The impact of body mass index on the progression-free survival of CDK 4/6 inhibitors in metastatic breast cancer patients.

Aim: Endocrine therapy (ET) plus cyclin-dependent kinase (CDK) 4/6 inhibitors is a standard treatment for hormone receptor (HR) positive HER-2-negative metastatic breast cancer patients. In this study, we aimed to investigate the effect of body mass index (BMI) on progression-free survival (PFS) in patients receiving ET plus CDK 4/6 inhibitors.Materials & methods: Patients with metastatic HR-positive breast cancer receiving CDK 4/6 inhibitors were included in the study. A total of 116 patients were retrospectively evaluated. Patients were divided into three groups according to BMI level: normal weight (group 1) 18.5-24.9 kg/m2, overweight (group 2) 25-29.9 kg/m2 and obese (group 3): ≥30 kg/m2. Median follow-up was 10.83 months. Comparisons of PFS and BMI categories were performed by Kaplan-Meier curve and log-rank test.Results: PFS was 9.3 (5.3-13.4) months in normal weight patients and 11.1 (9.7-12.56) months in obese patients and was not reached in overweight patients. This difference was statistically significant (p = 0.02).Conclusion: Low BMI has been shown to have a negative prognostic effect on survival in patients with metastatic breast cancer and overweight patients had a longer PFS.

[Box: see text].

Neoadjuvant Chemotherapy with Concurrent Letrozole for Estrogen Receptor-Positive and HER2-Negative Breast Cancer: An Open-Label, Single-Center, Nonrandomized Phase II Study (NeoCHAI).

The role of combining neoadjuvant endocrine therapy with conventional chemotherapy remains unclear; therefore, we conducted an open-label, single-center, nonrandomized phase II trial to assess the effect of this combination. Patients with previously untreated stage II or III HR-positive, HER2-negative breast cancer received concurrent letrozole 2.5 mg with standard neoadjuvant chemotherapy. The primary endpoint was pathologic complete response (pCR) at the time of surgery. We used Simon's minimax two-stage design; a pCR rate > 6% was necessary at the first stage to continue. Between November 2017 and November 2020, 53 women were enrolled in the first stage of the trial. Their median age was 49 years (range, 33-63), and 60% of them were premenopausal. Subsequently, 66% and 34% of patients with clinical stages II and III, respectively, were included; 93% had clinically node-positive disease. Two patients (4%) achieved pCR after neoadjuvant chemo-endocrine treatment, which did not satisfy the criteria for continuing to the second stage. The overall response rate was 83%. During the median follow-up of 53.7 months, the 3-year disease-free survival and overall survival rates were 87% and 98%, respectively. Neutropenia was the most common grade 3/4 adverse event (40%), but rarely led to febrile neutropenic episodes (4%). Myalgia (32%), nausea (19%), constipation (17%), heartburn (11%), oral mucositis (9%), and sensory neuropathy (9%) were frequently observed, but classified as grade 1 or 2. No deaths occurred during preoperative treatment. The addition of letrozole to standard neoadjuvant chemotherapy was safe and beneficial in terms of overall response rate, but did not provide a higher pCR rate in locally advanced HR-positive, HER2-negative breast cancer. Further research is needed to enhance neoadjuvant treatment strategies for this cancer subtype.

Application effect of case management nursing based on patient safety in patients with prostate cancer.

BACKGROUND: Globally, prostate cancer has become a major threat to men's health, with an increasing incidence and causes serious effects on the quality and length of life of patients. Despite the rapid development of medical technology, which provides treatments, including surgery, radiotherapy, and endocrine therapy, the treatment of patients with prostate cancer, especially with endocrine therapy, has become a major challenge in clinical treatment owing to the lengthy course of treatment, side effects of drugs, and impact of the disease on the psychological and physiological functioning of the patient, producing poor treatment adherence and a decline in quality of life. AIM: To explore effects of nursing intervention prioritizing patient safety and case management in patients with prostate cancer undergoing endocrine therapy. METHODS: Eighty patients with prostate cancer who received endocrine therapy at our hospital between January 2022 and January 2024 were divided into observation and control groups with 40 cases per group. The control group was treated using a routine nursing workflow while the observation group received case management nursing guidance prioritizing patient safety. Scores for anxiety and depression, prostate cancer symptoms, and quality of life and patient compliance and satisfaction were compared between the groups after three months of intervention. RESULTS: After the nursing intervention, the anxiety and depression scores of the observation group were significantly lower than those of the control group (P < 0.05). The quality of life score, sexual function, and hormone function were significantly higher than those in the control group (P < 0.05). CONCLUSION: Case management guidance based on patient safety effectively reduced anxiety and depression in patients undergoing endocrine therapy for prostate cancer and improved their quality of life, treatment compliance, and satisfaction.

Adjuvant and neoadjuvant therapy with or without CDK4/6 inhibitors in HR+/HER2- early breast cancer: a systematic review and meta-analysis.

Background: The combination of cyclin-dependent kinases 4/6 (CDK4/6) inhibitors and endocrine therapy is the standard treatment for patients with hormone receptor-positive (HR+)/HER2-negative (HER2-) advanced breast cancer. However, the role of CDK4/6 inhibitors in early breast cancer remains controversial. Methods: This study aimed to evaluate the efficacy and safety of CDK4/6 inhibitors combined with endocrine therapy versus endocrine therapy alone in patients with HR+, HER2- early breast cancer. A systematic review of Cochrane, PubMed and EMBASE databases was conducted. The efficacy endpoints of adjuvant therapy were invasive disease-free survival (IDFS), overall survival (OS) and distant relapse-free survival (DRFS). The efficacy endpoint included complete cell cycle arrest (CCCA) and complete pathologic response (PCR) with neoadjuvant therapy. Grade 3/4 adverse events (AEs) were assessed as safety outcomes. Results: Eight randomized controlled trials (RCTs) were included in the study. CDK4/6 inhibitors combined with endocrine therapy showed a significant improvement in IDFS (hazard ratio (HR) = 0.81, 95% confidence interval (CI) = 0.68-0.97, P = 0.024), but not DRFS (HR = 0.84, 95% CI = 0.56-1.29, P = 0.106) or OS (HR = 0.96, 95% CI = 0.77-1.19, P = 0.692) in adjuvant therapy. In the neoadjuvant therapy setting, CDK4/6 inhibitors improved CCCA compared with the control group (RR = 2.08, 95% CI = 1.33-3.26, P = 0.001). The risk of 3/4 grade AEs increased significantly with the addition of CDK4/6 inhibitors to endocrine therapy. Conclusion: The addition of CDK4/6 inhibitors in HR+/HER2- early breast cancer patients significantly improved IDFS in adjuvant therapy and CCCA in neoadjuvant. However, CDK4/6 inhibitors also showed significant toxicities during therapy. Systematic Review Registration: Identifier CRD42024530704.

Complete response and long-term survival to endocrine monotherapy in a patient with metastatic breast cancer in a low-income country: a case report.

BACKGROUND: Breast cancer is the most common cancer in women. Progression-free survival for hormone receptor-positive/human epidermal growth factor receptor-2-negative metastatic breast cancer treated with endocrine therapy in combination with cyclin4/6-dependent kinase is approximately 25 months. This case represents metastatic breast cancer treated with endocrine therapy, leading to long-term survival. CASE PRESENTATION: A 40-year-old Syrian woman diagnosed with hormone receptor-negative breast cancer was treated surgically with adjuvant chemotherapy and radiotherapy. She developed local and nodal recurrences that were hormone receptor-positive, followed by a recurrence of malignant pleural effusion. She was initially treated with chemotherapy and then placed on endocrine therapy with a complete response from 2014 until now. The patient also suffered from adverse events of medications, such as heart failure and osteoporosis, which were treated appropriately. CONCLUSION: This case demonstrates a long-lasting complete response to metastatic breast cancer with malignant pleural effusion. This shows the validity of endocrine therapy in recurrent hormone receptor-positive breast cancer, especially in countries that cannot afford targeted therapies or genetic tests. It also highlights the necessity for a better understanding of the prognostic and predictive factors.

Oral nano-formulations for endocrine therapy of endometrioid adenocarcinomas.

Endometrial cancer is one of the three major malignant tumors of the reproductive system that threaten women's lives and health. The incidence of this disease is on the rise globally. Most cases of endometrial cancer comprise endometrioid adenocarcinomas, whose treatment is challenged by factors such as their high recurrence rate and the need to preserve fertility among young patients. Thus, oral endocrine therapy has become the main treatment modality. The main drugs used in oral endocrine therapy are progestins, selective estrogen receptor antagonists, and aromatase inhibitors. However, their clinical use is hindered by their low solubility and low oral utilization. The rapid development of nanotechnology allows the combination of these drugs with oral nano-formulations to create a good carrier. Such nanocarriers, including nanospheres, nanocapsules, and micelles can protect the drug against clearance and increase the site specificity of drug delivery. This paper reviews the pathogenesis of endometrioid endometrial cancer (EEC) and oral nano-formulations for endocrine therapy.

Cost-effectiveness of CDK4/6 inhibitors in HR+/HER2- metastatic breast cancer: a systematic review and meta-analysis.

BACKGROUND: Cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors have emerged as a significant advancement in the treatment of HR+/HER2- metastatic breast cancer (MBC). Despite the clinical efficacy of CDK 4/6 inhibitors in HR+/HER2- metastatic breast cancer, there remains a significant gap in understanding their cost-effectiveness, particularly regarding the long-term economic impact and the key drivers of costs, when used in combination with endocrine therapy. This study aims to systematically review and conduct a meta-analysis of cost-effectiveness studies evaluating CDK4/6 inhibitors in treatment of HR+/HER2- advanced breast cancer and identify key drivers of costs of CDK4/6 inhibitors in combination with endocrine therapy. METHODS: A comprehensive search of PubMed and Embase was conducted to identify peer-reviewed studies from February 2015 to March 2022 reporting cost-effectiveness of CDK4/6 inhibitors in MBC treatment. Incremental net benefits (INBs) were estimated, and meta-analysis was conducted. This review adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: We identified 120 articles, of which 18 were eligible for systematic review and 16 for meta-analysis. None of the three CDK4/6 inhibitors had positive INB compared to endocrine/aromatase inhibitors therapy alone. The pooled INB was estimated at -$149,266.87 (95% Confidence Interval (CI) = -$196,961.54, -$101,572.20). CONCLUSION: The combination of CDK4/6 inhibitors and letrozole/endocrine therapy for the treatment of postmenopausal patients with advanced HR+/HER2 - MBC was not cost-effective.

Breast cancer, a significant health concern worldwide, represents around 30% of new cancer diagnoses and 25% of cancer related fatalities. Among these cases, approximately two-thirds are characterized by hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2−) tumors. In the metastatic stage, up to half of patients exhibit inherent resistance to endocrine therapy, leading to poorer survival rates, while others, initially responsive, eventually develop resistance, leading to disease progression and eventual mortality. Nevertheless, recent advancements in CDK4/6 inhibitors have shown efficacy in overcoming both inherent and acquired endocrine resistance, representing a substantial breakthrough in HR+/HER2− metastatic breast cancer treatment. This study conducts a review of literature focusing on comparative cost-effectiveness and economic evaluations of the three CDK4/6 inhibitors, evaluating the pooled incremental net benefit (INB) reported in these studies. It marks the first attempt to compare all three CDK4/6 inhibitors and employs a meta-analysis approach to ascertain the option demonstrating the most positive INB. Our findings indicate that CDK4/6 inhibitors fail to provide an economic advantage over letrozole or endocrine therapy alone. The aim of this study is to offer insights for clinical and reimbursement decision-making in the treatment of postmenopausal patients with advanced HR+/HER2− breast cancer, providing valuable guidance for policymakers, payers, and clinicians.

Dalpiciclib in combination with letrozole/anastrozole or fulvestrant in HR-positive and HER2-negative advanced breast cancer: results from a phase Ib study.

Background: Dalpiciclib is a novel cyclin-dependent kinase 4/6 inhibitor which showed tolerability and preliminary efficacy as monotherapy for pretreated advanced breast cancer (BC). Objectives: To further assess dalpiciclib with endocrine therapy (ET) in hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative BC. Design: A multicenter, open-label, phase Ib trial. Methods: Patients with locally recurrent or metastatic BC were enrolled in five cohorts. Patients without prior treatment for advanced disease (cohorts 1-2) were given dalpiciclib (125 or 150 mg) plus letrozole/anastrozole; patients who progressed after ET (cohorts 3-5) were given dalpiciclib (125, 150, or 175 mg) plus fulvestrant. Dalpiciclib was administered orally once daily in 3-weeks-on/1-week off schedule. The primary endpoint was safety. Results: A total of 58 patients received dalpiciclib with letrozole/anastrozole and 46 received dalpiciclib with fulvestrant. No maximum tolerated dose of dalpiciclib was reached with letrozole/anastrozole or fulvestrant. Across all cohorts, 86.7%-93.8% of patients had a grade ⩾3 adverse event, with the most common being neutropenia (grade 3, 40.0% for dalpiciclib 175 mg and 61.8%-87.5% for lower doses; grade 4, 46.7% and 4.2%-20.6%, respectively) and leukopenia (grade 3, 80.0% for 175 mg and 33.3%-54.2% for lower doses; grade 4, 0% for all doses). At tested dose levels, steady-state areas under the concentration curve and peak concentration of dalpiciclib increased with dose when combined with letrozole/anastrozole and fulvestrant. Dalpiciclib at 150 mg was associated with a numerically higher objective response rate in both patients untreated for advanced disease (67.6%; 95% confidence interval (CI) 49.5-82.6) and patients progressing after ET (53.3%; 95% CI 26.6-78.7); as of July 30, 2022, the median progression-free survival with dalpiciclib 150 mg was 24.1 months (95% CI 16.9-46.0) with letrozole/anastrozole and 16.7 months (95% CI 1.9-24.1) with fulvestrant. Conclusion: Dalpiciclib plus letrozole/anastrozole or fulvestrant showed an acceptable safety profile. The recommended phase III dose of dalpiciclib was 150 mg. Trial registration: ClinicalTrials.gov identifier: NCT03481998.

First­line endocrine therapy for hormone receptor positive and HER­2 negative metastatic breast cancer: A Bayesian network meta­analysis.

Endocrine therapy has become the fundamental treatment option for hormone receptor-positive (HR+) and receptor tyrosine-protein kinase erbB-2-negative (HER2-) metastatic breast cancer (mBC). While treatments incorporating cyclin-dependent kinase (CDK)4 and 6 inhibitors are more prevalent than ever, comparisons among those regimens are scarce. The aim of the present study was to identify the most effective maintenance treatment for patients with HR+ and HER2- mBC. To this end, databases including PubMed, Embase, Cochrane Library, Scopus and Google Scholar were searched from inception to August, 2023. The endpoints comprised overall survival (OS) and progression free survival (PFS). For dichotomous variants, hazard ratios (HRs) and odds ratios (ORs) were generated, while standard mean difference (SMD) was used for consecutive variants by Bayesian network meta-analysis to make pairwise comparisons among regimens, to determine the optimal therapy. These processes were conducted using Rstudio 4.2.2 orchestrated with STATA 17.0 MP. A total of 16 randomized controlled trials including 7,174 patients with 11 interventions were analyzed. Compared with aromatase inhibitor (AI), palbociclib plus AI (PalboAI) exhibited a significantly longer PFS up to the 36th month of follow-up [HR=1.7; 95% credible interval, 1.36-2.16], including on the 3rd [OR=2.22; 95% confidence interval (CI), 1.10-4.47], 6th (OR=2.39; 95% CI, 1.21-4.69), 12th (OR=1.94; 95% CI, 1.34-2.79), 18th (OR=2.38; 95% CI, 1.65-3.44), 24th (OR=2.39; 95% CI, 1.67-3.43), 30th (OR=2.10; 95% CI, 1.62-2.74) and 36th (OR=2.66; 95% CI, 1.37-5.18) month of follow-up. Additionally, abemaciclib plus fulvestrant exhibited significant effects compared with AI alone between 12 and 36 months. Ribociclib plus fulvestrant, ribociclib plus AI and dalpiciclib plus AI exerted significant effects compared with AI alone between 12 and 30 months. Considering the effect on OS and PFS together with adverse reactions, safety, medical compliance and route of administration, PalboAI was found to be the optimal treatment for HR+/HER2-mBC. However, additional head-to-head clinical trials are warranted to confirm these findings.

Adherence, clinical benefits, and adverse effects of endocrine therapies among women with nonmetastatic breast cancer in developing countries: A systematic review and meta-analysis.

BACKGROUND: Despite significant advances in breast cancer control and survival with endocrine therapies (ETs), treatment utilization and outcomes in developing countries have not been adequately explored. This review evaluated ET adherence, potential benefits, and harms in populations across developing countries. METHODS: A literature search was conducted through August 2023 in five databases: PubMed, Cochrane Library, Web of Science, Global Health, and WHO Global Index Medicus. Retrieved records were screened to identify observational research presenting at least one outcome in women with nonmetastatic breast cancer in developing countries who received ET (tamoxifen or aromatase inhibitors). A random effects model was used to compute the rates of adherence, discontinuation, adverse events (AEs), disease progression, and death. RESULTS: A total of 104 studies met the inclusion criteria. Risk of bias was low in most studies, and a large portion of the patients involved Asians. The overall heterogeneity between studies was partially attributed to variations in study design or outcome measurement method. Results showed a pooled adherence rate of 75% (95% confidence interval [CI], 67%-81%) and a discontinuation rate of 16% (95% CI, 10%-25%). Treatment side effects and young age consistently emerged as significant predictors of nonadherence. A wide range of AEs was identified in our analysis. The estimated average rates of cancer recurrence and mortality at 5-years were 16% and 8%, respectively. CONCLUSIONS: The findings of this study underscore suboptimal ET use in developing countries and provide comprehensive insights into treatment experiences in the real-world setting. Targeted strategies are warranted to enhance adherence and subsequently optimize treatment benefits.

Chemotherapy Combined With Endocrine Therapy: Old Wine in a New Bottle?

Both chemotherapy (CT) and endocrine therapy (ET) play important roles in the systemic treatment of breast cancer (BC). However, previous studies have shown an antagonistic effect when CT and ET are administered simultaneously. Therefore, sequential administration is more effective than combined administration. The current guidelines and consensus recommend a sequential schedule of CT and ET for patients with hormone receptor-positive (HR+) BC. However, with the continuous introduction of new endocrine drugs, the question of whether the simultaneous administration of CT and ET is superior to sequential therapy has surfaced again as a hot topic of clinical concern. Recent studies have shown that the combination of certain chemotherapeutic agents with endocrine drugs has a synergistic effect. This review aims to summarize the new advances achieved in recent years on the old topic of CT combined with ET in the treatment of BC.

Breaking through therapeutic barriers: Insights into CDK4/6 inhibition resistance in hormone receptor-positive metastatic breast cancer.

The therapeutic landscape for hormone receptor-positive (HR+) breast carcinoma has undergone a significant transformation with the advent of cyclin-dependent kinase (CDK)4/6 inhibitors, particularly in combination with endocrine therapy as the primary regimen. However, the evolution of resistance mechanisms in response to CDK4/6 inhibitors in HR+ metastatic breast cancer presents substantial challenges in managing the disease. This review explores the diverse genomic landscape underlying resistance, including disturbances in the cell cycle, deviations in oncogenic signaling pathways, deficiencies in DNA damage response (DDR) mechanisms, and changes in the tumor microenvironment (TME). Additionally, it discusses potential strategies to surmount resistance, including advancements in endocrine therapy, targeted inhibition of cell cycle components, suppression of AKT/mTOR activation, exploration of the FGFR pathway, utilization of antibody-drug conjugates (ADCs), and integration of immune checkpoint inhibitors (ICIs) with endocrine therapy and CDK4/6 inhibitors, providing pathways for enhancing patient outcomes amidst treatment challenges.

Prognosis in HR-positive metastatic breast cancer with HER2-low versus HER2-zero treated with CDK4/6 inhibitor and endocrine therapy: a meta-analysis.

Background: The combination of CDK4/6 inhibitors (CDK4/6i) and endocrine therapy (ET) is currently the standard first-line treatment for patients with metastatic hormone receptor positive (HR+), and HER2-negative (HER2-) breast cancer. However, the impact of HER2 status on the prognosis of patients receiving CDK4/6i and ET remains unclear. The meta-analysis was conducted to evaluate different outcomes between HER2-low and HER2-zero patients in advanced HR+ breast cancer receiving CDK4/6i and ET. Methods: A systematic search was performed in PubMed and EMBASE databases for relevant published literature. Objective response rate (ORR), overall survival (OS), and progression-free survival (PFS) were pooled by fixed or random effects models. Results: Overall, 12 studies with 3567 patients were eligible for analysis. The pooled analysis suggested that no significant differences were observed in terms of ORR and OS between HER2-low and HER2-zero patients who underwent CDK4/6i and ET. Similarly, no significant difference in PFS was found between HER2-low and HER2-zero patients who underwent post-line CDK4/6i and ET or first-line Palbociclib and ET. However, in patients who received mixed-line (not a single treatment line) or first-line CDK4/6i and ET, the PFS was significantly shorter in the HER2-low subgroup than in the HER2-zero subgroup (mixed-line: HR = 1.36; 95% CI = 1.11-1.65; P = 0.002; first-line: HR = 1.14; 95% CI = 1.01-1.28; P = 0.04). A similar phenomenon was observed in patients who received mixed-line or post-line Palbociclib and ET (mixed-line: HR = 1.60; 95% CI = 1.09-2.34; P = 0.02; post-line: HR = 1.43; 95% CI = 1.03-2.00; P = 0.03). Conclusion: These results indicated that HER2-low status did not have a significant association with ORR and OS, but it may have a worse impact on PFS in patients who received mixed-line or first-line CDK4/6i and ET, as well as mixed-line or post-line palbociclib plus ET.

Case report: Two cases of prostate adenocarcinoma progressing to rare sarcomatoid carcinoma with normal PSA levels following endocrine therapy.

Background: Patients with prostate adenocarcinoma undergoing regular endocrine therapy may maintain normal PSA levels during follow-up, yet still progress to the highly malignant and rare prostatic sarcomatoid carcinoma, which is seldom reported. This article presents two case studies of prostatic sarcomatoid carcinoma. To date, only a few publications have described prostatic sarcomatoid carcinoma, and the clinical, morphological, and molecular dimensions of prostate adenocarcinoma warrant further investigation. Case description: Patient A was admitted two years ago due to difficulty urinating, with a PSA level of 6.35 ng/ml. A prostate needle biopsy was performed, and the postoperative pathology diagnosed prostate adenocarcinoma with a Gleason score of 9 (5 + 4, grade group 5). Citing personal reasons, the patient declined a radical prostatectomy and instead received ongoing androgen deprivation therapy (ADT), comprising goserelin, abiraterone, and prednisone. During follow-up, regular PSA tests showed no abnormalities. One year ago, the patient was admitted again due to difficulty urinating and hematuria, choosing to address only the urethral obstruction. Transurethral resection of the prostate was performed, and the postoperative pathology diagnosed sarcomatoid carcinoma of the prostate. Patient B was admitted three years ago due to difficulty urinating accompanied by hematuria. A prostate MRI and a whole-body radionuclide bone scan suggested prostate cancer with bone metastasis. Prostate needle biopsy confirmed the diagnosis. The patient was then regularly treated with androgen deprivation therapy, using goserelin. Throughout the follow-up period, the PSA levels consistently remained within normal limits. One year ago, the patient was admitted due to rectal bleeding. It was speculated that the symptoms of rectal bleeding might have been caused by the prostate cancer invading the rectal wall. A prostate needle biopsy was performed, and the pathology diagnosed sarcomatoid carcinoma of the prostate. Conclusions: This case underscores the inadequacy of relying solely on PSA levels to monitor high-grade prostate adenocarcinoma during endocrine therapy, as patients may progress to highly malignant atypical variants despite normal PSA levels. We propose that for high-grade prostate cancer patients who are unable to undergo radical prostatectomy, regular and frequent MRI screenings or repeat biopsies should be integral during endocrine therapy and follow-up. Furthermore, a detailed review of the patient's treatment history and clinical data, including immunohistochemical findings, might offer deeper clinical insights into prostatic sarcomatoid carcinoma.

Neoadjuvant Therapy: Current Landscape and Future Horizons for ER-Positive/HER2-Negative and Triple-Negative Early Breast Cancer.

OPINION STATEMENT: Navigating the complex landscape of breast cancer treatment involves distinct strategies for luminal and triple-negative subtypes. While neoadjuvant chemotherapy historically dominates the approach for aggressive triple-negative tumors, recent evidence highlights the transformative impact of immunotherapy, alongside chemotherapy, in reshaping treatment paradigms. In luminal cancers, endocrine therapy, notably aromatase inhibitors, demonstrates promising outcomes in postmenopausal patients with low-grade luminal A tumors. However, integrating targeted therapies like CDK4/6 inhibitors in neoadjuvant setting remains inconclusive. Identifying predictive factors for treatment response, especially in luminal tumors, poses a challenge, emphasizing the necessity for ongoing research. A multidisciplinary approach, tailored to individual patient profiles, is crucial for maximizing efficacy while minimizing toxicity. As we strive to optimize breast cancer management, a comprehensive understanding of the distinct characteristics and treatment implications of luminal and triple-negative subtypes, including the transformative role of immunotherapy, is essential for informed decision-making and personalized care.

Prognostic and Clinical Significance of the Proliferation Marker MCM7 in Breast Cancer.

INTRODUCTION: Minichromosome maintenance complex component 7 (MCM7) plays an essential role in proliferation and DNA replication of cancer cells. However, the expression and prognostic significance of MCM7 in breast cancer (BC) remain to be defined. In this study, we aimed to evaluate the role of MCM7 in BC. METHODS: We conducted immunohistochemistry staining of MCM7 in 1,156 operable early-stage BC samples and assessed MCM7 at the transcriptomic levels using publicly available cohorts (n = 13,430). MCM7 expression was evaluated and correlated with clinicopathological parameters including Ki67 labelling index and patient outcome. RESULTS: At the transcriptomic level, there was a significant association between high MCM7 mRNA levels and shorter patient survival in the whole cohort and in luminal BC class but not in the basal-like molecular subtype. High MCM7 protein expression was detected in 43% of patients and was significantly associated with parameters characteristic of aggressive tumour behaviour. MCM7 was independently associated with shorter survival, particularly in oestrogen receptor-positive (luminal) BC. MCM7 stratified luminal tumours with aggressive clinicopathological features into distinct prognostic groups. In endocrine therapy-treated BC patients, high MCM7 was associated with poor outcome, but such association disappeared with administration of adjuvant chemotherapy. Patients with high expression of Ki67 and MCM7 showed worst survival, while patients with double low expression BC showed the best outcome compared with single expression groups. CONCLUSION: The current findings indicate that MCM7 expression has a prognostic value in BC and can be used to identify luminal BC patients who can benefit from adjuvant chemotherapy.

Nodal Response and Survival After Neoadjuvant Endocrine Therapy in Hormone Receptor-Positive Breast Cancer: 20-Year Experience from a Single Institution.

INTRODUCTION: Axillary response to neoadjuvant endocrine therapy (NET) for the treatment of hormone receptor-positive breast cancer (HR+ BC) is not well-described. This study was designed to characterize nodal response after NET. METHODS: Patients receiving NET followed by curative intent surgery at a comprehensive cancer center from 1998 to 2022 in a prospectively collected registry were included. Patients with distant metastasis were excluded. Primary outcome was nodal pathologic complete response (pCR). Downstaging was defined as post-NET decrease in category. RESULTS: We included 123 patients; the majority were cT2 (n = 59) or cT3 (n = 35), and cN0 (n = 81). Median age was 70.0 years (interquartile range 62.1-76.0). Forty-two patients (34.1%) were clinically node-positive. After NET, 73 (59.8%) underwent breast-conserving surgery. All patients underwent sentinel lymph node biopsy, and 12 (9.8%) underwent completion axillary lymph node dissection. In-breast downstaging was achieved in 51 (41.5%) patients, 1 (0.8%) had breast pCR, and 14 (11.4%) had breast upstaging. Axillary downstaging was achieved in 10 (23.8%), 6 patients (14.3%) had nodal pCR, and 14 (33.3%) had axillary upstaging. At 10-year follow-up, local recurrence was 1% and distant recurrence was 14%, while disease-free survival was 82%. After adjusting for demographic and clinical factors, age was the only characteristic associated with mortality (hazard ratio 1.07, 95% confidence interval 1.01-1.13). CONCLUSIONS: In HR+ BC treated with NET, long-term disease-free survival is good, although nodal pCR is uncommon for cN+ patients. Future studies are needed to elucidate optimal neoadjuvant systemic therapy and to delineate oncologically safe strategies to deescalate axillary management for residual microscopic disease.

Essential gene screening identifies the bromodomain-containing protein BRPF1 as a new actionable target for endocrine therapy-resistant breast cancers.

Identifying master epigenetic factors controlling proliferation and survival of cancer cells allows to discover new molecular targets exploitable to overcome resistance to current pharmacological regimens. In breast cancer (BC), resistance to endocrine therapy (ET) arises from aberrant Estrogen Receptor alpha (ERα) signaling caused by genetic and epigenetic events still mainly unknown. Targeting key upstream components of the ERα pathway provides a way to interfere with estrogen signaling in cancer cells independently from any other downstream event. By combining computational analysis of genome-wide 'drop-out' screenings with siRNA-mediated gene knock-down (kd), we identified a set of essential genes in luminal-like, ERα + BC that includes BRPF1, encoding a bromodomain-containing protein belonging to a family of epigenetic readers that act as chromatin remodelers to control gene transcription. To gather mechanistic insights into the role of BRPF1 in BC and ERα signaling, we applied chromatin and transcriptome profiling, gene ablation and targeted pharmacological inhibition coupled to cellular and functional assays. Results indicate that BRPF1 associates with ERα onto BC cell chromatin and its blockade inhibits cell cycle progression, reduces cell proliferation and mediates transcriptome changes through the modulation of chromatin accessibility. This effect is elicited by a widespread inhibition of estrogen signaling, consequent to ERα gene silencing, in antiestrogen (AE) -sensitive and -resistant BC cells and pre-clinical patient-derived models (PDOs). Characterization of the functional interplay of BRPF1 with ERα reveals a new regulator of estrogen-responsive BC cell survival and suggests that this epigenetic factor is a potential new target for treatment of these tumors.

Re-Evaluating the Omission of Radiation Therapy in Low-Risk Patients With Early-Stage Breast Cancer.

Traditionally, management of early-stage breast cancer has required adjuvant radiation therapy following breast conserving surgery, due to decreased local recurrence and breast cancer mortality. However, over the past decade, there has been an increasing emphasis on potential overtreatment of patients with early-stage breast cancer. This has given rise to questions of how to optimize deintensification of treatment in this cohort of patients while maintaining clinical outcomes. A multitude of studies have focused on identification of a subset of patients with invasive breast cancer who were at low risk of local recurrence based on clinicopathologic features and therefore suitable for RT omission. These studies have failed to identify a subset that does not from RT with respect to local control. Several ongoing trials are evaluating alternative approaches to deintensification while focusing on tumor biology. With regards to ductal carcinoma in situ (DCIS), the role of RT has been questioned since breast conservation was utilized. Paralleling invasive disease studies, studies have sought to use clinicopathologic features to identify low risk patients suitable for RT omission but have failed to identify a subset that does not from RT with respect to local control. Use of new assays in patients with DCIS may represent the ideal approach for risk stratification and appropriate deintensification. At this time, when considering deintensification, individualizing treatment decisions with a focus on shared decision making is paramount.

Racial Disparity in Adherence to Endocrine Therapy among Women with Early-Stage Hormone Receptor Positive Breast Cancer: An Analysis of Arkansas All-Payers Claims Database.

INTRODUCTION/BACKGROUND: To assess racial/ethnic disparities in endocrine therapy (ET) adherence among women with breast cancer. MATERIALS AND METHODS: A retrospective cohort study of Arkansas All-Payer Claims Database (APCD) linked to Arkansas Cancer Registry (ACR). Women with stages 0-3 HR+ breast cancer diagnosed in 2013-2017 were followed from cancer diagnosis for a year to determine ET initiation. Among women who initiated ETs within 1 year of diagnosis, we assessed first-year compliance (proportion of days covered ≥ 0.8) and followed them for 5 years, censoring at death, end of data availability (December 21, 2019), or disenrollment from insurance coverage, whichever occurred first, to determine time to discontinuation. Regression analysis was conducted to determine racial/ethnic disparities in ET use adjusting for patients demographic, clinical, tumor characteristics and county-level socioeconomic factors. RESULTS: Among women with continuous insurance coverage, 81% initiated ET within 1 year of diagnosis; 80% were compliant in the first year of ET use and 27.4% discontinued ET by year 5 among those who initiated ET in the first year. There were no racial/ethnic differences in ET initiation or first-year compliance adjusting for covariates. NHB women were significantly less likely to discontinue ET within 5 years after ET initiation compared to NHW women after (HR, 95% CI, 0.76, 0.58-0.98; P = .035). CONCLUSION: After adjusting for patients' and tumor characteristics, there were no racial/ethnic differences in ET initiation within 1 year of diagnosis and ET compliance within first year of ET use. However, NHB women were less likely to discontinue ET within 5 years of initiation.