Defect of SLC38A3 promotes epithelial-mesenchymal transition and predicts poor prognosis in esophageal squamous cell carcinoma

Objective: Solute carrier family 38(SLC38 s) transporters play important roles in amino acid transportation and signaling transduction. However, their genetic alterations and biological roles in tumors are still largely unclear.This study aimed to elucidate the genetic signatures of SLC38 s transporters and their implications in esophageal squamous cell carcinoma(ESCC).Methods: Analyses on somatic mutation and copy number alterations(CNAs) of SLC38 A3 were performed as described. Immunohistochemistry(IHC) assay and Western blot assay were used to detect the protein expression level. MTS assay, colony formation assay, transwell assay and wound healing assay were used to explore the malignant phenotypes of ESCC cells. Immunofluorescence assay was used to verify the colocalization of two indicated proteins and immunopreciptation assay was performed to confirm the interaction of proteins.Results: Our findings revealed that SLC38 s family was significantly disrupted in ESCC, with high frequent CNAs and few somatic mutations. SLC38 A3 was the most frequent loss gene among them and was linked to poor survival and lymph node metastasis. The expression of SLC38 A3 was lower in tumor tissues compared to that in normal tissues, which was also significantly associated with worse clinical outcome. Further experiments revealed that depletion of SLC38 A3 could promote EMT in ESCC cell lines, and the interaction of SLC38 A3 and SETDB1 might lead to the reduced transcription of Snail. Pharmacogenomic analyses demonstrated that fifteen inhibitors were showed significantly correlated with SLC38 A3 expression.Conclusions: Our investigations have provided insights that SLC38 A3 could act as a suppressor in EMT pathway and serve as a prognostic factor and predictor of differential drug sensitivities in ESCC.

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[PDL1]).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.

Safety,tolerability,and pharmacokinetics of BAT8001 in patients with HER2-positive breast cancer:An open-label,dose-escalation,phase I study

Background:The introductions of anti-human epidermal growth factor receptor-2(HER2)agents have significantly improved the treatment outcome of patients with HER2-positive breast cancer.BAT8001 is a novel antibodydrug conjugate targeting human epidermal growth factor receptor-2(HER2)-expressing cells composed of a trastuzumab biosimilar linked to the drug-linker Batansine.This dose-escalation,phase I study was designed to assess the safety,tolerability,pharmacokinetics,and preliminary anti-tumor activity of BAT8001 in patients with HER2-positive locally advanced or metastatic breast cancer.Methods:This trial was conducted in subjects with histologically confirmed HER2-positive breast cancer(having evaluable lesions and an Eastern Cooperative Oncology Group performance status of 0 or 1)using a 3+3 design of escalating BAT8001 doses.Patients received BAT8001 intravenously in a 21-day cycle,with dose escalation in 5 cohorts:1.2,2.4,3.6,4.8,and 6.0 mg/kg.The primary objective was to evaluate the safety and tolerability of BAT8001.Preliminary activity of BAT8001 was also assessed as a secondary objective.Results:Between March 2017 to May 2018,29 HER2-positive breast cancer patients were enrolled.The observed dose-limiting toxicities were grade 4 thrombocytopenia and grade 3 elevated transaminase.The maximum tolerated dose was determined to be 3.6 mg/kg.Grade 3 or greater adverse events(AEs)occurred in 14(48.3%)of 29 patients,including thrombocytopenia in 12(41.4%)patients,aspartate aminotransferase increased in 4(13.8%)patients,γ-glutamyl transferase increased in 2(6.9%)patients,alanine aminotransferase increased in 2(6.9%)patients,diarrhea in 2(6.9%)patients.Objective response was observed in 12(41.4%,95%confidence interval[CI]=23.5%-61.1%)and disease control(including patients achieving objective response and stable disease)was observed in 24(82.8%,95%CI=64.2%-94.2%)patients.Conclusions:BAT8001 demonstrated favorable safety profiles,with promising anti-tumor activity in patients with HER2-positive locally advanced or metastatic breast cancer.BAT8001 has the potential to provide a new therapeutic option in patients with metastatic HER2-positive breast cancer.

Metronomic chemotherapy of cyclophosphamide plus methotrexate for advanced breast cancer:Real-world data analyses and experience of one center

Background:Real-world data of the CM regimen[cyclophosphamide(CTX)plus methotrexate(MTX)]in metronomic pattern for advanced breast cancer is limited to small-sample or retrospective studies.This study was aimed to determine the effectiveness and safety of CM regimen in treating advanced breast cancer and to identify which patients are most likely to benefit from metronomic CM regimen.Methods:Patients with advanced breast cancer who received the metronomic CM regimen at least once between January 2009 and February 2019 in Sun Yat-sen University Cancer Center were included.Clinicopathological characteristics were collected.Overall survival(OS)and progression-free survival(PFS)were assessed using Kaplan-Meier estimates.Characteristics between patients with PFS<6 months and≥6 months were compared using the Chi-square test.Univariate and multivariate Cox regression model was used to estimate the prognostic factors for PFS and OS.Results:A total of 186 patients were included.The median age and follow-up were 49 years and 13.3 months,respectively.Over 50%of the patients were estrogen receptor/progesterone receptor-positive,and 60.8%had been heavily treated(≥3 lines).The objective response rate was 3.8%,the disease control rate at 12 weeks was 41.4%,and the clinical benefit rate at 24 weeks was 31.2%(58/186).The median PFS was 4.0 months[95%confidence interval(CI):3.6-4.7 months],the median duration of clinical benefit was 9.5 months(95%CI:8.2-10.8 months),and the median OS was 26.8 months(95%CI:20.9-37.7 months).Multivariate analysis for PFS revealed the CM regimen as maintenance therapy and no liver metastasis as favorable prognostic factors.Furthermore,patients without liver metastasis were more likely to have a PFS over 6 months than those with liver involvement(P=0.022).Liver,lymph node,and brain metastases were unfavorable prognostic factors for OS.The CM regimen was well-tolerated without newly reported adverse events.Conclusions:The CM regimen was effective in selected patients.In clinical practice,it would be better used as maintenance therapy and in patients without liver metastasis.Further follow-up investigation should be performed to examine its effect when used in combination with other treatments and determine predictive biomarkers.

CPSF4 promotes triple negative breast cancer metastasis by upregulating MDM4

Dear Editor,Breast cancer(BrC)is the most common cancer in women.Triple negative BrC(TNBC)is the subtype with highly aggressive clinical behaviors and heterogeneity.Metastasis is the leading cause of TNBC-related deaths,but its mechanism is not well-understood.Apart from PIK3CA,TP53,and PTEN,few recurrent mutations have been identified in TNBC so far,suggesting that TNBC phenotype could be driven by nongenetic alterations such as aberrant expression of oncogenes.

Nail pigmentation induced by chemotherapy:an observational study of patients with early-stage breast cancer

Purpose:Chemotherapy-induced nail pigmentation is a common adverse efect,but prospective studies focussing on its onset,recovery,and severity are few.We aim to evaluate the pattern of chemotherapy-induced nail pigmentation in early-stage breast cancer patients by calculating the comprehensive score based on hyperpigmentation area and color depth of the nail plate.Methods:This prospective,observational study was conducted between February 2019 and December 2019.Early-stage breast cancer patients scheduled to receive anthracyclines combined with cyclophosphamide or taxanecontaining regimens were enrolled.The clinicopathologic characteristics and treatment protocols were collected.The onset,patterns,and duration of nail changes were photographed and recorded regularly.Results:A total of 90 patients were enrolled.The most common nail change was nail pigmentation(n=81,90.0%),followed by onycholysis(n=39,43.3%),Beau’s lines(n=19,21.1%),Mees’lines(n=16,17.8%),Muehrcke’s lines(n=7,7.8%),and hemorrhage(n=1,1.1%).Forty-four(48.9%)patients developed severe nail pigmentation.The median onset time of nail pigmentation was 37 days after the initiation of chemotherapy.At the latest follow-up,55(67.9%)patients achieved remission of melanonychia with the median recovery time of 118 days.The median duration of nail pigmentation was 214 days.Conclusion:Our study revealed the specifc pattern of chemotherapy-induced nail pigmentation,which onsets early and recovers slowly with a high incidence of severe nail pigmentation,in early-stage breast cancer patients.The results provide reference for further intervention studies.Trial Registration:ClinicalTrials.gov Identifer:NCT04215744.Registered 30 December 2019—Retrospectively registered.