Breast Cancer Research and Treatment最新文献

Purpose: Hormone receptor (HR) status may be unstable during breast cancer (BC) progression, and changes occur in approximately 20-30% of BC patients at the time of recurrence. The biologic tumor switch from HR+ to HR- status is associated with worse clinical outcomes and warrants alternative management. We aimed to characterize clinical and pathologic features of a subset of ER+/HER2- breast cancer patients who converted to triple negative phenotype upon recurrence, and investigate the molecular alterations associated with HR loss during BC progression.

Methods: We retrospectively identified 112 patients who had primary ER+/HER2- breast cancer and developed local or distant recurrence through our institutional database. Patients were divided into two cohorts based on receptor profile of recurrent tumor: discordant TNBC (n = 20) and concordant ER+/HER2- tumors. The following variables were collected: tumor histology, grade, pT, pN, ER, PR, HER2 expression in primary and recurrent tumors, molecular profiling, and adjuvant treatment history.

Results: The average time for HR+ tumors to recur as TNBC was 148 months. The two cohorts showed similar clinicopathologic characteristics, including patient's age at diagnosis, tumor type, grade, stage, ER expression, and treatment history before tumor recurrence. PTEN inactivating mutations were more frequently identified in the discordant TNBC (6/20, 30%) compared to the concordant ER+/HER2- tumors (6/92, 5.5%) (p = 0.007).

Conclusion: Increased signaling via the PI3K/AKT/PTEN pathway may be a mechanism for the transition to hormone independence in recurrent diseases.

Purpose: Forkhead box P3 (FOXP3), a key marker of regulatory T cells (Tregs), is crucial for Treg differentiation and development. Emerging evidence suggests that FOXP3 is also expressed in various tumor cells; however, its role in tumor progression remains controversial. This study aimed to elucidate the impact of FOXP3 on breast cancer development.

Methods: Breast cancer cell lines, including HCC1937, HCC1806, Hs 578T, MDA-MB-231, and MCF-7, along with xenograft mouse models, to assess the effects of FOXP3 on cell proliferation and tumor growth. FOXP3 expression in human breast cancer samples was analyzed using quantitative PCR and immunohistochemistry analyses. Cell proliferation and invasion were evaluated through MTS and transwell assays, respectively. Chromatin immunoprecipitation (ChIP) assays were performed to determine FOXP3 binding to the β-catenin gene promoter.

Results: FOXP3 expression was elevated in advanced breast cancer and correlates with poor clinical outcomes. FOXP3 directly binds to β-catenin gene promoter - 986 to - 1168 region to facilitate β-catenin transcription, consequently resulting in increased breast cancer cell proliferation, migration, and invasion in vitro and tumor growth in vivo. Furthermore, IGF1R activated FOXP3-β-catenin signaling to promote breast tumor growth. Moreover, elesclomol, a potent copper ionophore, significantly inhibited FOXP3 expression to suppress breast tumor growth.

Conclusion: This study indicates that FOXP3 plays an oncogenic role in breast cancer development and suggests that targeting IGF1R-FOXP3-β-catenin signaling may be a putative therapeutic strategy for human breast cancer treatment.

Purpose: The detection of circulating tumor DNA (ctDNA) is a valuable method to predict the risk of recurrence and to detect real-time gene changes. The amount of ctDNA is affected by many factors. Moreover, the detection rate of ctDNA varies from report to report.

Methods: The present study evaluated differentially expressed genes using a DNA microarray assay for gene expression in tumors with and without detected ctDNA and constructed a prediction model for the detectability of ctDNA in breast tumor tissues. The model, named Cir-Predict, consisted of 126 probe sets (111 genes) and was constructed in a training set of breast cancer patients (n = 35) and validated in a validation set (n = 13).

Results: The accuracy, sensitivity, and specificity in training and validation sets were over 90%, and Cir-Predict was significantly associated with ctDNA detection independently of the other conventional clinicopathological parameters in training and validation sets (P < 0.001, P = 0.014, respectively). Cir-Predict (+) was significantly associated with worse recurrence-free survival (P = 0.006). Pathway analysis revealed that nine pathways including tight junction and cell cycle tended to be related to ctDNA detectability.

Conclusion: Cir-Predict not only provides information useful for breast cancer treatment, but also helps the understanding of the mechanism by which ctDNA is detected.

Purpose: Combination therapy has emerged as a leading trend in cancer treatment, having had a significant impact on the management of advanced-stage breast cancer. This approach, which relies on immune checkpoint modulation, has revolutionized the therapeutic landscape. However, the precise mechanisms underlying its therapeutic effects remain unclear.

Methods: Previously, we designed a bispecific antibody (BsAb) targeting PD-L1 (programmed cell death ligand 1) and the T cell immune checkpoint, LAG-3 (lymphocyte activation gene-3). In the present study, we evaluated the combination treatment of the BsAb (named Ba-PL) with doxorubicin (DOX) in a tumor-bearing mouse model and comprehensively investigated the underlying mechanisms involved.

Results: The animal experiments demonstrated that the Ba-PL exerted an anti-tumor effect. Notably, mice treated with a combination of Ba-PL and DOX exhibited superior antitumor responses, mediated by the induction of robust immune cytokine responses. Furthermore, our findings revealed that this combination therapy restored depleted T cell activity and reinstated immune surveillance against tumors by reducing regulatory T cell levels. This immunotherapy combination exhibited favorable safety profiles and effectively prolonged the survival of tumor-bearing mice.

Conclusion: Blocking PD-L1 and LAG-3 in combination with doxorubicin is therapeutic potential approach for breast cancer and offers hope for improved patient outcomes.

Purpose: Clinical trials demonstrated every 3-month goserelin 10.8 mg to be non-inferior to monthly goserelin 3.6 mg in premenopausal patients with ER-positive breast cancer. However, real-world studies comparing 3-month goserelin 10.8 mg with monthly goserelin 3.6 mg are scarce.

Methods: Electronic medical records from the ConcertAI Patient360™ database were analyzed in U.S. patients exposed to goserelin 3.6 mg or 10.8 mg post-breast cancer diagnosis. Inverse probability of treatment weighting (IPTW) was used to ensure the comparability between the two cohorts (goserelin 3.6 mg and goserelin 10.8 mg). The non-inferiority of goserelin 10.8 mg compared with goserelin 3.6 mg was assessed by 12-month real-world event-free survival (rwEFS) rates (- 15% margin) for the overall group of patients and separately for patients with early-stage/locally advanced and metastatic breast cancer.

Results: A total of 575 patients received goserelin 3.6 mg and 123 received goserelin 10.8 mg. Goserelin 10.8 mg was non-inferior to goserelin 3.6 mg based on observed 12-month rwEFS rates (79.2% versus 76.6%, respectively; treatment difference 2.7%). Goserelin 10.8 mg was observed to be non-inferior in patients who initiated goserelin in early-stage/locally advanced (treatment difference - 2.3%) and metastatic (treatment difference 10.4%) breast cancer.

Conclusion: This real-world analysis indicates that 3-month goserelin 10.8 mg is non-inferior to monthly 3.6 mg among premenopausal women with breast cancer in terms of 12-month rwEFS rate. These findings may support the use of the 3-month goserelin 10.8 mg as an alternative treatment option to monthly goserelin 3.6 mg for this patient population.

Background: Despite increasing evidence to support risk-based breast cancer screening, individuals' understanding of personal risk is not well understood. This study compares women's perceptions of risk to their estimated risk, and examines factors associated with perceived risk, including breast density notification, within a population-based screening program.

Methods: A survey of 5784 women measured their perceived risk via three questions: a number from 0 to 100 (numeric), a category from very low to very high (verbal), a comparative category relative to an average woman (comparative). Descriptive analyses assessed correlations between perceived risk variables and estimated risk (using the Gail Model), and modelled relationships using K-fold cross-validation. A Graded Response Model was used to obtain an index of unobserved (latent) overall perceived risk from the three questions. Multivariable modelling was used to investigate factors associated with overall perceived risk.

Results: Most participants perceived themselves as being at neither high nor low risk, although perceived risk was higher than estimated risk, on average. All three perceived risk measures were positively correlated with each other and with estimated risk. Overall perceived risk was weakly associated with estimated risk (adjusted R² = 0.12). Women who received multiple breast density notifications, were younger, or had a family history, perceived their risk as higher relative to respective reference groups. Those who identified as Asian perceived their risk as lower than those who identified as European/Caucasian.

Conclusion: Individuals' understanding of breast cancer risk is poor. New strategies are needed to improve education and awareness of personal risk.

Purpose: Our previous data showed that carriers of germline BRCA1/2 pathogenic variants (PV) with breast cancer (BC) treated with mastectomy without post-mastectomy radiation therapy (PMRT) had higher rates of loco-regional recurrence (LRR) compared to those who underwent PMRT or breast-conserving therapy (BCT), despite earlier stage BC. Our aim was to verify our previous findings in a larger cohort.

Methods: Clinical data were extracted from the medical records of BRCA1/2 mutation carriers with BC, treated at a single institution between 1/2006 and12/2022. The data included demographics, treatment modalities, and BC outcomes.

Results: A total of 464 patients with 484 primary tumors were analyzed. Of these, 48.3% mastectomies were performed: 66% (154) without PMRT (non-PMRT) and 34% (80) with PMRT; 51.8% (250) underwent BCT. The non-PMRT group had earlier disease stages at diagnosis (77.3% were Tis and T1N0 stage) compared to the PMRT and BCT groups (3.8% and 45%, respectively, p < 0.001). During the study period with a median follow-up time of 75 months (range 12-211), the LRR rate was 13% (20/154) in the non-PMRT cohort compared with 1.25% (1/80) in the PMRT group (p = 0.003), and 6.4% (16/250) in the BCT group (p = 0.03). Cumulative incidence of LRR at 5 and 15 years was 14.7%, and 16.6% in the non-PMRT, compared to 5.1% and 35% in the BCT group, respectively (p = 0.081). No significant difference in overall survival was observed (p = 0.202).

Conclusions: The timing and rates of LRRs differ according to the loco-regional therapy, which might indicate a different etiology driving these events.

Background: The management of locally advanced breast cancer poses significant challenges, with contemporary strategies involving an approach that combines systemic and local treatment. The current study was performed to validate the clinical impression that locoregional recurrences have become increasingly uncommon after standardized multimodal treatment protocol.Please check and confirm that the authors and their respective affiliations have been correctly identified and amend if necessary.All authors and affiliations are correct.

Methods: A retrospective analysis was performed using a single-institution database that included clinical, radiographic, and pathologic parameters for all non-metastatic and non-inflammatory breast cancer patients treated with neoadjuvant chemotherapy (NAC) from 2015 to 2023. Uni- and multivariable analyses were performed to define associations between clinical factors, recurrence, and RFS.

Results: The median age was 51 years for 274 predominantly Hispanic (78%) patients, with a median follow-up of 38.1 months. The recurrence rates were 4% local, 2% regional, and 18% distant. Median time from surgery to local recurrence was 8.2 months and to regional recurrence was 9.7 months. There were no locoregional clinical recurrences in 92 (34%) patients who had pCR or in 85 (31%) patients who had radiological complete response after NAC. Locoregional recurrences were uncommon > 12 months after surgery. Five of 11 local recurrences occurred in patients who had a poor response to NAC (ypT4b). All 6 patients having regional recurrences had adjuvant radiation therapy, and only 2 occurred in patients who were pathologically node-negative (ypN0) post-NAC.

Conclusions: Favorable responses to NAC were associated with excellent locoregional control rates. Results achieved for predominantly Hispanic patients at a safety net medical center were similar to those reported in prospective, randomized clinical trials.

Purpose: RxPONDER showed that in postmenopausal women with early-stage hormone receptor + /HER2- breast cancer (BC) with 1-3 positive axillary lymph nodes (LN) and a recurrence score ≤ 25, the addition of chemotherapy to endocrine therapy did not improve distant recurrence-free survival. We sought to evaluate Oncotype DX recurrence score (ODX RS) distribution in LN negative and LN positive patients aged ≥ 50 years (y) and to determine clinicopathologic factors associated with RS.

Methods: ODX RS, demographic, and pathologic information was collected for patients with ER + /HER2- BC with 0 (patients < 50y) or 0-3 positive (patients ≥ 50y) LN treated at our institution between January 2021 and December 2022. Statistical analyses were conducted using Pearson chi-square and two-tailed t tests.

Results: The study cohort included 2378 BC from 2285 women. Among women ≥ 50y, there was no significant difference in RS distribution between pN0, pN1mi, and pN1a patients; with 85.4%, 86.5%, and 81% having a RS ≤ 25, respectively. Among LN + women ≥ 50y, RS > 25 was significantly associated with higher grade (P = .001), lower ER (P = .007), and lower PR (P < .001). Among LN- women ≥ 50y, RS > 25 was significantly associated with higher grade (P < .001), lower ER (P < .001), and lower PR (P < .001).

Conclusion: ODX RS distribution among LN + and LN- women aged ≥ 50y was similar. In this population, RS is significantly associated with tumor grade, ER, and PR, regardless of LN status. In our post-RxPONDER era cohort, over 80% of women aged ≥ 50y with early-stage ER + /HER2- BC with ≤ 3 positive axillary LN would be spared chemotherapy based on RS, regardless of nodal status.