Breast Cancer最新文献

Background: Triple-negative breast cancer (TNBC) is a serious disease with limited treatment options. We explored the significance of androgen receptor (AR) expression and tumor-infiltrating lymphocytes (TILs) in predicting neoadjuvant chemotherapy (NAC) resistance in TNBC, hypothesizing that AR/TIL classification using pretreatment biopsies can identify NAC-resistant subgroups and improve the understanding of apocrine differentiation.

Methods: This retrospective study included 156 consecutive patients with TNBC treated with NAC. AR immunostaining was defined positive if ≥ 1% of the tumor cell nuclei were stained. Stromal TIL levels were assessed, with high levels defined as ≥ 50%. Apocrine differentiation was detected using an anti-15-PGDH antibody. The pathological response to NAC was evaluated.

Results: Overall, 36% (n = 56) of the patients achieved a pathological complete response (pCR). AR⁺/TIL^low tumors had a high non-pCR rate (76%, 42/55) and were resistant to NAC. Kaplan-Meier plots showed significant differences in overall survival (OS) and distant metastasis-free survival (DMFS) among the four AR/TIL subgroups (OS: p = 0.013; DMFS: p = 0.0016). All 11 cases with some degree of apocrine differentiation were AR⁺/TIL^low, 15-PGDH-positive, and NAC-resistant. AR⁺/TIL^low status was significantly associated with a high likelihood of non-pCR (OR = 0.26, p = 0.009). Multivariate analysis confirmed pCR as an independent predictor of better prognosis (OS, HR = 0.13, p = 0.006; DMFS, HR = 0.15, p = 0.002), whereas AR⁺/TIL^low status was not significantly associated with OS or DMFS.

Conclusions: AR/TIL classification using pretreatment biopsies identified TNBC subgroups with distinct NAC responses and prognoses. AR⁺/TIL^low TNBC, including apocrine differentiation cases, were NAC-resistant, highlighting the need for alternative therapies.

Breast cancers (BCs) are frequently linked to an immunosuppressive microenvironment that facilitates tumor evasion of anti-cancer immunity. The cells that suppress the immune system such as regulatory B cells (Bregs), regulatory T cells (Tregs), tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs), myeloid-derived suppressor cells (MDSCs), play a crucial role in immune resistance. Also, tumor progression and immune evasion of cancers are facilitated by cytokines and factors released by tumor cells or immunosuppressive cells. Targeting these regulatory cells therapeutically, whether through elimination, inactivation, or reprogramming, has resulted in hopeful anti-tumor reactions. Yet, the substantial diversity and adaptability of these cells, both in terms of appearance and function, as well as their variation over time and depending on where they are in the body, have posed significant challenges for using them as reliable biomarkers and creating focused therapies that could target their creation, growth, and various tumor-promoting roles. The immunotherapy approaches in BC and their effectiveness in treating certain subtypes are still in their initial phases. In this review, we thoroughly outlined the characteristics, roles, and possible treatment options for these immune-suppressing cells in the tumor environment.

Antibody-drug conjugates (ADCs) are an emerging class of anticancer therapy that combines the specificity and long circulation half-life of monoclonal antibodies with the cytotoxic potency of the payload connected through a chemical linker. The optimal management of toxicities is crucial for improving quality of life in patients undergoing ADCs and for avoiding improper dose reductions or discontinuations. This article focuses on the characteristics and management of nausea and vomiting (NV) induced by three ADCs: trastuzumab deruxtecan (T-DXd), sacituzumab govitecan (SG), and datopotamab deruxtecan (Dato-DXd). We summarize the proposed mechanism of NV, clinical study data on NV, and recommendations from clinical guidelines. We also discuss three prospective studies evaluating prophylactic antiemetic therapy in patients receiving T-DXd, along with future perspectives.

Background: Adipose-derived stem cells (ADSCs)-assisted fat grafting has emerged as a widely used procedure for breast reconstruction post mastectomy and for aesthetic augmentation. Given the limited cases of breast cancer following grafting, the oncological safety of this procedure remains controversial.

Methods: The effects of ADSCs on the oncogenic features of premalignant MCF-10AT cells were investigated using co-culture and xenograft models. We further evaluated the malignancy-promoting effect of ADSCs in a 7,12-Dimethylbenz(a)anthracene (DMBA)-induced breast cancer model. RNA-sequencing was performed on ADSCs, MCF-10AT cells, and ADSC-co-cultured MCF-10AT cells. Protein changes in ADSC/MCF-10AT co-culture medium and MCF-10AT cells were determined by proteomic analysis. Pathway inhibitors were used to investigate signaling pathways involved in the ADSC-induced oncogenic changes of MCF-10AT cells.

Results: We found that ADSCs promoted the proliferation and migration of MCF-10AT cells, and co-injection of ADSCs increased the tumor incidence of MCF-10AT cells from 29% to 58% in nude mice. Additionally, grafted ADSCs significantly enhanced tumor incidence, growth, and distant metastasis in the DMBA-induced rats, while it could not induce tumorigenesis in normal breast tissues. Combined RNA-sequencing and proteomic analysis demonstrated that the paracrine factors secreted by ADSCs robustly activated the oncogenic PI3K-AKT signaling in MCF-10AT cells. We also revealed the auto-activated TGF-beta and Wnt pathways in co-cultured MCF-10AT cells, which may be synergistic in tumor formation and progression. As expected, blocking these pathways, especially the PI3K-AKT pathway, strongly diminished the promoting effects of ADSCs, suggesting their potential as therapeutic targets for ADSC grafting-associated breast tumors.

Conclusions: Our data illustrated the synergistic effect between ADSC paracrine factors and MCF-10AT auto-activated pathways in the carcinogenesis of MCF-10AT cells through activation of the oncogenic PI3K-AKT pathway. Based on these findings, we strongly recommend pre-operative examinations for breast cancer risk factors before ADSC-associated transplantation.

Background: This study investigated fluctuations in levels of chosen cytokines among patients with breast cancer before to after chemotherapy. Contemporaneous changes in cognitive function were examined.

Methods: Adult patients with breast cancer stages I-III without brain metastasis were invited to participate in this longitudinal follow-up study. A multidimensional neuropsychological examination was administered at two timepoints evaluating multiple subjective and objective cognitive domains, depression, anxiety, or fatigue before and at least 3 months after chemotherapy, and baseline demographic information. Cytokine levels were taken at the same times. Stepwise multivariate Generalized Linear Mixed Model was used to examine changes in cytokines and associations with changes in cognitive function.

Results: Over a mean interval of 10.46 months, Event-based prospective memory (p<0.001), Word list immediate (p<0.001) or delayed recall (p = 0.024), and self- perceived cognitive impairment (p = 0.026) were significantly improved following chemotherapy. Higher levels of IFNγ and worse performance on the Color Trails Test Part 1, inverse associations of IFNγ or IL-12p70 with Block Design, and TNFα with Digit Symbol Substitution were found, but no significant time effects were noted. However, significant group and time effects were only observed in IL-2 and IL-12p70 with improvements in Event-based prospective memory. That is, from baseline to follow-up, each increase in log values of IL-12p70 and IL-2 were associated with 2.18 (SE = 0.65, p = 0.001) and 2.16 (0.68, p = 0.002) points of increase in Event-based prospective memory. No significant effects were detected for other cytokines or cognitive tests.

Conclusion: Improvements in Event-based prospective memory were positively associated with contemporaneous changes in IL-2 and IL-12p70. Our finding may not only reduce BC patients' concerns about chemotherapy-related cognitive adverse effects, but also demonstrates the possible needs for further replications and investigations on interactions of systemic cytokines, inflammation, and cognitive functions associated with cancer and chemotherapy.

Background: Immune and inflammatory blood parameters have been reported as biomarkers for treatment efficacy. This study aimed to establish a predictive model that includes blood parameters for patients with metastatic breast cancer treated with eribulin.

Methods: A total of 297 patients were enrolled, and their baseline neutrophil-to-lymphocyte ratio, absolute lymphocyte count (ALC), platelet-to-lymphocyte ratio (PLR), prognostic nutritional index (PNI), lymphocyte-to-monocyte ratio (LMR), lactate dehydrogenase (LDH), C-reactive protein (CRP), and clinical data were retrospectively collected.

Results: We constructed nomograms to predict overall survival (OS) and progression-free survival (PFS) using blood parameters, including clinical factors. For OS, menopausal status, hormone receptor status, HER2 status, de novo or recurrent, metastatic site, treatment line, ALC, PLR, PNI, LMR, LDH, and CRP were selected to predict the model. We used menopausal status, hormone receptor status, HER2 status, treatment line, PLR, LMR, LDH, and CRP to predict PFS. Both the OS and PFS of patients according to the risk scores were significantly different (p < 0.001). The optimism-corrected C-indices of the nomograms for OS and PFS were 0.680 and 0.622, respectively. The mean time-dependent area under the receiver operating curve values for OS at 1, 2, and 3 years were 0.752, 0.761, and 0.784, respectively, and for PFS at 3, 6, and 12 months were 0.660, 0.661, and 0.650, respectively.

Conclusion: Nomograms incorporating peripheral blood parameters may improve the accuracy of predicting OS and PFS in patients treated with eribulin. Our prediction model may help decision-making for breast cancer patients who are considering eribulin treatment.

Background: The single-nucleotide polymorphism rs6507583 at the promoter of SET-binding protein 1 (SETBP1) was implicated in estrogen receptor (ER)-positive breast carcinogenesis. Here, we evaluated the clinical and biological relevance of SETBP1 expression in ER-positive breast cancer (BC).

Methods: The associations between SETBP1 expression and clinical outcomes in BC patients were analyzed in independent cohorts. The localizations of SETBP1 expression in BC tissues were observed by immunohistochemical staining. Pathway analyses were conducted using TCGA dataset. In vitro proliferation assay, protein phosphatase 2A (PP2A) activity assay, and gene expression analysis were performed in SETBP1-knockdown ER-positive BC cells. We investigated the factors influencing SETBP1 mRNA expression using TCGA dataset. rs6507583 presence and SETBP1 mRNA expression in 11 mammary cell lines and 56 BC tissue samples were examined by target sequencing and RT-qPCR, respectively.

Results: SETBP1 was downregulated in BC cells compared with normal ductal epithelial cells. Low SETBP1 mRNA expression was an independent prognostic factor for poor recurrence-free survival. Pathway analyses revealed an inverse relationship between decreased SETBP1 expression and the expression of E2F, MYC, and G2M checkpoint target genes in BC tissues. SETBP1 knockdown promoted proliferation, inhibition of PP2A activity, and phosphorylation of MAPK in ER-positive BC. Low SETBP1 expression was influenced by high SETBP1 promoter methylation and DNA copy number SETBP1 deletion. SETBP1 expression with rs6507583 was lower than without rs6507583 in BC.

Conclusions: We demonstrated that low SETBP1 expression could be a poor prognostic biomarker that promotes ER-positive BC proliferation, possibly via phosphorylation of MAPK.

Background: The MonarchE trial demonstrated the additional benefit of abemaciclib as an adjuvant endocrine therapy for high-risk patients with hormone receptor (HR)-positive HER2-negative breast cancer. Meanwhile, the ACOSOG Z0011 trial established the omission of axillary lymph-node dissection (ALND) as a standard practice in certain patients with positive sentinel lymph-node biopsy (SNB). However, as the MonarchE eligibility criteria include the presence of four or more lymph-node metastases, omitting ALND may hinder the assessment of abemaciclib eligibility in some cases.

Methods: The study population consisted of patients with clinically node-negative, HR-positive, HER2-negative breast cancer who underwent SNB at our institution between January 2008 and December 2021. The proportion of patients meeting the MonarchE cohort1 criteria, and the potential impact of ALND omission on abemaciclib eligibility were assessed.

Results: Among the 1537 patients, 189 underwent SNB followed by ALND due to the presence of one or more positive sentinel nodes. Of these, 69 (36.5%) were eligible for abemaciclib. Eligibility was uncertain without ALND in 138 patients. Among the 138 patients, 124 were candidates for ALND omission, including 11 who were found to have four or more metastatic lymph nodes after completing ALND.

Conclusions: A few cases were identified in which abemaciclib eligibility was not properly determined due to ALND omission. This suggests that omitting ALND following SNB, when two of fewer positive nodes are detected, may not significantly impact the determination of abemaciclib eligibility.

Background: Early prediction and management are crucial for treating breast cancer-related lymphedema (BCRL), yet the risk factors remain poorly understood. This study aims to explore the relationship between postoperative changes in serum cholesterol levels and the development of lymphedema.

Methods: This retrospective study analyzed breast cancer patients who underwent surgery between March 2014 and March 2019. We assessed the development of lymphedema and changes in high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglyceride (TG), and total cholesterol (TC) levels. Preoperative values were compared with those measured within 6 months post-surgery, and logistic regression models were used for statistical analysis.

Results: Among the 906 patients studied, 87 (9.6%) developed lymphedema, with a median onset of 15 months. An increase in serum HDL levels relative to baseline was associated with a reduced risk of lymphedema (odds ratio [OR] 0.94 per unit increase, 95% confidence interval [CI]: 0.92-0.95), even after adjusting for established factors such as body mass index, type of axillary surgery, number of lymph nodes removed, regional radiotherapy, and chemotherapy. In contrast, elevated serum TG levels were linked to a higher risk of lymphedema (OR 1.003 per unit increase, 95% CI: 1.001-1.006). No significant associations were found with changes in LDL or TC levels (p > 0.05).

Conclusion: Postoperative changes in HDL and TG levels are significantly associated with the risk of developing lymphedema, suggesting their potential role as early indicators. These results have important clinical implications for guiding follow-up care and early intervention strategies, although further validation is needed.