Breast Cancer : Basic and Clinical Research最新文献

Background: The application of sentinel lymph node biopsy (SLNB) has expanded from early breast cancer to locally advanced breast cancer with neoadjuvant chemotherapy (NAC). For patients with negative axillary lymph nodes, performing SLNB before or after NAC remains controversial.

Objectives: To evaluate the diagnostic feasibility and reliability of SLNB after NAC in breast cancer patients with negative axillary nodes at initial diagnosis.

Design: To calculate pooled identification rate (IR) and false negative rate (FNR) of SLNB after NAC on breast cancer patients with initially negative axillary nodes by enrolling relevant studies and perform subgroup analysis by the type of tracer and the number of biopsied sentinel lymph nodes in average.

Data sources and methods: The PubMed, Embase, Cochrane, Web of Science, and Scopus databases from January 1, 2002, to March 1, 2022, were searched for studies. The QUADAS-2 tool and MINORS item were employed to evaluate the quality of the included studies. I² and Q tests were used to evaluate the heterogeneity among the studies. Random-effects model and fixed-effects model were employed to calculate the pooled IR, FNR, and 95% confidence interval (CI). Publication bias was evaluated, and sensitivity analysis was performed. Subgroup analysis was performed according to the type of tracer (single/double) and the number of biopsied sentinel lymph nodes in average (⩽2/>2).

Results: A total of 21 studies covering 1716 patients were enrolled in this study (IR = 93%, 95% CI = 90-96; FNR = 8%, 95% CI = 6-11).

Conclusion: The SLNB after NAC can serve as a feasible and reliable approach in breast cancer patients with negative axillary lymph node. In our study, no significant impact of tracer was found on the IR and FNR of SLNB, and the number of biopsy nodes >2 leads to the decreased FNR of SLNB.

Background: Oncotype-Dx (ODx) is a 21-gene assay used as a prognostic and predictive tool for hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative, node-negative, or 1 to 3 lymph node-positive early breast cancers (EBCs). The cost of the test, which is not available in low-middle income countries (LMICs), is not within the means of most individuals. The Ki-67 index is a marker of tumor proliferation that is cost-effective and easily performed and has been substituted in many cases to obtain prognostic information.

Objective: We aimed to identify the correlation between the ODx recurrence score (RS) and the Ki-67 index in HR-positive EBCs and to determine whether Ki-67, like the ODx, can help facilitate clinical decision-making.

Design: Systematic review correlating Ki-67 index and ODx in HR-positive and HER2-negative EBCs as per Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.

Data sources and methods: We searched different databases between January 2010 and May 2023 and included retrospective/prospective cohorts, clinical trials, case-control, and cross-sectional studies involving HR-positive and HER2-negative EBCs correlating the Ki-67 index and ODx RS categories.

Results: Of the 18 studies included, 16 indicated a positive or weakly positive correlation between ODx and the Ki-67 index. The combined P value of the included studies is <0.05 (P = .000), which shows a statistical significance between the 2. Our review also discusses the potential of machine learning and artificial intelligence (AI) in Ki-67 assessment, offering a cost-effective and reproducible alternative.

Conclusion: Even although there are limitations, studies indicate a favorable association between ODx and the Ki-67 index in specific situations. This implies that Ki-67 can offer important predictive details, especially regarding the likelihood of relapse in HR-positive EBC. This is particularly significant in LMICs where financial constraints often hinder the availability of costly diagnostic tests.

Background: Endocrine therapy (ET) adherence leads to increased survival in breast cancer (BC). How follow-up should be done to maximize adherence is not known.

Objectives: To assess adherence to ET, factors favouring adherence to ET and effects on survival in a population-based cohort of BC patients in western Sweden.

Design: This is a retrospective study.

Methods: We included 358 patients operated for oestrogen receptor-positive BC and recommended 5 years of ET, in Region Halland, Sweden, year 2015 to 2016. Demographical, clinical and pathological data and use of ET were retrieved from the electronic medical records. Patients were considered adherent if taking ET for 5 years or during the full extent of the follow-up, until termination of ET due to BC relapse or death and where renewals of prescriptions of ET covered ⩾80% of the ordinated dose. Two follow-up routines were employed, ie, routine A where patients were contacted annually by nurses and a more passive follow-up routine B where patients were only contacted by nurses at 2 years and 5 years following start of ET.

Results: Medication persistence for 4 years and more was good and similar between patients initiating aromatase inhibitor (AI) and tamoxifen (75.7% and 72.0%, respectively, P = .43). More patients initiating AIs changed ET due to side effects compared with patients initiating tamoxifen (24.3% vs 9.9%, respectively, P < .0001). Endocrine therapy adherence was better for follow-up routine B than for follow-up routine A (hazard ratio [HR] = 2.71 [1.44-5.09], P = .0027).

Conclusions: Adherence to ET in BC is high in Western Sweden. Less regular nurse-initiated contacts between BC patients and nursesled surprisingly to a better adherence than a more regular nurse-initiated contact.

Backgrounds: About 25% to 30% of estrogen receptor (ER)-positive breast cancer patients develop resistance to endocrine therapy. Human epidermal growth factor receptor 2 (HER2) has been shown to cooperate with several growth factors that regulate cellular energy metabolism, including the insulin-like growth factor 1 receptor (IGF-1R).

Objective: As the first-line therapy for type 2 diabetes mellitus (T2DM) patients, metformin is widely known to inhibit the metabolic reprogramming of cancer cells. This study aims to investigate metformin's efficacy in inhibiting endocrine resistance related to genes regulating energy metabolism in both ER-positive and ER-negative breast cancer cell lines under hyperglycemic conditions.

Design and methods: MDA-MB-361 (ER-positive, HER2-positive) and SKBR3 (ER-negative, HER2-positive) cancer cell lines were used to represent ER status. Cell viability and cell survival rate were measured using the colorimetric assay of Cell Counting Kit-8. All mRNA levels were quantified using real-time quantitative polymerase chain reaction preceded by reverse transcription. A P value of <.05 was considered statistically significant.

Results: Unlike MDA-MB-361, SKBR3 were found to acquire resistance upon metformin treatment in hyperglycemic conditions. Moreover, the mRNA expression of IGF-1R and its downstream signaling, such as the mammalian target of rapamycin (mTOR), was not affected by metformin. Meanwhile, the mRNA expression level of ribosomal S6 kinase 1 (S6K1) was upregulated, whereas forkhead box O1 (FOXO1) was downregulated after metformin treatment in hyperglycemic conditions.

Conclusions: This preliminary study suggests that an alternative pathway of metformin resistance may exist in the absence of ERα. Therefore, relying solely on metformin may be inadequate to inhibit the aggressiveness of breast cancer cells.

Background: In the year 2020, breast cancer was the most common form of cancer worldwide. Roughly 70% of breast cancers are estrogen receptor-positive (ER+). MicroRNA-190b (miR-190b) has previously been reported to be upregulated in ER+ breast cancers. Previously, we have demonstrated that miR-190b is hypomethylated in ER+ breast cancers, potentially leading to its upregulation.

Objectives: To further study the role of miR-190b in ER+ breast cancer and to identify its clinically relevant targets in breast cancer.

Design: Patient cohort and cell line-based RNA-sequencing analysis.

Methods: The Cancer Genome Atlas was used to obtain gene expression data and clinical information on patients with breast cancer. To identify messenger RNA (mRNA) targets for miR-190b, the ER+ breast cancer cell line T-47D was used to immunoprecipitate biotin-labeled miR-190b followed by RNA sequencing. Western blot was used to confirm miR-190b target. Patient survival based on miR-190b and selected target was studied using the Cancer Genome Atlas.

Results: In this study, we confirm that miR-190b is overexpressed in breast cancer via differential expression analysis and show that high expression of miR-190b results in more favorable outcomes in Luminal A patients, hazard ratio (HR) = 0.29, 95% confidence interval [CI] = 0.12-0.71, P = .0063. MicroRNA-190b target analysis identified RING finger and WD repeat domain 3 (RFWD3) as one of miR-190b regulatory targets in ER+ breast cancer. Survival analysis of RFWD3 showed that elevated levels result in poorer overall survival in patients with Luminal A breast cancer (HR = 2.22, 95% CI = 1.33-3.71, P = .002). Gene ontology analysis of our sequencing results indicates that miR-190b may have a role in breast cancer development and/or tumorigenesis and that it may be a suitable tool in characterization between the ER+ subtypes, Luminal A, and Luminal B.

Conclusions: We show that miR-190b targets RFWD3 in ER+ breast cancers leading to lower RFWD3 protein expression. Low levels of RFWD3 are associated with better outcomes in patients with Luminal A breast cancer but not in patients with Luminal B breast cancer. These findings provide novel insights into miR-190b role in breast cancer and that its clinical relevance is subtype specific.

Despite recent improvements in detecting and managing breast cancer (BC), it continues to be a major worldwide health concern that annually affects millions of people. Exploring the anti-BC potentials of natural compounds has received a lot of scientific attention due to their multi-target mode of action and good safety profiles because of these unmet needs. Drugs made from herbs are secure and have a lot fewer negative effects than those made from synthetic materials. Early stage patients benefit from breast-conserving surgery, but the risk of local recurrence remains, necessitating implanted scaffolds. These scaffolds provide residual cancer cell killing and tailored drug delivery. This review looks at plant extract-infused tissue engineering scaffolds, which provide a novel approach to treating BC. By offering patient individualized, safer treatments, these scaffolds could completely change how BC is treated.

Prior to the advent of the HER2-targeted monoclonal antibody trastuzumab, HER2+ breast cancer (BC) was considered an aggressive disease with a poor prognosis. Over the past 25 years, innovations in molecular biology, pathology, and early therapeutics have transformed the treatment landscape. With the advent of multiple HER2-directed therapies, there have been immense improvements in oncological outcomes in both adjuvant and metastatic settings. Currently, 8 HER2-targeted therapies are approved by the Food and Drug Administration (FDA) for the treatment of early-stage and/or advanced/metastatic disease. Nonetheless, approximately 25% of patients develop recurrent disease or metastasis after HER2-targeted therapy and most patients with HER2+ metastatic breast cancer (MBC) die from their disease. Given the many mechanisms of resistance to HER2-directed therapy, there is a pressing need to further personalize care for patients with HER2+ MBC, by the identification of reliable predictive biomarkers, and the development of novel therapies and combination regimens to overcome therapeutic resistance. Of particular interest are established and novel antibody-drug conjugates, as well as other novel therapeutics and multifaceted approaches to harness the immune system (checkpoint inhibitors, bispecific antibodies, and vaccine therapy). Herein, we discuss standard-of-care treatment of HER2+ MBC, including the management of breast cancer brain metastases (BCBM). Furthermore, we highlight novel treatment approaches for HER2+ MBC, including endeavors to personalize therapy, and discuss ongoing controversies and challenges.

Background: Male breast cancer (MBC) accounts for 1% of global breast cancer cases. On account of its rarity, very few prospective clinical trials have been carried out on MBC. Pakistan has the highest incidence of breast cancer in Asia, but very limited data are available on MBC.

Objectives: The objective is to determine the clinicopathological characteristics and treatment patterns of MBC in Pakistani population.

Design: This is a retrospective cross-sectional study.

Methods: A retrospective cross-sectional study carried out using the cancer database of Shaukat Khanum Memorial Cancer Hospital & Research Center. Men with a histologically proven breast cancer, stage 0 to III disease and requiring surgical intervention were included. The Kaplan-Meier curve and log-rank test were used for survival analysis.

Results: Sixty-eight patients with MBC were included with a median age at diagnosis of 55 years. Most patients were stage II (47.1%). Invasive ductal carcinoma (IDC) was the commonest type (89.7%). Estrogen receptor (ER), progesterone receptor (PR), and Her-2 receptor positivity were 92.6%, 86.8%, and 32.4%, respectively. Mastectomy was performed in 95.6% of the cases. Neoadjuvant and adjuvant chemotherapy was administered in 25 (36.8%) and 26 (38.2%) patients, respectively. Fifty-five (80.9%) patients received adjuvant radiotherapy. Most of the patients (89.7%) received tamoxifen. The 5-year overall and disease-free survival was 88.2% and 80.9%, respectively. Patients receiving neoadjuvant chemotherapy had a better overall and disease-free survival (P = .025).

Conclusions: Male breast cancer occurs at a relatively earlier age in Pakistani population as compared with Western men. Mastectomy is the preferred surgical option for MBC on account of the advanced disease and delayed presentation. Neoadjuvant chemotherapy has a statistically significant effect on overall and disease-free survival, but in spite of these benefits, it remains underutilized.

Background: The scaffolding protein, caveolin-1 (Cav-1), participates in multiple cellular functions including promotion of sodium excretion from the kidney. Loss of expression of Cav-1 is associated with tumorigenesis of various types of cancer. We have shown the potential link between hypertension and breast cancer via abnormal function of the G protein-coupled receptor kinase type 4 (GRK4).

Objective: The current studies tested the hypothesis that Cav-1 acts as a tumor-suppressive factor in breast cancer cells and enhances the sensitivity to the inhibitory effect of the type 1 dopaminergic receptor (D₁R).

Methods: Michigan Cancer Foundation (MCF) MCF-7 cells stably expressing a Cav-1/mCherry fusion protein or mCherry alone were used as models to examine the effect of Cav-1 on cell growth, apoptosis, and senescence. Cell proliferation was determined by cell counting, cell cycle analysis (flow cytometry), and BrdU incorporation. Apoptosis was determined using the Cell Death Detection ELISA kit from Roche Diagnosis. Senescence was determined using the senescence associated beta galactosidase (SA-β-gal) assay. Reactive oxygen species (ROS) was measured using 2',7'-dichlorodihydrofluorescein diacetate. Western blot analysis was used to measure activation of signaling pathway molecules. All statistical analyses were conducted with Microsoft Excel.

Results: Overexpression of Cav-1 in MCF-7 cells reduced cellular growth rate. Both inhibition of proliferation and induction of cell death are contributing factors. Multiple signaling pathways were activated in Cav-1-expressing MCF-7 cells. Activation of Akt was prominent. In MCF-7-expressing Cav-1 (MCF-7 Cav-1) cells, the levels of phosphorylated Akt at S⁴⁷³ and T³⁰⁸ were increased 28- and 8.7-fold, respectively. Instead of protecting cells from apoptosis, extremely high levels of activated Akt resulted in increased levels of ROS which led to apoptosis and senescence. The tumor-suppressive effect plus downregulation of GRK4 makes Cav-1-expressing MCF-7 cells significantly more sensitive to the inhibitory effect of the D₁R agonist, SKF38393.

Conclusion: Caveolin-1 acts as a tumor-suppressing factor via extreme activation of Akt and down regulation of survival factors such as GRK4, survivin, and cyclin D1.