Search Results (33)

De novo metastatic breast cancer (dnMBC) accounts for 3–10% of newly diagnosed cases, with 20–40% presenting as a bone-only metastatic disease, which can achieve survival outcomes exceeding 10 years with multimodal therapy. However, the role of multimodal therapy remains controversial in the guidelines. Objective: This study aims to identify dnBOMBC subgroups to develop a pragmatic staging system for guiding locoregional therapy decisions. Materials and Methods: Data from the MF07-01 phase III randomized trial (2021, median follow-up time (mFT): 40 months (range 1–131)) and the BOMET prospective multi-institutional registry trial (2021, mFT: 34 months (range 25–45)) were combined for analysis, including only patients who presented with bone-only metastases. Exclusion criteria were patients under 18 and those with a history of prior cancer or cancer metastases. Patients with missing data and positive surgical margins were excluded. Out of 770 patients, 589 were included. Survival analyses were first conducted according to molecular subgroups, after which patients were further stratified by hormone receptor status, human epidermal human epidermal growth factor receptor 2 (HER2) status, tumor grade, and clinical T (cT) stage. Group A (GrA) included hormone receptor (HR)-positive, low- or intermediate-grade tumors at any cT; HR-positive, high-grade tumors with cT0–3; or any HER2-positive tumors. Group B (GrB) included HR-positive, high-grade tumors with cT4 disease or any triple-negative (TN) tumors. Results: The hazard of death (HoD) was 43% lower in GrA than in GrB. Median OS was 65 months (39–104) for GrA patients and 44 months (28–72) for GrB patients (HR 0.57, 95% CI 0.41–0.78, p = 0.0003). Primary tumor surgery (PTS) significantly improved OS in GrA patients, regardless of the number of metastases (solitary: HR, 0.375, 95% CI 0.259–0.543, p < 0.001; multiple: HR 0.435, 95% CI 0.334–0.615, p < 0.001). Conversely, GrB patients did not experience a significant benefit from PTS. Conclusions: This study demonstrates that GrA patients have better OS than GrB patients, and PTS reduces the HoD in GrA patients compared to systemic therapy alone. These findings support using a modified staging system in dnBOBMC to identify patients who may benefit from multimodal therapy including PTS. Full article

Background: About 15–20% of breast cancers are HER2 positive. Approximately 15–24% of individuals with localized HER2-positive cancer develop metastatic disease after curative treatment, while 3–10% present with de novo metastasis. Survival has significantly improved with various anti-HER2 agents, but there is considerable heterogeneity at the individual level. Our study aims to identify factors influencing survival in de novo metastatic HER2-positive breast cancer using a large sample from the National Cancer Database (NCDB). Methods: Women with metastatic HER2-positive breast cancer diagnosed from 2010 to 2020 in the NCDB were included. Demographic, clinicopathological, treatment data, and overall survival (OS) were collected. Kaplan–Meier curves estimated OS. The log-rank test identified OS differences between groups in univariate analysis. The Cox proportional hazard model with backward elimination identified factors affecting OS in multivariate analysis. The 12-month, 36-month, and 60-month survival estimates, 95% confidence intervals (CIs), and adjusted hazard ratios were reported. Results: Among 5376 women with metastatic HER2-positive breast cancer from 2010 to 2020, the median OS was 55.95 months (95% CI 53.55-NE). Multivariate analysis identified age, Charlson–Deyo comorbidity score, histology, HER2 IHC expression, hormone receptor status, the number of metastatic sites, metastasis location, first-line chemotherapy, anti-HER2 therapy, hormone-blocking therapy, surgery at primary/non-primary sites, and palliative treatment as significant factors affecting OS. Race and radiation receipt were not significant. Conclusions: This is the largest analysis of overall survival estimates in de novo metastatic HER2-positive breast cancer to date in the real-world setting. We identified several independent prognostic factors influencing OS in this population. These findings will help individualize prognostication at diagnosis, optimize treatment strategies, and facilitate patient stratification in future trials. Full article

Introduction: Primary site locoregional treatment (LRT) of metastatic breast cancer has been performed and evaluated with the aim to improve survival, prevent complications, and alleviate local symptoms. As some studies fail to show a survival benefit, the quality of life is important to consider when deciding on LRT. The aim of this study was to evaluate and quantify the impact of LRT on the quality of life of patients with de novo metastatic breast cancer (dnMBC) through a systematic review of the literature and a meta-analysis. Methods: Multiple databases were searched on May 2024 with the following keywords: (i) dnMBC; (ii) LRT, including surgery +/− radiotherapy; and (iii) QOL. Results: Six studies were included in the qualitative synthesis and four in meta-analysis (481 women, n = 251 in the LRT and n = 230 in the control groups). There was a significant QOL decrease in the LRT group at 18 months (standardized mean difference [SMD] = −0.63; 95% confidence interval [CI] −0.98–−0.26; p < 0.001, low heterogeneity I² = 33%) and after 30 months (SMD −0.82; 95%CI −1.58–−0.06; p = 0.034, high heterogeneity I² = 93%), while no statistically significant difference was observed at short term (6 months, p = 0.333). Conclusions: This study shows that there is lacking evidence regarding the QOL benefits after LRT in this population, and even a numerical deterioration in global QOL several months after the treatment. Future and ongoing research may provide additional insights into this question on dnMBC and specifics subgroups. Full article

Background/Objectives: CDK4/6 inhibitors have changed the landscape of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (BC) management. It is essential to identify predictive and prognostic factors for the efficacy of CDK4/6 inhibitors. We aimed to investigate the differences in characteristics and outcomes of patients receiving first-line CDK4/6 inhibitors according to PgR status. Methods: This multicenter retrospective study included 351 patients treated with first-line CDK 4/6 inhibitors for HR-positive/HER2-negative metastatic BC. Patients were categorized based on their PgR expression levels, including the PgR-low (<20%) and PgR-high (≥20%) groups, and baseline characteristics, treatment responses, and survival outcomes were analyzed. Results: The median age was 57 years (range: 26–85). A total of 99 patients were premenopausal, and 252 patients were postmenopausal. There were 115 (32.8%) patients in the PgR-low group, while 236 (67.2%) were in the PgR-high group. The majority of patients (56.7%) presented with de novo metastatic disease. Visceral metastases presented in 44.2% of patients. Low PgR expression was significantly associated with lower estrogen receptor levels (p = 0.031), elevated Ki-67 levels (p = 0.002), a higher incidence of visceral metastases (p = 0.035), and recurrent disease (p = 0.019). In the multivariate analysis, low PgR expression was a significant independent predictor of worse progression-free survival (PFS) and overall survival (OS). Conclusions: We demonstrated that low PgR expression is independently and significantly correlated with shorter PFS and OS. These findings support low PgR expression as a valuable prognostic biomarker in metastatic BC patients treated with first-line CDK4/6 inhibitors. Full article

Introduction: CDK4/6 inhibitors in combination with aromatase inhibitors (AIs) are the standard first-line treatment for hormone receptor-positive (HR+), HER2-negative (HER2−) metastatic breast cancer. Landmark trials have demonstrated a comparable progression-free survival (PFS) across CDK4/6 inhibitors, but the overall survival (OS) outcomes have varied. This study aimed to evaluate the real-world PFS and OS for palbociclib and ribociclib when combined with AIs in patients with HR+/HER2− advanced breast cancer. Materials and Methods: This was a retrospective chart review of adult patients with HR+/HER2− metastatic breast cancer treated at a single academic center between 1 January 2015 and 1 December 2022. The baseline demographics, clinical characteristics, and treatment details were extracted. A Kaplan–Meier analysis was used to estimate the PFS and OS, and differences between the treatment groups were assessed using the log-rank test. Cox proportional hazards models were constructed to adjust for confounding factors. Results: Seventy-five patients were included in the final analysis. The cohort was predominantly female (98.7%) and postmenopausal (77.3%), with 52.0% having de novo stage IV disease. Palbociclib was prescribed to 74.7% of the patients, and ribociclib to 25.3%. The patients receiving ribociclib were significantly younger (57.6 vs. 67.5 years, p = 0.013) and more likely to be premenopausal (42.1% vs. 5.4%, p < 0.001). The real-world median PFS and OS for palbociclib were 20.3 months (95% CI: 14.8–46) and 37.2 months (95% CI: 20.3–not reached [NR]), respectively. For ribociclib, the median PFS and OS were not reached. The Cox proportional hazards models adjusting for age and menopausal status found no significant differences between ribociclib and palbociclib for the PFS (HR = 0.92, p = 0.86) or OS (HR = 0.95, p = 0.92). Conclusion: In this real-world analysis, palbociclib demonstrated a median PFS consistent with the results from landmark trials, although the observed OS was shorter. The ribociclib-treated patients had a numerically longer PFS and OS compared with those treated with palbociclib, but the differences were not statistically significant. The discontinuation rates were similar between the two groups. Full article

Estrogen receptor (ER)-positive breast cancer (BC) is the most common BC subtype. Endocrine therapy (ET) targeting ER signaling still remains the mainstay treatment option for hormone receptor (HR)-positive BC either in the early or in advanced setting, including different strategies, such as the suppression of estrogen production or directly blocking the ER pathway through SERMs—selective estrogen receptor modulators—or SERDs—selective estrogen receptor degraders. Nevertheless, the development of de novo or acquired endocrine resistance still remains challenging for oncologists. The use of novel ET combined with targeted drugs, such as cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, has significantly improved long-term outcome rates, thus changing the therapeutic algorithm for metastatic BC (MBC) and recently the therapeutic strategy in the adjuvant setting for early high-risk BC. Eluding the resistance to CDK4/6 inhibitors combined with ET is currently an unmet medical need, and there is disagreement concerning the best course of action for patients who continue to progress after this combination approach. Genetic changes in the tumor along its growth uncovered by genomic profiling of recurrent and/or metastatic lesions through tumor and/or liquid biopsies may predict the response or resistance to specific agents, suggesting the best therapeutic strategy for each patient by targeting the altered ER-dependent pathway (novel oral SERDs and a new generation of anti-estrogen agents) or alternative ER-independent signaling pathways such as PI3K/AKT/mTOR or tyrosine kinase receptors (HER2 mutations or HER2 low status) or by inhibiting pathways weakened through germline BRCA1/2 mutations. These agents are being investigated as single molecules and in combination with other target therapies, offering promising weapons to overcome or avoid treatment failure and propose increasingly more personalized treatment approaches. This review presents novel insights into ET and other targeted therapies for managing metastatic HR⁺/HER2⁻ BC by exploring potential strategies based on clinical evidence and genomic profiling following the failure of the CDK4/6i and ET combination. Full article

Early-onset breast cancer (EoBC), defined by a diagnosis <40 years of age, is associated with poor prognosis. This study investigated the mutational landscape of non-metastatic EoBC and the prognostic relevance of mutational signatures using 100 tumour samples from Alberta, Canada. The MutationalPatterns package in R/Bioconductor was used to extract de novo single-base substitution (SBS) and insertion–deletion (indel) mutational signatures and to fit COSMIC SBS and indel signatures. We assessed associations between these signatures and clinical characteristics of disease, in addition to recurrence-free (RFS) and overall survival (OS). Five SBS and two indel signatures were extracted. The SBS13-like signature had higher relative contributions in the HER2-enriched subtype. Patients with higher than median contribution tended to have better RFS after adjustment for other prognostic factors (HR = 0.29; 95% CI: 0.08–1.06). An unsupervised clustering algorithm based on absolute contribution revealed three clusters of fitted COSMIC SBS signatures, but cluster membership was not associated with clinical variables or survival outcomes. The results of this exploratory study reveal various SBS and indel signatures may be associated with clinical features of disease and prognosis. Future studies with larger samples are required to better understand the mechanistic underpinnings of disease progression and treatment response in EoBC. Full article

Breast cancer in men represents approximately 1% of all breast cancer diagnoses. Among all patients with breast cancer, approximately 30% will develop brain metastases. Over the past decade, there have been multiple advances in the treatment of metastatic breast cancer; however, long-term outcomes of this presentation in male patients are lacking. We evaluated male patients with de novo stage IV breast cancer using the Surveillance, Epidemiology and End Results (SEER) database from 2010 to 2019. Overall survival (OS) was estimated using the Kaplan–Meier method and differences between groups were compared using log rank tests. In total, 22 male patients with brain metastases at initial breast cancer diagnosis were included. Patients with HR-positive/HER2-negative tumors had the longest OS (median 13 months). Factors associated with shorter overall survival were advanced age, unmarried marital status, lower household income, and grade III disease, among others. Brain metastases remains an unmet medical need for patients with breast cancer; the development of new drugs may provide an improvement in overall survival for male patients in the future. Full article

We investigated whether we could identify a panel of miRNAs associated with response to treatment in tumor tissues of patients with Hormone Receptor-positive/HER2-negative metastatic breast cancer treated with endocrine therapy (ET) and the CDK4/6 inhibitor (CDK4/6i)i palbociclib. In total, 52 patients were evaluated, with 41 receiving treatment as the first line. The overall median PFS was 20.8 months (range 2.5–66.6). In total, 23% of patients experienced early progression (<6 months). Seven miRNAs (miR-378e, miR-1233, miR-99b-5p, miR-1260b, miR-448, -miR-1252-5p, miR-324-3p, miR-1233-3p) showed a statistically significant negative association with PFS. When we considered PFS < 6 months, miR-378e, miR-99b-5p, miR-877-5p, miR-1297, miR-455-5p, and miR-4536-5p were statistically associated with a poor outcome. In the multivariate analysis, the first three miRNAs confirmed a significant and independent impact on PFS. The literature data and bioinformatic tools provide an underlying molecular rationale for most of these miRNAs, mainly involving the PI3K/AKT/mTOR pathway and cell-cycle machinery as cyclin D1, CDKN1B, and protein p27^Kip1 and autophagy. Our findings propose a novel panel of miRNAs associated with a higher likelihood of early progression in patients treated with ET and Palbociclib and may contribute to shed some light on the mechanisms of de novo resistance to CDK4/6i, but this should be considered exploratory and evaluated in larger cohorts. Full article

Background The lifespan of patients diagnosed with de novo metastatic breast cancer (dnMBC) has been prolonged. Nonetheless, there remains substantial debate regarding immediate breast reconstruction (IBR) for this particular subgroup of patients. The aim of this study was to construct a nomogram predicting the breast cancer-specific survival (BCSS) of dnMBC patients who underwent IBR. Methods A total of 682 patients initially diagnosed with metastatic breast cancer (MBC) between 2010 and 2018 in the Surveillance, Epidemiology, and End Results (SEER) database were included in this study. All patients were randomly allocated into training and validation groups at a ratio of 7:3. Univariate Cox hazard regression, least absolute shrinkage and selection operator (LASSO), and best subset regression (BSR) were used for initial variable selection, followed by a backward stepwise multivariate Cox regression to identify prognostic factors and construct a nomogram. Following the validation of the nomogram with concordance indexes (C-index), receiver operating characteristic (ROC) curves, calibration curves, and decision curve analyses (DCAs), risk stratifications were established. Results Age, marital status, T stage, N stage, breast subtype, bone metastasis, brain metastasis, liver metastasis, lung metastasis, radiotherapy, and chemotherapy were independent prognostic factors for BCSS. The C-indexes were 0.707 [95% confidence interval (CI), 0.666–0.748] in the training group and 0.702 (95% CI, 0.639–0.765) in the validation group. In the training group, the AUCs for BCSS were 0.857 (95% CI, 0.770–0.943), 0.747 (95% CI, 0.689–0.804), and 0.700 (95% CI, 0.643–0.757) at 1 year, 3 years, and 5 years, respectively, while in the validation group, the AUCs were 0.840 (95% CI, 0.733–0.947), 0.763 (95% CI, 0.677–0.849), and 0.709 (95% CI, 0.623–0.795) for the same time points. The calibration curves for BCSS probability prediction demonstrated excellent consistency. The DCA curves exhibited strong discrimination power and yielded substantial net benefits. Conclusions The nomogram, constructed based on prognostic risk factors, has the ability to provide personalized predictions for BCSS in dnMBC patients undergoing IBR and serve as a valuable reference for clinical decision making. Full article

Purpose: To retrospectively review the clinical outcomes of patients with metastatic breast cancer (MBCa) following liver directed ablative intent radiotherapy (RT). Methods: Demographics, disease and treatment characteristics of patients with MBCa who received liver metastasis (LM) directed ablative RT between 2004–2020 were analysed. The primary outcome was local control (LC), secondary outcomes included overall survival (OS) and progression-free survival (PFS) analyzed by univariate (UVA) and multi-variable analysis (MVA). Results: Thirty MBCa patients with 50 LM treated with 5–10 fraction RT were identified. Median follow-up was 14.6 (range 0.9–156.2) months. Class of metastatic disease was described as induced (12 patients, 40%), repeat (15 patients, 50%) and de novo (three patients, 10%). Median size of treated LM was 3.1 cm (range 1–8.8 cm) and median biologically effective dose delivered was 122 (Q1–Q3; 98–174) Gy₃. One-year LC rate was 100%. One year and two-year survival was 89% and 63%, respectively, with size of treated LM predictive of OS (HR 1.35, p = 0.023) on UVA. Patients with induced OMD had a significantly higher rate of progression (HR 4.77, p = 0.01) on UVA, trending to significance on MVA (HR 3.23, p = 0.051). Conclusions: Hypo-fractionated ablative liver RT in patients with MBCa provides safe, tolerable treatment with excellent LC. Full article

Metastatic castration-resistant prostate cancer (mCRPC) cells can de novo biosynthesize their own cholesterol and overexpress proprotein convertase subtilisin/kexin type 9 (PCSK9). PCSK9 proved to contribute to mCRPC cell motility since PCSK9 knockdown (KD) in mCRPC CWR-R1ca cells led to notable reductions in cell migration and colony formation. Human tissue microarray results proved a higher immunohistoscore in patients ≥ 65 years old, and PCSK9 proved to be expressed higher at an early Gleason score of ≤7. The fermentation product pseurotin A (PS) suppressed PCSK9 expression, protein–protein interactions with LDLR, and breast and prostate cancer recurrences. PS suppressed migration and colony formation of the CWR-R1ca cells. The progression and metastasis of the CWR-R1ca-Luc cells subcutaneously (sc) xenografted into male nude mice fed a high-fat diet (HFD, 11% fat content) showed nearly 2-fold tumor volume, metastasis, serum cholesterol, low-density lipoprotein cholesterol (LDL-C), prostate-specific antigen (PSA), and PCSK9 levels versus mice fed a regular chow diet. Daily oral PS 10 mg/kg treatments prevented the locoregional and distant tumor recurrence of CWR-R1ca-Luc engrafted into nude mice after primary tumor surgical excision. PS-treated mice showed a significant reduction in serum cholesterol, LDL-C, PCSK9, and PSA levels. These results comprehensively validate PS as an mCRPC recurrence-suppressive lead by modulating the PCSK9-LDLR axis. Full article

This multicenter registry study aims to analyze time-related changes in the treatment patterns and outcome of patients with metastatic breast cancer (MBC) over a ten-year period. Correlations between demographic, prognostic variables and survival outcomes were carried out in database aggregates consisting of cohorts based on disease presentation (recurrent vs. de novo) and the diagnosis date of MBC (Cohort I: patient diagnosed between January 2010 and December 2014; and Cohort II: between January 2015 and December 2019). Out of 1382 patients analyzed, 52.3% patients had recurrent disease, with an increased frequency over time (47.9% in Cohort I vs. 56.1% in Cohort II, p < 0.001). In recurrent patients, 38.4% (n = 277) relapsed within two years from initial diagnosis, among which triple-negative BC (TNBC) was the most frequent (51.7%). Median overall survival (OS) was 51.0 (48.0–55.0) months for all patients, which was similar across both cohorts. HER2+ subtype had the highest OS among subgroups (HER2+ vs. HR+ vs. TNBC; 57 vs. 52 vs. 27 months, p < 0.001), and the dnMBC group showed a better outcome than recMBC (53 vs. 47 months, p = 0.013). Despite the lack of CDK inhibitors, luminal A patients receiving endocrine therapy had a favorable outcome (70 months), constituting an appealing approach with limited resources. The only survival improvement during the timeframe was observed in HER2+ dnMBC patients (3-year OS Cohort I: 62% vs. Cohort II: 84.7%, p = 0.009). The incorporation of targeted agents within standard treatment has improved the outcome in HER2+ MBC patients over time. Nevertheless, despite advances in early diagnosis and treatment, the prognosis of patients with TNBC remains poor, highlighting the need for more effective treatment options. Full article

The latest and newest discoveries for advanced and metastatic hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) breast cancer are the three cyclin-dependent kinases 4 and 6 inhibitors (CDK4/6i) in association with endocrine therapy (ET). However, even if this treatment revolutionized the world and continued to be the first-line treatment choice for these patients, it also has its limitations, caused by de novo or acquired drug resistance which leads to inevitable progression after some time. Thus, an understanding of the overview of the targeted therapy which represents the gold therapy for this subtype of cancer is essential. The full potential of CDK4/6i is yet to be known, with many trials ongoing to expand their utility to other breast cancer subtypes, such as early breast cancer, and even to other cancers. Our research establishes the important idea that resistance to combined therapy (CDK4/6i + ET) can be due to resistance to endocrine therapy, to treatment with CDK4/6i, or to both. Individuals’ responses to treatment are based mostly on genetic features and molecular markers, as well as the tumor’s hallmarks; therefore, a future perspective is represented by personalized treatment based on the development of new biomarkers, and strategies to overcome drug resistance to combinations of ET and CDK4/6 inhibitors. The aim of our study was to centralize the mechanisms of resistance, and we believe that our work will have utility for everyone in the medical field who wants to deepen their knowledge about ET + CDK4/6 inhibitors resistance. Full article

We examined differences in HER2 expression between primary tumors and distant metastases, particularly within the HER2-negative primary breast cancer cohort (HER2-low and HER2-zero). The retrospective study included 191 consecutive paired samples of primary breast cancer and distant metastases diagnosed between 1995 and 2019. HER2-negative samples were divided into HER2-zero (immunohistochemistry [IHC] score 0) and HER2-low (IHC score 1+ or 2+/in situ hybridization [ISH]-negative). The main objective was to analyze the discordance rate between matched primary and metastatic samples, focusing on the site of distant metastasis, molecular subtype, and de novo metastatic breast cancer. The relationship was determined by cross-tabulation and calculation of Cohen′s Kappa coefficient. The final study cohort included 148 paired samples. The largest proportion in the HER2-negative cohort was HER2-low [primary tumor 61.4% (n = 78), metastatic samples 73.5% (n = 86)]. The discordance rate between the HER2 status of primary tumors and corresponding distant metastases was 49.6% (n = 63) (Kappa −0.003, 95%CI −0.15–0.15). Development of a HER2-low phenotype occurred most frequently (n = 52, 40.9%), mostly with a switch from HER2-zero to HER2-low (n = 34, 26.8%). Relevant HER2 discordance rates were observed between different metastatic sites and molecular subtypes. Primary metastatic breast cancer had a significantly lower HER2 discordance rate than secondary metastatic breast cancer [30.2% (Kappa 0.48, 95%CI 0.27–0.69) versus 50.5% (Kappa 0.14, 95% CI −0.03–0.32)]. This highlights the importance of evaluating potentially therapy-relevant discordance rates between a primary tumor and corresponding distant metastases. Full article