Breast Cancer Research and Treatment最新文献

Purpose: Breast cancer (BC) treatment can induce adverse events, such as cardiovascular disease (CVD). Defective DNA repair, as in carriers of BRCA1/2 pathogenic variants (BRCA1/2pv), may contribute to CVD risk. We aimed to study if female BRCA1/2pv carriers are more sensitive to develop CVD after BC treatment than BC patients without a known BRCA1/2pv.

Methods: In a hospital-based cohort of 17,300 female BC patients, we identified 509 BRCA1/2pv carriers. Cardiovascular morbidity and mortality were assessed through hospital charts and general practitioner questionnaires. We performed Cox regression analyses comparing BRCA1/2pv carriers with all other BC patients, adjusting for age, radiotherapy regimen, chemotherapy regimen, and smoking status.

Results: Median follow-up time since BC treatment was 14 years. In total, 1108 women experienced ischemic heart disease (IHD), of whom 20 (1.8%) were BRCA1/2pv carriers. Heart failure (HF) was diagnosed in 638 women, of whom 10 (1.6%) were BRCA1/2pv carriers. BRCA1/2pv carriership was associated with a slight not statistically significant increase of IHD (adjHR 1.51, 95%CI 0.93; 2.42), but not with risk of HF (adjHR 0.86, 95%CI 0.44; 1.69). The association between radiotherapy and IHD risk was not significantly different between BRCA1/2pv carriers [HR 2.30 (95%CI 0.79; 6.66)] and other BC patients (HR 1.50, 95%CI 1.30; 1.73). Associations between anthracycline-based chemotherapy and HF risk also did not differ between carriers and other BC patients (HRs of 4.02 (95%CI 1.02; 15.77) and 2.31 (95%CI 1.77; 3.01), respectively).

Conclusions: In BRCA1/2pv BC patients, we found no evidence for a higher risk of BC treatment-related CVD than in other BC patients.

Purpose: This study aimed to explore exercise behavior changes among employed breast cancer survivors, focusing on those who did not engage in physical activity prior to their diagnosis, and to identify factors associated with exercise initiation post-treatment in an ethnically and socioeconomically diverse population.

Methods: A prospective, longitudinal study was conducted involving 497 employed women aged 18-64 with stage I-III breast cancer. Participants completed surveys about their exercise habits before diagnosis and four months post-treatment. Statistical analyses, including chi-squared tests and multivariable logistic regression, were used to identify factors associated with exercise initiation.

Results: Among the 130 participants who did not exercise before diagnosis, 64% initiated exercise post-treatment. Key factors influencing exercise initiation included not having employer-provided health insurance and receiving radiotherapy. No significant associations were found with age, income, or comorbidities.

Conclusions: The study highlights that a substantial proportion of employed breast cancer survivors who did not exercise before their diagnosis began exercising after treatment. Factors such as insurance type and treatment modality play a role in this behavior change.

Implications for cancer survivors: Understanding these factors can inform interventions aimed at increasing exercise participation among breast cancer survivors, which is crucial for improving physical function, symptom management, and potentially survival outcomes.

Purpose: Comprehensive genomic profiling is becoming increasingly important in the management of patients with metastatic breast cancer (mBC). Real-world clinical outcomes from applying molecular tumor boards (MTBs) recommendations in this context remain limited. Accordingly, we conducted a retrospective, single-institution analysis to evaluate the clinical impact of discussing patients affected by mBC at the MTB.

Methods: Clinicogenomic data of patients affected by mBCs referred to the European Institute of Oncology MTB between August 2019 and December 2023 were reviewed. Genomic alterations were classified by ESCAT framework. Clinical outcomes of patients showing actionable alterations and receiving molecular-matched therapy (MMT) were compared to those receiving standard therapy (ST).

Results: Ninety-six patients were included. Following MTB discussion, genetic counseling was recommended in 27% (n = 26) of patients, while additional molecular analyses were requested in 25% (n = 24) cases. Fifty-six patients (58%) displayed at least one actionable alteration. For patients with available follow-up (n = 50), 32 (64%) received MMTs and 18 (36%) ST. No differences in real-world progression-free survival (rwPFS) (4.07 months [95% CI 2.14-8.28] vs. 3.12 months [95% CI 1.51-NE], P = 0.8) and 12-month overall survival (OS) (58% [95%CI 43-78] vs. 57% [95%CI 34-97), P = 0.9) were observed between the MMT- and ST-group. Level I ESCAT alterations yielded longer rwPFS (5.82 months [95% CI 3.12-8.41]) compared to ESCAT II (2.14 months [95%CI 1.61-NE]) and ESCAT III (2.10 months [95% CI 2.04-NE]; P = 0.03). Twenty-four percent of patients showed a PFS2/PFS1 ratio > 1.3 from MMT.

Conclusion: Molecular tumor boards can provide additional treatment options for patients affected by mBC. Besides treatment recommendations, MTBs also have the utility to assess the validity of discussed genomic reports and to identify alterations worthy of genetic counseling.

Purpose: The association between obesity and triple-negative breast cancer (TNBC) prognosis has been equivocal, with considerable heterogeneity between and within studies. Recent meta-analyses report adverse associations with overall survival (OS) and disease-free survival (DFS) in TNBC. We update this evidence and examine study- and disease-specific sources of heterogeneity.

Methods: A systematic search of four databases was conducted until February 22, 2023. Random-effects meta-analyses were used to pool hazard ratios (HR) for OS, DFS, and breast cancer-specific mortality (BCSM). Subgroup analyses examined sources of study heterogeneity.

Results: In meta-analyses of included studies (n = 33), significant associations were observed between excess body weight and worse OS (n = 24; HR = 1.20; 95%CI 1.20-1.34), DFS (n = 26; HR = 1.15; 1.05-1.27), and BCSM (n = 9; HR = 1.13; 1.00-1.27). In subgroup meta-analyses, significant inter-study survival differences were observed for study location (OS, DFS), time period of diagnoses (DFS), menopausal status (OS), and body mass index cut points examined (OS). Asian and European studies reported significant associations with OS (HR = 1.31; 1.11-1.54 and HR = 1.38; 1.00-1.89, respectively) and DFS (HR = 1.28; 1.07-1.54 and HR = 1.44; 1.13-1.84, respectively); however, no association was observed between obesity and TNBC prognosis in North American studies (OS: HR = 1.03; 0.89-1.19; DFS: HR = 1.05; 0.95-1.15). Location subgroup differences remained robust after excluding poor-quality studies. Post hoc analysis in the subset of studies reporting predominantly (≥ 70%) White sample showed no statistically significant associations for OS (HR = 1.13; 95%CI 0.96, 1.34), DFS (HR = 1.03; 95%CI 0.86, 1.23), or BCSM (HR = 1.08; 95%CI 0.91, 1.27).

Conclusion: This study further confirms that obesity is associated with poor prognosis in TNBC and identified subgroups at higher risk. Ethnic differences in the association between excess body weight and TNBC are reported. Further exploration of study and patient characteristics is needed to properly understand the populations most at risk.

Purpose: Breast cancer is the most prevalent cancer type in Mexico, with male breast cancer accounting for only 1% of all breast cancer cases. A limited number of studies have described the clinical-pathological profiles of males with breast cancer in low- and middle-income countries. This study presents an analysis of patients with breast cancer seen at three different institutions in México.

Methods: A retrospective review of the medical records was performed to analyze the clinical and pathological characteristics of 49 men diagnosed with breast cancer and their overall survival.

Results: The mean age at diagnosis was 64.65 years. A significant proportion of patients presented at diagnosis with stage IV disease (n = 11, 22.45%), had triple-negative subtype (n = 6, 12.24%), and nuclear grade III (n = 20, 40.8%). Primary endocrine resistance was observed in 10 patients (31.25%). Genetic analysis was performed on 24 patients (48.9%), revealing a germline BRCA pathogenic variant in 8.33%.

Conclusion: Our findings described the clinical and pathological profile of breast cancer in a male cohort in Mexico, with a significantly high proportion of advanced disease, triple-negative subtype, nuclear grade III, and endocrine resistance. Further comprehensive studies, including research into somatic mutations, are needed.

Purpose: All patients with metastatic breast cancer (MBC) expressing estrogen receptor-α (ESR1) will eventually develop resistance to endocrine therapies. In up to 40% of patients, this resistance is caused by activating mutations in the ligand-binding domain (LBD) of ESR1. Accumulating clinical evidence indicate adverse outcomes for these patients, beyond that expected by resistance to endocrine therapy. Here we aimed to study the role of ESR1 mutations in conferring chemoresistance in BC cells.

Methods: MCF-7 cells harboring Y537S and D538G ESR1 mutations (mut-ER) were employed to study the response to chemotherapy drugs, paclitaxel and doxorubicin, using viability and apoptotic assay in vitro, and tumor growth in vivo. JNK/c-Jun/MDR1 pathway was studied using qRT-PCR, western-blot, gene-reporter and ChIP assays. MDR1 expression was analyzed in clinical samples using IHC.

Results:  Cell harboring ESR1 mutations displayed relative chemoresistance compared to WT-ER, evidenced by higher viability and reduced apoptosis as well as resistance to paclitaxel in vivo. To elucidate the underlying mechanism, MDR1 expression was examined and elevated levels were observed in mut-ER cells, and in clinical BC samples. MDR1 is regulated by the c-Jun pathway, and we showed high correlation between these two genes in BC using TCGA databases. Accordingly, we detected higher JNK/c-Jun expression and activity in ESR1-mutated cells, as well as increased occupancy of c-Jun in MDR1 promoter. Importantly, JNK inhibition decreased MDR1 expression and restored sensitivity to chemotherapy.

Conclusions: Taken together, these data indicate that ESR1 mutations confer chemoresistance through activation of the JNK/MDR1 axis. These finding suggest a novel treatment option for BC tumors expressing ESR1 mutations.

Purpose: To assess the frequency and outcomes of indeterminate enhancing findings on breast MRI unrelated to the index primary tumor(s) in patients on neoadjuvant therapy (NAT).

Materials and methods: This retrospective review identified all diagnostic breast MRIs performed to evaluate response to NAT at our institution between 2017 and 2020. All exams with indeterminate enhancing findings (BI-RADS 3-5) unrelated to the index tumor(s) for which follow-up imaging or tissue diagnosis was recommended were included. Cases lacking a pre-treatment MRI or those with insufficient follow-up were excluded. Imaging of all post-NAT breast MRIs were re-reviewed. The electronic medical record was reviewed to evaluate patient and lesion characteristics and outcomes.

Results: Between 2017 and 2020, 614/4042 (15.2%) breast MRIs were performed to evaluate response to NAT. After exclusions, 38 of these exams (6.2%) identified 42 indeterminate enhancing findings unrelated to the index tumor for which follow-up imaging (15 exams) or tissue diagnosis (23 exams) was recommended. Fifteen of 42 (35.7%) of the findings were new compared to the pre-treatment baseline MRI, 8/42 (19.0%) increased and 19/42 (45.2%) were present on pre-treatment MRI. Most findings were contralateral to the index tumor (28, 66.7%). Findings were masses (17, 40.4%), focus (15, 35.7%), and non-mass enhancement (10, 23.8%). Of the 42 findings, 19 (45.2%) underwent percutaneous biopsy, 10 (23.8%) underwent surgical biopsy or mastectomy, and 13 (31%) were followed by imaging. Thirty-seven were benign, 4 were high-risk lesions without upgrade (atypical ductal hyperplasia, atypical lobular hyperplasia, and papillomatosis with atypical ductal hyperplasia), and one (2.4%) was malignant (invasive lobular carcinoma), which was non-mass enhancement present on the pre-treatment MRI.

Conclusion: Indeterminate enhancing lesions unrelated to the index tumor(s) on breast MRIs performed to assess response to neoadjuvant chemotherapy are uncommon. When present, these lesions have an extremely low likelihood of malignancy, especially when new compared to the pre-treatment MRI.

Clinical relevance: Because incidental indeterminate enhancing lesions on breast MRI at post-NAT follow-up are rarely malignant, radiologists should be judicious in recommending follow-up or tissue diagnosis for such lesions after NAT.

Purpose: To evaluate clinicopathological features in women with mucinous breast cancer (MBC), distinguishing between pure (PMC) and mixed (MMC) subtype.

Methods: A retrospective analysis of all 358 women with MBC treated at Vietnam National Cancer hospital from June 2015 to December 2020. PMC was defined by ≥ 90% mucinous components.

Results: We identified 358 women with MBC (245 PMC and 113 MMC) representing 2.7% of all 13,254 BC patients. The proportions of stage I, II, III and IV were 34.9%, 50.8%, 10.4% and 3.9% respectively. The rate of HER2 overexpression was 12%, and only 1.4% of patients was treated with anti-HER2. 193 patients (53.9%) had chemotherapy, including 55 patients (15.4%) treated in the neoadjuvant setting. Only 3 patients (5.5%) achieved pCR. PMC patients were older (54.4 ± 13.3 vs 51.1 ± 13.1 years), had lower Ki67 expression, lower incidence of nodal metastasis (N +) (p values < 0.05). At a median follow-up of 58 months, the 5-year overall survival rate of non-metastatic patients was 86.6%. Multivariate analysis showed N + to be the most significant prognostic factor (HR = 3.3; 95%CI 1.5-7.1), followed by T-stage (HR = 2.9; 95%CI 1.4-6.3), HER2 + (HR = 2.5; 95%CI 1.2-5.3) and MMC subtype (HR = 1.9; 95%CI 1.0-3.9).

Conclusion: Poor prognostic factors of MBC include high T-stage, N-positivity, HER2 overexpression and MMC subtype. Given the low response rate to neoadjuvant CT, upfront surgery is appropriate for MBC patients.

Background: Breast cancer (BC) is the most prevalent malignancy in females worldwide. Mutations in the DNA repair pathway genes contribute to a significant increase in BC risk. The present study aimed to assess the frequency of polymorphisms in BRCA1, ATM, and CHEK2 genes and their association with BC susceptibility in the Kurdish population from the West of Iran.

Methods: In the present case-control study, the distribution of single nucleotide polymorphisms (SNPs) in CHEK2 (rs17879961), ATM (rs28904921), and BRCA1 (rs80357906, rs1555576855, rs1555576858, and rs397509247) genes were investigated in 335 BC cases and 354 healthy-matched controls by Taqman allelic discrimination assay. The chi-square goodness-of-fit test was employed for the assessment of Hardy-Weinberg Equation. Relative risk and odds ratios were calculated based on the Koopman asymptotic score and the Baptista-Pike method, respectively. Also, the sensitivity and specificity of each polymorphism were assessed using the Wilson-Brown test and a P-value < 0.05 indicating significant differences between the two groups in all assessments.

Results: Data showed there was a strong association between rs397509247 (OR = 7.53, 95% CI 1.88-90.91, p = 0.004), rs1555576858 (OR = 10.53, 95% CI 0.01-0.51, p = 0.0005), and rs80357906 (OR = 6.33, 95% CI 0.05-0.043, p < 0.0001) in BRCA1 gene and rs17879961 (OR = 3.52, 95% CI 0.084-0.946, p = 0.02) in CHEK2 gene, with BC risk in the population of interest. Among these, rs28904921 in ATM gene demonstrated the strongest association (OR = 72.66, 95% CI 0.007-0.214, p < 0.0001). This suggests that these SNPs, particularly rs28904921, are significantly associated with an increased risk of BC in the studied population.

Conclusion: Our results indicated that BRCA1, ATM, and CHEK2 polymorphisms have a high frequency in the Iranian breast cancer population, with some mutant allele frequencies being much higher than those reported in other populations. We have also provided a simple, multiplex, rapid, and accurate genotyping assay that is useful in clinical settings.