Breast Cancer Research and Treatment最新文献

Purpose: To use robust consensus methods with individuals with lived breast cancer experience to agree the top 10 research priorities to improve information and support for patients undergoing breast cancer surgery in the UK.

Methods: Research uncertainties related to information and support for breast cancer surgery submitted by patients and carers were analysed thematically to generate summary questions for inclusion in an online Delphi survey. Individuals with lived breast cancer experience completed two Delphi rounds including feedback in which they selected their top 10 research priorities from the list provided. The most highly ranked priorities from the survey were discussed at an in-person prioritisation workshop at which the final top 10 was agreed.

Results: The 543 uncertainties submitted by 156 patients/carers were categorised into 63 summary questions for inclusion in the Delphi survey. Of the 237 individuals completing Round 1, 190 (80.2%) participated in Round 2. The top 25 survey questions were carried forward for discussion at the in-person prioritisation workshop at which 17 participants from across the UK agreed the final top 10 research priorities. Key themes included ensuring patients were fully informed about all treatment options and given balanced, tailored information to support informed decision-making and empower their recovery. Equity of access to treatments including contralateral mastectomy for symmetry was also considered a research priority.

Conclusion: This process has identified the top 10 research priorities to improve information and support for patients undergoing breast cancer surgery. Work is now needed to develop studies to address these important questions.

Purpose: To compare CDK4/6 inhibitor (CDK4/6i) with endocrine therapy (ET) in the first- versus second-line setting for treatment of hormone receptor positive (HR+), HER2 negative, metastatic breast cancer (MBC) using real-world evidence.

Methods: Patients with HR+, HER2 negative MBC, diagnosed between 2/3/2015 and 11/2/2021 and having ≥ 3 months follow-up were identified from the nationwide electronic health record-derived Flatiron Health de-identified database. Treatment cohorts included: (1) first-line ET with a CDK 4/6i (1st-line CDK4/6i) versus (2) first-line ET alone followed by second-line ET with a CDK4/6i (2nd-line CDK4/6i). Differences in baseline characteristics were tested using chi-square tests and two-sample t-tests. Time to third-line therapy, time to start of chemotherapy, and overall survival were compared using Kaplan-Maier method.

Results: The analysis included 2771 patients (2170 1st-line CDK4/6i and 601 2nd-line CDK4/6i). Patients receiving 1st-line CDK4/6i were younger (75% vs 68% < 75 years old, p = 0.0001), less likely uninsured or not having insurance status documented (10% vs. 13%, p = 0.04), of better performance status (50% vs 43% with ECOG 0, p = 0.03), and more likely to have de novo MBC (36% vs. 24%, p < 0.001). Time to third-line therapy (49 vs 22 months, p < 0.001) and time to chemotherapy (68 vs 41 months, p < 0.001) were longer in those receiving first-line CDK4/6i. Overall survival (54 vs 49 months, p = 0.33) was similar between groups.

Conclusion: Use of CDK4/6i with first-, vs second-, line ET was associated with longer time to receipt of 3rd-line therapy and longer time to receipt of chemotherapy.

Background: Vitamin D is critical to bone health by regulating intestinal absorption of calcium, whereas proinflammatory cytokines, including IL-1, IL-6, IL-12, and TNF-α, are known to increase bone resorption. We hypothesized that vitamin D and these cytokines at the time of breast cancer diagnosis were predictive for fragility fractures in women receiving aromatase inhibitors (AIs).

Methods: In a prospective cohort of 1,709 breast cancer patients treated with AIs, we measured the levels of 25-hydroxyvitamin D (25OHD), IL-1β, IL-6, IL-12, and TNF-α from baseline blood samples. The associations of these biomarkers were analyzed with bone turnover markers (BALP and TRACP), bone regulatory markers (OPG and RANKL), bone mineral density (BMD) close to cancer diagnosis, and risk of fragility fractures during a median of 7.5 years of follow up.

Results: Compared to patients with vitamin D deficiency, patients with sufficient levels had higher bone turnover, lower BMD, and higher fracture risk; the latter became non-significant after controlling for covariates including BMD and no longer existed when patients taking vitamin D supplement or bisphosphonates or with history of fracture or osteoporosis were excluded. There was a non-significant trend of higher levels of IL-1β and TNF-α associated with higher risk of fracture (highest vs. lowest tertile, IL-1β: adjusted HR=1.37, 95% CI=0.94-1.99; TNF-α: adjusted HR=1.38, 95% CI=0.96-1.98).

Conclusions: Our results do not support proinflammatory cytokines or vitamin D levels as predictors for risk of fragility fractures in women receiving AIs for breast cancer.

Purpose: Breast cancer is a common malignancy in women, and its metastasis is a leading cause of cancer-related deaths. Single-cell RNA sequencing (scRNA-seq) can distinguish the molecular characteristics of metastasis and identify predictor genes for patient prognosis. This article explores gene expression in primary breast cancer tumor tissue against metastatic cells in the lymph node and liver using scRNA-seq.

Methods: Breast cancer scRNA-seq data from the Gene Expression Omnibus were used. The data were processed using R and the Seurat package. The cells were clustered and identified using Metascape. InferCNV is used to analyze the variation in copy number. Differential expression analysis was conducted for the cancer cells using Seurat and was enriched using Metascape.

Results: We identified 18 distinct cell clusters, 6 of which were epithelial. CNV analysis identified significant alterations with duplication of chromosomes 1, 8, and 19. Differential gene analysis resulted in 17 upregulated and 171 downregulated genes for the primary tumor in the primary tumor vs. liver metastasis comparison and 43 upregulated and 4 downregulated genes in the primary tumor in the primary tumor vs lymph node metastasis comparison. Several enriched terms include Ribosome biogenesis, NTP synthesis, Epithelial dedifferentiation, Autophagy, and genes associated with epithelial-to-mesenchymal transitions.

Conclusion: No single gene or pathway can clearly explain the mechanisms behind tumor metastasis. Several mechanisms contribute to lymph node and liver metastasis, such as the loss of differentiation, epithelial-to-mesenchymal transition, and autophagy. These findings necessitate further study of metastatic tissue for effective drug development.

Purpose: Data on the prognostic impact of the micropapillary component in breast cancer are limited. The purpose of this study was to investigate the clinicopathological characteristics and long-term outcomes of pure and mixed invasive micropapillary breast cancer (IMPC) patients compared to invasive ductal cancer (IDC) patients.

Methods: This retrospective study analysed all IMPC and IDC patients treated at the European Institute of Oncology (IEO) between 1997 and 2019. The overall cohort of IMPC patients was divided in two groups, pure and mixed IMPC. Each patient with mixed or pure IMPC was matched with one patient with IDC, based on year of surgery, age, pT, pN, and molecular subtype.

Results: A total of 30,115 IDC, 120 pure IMPC and 150 mixed IMPC patients were considered eligible. Compared to IDC, pure and mixed IMPC patients presented a higher rate of locally advanced disease (pT2-T3, pN2-N3), vascular invasion, and Luminal B subtype. After matching, pure and mixed IMPC showed a significant higher rate of vascular invasion compared to IDC patients (p < 0.001). Invasive disease-free survival was better in IDC compared to pure IMPC patients (p = 0.11). Long-term overall survival was significantly worse in pure IMPC group compared to IDC group (p = 0.004), being instead similar between mixed IMPC vs matched IDC (p = 0.07).

Conclusion: These real-world data reported the worse prognosis of pure IMPC compared to IDC, highlighting the peculiar prognostic value of the micropapillary subtype itself in the decision-making process of IMPC management. An accurate pre-surgical diagnostic evaluation and a multidisciplinary approach are pivotal to best personalize its treatment.

Purpose: Timeliness of care is an important healthcare outcome measure. The objective of this study was to explore patient perspectives on the timeliness of breast cancer diagnosis and treatment at accredited breast cancer centers.

Methods: In this qualitative study, 1 hour virtual interviews were conducted with participants 18-75 years old who were diagnosed and treated for stage 0-III breast cancer at a National Accreditation Program for Breast Centers facility from 2018 to 2022. Thematic analysis was used to identify key themes of participant experiences.

Results: Twenty-eight participants were interviewed. Two thematic domains were identified: etiologies of expedited or delayed care and the impact of delayed or expedited care on patients. Within these domains, multiple themes emerged. For etiologies of expedited or delayed care, participants discussed (1) the effect of scheduling appointments, (2) the COVID-19 pandemic, (3) dissatisfaction with the timeline for various parts of the diagnostic workup, and (4) delays related to patient factors, including socioeconomic status. For the impact of expedited or delayed care, patients discussed (1) the emotional and mental impact of waiting, (2) the importance of communication and clear expectations, and (3) the impact of electronic health portals. Patients desired each care interval (e.g., the time from mammogram to breast biopsy) to be approximately 7 days, with longer intervals sometimes preferred prior to surgery.

Conclusion: These patient interviews identify areas of delay and provide patient-centered, actionable items to improve the timeliness of breast cancer care.

Purpose: Cancer treatments often become ineffective because of acquired drug resistance. To characterize changes in breast cancer cells accompanying development of resistance to inhibitors of the oncogenic transcription factor, FOXM1, we investigated the suppression of cell death pathways, especially ferroptosis, in FOXM1 inhibitor-resistant cells. We also explored whether ferroptosis activators can synergize with FOXM1 inhibitors and can overcome FOXM1 inhibitor resistance.

Methods: In estrogen receptor-positive and triple-negative breast cancer cells treated with FOXM1 inhibitor NB73 and ferroptosis activators dihydroartemisinin and JKE1674, alone and in combination, we measured suppression of cell viability, motility, and colony formation, and monitored changes in gene and protein pathway expressions and mitochondrial integrity.

Results: Growth suppression of breast cancer cells by FOXM1 inhibitors is accompanied by increased cell death and alterations in mitochondrial morphology and metabolic activity. Low doses of FOXM1 inhibitor strongly synergize with ferroptosis inducers to reduce cell viability, migration, colony formation, and expression of proliferation-related genes, and increase intracellular Fe⁺² and lipid peroxidation, markers of ferroptosis. Acquired resistance to FOXM1 inhibition is associated with increased expression of cancer stem-cell markers and proteins that repress ferroptosis, enabling cell survival and drug resistance. Notably, resistant cells are still sensitive to growth suppression by low doses of ferroptosis activators, effectively overcoming the acquired resistance.

Conclusion: Delineating changes in viability and cell death pathways that can overcome drug resistance should be helpful in determining approaches that might best prevent or reverse resistance to therapeutic targeting of FOXM1 and ultimately improve patient clinical outcomes.

Purpose: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) have improved patient survival in hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic breast cancer (mBC) in clinical trials and real-world studies. However, investigations of survival gains in broader HR+/HER2- mBC populations using epidemiological approaches are limited.

Methods: This retrospective study used SEER registry data to assess breast cancer-specific survival (BCSS) in patients diagnosed with HR+/HER2- de novo mBC from 2010 to 2019. Kaplan-Meier and Cox proportional hazards models were used to compare BCSS in patients diagnosed before (2010‒2013 with follow-up to 2014) and after (2015‒2018 with follow-up to 2019) the 2015 guideline recommendations for CDK4/6i use. A comparison was made to patients with HR+/HER2-positive (HER2+) de novo mBC, for which no major guideline changes occurred during 2015-2018.

Results: Data from 11,467 women with HR+/HER2- mBC and 3260 women with HR+/HER2+ mBC were included. After baseline characteristic adjustment, patients with HR+/HER2- mBC diagnosed post-2015 (n = 6163), had an approximately 10% reduction in risk of BC-specific death compared with patients diagnosed pre-2015 (n = 5304; HR = 0.895, p < 0.0001). Conversely, no significant change was observed in HR+/HER2+ BCSS post-2015 (n = 1798) versus pre-2015 (n = 1462). Similar results were found in patients aged ≥ 65 years.

Conclusion: Using one of the largest US population-based longitudinal cancer databases, significant improvements in BCSS were noted in patients with HR+/HER2- mBC post-2015 versus pre-2015, potentially due to the introduction of CDK4/6i post-2015. No significant improvement in BCSS was observed in patients with HR+/HER2+ mBC post-2015 versus pre-2015, likely due to the availability of HER2-directed therapies in both time periods.

Introduction: To offer an extensive retrospective experience on the management of male breast cancer.

Methods: A multicenter retrospective observational cohort study was conducted, including male patients diagnosed with breast cancer (invasive or in situ) in 12 Italian breast units from January 1975 to December 2019. Patients aged 18 years or older were assessed for eligibility. Exclusion criteria were metastatic cancer at diagnosis, previous cancer(s), received neoadjuvant treatment, incomplete data on (neo) adjuvant treatment(s), and/or follow-up data. Data on radiological examinations, demographic characteristics, risk factors, histological features, receptor status, treatments, and follow-up were collected.

Results: In a series of 671 male patients with breast cancer assessed for eligibility, 403 (28 in situ and 375 invasive neoplasms) were included in the study. All included patients underwent surgery. The median age at surgery was 63.8 years (IQR 56.1-72.1). In 68% of cases, patients underwent echography, and in 55.1%, a mammography. Most patients were ER and PR positive (63.8%), HER2 negative (80.4%), with high (≥ 20%) Ki67 values (61.3%), and luminal B subtype (51.1%). The 10-year overall survival was 73.6% (95% CI 67.0-79.1) for invasive breast cancer and 90% (95% CI 65.6-97.4) for in situ breast cancer. In patients with invasive breast cancer, at univariable analysis, having a G3 tumor (vs. G1), pT2/3/4 (vs. pT1), pN2/3 (vs. pN0), luminal B subtype with Ki67 ≥ 20% (vs. Luminal A), were significantly associated with a higher risk of death. In multivariable analyses, pT2/3/4 (vs. pT1) remained significantly associated with a higher risk of death (HR 3.14, 95% CI 1.83-5.39), and having a HER2 positive or a triple-negative subtype (vs. Luminal A) was also significantly associated with a higher risk of mortality (HR 4.76, 95% CI 1.26-18.1).

Conclusion: Male breast cancer is a rare disease, the better understanding of which is necessary for a more effective diagnostic and therapeutic approach.

Purpose: In East Asia, the incidence of breast cancer has been increasing rapidly, particularly among premenopausal women. An elevated ratio of estrogen-DNA adducts was linked to a higher risk of breast cancer. The present study explored the influence of the interaction between base excision repair (BER) gene polymorphisms and estrogen-DNA adducts on breast cancer risk.

Methods: We conducted a case-control study comprising healthy volunteers and individuals with benign breast disease (control arm, n = 176) and patients with invasive carcinoma or carcinoma in situ (case arm, n = 177). Genotyping for BER-related genes, including SMUG1, OGG1, ERCC5, and APEX1, was performed. A logistic regression model, incorporating interactions between gene polymorphisms, estrogen-DNA adduct ratio, and clinical variables, was used to identify the risk factors for breast cancer.

Results: Univariate analysis indicated marginal associations between breast cancer risk and APEX1 rs1130409 T > G (P = 0.057) and APEX1 rs1760944 T > G (P = 0.065). Multivariate regression analysis revealed significant associations with increased breast cancer risk for APEX1_rs1130409 (GT/GG versus TT) combined with a natural logarithmic value of the estrogen-DNA adduct ratio (estimated OR 1.164, P = 0.023) and premenopausal status with an estrogen-DNA adduct ratio > 2.93 (estimated OR 2.433, P = 0.001).

Conclusion: APEX1_rs1130409 (GT/GG versus TT) polymorphisms, which are related to decreased BER activity, combined with an increased ratio of estrogen-DNA adducts, increase the risk of breast cancer in East Asian women.