Case report: Emerging BRCA mutation confers benefit from olaparib after chemotherapy intolerance in advanced triple-negative breast cancer.

Key Clinical Message: In a patient with metastatic breast cancer, an acquired BRCA mutation in the BRCA gene was detected, resulting in benefits from olaparib treatment. This underscores the importance of ongoing genetic phenotype testing after paclitaxel chemotherapy. Abstract: Triple-negative breast cancer (TNBC) is associated with a poor prognosis and elevated mortality risk. BRCA mutations are commonly regarded as prevalent mutations in TNBC patients, strongly associated with congenital familial heredity. Dynamic changes in mutation sites, however, are rarely reported. In this case report, we report a 59-year-old TNBC patient who developed pulmonary metastases post-chemoradiotherapy. No BRCA mutations were detected through NGS. After 7.6 months of nab-paclitaxel treatment, the patient experienced progression of lung metastases, and BRCA mutations were detected through NGS testing. Subsequent administration of olaparib resulted in a reduction in lung metastasis, demonstrating significant therapeutic efficacy. This case underscores the infrequent occurrence of treatment-induced BRCA mutations and emphasizes the significance of dynamic NGS genetic testing for real-time assessment of a patient's mutational status.

Proteomic and metabolomic characterization of bone, liver, and lung metastases in plasma of breast cancer patients.

BACKGROUND: Breast cancer (BC) is the second leading cause of cancer-related deaths among women, primarily due to metastases to other organs rather than the primary tumor. METHODS: In this study, a comprehensive analysis of plasma proteomics and metabolomics was conducted on a cohort of 51 BC patients. Potential biomarkers were screened by the Least Absolute Shrinkage and Selection Operator (LASSO) regression and Random Forest algorithm. Additionally, enzyme-linked immunosorbent assay (ELISA) kits and untargeted metabolomics were utilized to validate the prognostic biomarkers in an independent cohort. RESULTS: In the study, extracellular matrix (ECM)-related functional enrichments were observed to be enriched in BC cases with bone metastases. Proteins dysregulated in retinol metabolism in liver metastases and leukocyte transendothelial migration in lung metastases were also identified. Machine learning models identified specific biomarker panels for each metastasis type, achieving high diagnostic accuracy with area under the curve (AUC) of 0.955 for bone, 0.941 for liver, and 0.989 for lung metastases. CONCLUSIONS: For bone metastasis, biomarkers such as leucyl-tryptophan, LysoPC(P-16:0/0:0), FN1, and HSPG2 have been validated. dUDP, LPE(18:1/0:0), and aspartylphenylalanine have been confirmed for liver metastasis. For lung metastasis, dUDP, testosterone sulfate, and PE(14:0/20:5) have been established.

The reversal of anti-HER2 resistance in advanced HER2-positive breast cancer using apatinib: two cases reports and literature review.

Background: Human epidermal growth factor receptor 2 (HER2)-targeted treatment has yielded a notable clinical benefit in patients with HER2-positive breast cancer. However, nearly 50% of patients still suffer disease progression due to resistance to HER2-targeted therapy. After the failure of macromolecular monoclonal antibodies (mAbs) therapy, we can choose small molecule tyrosine kinase inhibitors (TKIs) to reverse HER2 resistance. When small molecule TKIs resistance, we can use mAb combined with small molecule TKI, or antibody-drug conjugates (ADCs) to reverse HER2 resistance. However, then due to the availability and price of ADCs, patients may not use them. Consequently, new therapeutic approaches are required to overcome HER2-targeted therapy resistance. Vascular endothelial growth factor and its receptors (VEGF/VEGFRs) promote tumor angiogenesis. They can also activate downstream signaling pathways to promote tumorigenesis. VEGFR is a key regulator of the tyrosine kinase signaling pathway and may be a potential target in HER2-positive breast cancer. Apatinib is a small molecule TKI that specifically binds to VEGFR2 and thus exerts an antitumor effect. Although there is no definite indication for apatinib in breast cancer, it has a good benefit in advanced gastric cancer. Case Description: The two patients we reported were both HER2-positive breast cancer who we followed for more than 10 years. After the failure of multi-line anti-HER2 treatment, apatinib combined with anti-HER2 treatment had PFS of 8.4 months and 10.6 months, respectively. One patient had grade 2 hand-foot syndrome. The other had grade 2 leukopenia and grade 2 thrombocytopenia, both of them improved after control. And the best response of them were PR and SD, respectively. Conclusions: Our cases demonstrate that, in HER2-positive breast cancer patients with HER2-targeted resistance, apatinib may be able to reverse HER2 resistance. These two cases suggest an alternative method for clinical HER2-targeted treatment of drug-resistant breast cancer patients and provide new insights for future research.

Chemotherapy modulates CDK4/6 inhibitors resistance in metastatic breast cancer by Rb1 mutations: a case report and literature review.

Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) plays a major role in breast cancer therapeutics acting through preventing the cell cycle from G1 to the S phase. Recently, Endocrine therapy combined with CDK4/6i represented a major milestone in hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer treatment. However, the resistance of CDK4/6i is clinically common, and the mechanism remains to be clarified. Retinoblastoma (Rb) is a negative regulator of cell cycle. It inhibits cell cycle transition by binding to E2F transcription factors, and prevent cells division in this way. Rb is regulated by phosphorylation. The CDK4/6i have been shown to affect cancer by blocking phosphorylation of Rb. In addition, decreasing estrogen signal has been confirmed to reduce cyclin D-CDK4/6 complexing. Currently, FCN-437c is a new CDK4/6i that is in clinical trials. Here, we present the case of an HR-positive and HER2-negative patient whose disease continued to rapidly progress after receiving FCN-437c. To determine why, we did a series of examinations and found that her Rb1 had mutated after using CDK4/6i. To our surprise, the Rb1 mutations recovered after treatment with eribulin, and CDK4/6i was shown to exert a renewed effect. In this way, a hypothesis was made that eribulin may influence the pathway of cyclin D- CDK4/6- Rb- E2F by effecting in Rb. This case provides new insights into strategies for CDK4/6i therapy resistance options and shows the significance of next-generation sequencing in the clinic.

Combined everolimus and endocrine therapy in advanced HR-positive, HER2-negative Chinese breast cancer patients: a retrospective study.

BACKGROUND: Everolimus (EVE) is an inhibitor of the mammalian target of rapamycin (mTOR) pathway, and it is approved for the treatment of advanced breast cancer (ABC). However, there is still little real-world data on using EVE in Chinese breast cancer patients. We retrospectively analyzed real-world data to determine the factors affecting EVE treatment efficacy and patient outcomes. METHODS: We retrospectively collected the treatment information of ABC patients treated with EVE from 2013 to 2020 in Zhejiang Cancer Hospital. Kaplan-Meier analysis and Cox regression methods were used to calculate and compare the progression-free survival (PFS), and identify the factors associated with EVE treatment efficacy. RESULTS: The study finally enrolled 84 patients meeting the requirement; the median PFS in all 84 patients was 6.87 months. Multivariate analysis showed that liver metastasis [hazard ratio, 1.69; 95% confidence interval (CI), 1.00-2.84; P=0.049], and brain metastasis (hazard ratio, 2.65; 95% CI, 1.07-6.58; P=0.036) were independent risk factors. Subgroup analyses demonstrated EVE + fulvestrant (FUL) was not superior to EVE + aromatase inhibitors (AIs) for PFS (5.77 vs. 7.97 months, P=0.0735). Furthermore, it showed EVE + AI was superior to EVE + FUL in some subgroups: postmenopausal group (hazard ratio, 0.50; 95% CI, 0.26-0.98); without bone metastasis group (hazard ratio, 0.22; 95% CI, 0.06-0.80); visceral disease group (hazard ratio, 0.37; 95% CI, 0.20-0.69). CONCLUSIONS: EVE combined with endocrine therapy is an effective treatment option for Chinese patients with hormone-receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2-) breast cancer, although EVE + FUL was not superior to EVE + AI. Liver metastasis and brain metastasis were independent risk factors for successful EVE + endocrine therapy.

Ki67 and progesterone receptor status predicts sensitivity to palbociclib: a real-world study.

BACKGROUND: Palbociclib combined with endocrine therapy has been approved as a front-line treatment for hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer (ABC). A key challenge remains to uncover biomarkers to identify those patients who may benefit from palbociclib treatment. METHODS: We retrospectively analyzed the values of Ki67 and progesterone receptor (PR) as detected by immunohistochemistry in 81 ABC patients with palbociclib and hormone therapy treatment, and evaluated the impact on progression-free survival (PFS). RESULTS: In the total population, women with Ki67 ≥14% had marginally significantly shorter PFS than those with Ki67 <14% (P=0.062). Patients with Ki67 ≥30% had significantly shorter PFS than those with Ki67 <30% (P=0.048). Meanwhile, PR ≥20% was associated with longer PFS. Moreover, the change of Ki67 or PR from primary tissue to metastatic lesions was related to PFS. As for the hormone therapy subgroup, there were significant associations between Ki67 and PR levels and PFS in the aromatase inhibitors (AIs) subgroup. Patients with Ki67 ≥14% or Ki67 ≥30% had shorter PFS than those with Ki67 <14% or Ki67 <30%, respectively (P=0.024, P<0.001). Additionally, the change of Ki67 or PR from primary tissue to metastatic lesions was related to PFS. When both Ki67 and PR were considered, there were significant differences between the different cohorts. Compared with patients with Ki67 ≥14% and PR <20%, those with Ki67 <14% and PR ≥20% had significantly longer PFS. In addition, patients with Ki67 <30% and PR ≥20% had significantly longer PFS than those with Ki67 ≥30% and PR <20%. Furthermore, in the AI cohort, patients with Ki67 <14% and PR ≥20% had significantly longer PFS than those with Ki67 ≥14% and PR <20%. Women with Ki67 <30% and PR ≥20% had significantly longer PFS than those with Ki67 ≥30% and PR <20%. CONCLUSIONS: The present study indicates that both Ki67 and PR have great impacts on palbociclib and hormone therapy and may contribute to selecting more effective partners for palbociclib.

Clinical Features and Short-Term Outcomes in COVID-19-Infected Patients with Cancer.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is an infectious disease that has been spreading very fast worldwide. Up to now, there is scarce information regarding the clinical features and short-term outcomes of infected patients with cancer. METHODS: We performed a retrospective study in Wuhan Union Hospital from Feb 14, 2020, to Mar 15, 2020, China. Data were retrieved including demographic and clinical features, laboratory findings, and outcome data. Patients were classified into the discharged group and undischarged group by the 4-week outcomes from admission. Difference analysis and correlation analysis were performed between the two groups. RESULTS: A total of 37 patients were enrolled in the study, including 27 cancer survivors in routine follow-up. Breast cancer (18.9%) was the most frequent cancer type, and common symptoms included cough (54.1%), fever (48.6%), and fatigue (27%). Lymphocytopenia and hypoproteinemia were much frequent in patients who had received chemotherapy, radiotherapy, or surgery within the past month. However, the concentration of D-dimer (median: 3.75 vs 0.43, P =0.010) and fibrin degradation products (median: 23.60 vs 1.80, P =0.002) were evidently increased in this population compared with cancer survivors. At the end of follow-up, 83.8% of the enrolled patients were discharged. Among the discharged, women (48.6%) and cancer survivors (67.6%) showed better short-term outcomes. The elevated level of FDP was significantly higher in the undischarged group (median: 21.85 vs 2.00, P =0.049). The proportion of CD3-positive lymphocyte cells and CD4-positive lymphocytes was correlated with short-term outcomes. CONCLUSION: Peripheral lymphocyte subset (CD3-positive and CD4-positive) on admission as a novel biomarker had a potential association with early efficacy. Cancer survivors in routine follow-up would achieve better short-term outcomes. COVID-19 patients with cancer should gain more attention and close monitoring.

Standard-dose epirubicin increases the pathological complete response rate in neoadjuvant chemotherapy for breast cancer: a multicenter retrospective study.

BACKGROUND: Neoadjuvant chemotherapy (NAC) has become the best comprehensive treatment choice for breast cancer. Epirubicin is a crucial drug widely used in breast cancer chemotherapy, but it is often used with a reduced dosage in NAC for Chinese patients for its notable cardiotoxicity and frequent adverse events. This study aimed to investigate the efficacy and safety of standard-dose epirubicin in NAC for Chinese breast cancer patients retrospectively. METHODS: We retrospectively collected clinicopathological parameters of breast cancer patients who underwent epirubicin-based NAC and a later surgery from three separate medical centers. Patients were divided into standard-dose and low-dose groups according to the epirubicin dose. The pathological complete response (pCR) rate, as the main therapeutic outcomes, and the incidence of adverse events were recorded and compared. RESULTS: The pCR rate of the standard-dose group was 41.2%, while the low-dose group was 10.1% (P<0.001). The univariate analysis showed that ER status (HR, 2.519; 95% CI, 1.057-5.988, P=0.037) and epirubicin dose (HR, 6.200; 95% CI, 2.374-16.193, P<0.001) were associated with pCR rates. The multivariate analysis showed that patients receiving standard-dose epirubicin chemotherapy (HR, 6.925; 95% CI, 2.537-18.902, P<0.001) showed more possibility to achieve pCR after NAC. There was no significant difference in the incidence rates of grade III/IV adverse events between these two different dose groups. CONCLUSIONS: Standard-dose epirubicin increases the pCR rate in breast cancer patients treated with NAC, and no other toxicity is noted.

Prognostic Significance Of Platelet-To-Lymphocyte Ratio (PLR) And Mean Platelet Volume (MPV) During Etoposide-Based First-Line Treatment In Small Cell Lung Cancer Patients.

BACKGROUND: Small cell lung cancer (SCLC) is a special type of lung cancer and it is responsive to chemotherapy. Blood parameters have been proved to be associated with survival for many types of malignancies. This study aimed to investigate the prognostic significance of platelet-to-lymphocyte ratio (PLR) and mean platelet volume (MPV) for SCLC patients with etoposide-based first-line treatment. METHODS: We retrospectively identified 138 patients diagnosed as SCLC who underwent etoposide-based first-line chemotherapy. The patients' baseline clinical characteristics and blood parameters were collected. Kaplan-Meier analysis and Cox regression methods were used to determine the factors associated with progression-free survival (PFS). RESULTS: The optimal cut-off value of diagnosis was depended on the ROC curve, the cut-off value of pretreatment PLR was 190 (sensitivity 39.0%, specificity 88.5%), and the cut-off value of pretreatment MPV was 10.0 (sensitivity 60.7%, specificity 61%). Kaplan-Meier analysis showed patients with high PLR levels in baseline had worse PFS than those with low PLR levels (P <0.001). Multivariate analysis revealed pretreatment MPV was an independent prognostic factor for PFS (HR: 0.815, 95% CI: 0.711-0.933, P =0.003). Further research suggested continuous high PLR indicated a poor therapy outcome (P =0.002). CONCLUSION: Pretreatment MPV can be an independent predictor for first-line treatment outcome and a continuously high level of PLR suggested inferior PFS in etoposide-treated SCLC patients.

miR-128 Functions as an OncomiR for the Downregulation of HIC1 in Breast Cancer.

Hypermethylated in cancer 1 (HIC1) is continually decreased in breast cancer. However, the underlying molecular basis of the upstream regulation of HIC1 remains elusive. Here, we showed that HIC1 was downregulated in breast cancer tissues. Bioinformatics analysis identified that miR-128 might potentially target HIC1. HIC1 was proved as the target gene of miR-128 by overexpressing or knocking down miR-128. Additionally, we observed that HIC1 suppression by miR-128 increased cell invasion, proliferation, and reduced apoptosis. Lastly, we found that miR-128 accelerated tumor growth in xenograft mice by inhibiting HIC1. Altogether, this study presents the first evidence that miR-128 suppresses the expression of HIC1 to accelerate breast cancerogenesis.

Peroxiredoxin 4 suppresses anoikis and augments growth and metastasis of hepatocellular carcinoma cells through the ß-catenin/ID2 pathway.

PURPOSE: Peroxiredoxin 4 (PRDX4) has been reported to play a dual role in the progression of hepatocellular carcinoma (HCC). As yet, however, the underlying molecular mechanism has not been fully elucidated. METHODS: We examined the effects of PRDX4 on the growth and survival of HCC cells in an anchorage-independent microenvironment. The regulation of ß-catenin stability and activity by PRDX4 was investigated. RESULTS: We found that PRDX4 depletion reduced, and PRDX4 overexpression increased, both anchorage-dependent and anchorage-independent growth of HCC cells. We also found that PRDX4 depletion caused an overproduction of reactive oxygen species (ROS) in HCC cells, especially under suspension conditions. PRDX4 knockdown predisposed HCC cells to anoikis, whereas PRDX4 overexpression induced resistance to anoikis. Subsequent in vivo studies confirmed that PRDX4 deficiency blocks HCC tumor growth and pulmonary metastasis. Mechanistically, we found that RDX4 reduced ß-TrCP-mediated ß-catenin ubiquitination and enhanced ß-catenin protein stability, consequently leading to activation of ß-catenin signaling. Silencing of ß-catenin impaired PRDX4-mediated anchorage-independent growth and survival, whereas ß-catenin overexpression increased the survival and growth of PRDX4-depleted cells under anchorage-independent conditions. Further investigation revealed that the ß-catenin downstream gene ID2 is responsible for the oncogenic activity of PRDX4 in HCC cells, promoting anchorage-independent growth and anoikis resistance. CONCLUSIONS: PRDX4 reduces anoikis and promotes tumorigenesis and metastasis of HCC cells through stabilization of the ß-catenin protein and upregulation of ID2. Targeting of PRDX4 may represent a promising strategy to block HCC cell growth and metastasis.

The Hemoglobin, Albumin, Lymphocyte, and Platelet (HALP) Score in Patients with Small Cell Lung Cancer Before First-Line Treatment with Etoposide and Progression-Free Survival.

BACKGROUND The hemoglobin, albumin, lymphocyte, and platelet (HALP) score is a prognostic factor in patients who have some types of malignant tumors. The aim of this study was to investigate the prognostic significance of the HALP score in patients with small cell lung cancer (SCLC) before first-line treatment with etoposide. MATERIAL AND METHODS A retrospective study included 178 patients with SCLC who received first-line chemotherapy with etoposide between September 2015 and May 2019. The baseline clinical characteristics and blood parameters were recorded. Univariate and multivariate analysis and Kaplan-Meier plots were used to identify the factors associated with progression-free survival (PFS). RESULTS The optimal cut-off values of the HALP score was determined by X-tile software to be 25.8. Univariate and multivariate analysis showed that in 178 patients, the HALP score, body mass index (BMI), and serum albumin levels had no prognostic significance. In the patient age group <65 years, a BMI ≥24 kg/m² was an independent prognostic factor (HR, 1.943; 95% CI, 1.251-3.018) (P=0.003). In the patient age group ≥65 years, a HALP score >25.8 was an independent positive prognostic factor for outcome following first-line treatment with etoposide (HR, 0.483; 95% CI, 0.270-0.865) (P=0.014). CONCLUSIONS In patients <65 years with SCLC who underwent first-line treatment with etoposide, a BMI ≥24 kg/m² an independent prognostic factor, and in patients ≥65 years, a HALP score >25.8 was an independent predictor of improved outcome, associated with increased PFS.

The p53/miR-193a/EGFR feedback loop function as a driving force for non-small cell lung carcinoma tumorigenesis.

BACKGROUND: Non-small cell lung carcinoma (NSCLC) is a major worldwide health threat due to its low cure rate and high lethality. Emerging evidence suggests that epidermal growth factor receptor (EGFR) plays vital roles in cancer initiation and progression, and is considered an important cancer-driving protein. However, how EGFR expression is regulated during NSCLC development remains to be fully elucidated. METHODS: In NSCLC clinical samples, EGFR protein levels were measured by western blotting and qRT-PCR, respectively. Combining microRNA (miRNA) target prediction software and the pulldown assay, we predicted microRNAs (miRNAs) that targeted EGFR. Next, three NSCLC cell lines, A549 (p53 WT), H322 (p53 mutant), and H1299 (p53 null), were used to demonstrate the direct targeting of EGFR by miR-193a. In addition, we investigated the biological effects of EGFR inhibition by miR-193a in vitro using Cell Counting Kit-8, 5-Ethynyl-2'-deoxyuridine (EdU), transwell, and apoptosis assays. Then, using ChIP and luciferase assays, we demonstrated that miR-193a was directly activated by p53 at the transcriptional level and that p53-induced-miR-193a and EGFR form a double-negative feedback loop. RESULTS: We found that EGFR mRNA and protein were upregulated in NSCLC. We predicted that EGFR was a target of miR-193a and validated that miR-193a bound directly to the 3'-UTR of the EGFR mRNA. Moreover, miR-193a inhibited NSCLC proliferation and invasion, and promotes NSCLC apoptosis by directly downregulating EGFR. Then, we demonstrated that p53 directly activated miR-193a transcription, whereas EGFR functioned as a transcriptional repressor to negatively control miR-193a expression, forming a feedback loop. The loop promoted NSCLC cell proliferation and migration and accelerated tumor growth in xenograft mice. CONCLUSIONS: This study highlights a double-negative feedback loop in NSCLC. The feedback loop is crucial because overexpressing EGFR strongly accelerated tumor growth, while miR-193a restoration blocked tumor growth in vivo. Our findings are in line with the emerging opinion that miRNAs and protein regulators form regulatory networks in critical biological processes and that their dysregulation can lead to cellular dysfunction. In conclusion, this study provides important insights into the molecular mechanisms of NSCLC progression and may help inform the development of new therapeutics for managing NSCLC.