Leptomeningeal metastasis of breast cancer during neo-adjuvant chemotherapy in a 38-year-old woman: a case report.

Background: Breast cancer accounts for 5% of the population who develop central nervous system metastasis, which is only second to the lung cancer. Breast cancer metastasis to the brain including parenchymal brain metastasis (BM) and leptomeningeal metastasis (LM). Compared with BM, LM is a more rare but aggressive metastatic diagnosis with poor outcome. Case Description: We reported a 38-year-old woman presented to the neurology department due to progressive headache for 1 month, accompanied with dizziness, nausea, vomiting and neck pain. During hospitalization, she experienced paroxysmal loss of consciousness twice. Five months prior to this visit, her first visit was diagnosed with breast cancer on the right side which was of triple-negative subtype and with homolateral axillary lymph node involvement by biopsy. After the clinician assessment she had received six cycles of TCb (docetaxel/carboplatin) neo-adjuvant chemotherapy. During the period of neo-adjuvant chemotherapy, she did not report the presence of severe neurological symptoms. Twenty days ago, she underwent right breast-conserving surgery and the postoperative evaluation was ypT1N3M0 stage and Miller-Payne grade 2. Head computed tomography (CT) scan and contrast-enhanced magnetic resonance imaging (MRI) didn't find typical brain imaging changes. No other signs of metastasis were seen in the CT examinations of the patient's chest and abdomen. Finally, lumbar puncture with cerebrospinal fluid (CSF) analysis showed the presence of malignant cells. Given the patient's clinical history and new neurologic symptoms, the diagnosis was LM from breast cancer. Various treatment modalities including intrathecal thiotepa, oral temozolomide (TMZ) and whole-brain radiation therapy (WBRT) had been used, but none of them showed significant benefit for survival. Conclusions: Breast cancer metastasis to the brain, especially LM, should be given sufficient vigilance and attention at the beginning of the diagnosis and treatment, particularly in triple-negative breast cancer patients who are at high risk. Symptoms of LM may be masked by the chemotherapy adverse effects. The results of MRI and CT may show negative results, thus lumbar puncture with CSF should be done promptly if LM is highly suspected in clinical practice. Early prevention, early detection and timely treatment are crucial according to the poor prognosis.

[Retracted] Propofol modulates the proliferation, invasion and migration of bladder cancer cells through the miR­145­5p/TOP2A axis.

Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that the tumour images shown in Fig. 6B on p. 8 were strikingly similar to data appearing in different form in other articles written by different authors at different research institutes, which had either already been published or were under consideration for publication at around the same time. Owing to the fact that the contentious data in the above article were already under consideration for publication prior to its submission to Molecular Medicine Reports, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused. [Molecular Medicine Reports 23: 439, 2021; DOI: 10.3892/mmr.2021.12078].

Germline RECQL gene mutations in Chinese patients with breast cancer.

Introduction: Breast cancer is the most common malignant tumor in women, seriously threatening health and survival. TP-dependent DNA helicase Q1 (RECQL) is a breast cancer susceptibility gene with possible familial links. However, RECQL gene mutations among Chinese women with breast cancer have not been evaluated. Therefore, this study assessed RECQL mutations and their relationships with clinicopathological and epidemiological characteristics in Chinese women with breast cancer. Method: Clinical information was also obtained via the hospital information system and a follow-up questionnaire. Peripheral venous blood (2 mL) was extracted from all patients and stored at -80°C for future use; the early venous blood samples were from our hospital's sample bank. RECQL gene sequencing were performed by the Shanghai Aishe Gene Company (China). Results: We found that a RECQL mutation is a susceptibility factor for breast cancer. Moreover, patients with RECQL mutations were more likely to have a family history of breast cancer than those without. Also, patients with RECQL variants of uncertain significance (VUS) were less likely to develop invasive ductal carcinoma than those without. In addition, unexplained RECQL mutations occurred more often in patients with human epidermal growth factor receptor 2+ breast cancer than in those with other subtypes. Discussion: These results provide a basis for creating screening criteria specific to Chinese women. However, the frequency of RECQL mutations was low, and the number of pathogenic mutations was too small and could not be analyzed. Thus, more extensive, long-term studies that include other functional experiments are needed to verify these results.

Can We Do Breast-Conserving Surgery Without Intraoperative Frozen Section of Margin?

PURPOSE: This study was a retrospective and nonrandomized study to assess the safety and reliability of identifying the surgical margin in breast cancer breast-conserving surgery (BCS) by using intraoperative ultrasonic location and specimen mammography instead of traditional intraoperative frozen pathological section. METHODS: Among the patients who underwent BCS from May 2019 to October 2021, according to the different methods of evaluating the intraoperative margin, 104 breast cancer patients were included in the frozen edge group, 53 breast cancer patients were included in the freeze-free group, and the surgeon judged whether extended resection was needed based on the results of pathological section or evaluation of intraoperative ultrasound and mammography. The surgical margins of the two groups were judged by postoperative pathological results as the gold standard. RESULTS: The median waiting pathology results time in the frozen edge group was 64 minutes, while the waiting time in the freeze-free group was 30 minutes, and the difference was statistically significant (P < .0001). The postoperative pathological results showed that the positive rate of the surgical margin in the frozen edge group was 0.96%. The coincidence rate of intraoperative frozen and postoperative pathological results was 99.04%. The coincidence rate between intraoperative mammography and postoperative pathological results was 100%. CONCLUSIONS: In BCS, the method of using intraoperative staining markers combined with mammography to evaluate the resection margin is highly accurate, reliable, economical and convenient, and at the same time reduces the waiting time of the operator during the operation. However, this was not a randomized controlled study, and there was patient selection bias, and its safety needs to be confirmed by long-term follow-up. In the future, it is expected to become the mainstream means of evaluating.

Why does HER2-positive breast cancer metastasize to the brain and what can we do about it?

Breast cancer is the most frequent malignancy in women. However, in the middle and late stages, some people develop distant metastases, which considerably lower the quality of life and life expectancy. The brain is one of the sites where metastasis frequently happens. According to epidemiological research, brain metastases occur at a late stage in 30-50% of patients with HER2-positive breast cancer, resulting in a poor prognosis. Additionally, few treatments are available for HER2-positive brain metastatic breast cancer, and the mortality rate is remarkable owing to the complexity of the brain's anatomical structure and physiological function. In this review, we described the stages of the brain metastasis of breast cancer, the relationship between the microenvironment and metastatic cancer cells, and the unique molecular and cellular mechanisms. It involves cancer cells migrating, invading, and adhering to the brain; penetrating the blood-brain barrier; interacting with brain cells; and activating signal pathways once inside the brain. Finally, we reviewed current clinically used treatment approaches for brain metastasis in HER2-positive breast cancer; summarized the traditional treatment, targeted treatment, immunotherapy, and other treatment modalities; compared the benefits and drawbacks of each approach; discussed treatment challenges; and emphasized the importance of identifying potential targets to improve patient survival rates and comprehend brain metastasis in breast cancer.

Toripalimab plus nab-paclitaxel in metastatic or recurrent triple-negative breast cancer: a randomized phase 3 trial.

The combination of immune-checkpoint blockade with chemotherapy for the first-line treatment of advanced triple-negative breast cancer (TNBC) has generated mixed results. TORCHLIGHT is a randomized, double-blinded phase 3 trial evaluating the efficacy and safety of first-line toripalimab and nab-paclitaxel (nab-P) (n = 353; experimental arm) versus placebo and nab-P (n = 178; control arm) for the treatment of women with metastatic or recurrent TNBC. The primary end point was progression-free survival (PFS) assessed by a blinded independent central review in the PD-L1-positive and intention-to-treat populations. The secondary end points included overall survival and safety. Overall, 200 and 100 patients, in the toripalimab and placebo arm respectively had PD-L1-positive TNBC. At the prespecified interim analysis, a statistically significant improvement in PFS assessed by a blinded independent central review was demonstrated in the experimental arm in the PD-L1-positive population (median PFS 8.4 versus 5.6 months; hazard ratio (HR) = 0.65, 95% confidence interval (CI) 0.470-0.906, P = 0.0102). The median overall survival was 32.8 versus 19.5 months (HR = 0.62, 95% CI 0.414-0.914, P = 0.0148). Similar incidences of treatment-emergent adverse events (AEs) (99.2% versus 98.9%), grade ≥3 treatment-emergent AEs (56.4% versus 54.3%) and fatal AEs (0.6% versus 3.4%) occurred in the experimental and control arms. The addition of toripalimab to nab-P provided a significant improvement in PFS for PD-L1-positive patients with metastatic or recurrent TNBC with an acceptable safety profile. ClinicalTrial.gov identifier NCT03777579 .

First-line CDK4/6 inhibitor-based combinations for HR+/HER2- advanced breast cancer: A Bayesian network meta-analysis.

BACKGROUND: International guidelines recommend cyclin-dependent kinase 4/6 inhibitor (CDK4/6i)-based first-line therapy for hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer (ABC). However, direct drug comparisons are lacking. We aimed to identify the most effective and safe therapy through network meta-analysis (NMA). METHODS: We searched PubMed, Embase, Web of Science, Cochrane Central Register of Controlled Trials, and OpenGrey up to September 30, 2023. Eligible studies included randomized controlled trials (RCTs) assessing endocrine therapy alone or in combination with CDK4/6i as first-line endocrine treatment for HR+/HER2- ABC patients. The hazard ratios for progression-free survival (PFS) and overall survival (OS) and relative risks for objective response rate and adverse events (AEs) were available in selected trials. We performed a Bayesian NMA following PRISMA guidelines. RESULTS: Thirteen RCTs, involving 10 treatments, were included. Most studies were at low risk of bias. Regarding PFS, ribociclib+fulvestrant ranked first with a surface under the cumulative ranking curve (SUCRA) of 85.0%, followed by dalpiciclib+nonsteroidal aromatase inhibitor (NSAI) (SUCRA = 78.9%). Considering OS, the top three ranked treatments were ribociclib+fulvestrant (SUCRA = 94.1%), abemaciclib+NSAI (SUCRA = 69.9%), and ribociclib+NSAI (SUCRA = 68.5%). Out of four CDK4/6is, ribociclib minimized the grade 3/4 AEs, while dalpiciclib demonstrated the worst safety. Publication bias could not be ignored in our analyses, and the certainty of evidence was downgraded primarily due to imprecision. CONCLUSIONS: Ribociclib+fulvestrant probably represents the best option in a first-line setting. When combined with NSAI, dalpiciclib likely showed the best efficacy but the worst safety. Abemaciclib+NSAI and ribociclib+NSAI could also be promising treatments, while palbociclib presented inferiority. (PROSPERO Registration No. CRD42022370271).

Safety of COVID-19 Vaccination in Patients With Breast Cancer: Cross-Sectional Study in China.

BACKGROUND: The widespread use of vaccines against the novel coronavirus disease (COVID-19) has become one of the most effective means to establish a population immune barrier. Patients with cancer are vulnerable to COVID-19 infection, adverse events, and high mortality, and should be the focus of epidemic prevention and treatment. However, real-world data on the safety of vaccines for patients with breast cancer are still scarce. OBJECTIVE: This study aims to compare the safety of COVID-19 vaccines between patients vaccinated before or after being diagnosed with breast cancer. METHODS: Patients with breast cancer who sought medical advice from October 2021 to December 2021 were screened. Those who received COVID-19 vaccines were enrolled in this study to analyze the safety of the vaccines. The primary outcome was patient-reported adverse events (AEs). All events after vaccine injection were retrospectively documented from the patients. RESULTS: A total of 15,455 patients with breast cancer from 41 hospitals in 20 provinces in China were screened, and 5766 patients who received COVID-19 vaccines were enrolled. Of those enrolled, 45.1% (n=2599) of patients received vaccines before breast cancer diagnosis, 41.3% (n=2379) were vaccinated after diagnosis, and 13.6% (n=784) did not known the accurate date of vaccination or cancer diagnosis. Among the patients vaccinated after diagnosis, 85.4% (n=2032) were vaccinated 1 year after cancer diagnosis and 95.4% (n=2270) were vaccinated during early-stage cancer. Of all 5766 vaccinated patients, 93.9% (n=5415) received an inactivated vaccine, 3.7% (n=213) received a recombinant subunit vaccine, and 2.4% (n=138) received other vaccines, including adenovirus and mRNA vaccines. In the first injection of vaccines, 24.4% (n=10, 95% CI 11.2-37.5) of patients who received an adenovirus vaccine reported AEs, compared to only 12.5% (n=677, 95% CI 11.6-13.4) of those who received an inactivated vaccine. Patients with metastatic breast cancer reported the highest incidence of AEs (n=18, 16.5%, 95% CI 9.5-23.5). Following the second injection, patients who received an inactivated vaccine (n=464, 8.7%, 95% CI 8.0-9.5) and those who received a recombinant vaccine (n=25, 8.7%, 95% CI 5.5-12.0) reported the same incidence of AEs. No significant differences in patient-reported AEs were found between the healthy population and patients with breast cancer (16.4% vs 16.9%, respectively); the most common AEs were local pain (11.1% vs 9.1%, respectively), fatigue (5.5% vs 6.3%, respectively), and muscle soreness (2.3% vs 3.6%, respectively). The type of vaccine and time window of vaccination had little impact on patient-reported AEs. CONCLUSIONS: Compared with patients vaccinated before breast cancer diagnosis, there were no significant differences in patient-reported AEs in the patients vaccinated after diagnosis. Thus, it is safe for patients with breast cancer, especially for those in the early stage, to receive COVID-19 vaccines. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2200055509; https://tinyurl.com/33zzj882.

Pyrotinib plus docetaxel as first-line treatment for HER2-positive metastatic breast cancer: the PANDORA phase II trial.

The role of pyrotinib in the treatment of HER2-positive metastatic breast cancer (MBC) has been well-established. This multicenter, single-arm phase II trial (NCT03876587) aimed to assess the benefit of pyrotinib plus docetaxel as a first-line treatment for HER2-positive MBC. Women with HER2-positive MBC who had not undergone HER2 blockade or chemotherapy for metastatic disease were enrolled in the study and received daily oral pyrotinib 400 mg plus intravenous docetaxel 75 mg/m2 every 3 weeks. The primary endpoint was the objective response rate (ORR), secondary endpoints included progression-free survival (PFS), duration of response (DoR), clinical benefit rate (CBR), overall survival (OS) and safety. From June 2019 to June 2021, 79 patients were enrolled. The confirmed ORR was 79.7% (95% confidence interval [CI], 70.8-88.6), and the CBR was 87.3% (95%CI, 80.0-94.6) in the intention-to-treat population. The pre-specified primary endpoint was met. The median DoR was 15.9 months (interquartile range, 8.3-19.5); the median PFS was 16.0 months (95% CI, 11.2-20.8), and the median OS was not reached. The most common grade ≥3 treatment-related adverse events observed were leukopenia (29.1%), neutropenia (27.8%), and diarrhea (21.5%). This study demonstrates that pyrotinib plus docetaxel show an acceptable safety profile and promising antitumor activity as a first-line treatment option for patients with HER2-positive MBC.

LncRNA TDRKH-AS1 promotes breast cancer progression via the miR-134-5p/CREB1 axis.

BACKGROUND: Breast cancer (BC) is a prevalent malignancy with complex etiology and varied clinical behavior. Long non-coding RNAs (lncRNAs) have emerged as key regulators in cancer progression, including BC. Among these, lncRNA TDRKH-AS1 has been implicated in several cancers, but its role in BC remains unclear. METHODS: We conducted a comprehensive investigation to elucidate the role of TDRKH-AS1 in BC. Clinical samples were collected from BC patients, and BC cell lines were cultured. Bioinformatics analysis using the starBase database was carried out to assess TDRKH-AS1 expression levels in BC tissue samples. Functional experiments, including knockdown, colony formation, CCK-8, Transwell, and wound-healing assays, were conducted to determine the role of TDRKH-AS1 in BC cell proliferation and invasion. Luciferase reporter and RIP assays were used to examine the interactions between TDRKH-AS1 and miR-134-5p. In addition, the downstream target gene of miR-134-5p, cAMP response element-binding protein 1 (CREB1), was identified and studied using various methods, including RT-qPCR, immunoprecipitation, and rescue experiments. In vivo experiments using mouse tumor xenograft models were conducted to examine the role of TDRKH-AS1 in BC tumorigenesis. RESULTS: TDRKH-AS1 was found to be significantly upregulated in BC tissues and cell lines. High TDRKH-AS1 expression correlated with advanced BC stages and worse patient outcomes. Knockdown of TDRKH-AS1 led to decreased BC cell proliferation and invasion. Mechanistically, TDRKH-AS1 acted as a sponge for miR-134-5p, thereby reducing the inhibitory effects of miR-134-5p on CREB1 expression. Overexpression of CREB1 partially rescued the effects of TDRKH-AS1 knockdown in BC cells. In vivo studies further confirmed the tumor-promoting role of TDRKH-AS1 in BC. CONCLUSIONS: Our study unveiled a novel regulatory axis involving TDRKH-AS1, miR-134-5p, and CREB1 in BC progression. TDRKH-AS1 functioned as an oncogenic lncRNA by promoting BC cell proliferation and invasion through modulation of the miR-134-5p/CREB1 axis. These findings highlighted TDRKH-AS1 as a potential diagnostic biomarker and therapeutic target for BC treatment.

Short-term effect of beinaglutide combined with metformin versus metformin alone on weight loss and metabolic profiles in obese patients with polycystic ovary syndrome: a pilot randomized trial.

Objective: To observe the effect of beinaglutide combined with metformin versus metformin alone on weight loss and metabolic profiles in obese patients with polycystic ovary syndrome(PCOS). Methods: A total of 64 overweight/obese women with PCOS diagnosed via the Rotterdam criteria were randomly assigned to metformin(MET) 850 mg twice a day(BID) or combined MET 850 mg BID with beinaglutide (COMB) starting at 0.1mg three times a day(TID)and increasing to 0.2mg TID two weeks later. The main endpoints were changes in anthropometric measurements of obesity. Glucose and lipid metabolic, gonadal profiles, and antral follicle count changes as secondary outcomes were also observed. Results: 60(93.75%) patients completed the study. In terms of lowering weight, body mass index (BMI),waist circumference(WC) and waist to height ratio(WHtR), COMB treatment outperformed MET monotherapy. Subjects in the COMB arm lost weight 4.54±3.16kg compared with a 2.47±3.59kg loss in the MET arm. In the COMB group, BMI,WC and WHtR were reduced significantly compared with that in the MET group, respectively. COMB therapy is also more favorable in the reduction of fasting insulin(FINS), total testosterone(TT), and homeostasis model assessment-insulin resistance(HOMA-IR) when compared to MET therapy. Antral follicle count and ovarian volume were non-significantly changed in both groups.The most frequent side effects in both groups were mild and moderate digestive symptoms. Itching and induration at the injection site were reported with COMB treatment. Conclusion: Short-term combined treatment with beinaglutide and metformin appears superior to metformin monotherapy in lowering body weight, BMI, WC,WHtR and improving insulin sensitivity and androgen excess in women with PCOS and obesity, with tolerable adverse events. Clinical trial registration: https://www.chictr.org.cn/listbycreater.aspx, identifier ChiCTR2000033741.

A prognostic signature associated with cell senescence predicts survival outcomes and strongly associates with immunotherapy and chemotherapy response in breast cancer.

The objective of this study is to assess the predictive potency of cell senescence-related genes (CSRGs) in breast cancer (BC) and establish a risk signature. Trascriptome data of CSRGs were obtained from the TCGA and GEO databases. Consensus clustering was used to generate CSRGs-based molecular clusters for BC patients. A CSRGs-derived risk signature was built using multiple Cox regression analyses of differentially expressed genes (DEGs) between clusters. The prognosis, immune infiltration, chemotherapy and immunotherapy response between different risk groups were analyzed and compared. Two molecular clusters of BC patients were generated on the basis of 79 differentially expressed CSRGs, which showed distinct prognosis and immune infiltration. A total of 1403 DEGs between the CSRGs-derived clusters were found, and 10 of them were independent prognostic genes that used to construct a risk signature. The results demonstrated that patients with older age and advanced stage presented with a higher risk scores. In addition, the risk signature was found to be associated with outcomes, immune infiltration, chemotherapy and immunotherapy response. Patients in the low-risk group showed a favorable prognosis and higher immunotherapy response than those in the high-risk group. Finally, we developed a highly stable nomogram that incorporates risk signature, chemotherapy, radiotherapy, and stage variables, enabling accurate prediction of the overall survival (OS) of individual patients. To conclude, the signature derived from CSRGs holds great promise as a biomarker for prognostic assessment of BC and may serve as a valuable tool in guiding immunotherapy.

Postmastectomy radiotherapy in patients with T1-2N1 breast cancer: a single center experience and a meta-analysis.

PURPOSE: Postmastectomy radiotherapy (PMRT) in patients with T1-2N1 breast cancer is still controversial. This study was to evaluate the survival prognosis of T1-2N1 patients with or without PMRT. PATIENTS AND METHODS: From January 2006 to May 2017, 2606 female breast cancer patients underwent mastectomy in our medical center, among whom 402 patients of T1-2N1 stage with or without PMRT were finally analyzed. The median follow-up duration was 59.5 months. The primary endpoint was overall survival (OS). The secondary endpoint was disease-free survival (DFS). RESULTS: In the study of our center, no statistically significant difference was observed between the T1-2N1 PMRT and non-PMRT subgroups for the 5-year OS (94.4% vs 95.4%, p = 0.667) and DFS (90.1% vs. 91.1%, p = 0.798). By the date of the last follow-up, 8.96% (n = 36) of the patients experienced any recurrence. Univariate analysis revealed that PMRT was not a prognostic factor for either OS (p = 0.667) or DFS (p = 0.798) in T1-2N1 patients. We then did a meta-analysis on the current treatment patterns, in which 2606 PMRT and 4281 non-PMRT T1-2N1 breast cancer patients with mastectomy were included. The meta-analysis showed that PMRT didn't improve the OS of the patients (HR = 0.85, p = 0.11), but patients with PMRT had better DFS than those in the non-PMRT group (HR = 0.62, p < 0.001). CONCLUSION: PMRT did not affect the survival of T1-2N1 breast cancer patients who underwent mastectomy, suggesting that radiotherapy may be safely omitted for them.

Effect of Bifidobacterium on osteoclasts: TNF-α/NF-κB inflammatory signal pathway-mediated mechanism.

Osteoporosis is a systemic multifactorial bone disease characterized by low bone quality and density and bone microstructure damage, increasing bone fragility and fracture vulnerability. Increased osteoclast differentiation and activity are important factors contributing to bone loss, which is a common pathological manifestation of bone diseases such as osteoporosis. TNF-a/NF-κB is an inflammatory signaling pathway with a key regulatory role in regulating osteoclast formation, and the classical pathway RANKL/RANK/OPG assists osteoclast formation. Activation of this inflammatory pathway promotes the formation of osteoclasts and accelerates the process of osteoporosis. Recent studies and emerging evidence have consistently demonstrated the potential of probiotics to modulate bone health. Secretions of Bifidobacterium, a genus of probiotic bacteria in the phylum Actinobacteria, such as short-chain fatty acids, equol, and exopolysaccharides, have indicated beneficial effects on bone health. This review discusses the molecular mechanisms of the TNF-a/NF-κB inflammatory pathway in regulating osteoclast formation and describes the secretions produced by Bifidobacterium and their potential effects on bone health through this pathway, opening up new directions for future research.

Pamiparib in patients with locally advanced or metastatic HER2-negative breast cancer with germline BRCA mutations: a phase II study.

PURPOSE: To evaluate the efficacy and safety of pamiparib in patients with locally advanced or metastatic human epidermal growth factor receptor 2-negative (HER2-) breast cancer, with deleterious or suspected deleterious germline BRCA1/2 mutations (gBRCA1/2 m). METHODS: In this open-label, phase II, multicenter study in China (NCT03575065), patients with triple-negative breast cancer (TNBC cohort) or hormone receptor-positive (HR+)/HER2- breast cancer (HR+/HER2- cohort) and ≤ 2 prior lines of chemotherapy received pamiparib 60 mg orally twice daily in 28-day, continuous cycles. The primary endpoint was objective response rate (ORR; RECIST v1.1) by independent review committee. RESULTS: In total, 88 patients were enrolled (TNBC cohort: 62; HR+/HER2- cohort: 26). Median age was 45.5 (range: 27-67) years, and 60 patients (68.2%) had received 1 or 2 prior lines of chemotherapy; 42 patients (47.7%) had previously received platinum chemotherapy. In the TNBC cohort, ORR was 38.2% (95% confidence interval [CI] 25.4-52.3) and median duration of response (DoR) was 7.0 months (95% CI 3.9-not estimable). In the HR+/HER2- cohort, ORR was 61.9% (95% CI 38.4-81.9) and median DoR was 7.5 months (95% CI 5.6-14.8). The most common treatment-emergent adverse events (TEAEs), treatment-related TEAEs, and ≥ Grade 3 TEAEs were hematologic (including anemia, decreased neutrophil count, and decreased white blood cell count). Overall, 64.8% of patients had TEAEs leading to dose reduction and 2.3% had TEAEs leading to treatment discontinuation. CONCLUSION: Pamiparib showed encouraging efficacy and an acceptable safety profile in patients with locally advanced and metastatic HER2- breast cancer with gBRCA1/2 m. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03575065; July 2, 2018.

Molecular Cluster Mining of Adrenocortical Carcinoma via Multi-Omics Data Analysis Aids Precise Clinical Therapy.

Adrenocortical carcinoma (ACC) is a malignancy of the endocrine system. We collected clinical and pathological features, genomic mutations, DNA methylation profiles, and mRNA, lncRNA, microRNA, and somatic mutations in ACC patients from the TCGA, GSE19750, GSE33371, and GSE49278 cohorts. Based on the MOVICS algorithm, the patients were divided into ACC1-3 subtypes by comprehensive multi-omics data analysis. We found that immune-related pathways were more activated, and drug metabolism pathways were enriched in ACC1 subtype patients. Furthermore, ACC1 patients were sensitive to PD-1 immunotherapy and had the lowest sensitivity to chemotherapeutic drugs. Patients with the ACC2 subtype had the worst survival prognosis and the highest tumor-mutation rate. Meanwhile, cell-cycle-related pathways, amino-acid-synthesis pathways, and immunosuppressive cells were enriched in ACC2 patients. Steroid and cholesterol biosynthetic pathways were enriched in patients with the ACC3 subtype. DNA-repair-related pathways were enriched in subtypes ACC2 and ACC3. The sensitivity of the ACC2 subtype to cisplatin, doxorubicin, gemcitabine, and etoposide was better than that of the other two subtypes. For 5-fluorouracil, there was no significant difference in sensitivity to paclitaxel between the three groups. A comprehensive analysis of multi-omics data will provide new clues for the prognosis and treatment of patients with ACC.

Specimen mammography for intraoperative margin assessment in breast conserving surgery: a meta-analysis.

In breast conserving surgery (BCS), specimen mammography is one of the most widely used intraoperative methods of assessing margin status. We performed a meta-analysis to evaluate the diagnostic accuracy of specimen mammography. Literature databases including PubMed, Cochrane Library, Web of Science, and EMBASE were searched prior to Jun 2022. A total of 1967 patients were included from 20 studies. A pooled analysis, heterogeneity testing, threshold effect testing, publication bias analysis, and subgroup analyses were performed from extracted data. The pooled weighted values were a sensitivity of 0.55 (95% confidence interval [CI], 0.47-0.63), a specificity of 0.85 (95% CI, 0.78-0.90), a diagnostic odds ratio of 7 (95% CI, 4-12), and a pooled positive likelihood ratio of 3.7 (95% CI 2.6-5.5). The area under the receiver operator characteristic curve was 0.75 (95% CI 0.71-0.78). In the subgroup analysis, the pooled specificity in the positive margin defined as tumor at margin subgroup was lower than the other positive margin definition subgroup (0.82 [95% CI: 0.71, 0.92] vs. 0.87 [95% CI: 0.80, 0.94], p = 0.01). Our findings indicated that specimen mammography was an accurate intraoperative imaging technique for margin assessment in BCS.

HMGN5 Escorts Oncogenic STAT3 Signaling by Regulating the Chromatin Landscape in Breast Cancer Tumorigenesis.

Cancer progression is highly dependent on the ability of cancer cell tumor formation, in which epigenetic modulation plays an essential role. However, the epigenetic factors promoting breast tumor formation are less known. Screened from three-dimensional (3D)-sphere tumor formation model, HMGN5 that regulates chromatin structures became the candidate therapeutic target in breast cancer, though its role is obscure. HMGN5 is highly expressed in 3D-spheres of breast cancer cells and clinical tumors, also an unfavorable prognostic marker in patients. Furthermore, HMGN5 controls tumor formation and metastasis of breast cancer cells in vitro and in vivo. Mechanistically, HMGN5 is governed by active STAT3 transcriptionally and further escorts STAT3 to shape the oncogenic chromatin landscape and transcriptional program. More importantly, interference of HMGN5 by nanovehicle-packaged siRNA effectively inhibits tumor growth in breast cancer cell-derived xenograft mice model. IMPLICATIONS: Our findings reveal a novel feed-forward circuit between HMGN5 and STAT3 in promoting breast cancer tumorigenesis and suggest HMGN5 as a novel epigenetic therapeutic target in STAT3-hyperactive breast cancer.

Cyclin-dependent kinase inhibition and its intersection with immunotherapy in breast cancer: more than CDK4/6 inhibition.

INTRODUCTION: Cyclin-dependent kinase (CDK) 4/6 inhibitors (CDK4/6i) have had clinical success in treating hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer. Notably, CDK4/6i have expanded to the neoadjuvant setting for early breast cancer and other cancer types and potently synergize with immunotherapy. Other CDKs, including CDK7, CDK9, and CDK12/13, mainly function in transcriptional processes as well as cell cycle regulation, RNA splicing, and DNA damage response. Inhibiting these CDKs aids in suppressing tumors, reversing drug resistance, increasing drug sensitivity, and enhancing anti-tumor immunity in breast cancer. AREAS COVERED: We reviewed the applications of CDK4/6i, CDK7i, CDK9i and CDK12/13i for various breast cancer subtypes and their potentials for combination with immunotherapy. A literature search of PubMed, Embase, and Web of Science was conducted in April 2022. EXPERT OPINION: The use of CDK4/6i represents a major milestone in breast cancer treatment. Moreover, transcription-related CDKs play critical roles in tumor development and are promising therapeutic targets for breast cancer. Some relevant clinical studies are underway. More specific and efficient CDKis will undoubtedly be developed and clinically tested. Characterization of their immune-priming effects will promote the development of combination therapies consisting of CDKi and immunotherapy.