER2-low breast tumors. Compared with HER2-zero tumors, HER2-low tumors had significantly lower pathological complete response rates after neoadjuvant therapy (15.9% vs. 37.5%, p = 0.042) and proportion of relapsed/progressed patients across follow-up time points (p = 0.031), but had comparable disease-free survival (p = 0.271). CONCLUSION: Our results demonstrate the distinct clinical and molecular features and clinical outcomes of HER2-low breast tumors.

Clinicopathologic and Genomic Features in Triple-Negative Breast Cancer Between Special and No-Special Morphologic Pattern.

Background: Triple-negative breast cancer (TNBC) is refractory and heterogeneous, comprising various entities with divergent phenotype, biology, and clinical presentation. As an aggressive subtype, Chinese TNBC patients with special morphologic patterns (STs) were restricted to its incidence of 10-15% in total TNBC population. Methods: We recruited 89 patients with TNBC at Guangdong Provincial People's Hospital (GDPH) from October 2014 to May 2021, comprising 72 cases of invasive ductal carcinoma of no-special type (NSTs) and 17 cases of STs. The clinical data of these patients was collected and statistically analyzed. Formalin-fixed, paraffin-embedded (FFPE) tumor tissues and matched blood samples were collected for targeted next-generation sequencing (NGS) with cancer-related, 520- or 33-gene assay. Immunohistochemical analysis of FFPE tissue sections was performed using anti-programmed cell death-ligand 1(PD-L1) and anti-androgen receptor antibodies. Results: Cases with NSTs presented with higher histologic grade and Ki-67 index rate than ST patients (NSTs to STs: grade I/II/III 1.4%, 16.7%,81.9% vs 0%, 29.4%, 58.8%; p<0.05; Ki-67 ≥30%: 83.3% vs. 58.8%, p<0.05), while androgen receptor (AR) and PD-L1 positive (combined positive score≥10) rates were lower than of STs cases (AR: 11.1% vs. 47.1%; PD-L1: 9.6% vs. 33.3%, p<0.05). The most commonly altered genes were TP53 (88.7%), PIK3CA (26.8%), MYC (18.3%) in NSTs, and TP53 (68.8%), PIK3CA (50%), JAK3 (18.8%), KMT2C (18.8%) in STs respectively. Compared with NSTs, PIK3CA and TP53 mutation frequency showed difference in STs (47.1% vs 19.4%, p=0.039; 64.7% vs 87.5%, p=0.035). Conclusions: In TNBC patients with STs, decrease in histologic grade and ki-67 index, as well as increase in PD-L1 and AR expression were observed when compared to those with NSTs, suggesting that TNBC patients with STs may better benefit from immune checkpoint inhibitors and/or AR inhibitors. Additionally, lower TP53 and higher PIK3CA mutation rates were also found in STs patients, providing genetic evidence for deciphering at least partly potential mechanism of action.

Heterogenous and Low Expression of HER2 in Breast Cancer Overcome by DS-8201a in a Heavily Treated Patient: Case Report and Review of the Literature.

Breast cancer is highly heterogenous with temporal and spatial heterogeneity making it necessary for rebiopsy. DS-8201a, a new potential therapy for human epidermal growth factor receptor 2 (HER2) low expression breast cancer, had been proved that it could overcome heterogenous HER2 expression in a preclinical setting. In January 2014, a 23-year-old woman was presented with a lump in the right breast with bone metastasis, diagnosed as infiltrating ductal carcinoma, estrogen receptor (ER)+, progesterone receptor (PR)+, HER2 immunohistochemistry (IHC) 2+, and fluorescence in situ hybridization negative. The patient received a series of therapies including surgery, radiotherapy, endocrine therapy, target therapy, and chemotherapy. The longest progression-free survival was 17 months after surgery. Biopsy of liver metastasis in February 2020 showed triple negative (HER2-, ER-, PR-), which was quite different from the initial diagnosis in 2014, so retesting was performed and the results showed ER-, PR+ by 10%, HER2 IHC score of 1+, indicating heterogeneity of HER2 expression. In May 2020, DS-8201a treatment was initiated and continued for 10 cycles until November 2020. Remarkable relief in symptoms was observed after the first dose. A reduction in the metastatic lesion size (liver and brain) and improved liver function was observed during the therapy. This case indicated the heterogeneity of breast cancer, and impressive efficacy of DS-8201a in a heavily treated patient with HER2-low and HER2 heterogeneity.

Submuscular Implant-Based Breast Reconstruction Using a Musculofascial Pocket Formed by the Pectoralis Major Muscle and the Serratus Anterior Muscle Fascia: A Novel Surgical Approach.

BACKGROUND: Subpectoral implant-based breast reconstruction following mastectomy commonly severs the inferior border of the pectoralis major muscle for better projection of the lower pole. This can affect a patient's postoperative motor function and result in animation deformity. Implant-based breast reconstruction using partial muscle coverage with an acellular dermal matrix (ADM) can be costly. There is an unmet clinical need for a novel surgical method for submuscular implant-based breast reconstruction. METHODS: We describe an innovative technique for submuscular implant-based breast reconstruction following mastectomy. The approach utilizes the serratus anterior muscle fascia connected to the lateral margin of the pectoralis major muscle to form a lateral tissue pocket for implant coverage. This method preserves the inferior border of the pectoralis major muscle and minimizes the size of ADM coverage. Patient satisfaction on the BREAST-Q Reconstruction Module and complications were assessed 12 months after surgery. RESULTS: The novel surgical design was safe and used minimal ADM (6 × 5cm2). Mean satisfaction with breasts was 61 ± 4.7 (range, 48-73), mean psychosocial well-being was 66 ± 10 (range, 50-93), and mean sexual well-being was 47 ± 7.8 (range, 27-70). Animation deformity was avoided by preserving the inferior border of the pectoralis major muscle. Rates of revision (7.6%) and postsurgical seroma (3.4%) were low, and capsular contracture was minimal. CONCLUSIONS: Submuscular implant-based breast reconstruction following mastectomy utilizing the serratus anterior muscle fascia connected to the lateral margin of the pectoralis major muscle to form a lateral tissue pocket for implant coverage is safe, feasible, and generates good aesthetic outcomes.

Spectrum of MAP3K1 mutations in breast cancer is luminal subtype-predominant and related to prognosis.

MAP3K1 is a MAPK family serine-threonine kinase that is frequently mutated in human cancer. The association between mutations in the MAP3K1 gene and the clinicopathological characteristics and prognosis of patients with breast cancer remain unclear in the Chinese population. Thus, the aim of the present retrospective study was to investigate the possible role and function of MAP3K1 in breast cancer. Data obtained from 412 consecutive patients with breast cancer were selected from Guangdong Provincial People's Hospital (GDPH) for analysis in the present study. Mutations were assessed using next-generation sequencing. The association between MAP3K1 mutations and clinicopathological features were analyzed and further compared with the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) cohort and data from The Cancer Genome Atlas (TCGA). In the GDPH cohort, a total of 45 mutations MAP3K1 were identified in 8.5% (n=35) of the 412 patients, compared with 9.7% (n=244) in METABRIC and 7.9% (n=88) in TCGA. The majority of the mutations identified in the in three cohorts were truncating mutations, followed by mis-sense mutations. Mutations in MAP3K1 were predominant in patients with the luminal A and B breast cancer subtypes in METABRIC datasets (P<0.001), although no significant differences were observed in the GDPH cohort (P=0.227). In the METABRIC cohort, patients with MAP3K1 mutations experienced a improved overall survival (OS) rate than patients without MAP3K1 mutations (P=0.006). In patient with hormone receptor (HR)+ breast cancer, a more significantly higher OS rate was observed in patients with MAP3K1 mutations (P<0.001). MAP3K1 expression was associated with OS in the HR+ subgroup. Moreover, the MAP3K1 methylation levels were reduced in primary breast cancer tissue, compared with normal tissue. Thus, the present findings identified MAP3K1 mutations in Chinese patients with breast cancer, and compared MAP3K1 mutations between the cohorts from Western and Eastern countries.

Genetic and immune characteristics of sentinel lymph node metastases and multiple lymph node metastases compared to their matched primary breast tumours.

BACKGROUND: Patients with breast cancer presenting with single lymph node metastasis (from a sentinel node) experience prolonged survival compared to patients with multiple lymph node metastases (≥3). However, little information is available on the genetic and immunological characteristics of breast cancer metastases within the regional lymph nodes as they progress from the sentinel lymph node (SLN) downstream to multiple regional lymph nodes (MLNs). METHODS: Genomic profiling was performed using a next-generation sequencing panel covering 520 cancer-related genes in the primary tumour and metastatic lymph nodes of 157 female patients with breast cancer. We included primary tumours, metastatic lymph nodes and adjacent clinically normal lymph nodes (20 patients from the SLN group and 28 patients from the MLNs group) in the whole transcriptome analysis. FINDINGS: The downstream metastatic lymph nodes (P = 0.029) and the primary breast tumours (P = 0.011) had a higher frequency of PIK3CA mutations compared to the SLN metastasis. We identified a distinct group of 14 mutations from single sentinel node metastasis and a different group of 15 mutations from multiple nodal metastases. Only 4 distinct mutations (PIK3CA, CDK4, NFKBIA and CDKN1B) were conserved in metastases from both lymph node settings. The tumour mutational burden (TMB) was significantly lower in single nodal metastasis compared to the paired primary breast cancer (P = 0.0021), while the decline in TMB did not reach statistical significance in the MLNs group (P = 0.083). In the gene set enrichment analysis, we identified 4 upregulated signatures in both primary tumour and nodal metastases from the MLNs group, including 3 Epithelial-mesenchymal transition(EMT) signatures and 1 angiogenesis signature. Both the CD8/Treg ratio and the CD8/EMT ratio were significantly higher in adjacent normal lymph nodes from patients with a single metastasis in the SLN compared with samples from the MLNs group (P = 0.045 and P = 0.023, respectively). This suggests that the immune defence from the MLNs patients might have a less favourable microenvironment, thus permitting multiple lymph nodes metastasis. INTERPRETATION: Single lymph node metastases and multiple lymph node metastases have significant differences in their molecular profiles and immune profiles. The findings are associated with more aggressive tumour characteristics and less favourable immune charactoristics in patients with multiple nodal metastases compared to those with a single metastasis in the sentinel node. FUNDING: This work was supported by funds from High-level Hospital Construction Project (DFJH201921), the National Natural Science Foundation of China (81902828 and 82002928), the Fundamental Research Funds for the Central Universities (y2syD2192230), and the Medical Scientific Research Foundation of Guangdong Province (B2019039).

CDKN1C as a prognostic biomarker correlated with immune infiltrates and therapeutic responses in breast cancer patients.

Breast cancer (BC) prognosis and therapeutic sensitivity could not be predicted efficiently. Previous evidence have shown the vital roles of CDKN1C in BC. Therefore, we aimed to construct a CDKN1C-based model to accurately predicting overall survival (OS) and treatment responses in BC patients. In this study, 995 BC patients from The Cancer Genome Atlas database were selected. Kaplan-Meier curve, Gene set enrichment and immune infiltrates analyses were executed. We developed a novel CDKN1C-based nomogram to predict the OS, verified by the time-dependent receiver operating characteristic curve, calibration curve and decision curve. Therapeutic response prediction was followed based on the low- and high-nomogram score groups. Our results indicated that low-CDKN1C expression was associated with shorter OS and lower proportion of naïve B cells, CD8 T cells, activated NK cells. The predictive accuracy of the nomogram for 5-year OS was superior to the tumour-node-metastasis stage (area under the curve: 0.746 vs. 0.634, p < 0.001). The nomogram exhibited excellent predictive performance, calibration ability and clinical utility. Moreover, low-risk patients were identified with stronger sensitivity to therapeutic agents. This tool can improve BC prognosis and therapeutic responses prediction, thus guiding individualized treatment decisions.

Characterization of AKT Somatic Mutations in Chinese Breast Cancer Patients.

PURPOSE: This study aimed to investigate AKT gene mutation status in Chinese breast cancer patients. METHODS: The study included 411 breast cancer patients hospitalized in Guangdong Provincial People's Hospital (GDPH) from June 1, 2017 to September 27, 2018. Mastectomy or breast conserving surgery was performed, and tissue samples were subjected to next-generation sequencing (NGS) to determine AKT gene mutation status. Meanwhile, the expression of human epidermal growth factor receptor 2 (Her2), progesterone receptor (PR), and estrogen receptor (ER) was analyzed by immunohistochemistry staining. The Cancer Genome Atlas (TCGA) database was used for comparative studies. RESULTS: Patients in the GDPH cohort had an older age (P < 0.001), higher postmenopausal rate (P < 0.001), larger tumor size (P < 0.001), higher histologic type of infiltrating duct cancer (P < 0.001), higher metastatic rate (P < 0.001), higher expression of ER (P = 0.015) and HER2 (P < 0.001), and higher percentage of the HR/HER2 subtype (P < 0.001) than those in the TCGA cohort. The GDPH cohort displayed lower rates of overall AKT and AKT3 mutation (P < 0.001), but a higher AKT1 mutation rate (P < 0.0001) compared with the TCGA cohort. Notably, the NGS studies identified missense mutation and copy number amplification as the most common AKT variation type in the GDPH and TCGA cohorts, respectively. Specifically, E17K mutation in AKT1 was predominantly detected in GDPH cohort, while being absent in TCGA cohort. Moreover, in the GDPH cohort, AKT variation was correlated with a number of clinicopathological variables, including age over 50, HER2-, HR+/HER2-, and PR+. CONCLUSION: Patients in the GDPH cohort had lower rates of AKT and AKT3 mutation and higher AKT1 mutation rate than those in the TCGA cohort, while harboring missense mutations detected predominantly as E17K mutation in AKT1. In GDPH cohort, there were correlations between AKT mutation and the clinicopathological characteristics of patients.

Association of Body Mass Index With Somatic Mutations in Breast Cancer.

BACKGROUND: The relationship between body mass index (BMI) and the prognosis or treatment response in patients with breast cancer has been demonstrated in previous studies, but the somatic mutation profiles in breast cancer patients with different BMIs have not been explored. METHODS: In the present study, the somatic mutation profiles in 421 female breast cancer patients who were stratified into three subgroups based on BMI (normal weight, overweight/obese, and underweight) were investigated. Capture-based targeted sequencing was performed using a panel comprising 520 cancer-related genes. RESULTS: A total of 3547 mutations were detected in 390 genes. In breast cancer patients with different BMI statuses, the tumors exhibited high mutation frequency and burden. TP53 was the most common gene in the three groups, followed by PIK3CA, ERBB2, and CDK12. Meanwhile, the mutation hotspots in TP53 and PIK3CA were the same in the three BMI groups. More JAK1 mutations were identified in underweight patients than those in normal patients. Except for JAK1, differentially mutated genes in postmenopausal patients were completely different from those in premenopausal patients. The distribution of mutation types was significantly different among BMI groups in the postmenopausal group. Underweight patients in the postmenopausal group harbored more TP53 mutations, more amplifications, and more mutations in genes involved in the WNT signaling pathway. CONCLUSIONS: Our next-generation sequencing (NGS)-based gene panel analysis revealed the gene expression profiles of breast cancer patients with different BMI statuses. Although genes with high mutation frequency and burden were found in different BMI groups, some subtle differences could not be ignored. JAK1 mutations might play a vital role in the progression of breast cancer in underweight patients, and this needs further analysis. Postmenopausal underweight patients with breast cancer have more aggressive characteristics, such as TP53 mutations, more amplifications, and more mutations in genes involved in the WNT signaling pathway. This study provides new evidence for understanding the characteristics of breast cancer patients with different BMIs.

Inflammatory indicator levels in patients undergoing aortic valve replacement via median sternotomy with preoperative anxiety and postoperative complications: a prospective cohort study.

OBJECTIVE: This study was performed to evaluate the association of preoperative anxiety with inflammatory indicators and postoperative complications in patients undergoing scheduled aortic valve replacement surgery. METHODS: A prospective cohort study was performed. The Hamilton Anxiety Scale was used to assess preoperative anxiety. The serum white blood cell (WBC) count and concentrations of C-reactive protein, interleukin (IL)-6, and IL-8 were measured 1 day preoperatively and 3 and 7 days postoperatively. Postoperative complications were also recorded. RESULTS: Seventy-three patients were included. The incidence of preoperative anxiety was 30.1% (22/73). The payment source was the only independent risk factor for preoperative anxiety. The incidence of postoperative complications was lowest in the mild anxiety group. The WBC count 3 days postoperatively was significantly lower in the mild than moderate-severe anxiety group. The IL-8 concentration 1 day preoperatively was highest in the no anxiety group. CONCLUSIONS: Mild preoperative anxiety might help to improve clinical outcomes. However, further investigations with more patients are warranted. Patients with different degrees of anxiety may have different levels of inflammatory cytokines.

PIK3CA somatic alterations in invasive breast cancers: different spectrum from Caucasians to Chinese detected by next generation sequencing.

PURPOSE: Somatic alteration of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) is a crucial therapeutic target in breast cancer (BC) and PI3Kα-specific inhibitor Alpelisib has been used in clinics. This study investigates the PIK3CA alterations in Chinese and Caucasians BC patients for the purpose of selecting anti-PI3K therapy. METHODS: The molecular profile of the PIK3CA gene was analyzed in 412 Chinese patients with untreated invasive BC using a 540 gene next-generation sequencing panel. The results were compared with data of the Caucasian BC patients in The Cancer Genome Atlas (TCGA-white). RESULTS: PIK3CA alterations were frequently found in BC of estrogen receptor (ER) positive (49.3%, p = 0.024), low ki67 proliferation index (58.3%, p = 0.007) and low pathological grade (grade I/II/III 80%, 53.4%, 35.9%, p < 0.001). Compared to TCGA-white, Chinese BC patients had a higher alteration frequency (45.6% vs. 34.7%, p < 0.001) with larger proportion of p.H1047R mutation among three common mutation sites (p.E545K, p.E542K and p.H1047R) (66.1% vs. 43.7%, p = 0.01). Across four molecular subtypes, ER + /human epidermal growth factor receptor 2 positive (HER2 +) tumors harbored the most PIK3CA alterations (51.6%), while ER-/HER2- harbored the least alteration (30.0%) but the most copy number amplification (19.05%). CONCLUSION: PIK3CA alterations prevail in Chinese BC patients and have different molecular features compared to that of Caucasians. The results provide precise annotations of PIK3CA genomic alterations of Chinese in the context of application of PIK3CA inhibitor.

Molecular characterization of breast cancer: a potential novel immune-related lncRNAs signature.

BACKGROUND: Accumulating evidence has demonstrated that immune-related lncRNAs (IRLs) are commonly aberrantly expressed in breast cancer (BC). Thus, we aimed to establish an IRL-based tool to improve prognosis prediction in BC patients. METHODS: We obtained IRL expression profiles in large BC cohorts (N = 911) from The Cancer Genome Atlas (TCGA) database. Then, in light of the correlation between each IRL and recurrence-free survival (RFS), we screened prognostic IRL signatures to construct a novel RFS nomogram via a Cox regression model. Subsequently, the performance of the IRL-based model was evaluated through discrimination, calibration ability, risk stratification ability and decision curve analysis (DCA). RESULTS: A total of 52 IRLs were obtained from TCGA. Based on multivariate Cox regression analyses, four IRLs (A1BG-AS1, AC004477.3, AC004585.1 and AC004854.2) and two risk parameters (tumor subtype and TNM stage) were utilized as independent indicators to develop a novel prognostic model. In terms of predictive accuracy, the IRL-based model was distinctly superior to the TNM staging system (AUC: 0.728 VS 0.673, P = 0.010). DCA indicated that our nomogram had favorable clinical practicability. In addition, risk stratification analysis showed that the IRL-based tool efficiently divided BC patients into high- and low-risk groups (P < 0.001). CONCLUSIONS: A novel IRL-based model was constructed to predict the risk of 5-year RFS in BC. Our model can improve the predictive power of the TNM staging system and identify high-risk patients with tumor recurrence to implement more appropriate treatment strategies.

Genetic mutation profile of Chinese HER2-positive breast cancers and genetic predictors of responses to Neoadjuvant anti-HER2 therapy.

PURPOSE: Despite the therapeutic success of existing HER2-targeted therapies, tumors respond quite differently to them. This study aimed at figuring out genetic mutation profile of Chinese HER2-positive patients and investigating predictive factors of neoadjuvant anti-HER2 responses. METHODS: We employed two cohorts. The first cohort was comprised of 181 HER2-positive patients treated at Guangdong Provincial People's Hospital from 2012 to 2018. The second cohort included 40 patients from the first cohort who underwent HER2-targeted neoadjuvant chemotherapy. Genetic mutations were characterized using next-generation sequencing. We employed the most commonly used definition of pathological complete response (pCR)-eradication of tumor from both breast and lymph nodes (ypT0/is ypN0). RESULTS: In Chinese HER2-positive breast cancer patients, TP53 (74.6%), CDK12 (64.6%) and PIK3CA (46.4%) have the highest mutation frequencies. In cohort 2, significant differences were found between pCR and non-pCR groups in terms of the initial Ki67 status, TP53 missense mutations, TP53 LOF mutations, PIK3CA mutations and ROS1 mutations (p = 0.028, 0.019, 0.005, 0.013, 0.049, respectively). Furthermore, TP53 LOF mutations and initial Ki67 status (OR 7.086, 95% CI 1.366-36.749, p = 0.020 and OR 6.007, 95% CI 1.120-32.210, p = 0.036, respectively) were found to be predictive of pCR status. CONCLUSION: TP53 LOF mutations and initial Ki67 status in HER2-positive breast cancer are predictive of pCR status after HER2-targeted NACT.

Comprehensive analysis of autophagy-related prognostic genes in breast cancer.

Accumulating evidence revealed that autophagy played vital roles in breast cancer (BC) progression. Thus, the aim of this study was to investigate the prognostic value of autophagy-related genes (ARGs) and develop a ARG-based model to evaluate 5-year overall survival (OS) in BC patients. We acquired ARG expression profiling in a large BC cohort (N = 1007) from The Cancer Genome Atlas (TCGA) database. The correlation between ARGs and OS was confirmed by the LASSO and Cox regression analyses. A predictive model was established based on independent prognostic variables. Thus, time-dependent receiver operating curve (ROC), calibration plot, decision curve and subgroup analysis were conducted to determine the predictive performance of ARG-based model. Four ARGs (ATG4A, IFNG, NRG1 and SERPINA1) were identified using the LASSO and multivariate Cox regression analyses. A ARG-based model was constructed based on the four ARGs and two clinicopathological risk factors (age and TNM stage), dividing patients into high-risk and low-risk groups. The 5-year OS of patients in the low-risk group was higher than that in the high-risk group (P < 0.0001). Time-dependent ROC at 5 years indicated that the four ARG-based tool had better prognostic accuracy than TNM stage in the training cohort (AUC: 0.731 vs 0.640, P < 0.01) and validation cohort (AUC: 0.804 vs 0.671, P < 0.01). The mutation frequencies of the four ARGs (ATG4A, IFNG, NRG1 and SERPINA1) were 0.9%, 2.8%, 8% and 1.3%, respectively. We built and verified a novel four ARG-based nomogram, a credible approach to predict 5-year OS in BC, which can assist oncologists in determining effective therapeutic strategies.

Comparison of BRCA versus non-BRCA germline mutations and associated somatic mutation profiles in patients with unselected breast cancer.

The data on the phenotypes associated with some rare germline mutations in Chinese breast cancer patients are limited. The difference in somatic mutation profiles in breast cancer patients with germline BRCA and non-BRCA mutations remains unexplored. We interrogated the germline and somatic mutational profile of 524 Chinese breast cancer patients with various stages unselected for predisposing factors using a panel consisting of 520 cancer-related genes including 62 cancer susceptibility genes. We divided the patients into three groups according to germline mutations: Germline-BRCA1/2, Germline-others (non-BRCA) and Others (non-carriers). A total of 58 patients (11.1%) carried 76 likely pathogenic or pathogenic (LP/P) germline variants in 15 cancer predisposition genes. Germline BRCA1/2 mutations were detected from 29 (5.53%) patients; with 11 (2.10%) BRCA1 carriers and 18 (3.44%) BRCA2 carriers. In addition, LP/P germline mutations were detected in other genes including MUTYH (n=4), PALB2 (n=4), ATM (n=3), BRIP1 (n=3), CDH1 (n=3), RAD51C (n=3), CHEK2 (n=2), FANCA (n=2), PMS2 (n=2), TP53 (n=2), FANCI (n=1), FANCL (n=1) and PTEN (n=1). At least one variant of uncertain significance (VUS) was identified in 490 (93.5%) patients. Young age (P=0.011), premenopausal status (P=0.013), and breast/ovarian cancer family history (P=0.001) were correlated with germline mutations. Germline-BRCA1/2 group was detected with more missense (P=0.02) and less copy-number amplification (P=0.04) than Germline-others group. Meanwhile, Germline-others group and Others group are very similar (P>0.05). The mutation rates of AKT1, CCND1, FGFR1, and PIK3CA were different among the three groups. By investigating all breast and ovarian cancer-related genes listed in the US genetic guidelines, we identified 15 cancer susceptibility genes frequently mutated in the germline of our population and must be included in cancer predisposition screening. Our study contributed a better understanding of the tumor characteristics of patients with LP/P germline mutations.

Heterogeneity of genomic profile in patients with HER2-positive breast cancer.

HER2-positive breast cancer is a biologically and clinically heterogeneous disease. Based on the expression of hormone receptors (HR), breast tumors can be further categorized into HR positive and HR negative. Here, we elucidated the comprehensive somatic mutation profile of HR+ and HR- HER2-positive breast tumors to understand their molecular heterogeneity. In this study, 64 HR+/HER2+ and 43 HR-/HER2+ stage I-III breast cancer patients were included. Capture-based targeted sequencing was performed using a panel consisting of 520 cancer-related genes, spanning 1.64 megabases of the human genome. A total of 1119 mutations were detected among the 107 HER2-positive patients. TP53, CDK12 and PIK3CA were the most frequently mutated, with mutation rates of 76, 61 and 49, respectively. HR+/HER2+ tumors had more gene amplification, splice site and frameshift mutations and a smaller number of missense, nonsense and insertion-deletion mutations than HR-/HER2+ tumors. In KEGG analysis, HR+/HER2+ tumors had more mutations in genes involved in homologous recombination (P = 0.004), TGF-beta (P = 0.007) and WNT (P = 0.002) signaling pathways than HR-/HER2+ tumors. Moreover, comparative analysis of our cohort with datasets from The Cancer Genome Atlas and Molecular Taxonomy of Breast Cancer International Consortium revealed the distinct somatic mutation profile of Chinese HER2-positive breast cancer patients. Our study revealed the heterogeneity of somatic mutations between HR+/HER2+ and HR-/HER2+ in Chinese breast cancer patients. The distinct mutation profile and related pathways are potentially relevant in the development of optimal treatment strategies for this subset of patients.