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.

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.

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.

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.

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.

Changes in immunophenotypes after neoadjuvant endocrine therapy for prostate cancer and their clinical significance.

Background: To investigate changes in the immunophenotypes of androgen receptor (AR), prostate-specific antigen (PSA), synaptophysin (Syn), chromogranin A (CgA), p53 and Ki-67 after neoadjuvant endocrine therapy (NET) for prostate cancer (PCa) and to analyze their clinical significance. Methods: Paired paraffin samples were collected from 40 PCa patients before and after NET, and immunohistochemistry were used to detect AR, PSA, Syn, CgA, p53 and Ki-67 expression. Based on The Cancer Genome Atlas (TCGA), Kaplan‒Meier survival curves were plotted for analysis of PSA and Ki-67 expression in relation to progression-free survival (PFS). Results: After NET, the mean scores for PSA and Ki-67 expression in PCa patients were lower than those before NET (P < 0.05), while the mean scores for Syn and CgA expression were higher than those before NET (P < 0.05). The mean Gleason score and WHO/ISUP (World Health Organization/International Society of Urological Pathology) grade after NET were lower than those before NET (P < 0.05). In PCa patients who had not yet received NET, PSA expression correlated positively with Gleason score and WHO/ISUP grade and negatively with Ki-67 expression (P < 0.05); p53 expression correlated negatively with Gleason score and WHO/ISUP grade (P < 0.05). TCGA showed that PFS was lower in PCa patients with high PSA and Ki-67 expression (P < 0.05). Conclusions: PSA and Ki-67 protein expressions decreased significantly in PCa patients after NET and can be used as biological markers for prognostic assessment of PCa patients. NETs may induce a neuroendocrine (NE) phenotype in PCa. Monitoring the immunophenotypes of PCa patients after NET may inform assessment of efficacy and prognosis.

Overexpression of cytoplasmic poly(A)-binding protein 1 as a biomarker for the prognosis and selection of postoperative regimen in breast cancer.

PURPOSE: The dysregulation of the cytoplasmic poly(A)-binding protein 1 (PABPC1) is involved in a variety of tumors but little is known about its role in human breast cancer. Therefore, the effect of PABPC1 in the prognosis and regimen selection in breast cancer patients was evaluated. METHODS: A total of 791 cases of invasive breast cancer were included in this study, although only 416 were involved in subsequent analyses after the propensity score matching (PSM) test. PABPC1 expression was detected by immunohistochemistry. The relationship between PABPC1 expression and clinicopathological factors, postoperative regimens, and outcomes was determined. RESULTS: In the total 791 cases, 583 cases were positive for PABPC1, but only 212 (26.8%) showed high PABPC1 expression (PABPC1-HE). The overall survival (OS) and disease-free survival (DFS) of PABPC1-HE patients after PSM were significantly worse than those in patients with PABPC1 low expression (PABPC1-LE), regardless of age, molecular type, tumor size, nodal status, or pStage. Postoperative chemotherapy (CT) increased the OS of PABPC1-HE patients but not that of PABPC1-LE patients. Among patients receiving endocrine therapy, those in the PABPC-LE group had an extended OS, while CT or chemoradiotherapy (CT/CRT) only significantly extended the OS time of PABPC-HE patients. CT/CRT did not significantly extend the survival of PABPC1-LE HER2-positive patients but extended the OS of PABPC1-HE HER2-positive patients. However, the OS of patients treated with CT/CRT + trastuzumab therapy was significantly longer than that of other patients under other therapies in the PABPC1-HE group, suggesting that PABPC1-HE might be sensitive to trastuzumab-based therapy. The multivariate analysis revealed that PABPC1-HE was an independent prognostic factor for both poor OS and DFS in breast cancer except luminal A type. CONCLUSIONS: Our results revealed that PABPC1 might be considered as a biomarker to help in subtyping, as well as in the prognosis and regimen selection of breast cancer patients.

A Research Protocol for a Phase II Single-Arm Clinical Trial Assessing the Feasibility and Efficacy of Neoadjuvant Anastrozole in Patients With Luminal Breast Cancer and Low Proliferative Index: The ANNE Trial.

INTRODUCTION: Neoadjuvant endocrine therapy (NET) is recommended for the treatment of invasive breast cancer (BC), particularly luminal subtypes, in locally advanced stages. Previous randomized studies have demonstrated the benefits of aromatase inhibitors in this context. However, NET is typically reserved for elderly or frail patients who may not tolerate neoadjuvant chemotherapy. Identifying non-responsive patients early and extending treatment for responsive ones would be ideal, yet optimal strategies are awaited. AIMS: This non-randomized phase 2 clinical trial aims to assess NET feasibility and efficacy in postmenopausal stage II and III luminal BC patients, identifying predictive therapeutic response biomarkers. Efficacy will be gauged by patients with Ki67 ≤ 10% after 4 weeks and Preoperative Endocrine Prognostic Index (PEPI) scores 0 post-surgery. Study feasibility will be determined by participation acceptance rate (recruitment rate ≥50%) and inclusion rate (>2 patients/month). METHODS: Postmenopausal women with luminal, HER2-tumors in stages II and III undergo neoadjuvant anastrozole treatment, evaluating continuing NET or receiving chemotherapy through early Ki67 analysis after 2 to 4 weeks. The study assesses NET extension for up to 10 months, using serial follow-ups with standardized breast ultrasound and clinical criteria-based NET suspension. Clinical and pathological responses will be measured overall and in the luminal tumor A subgroup. Toxicity, health-related quality of life, and circulating biomarkers predicting early NET response will also be evaluated.

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.

Overtreatment and Undertreatment of Early-Stage Breast Cancer in Older Women: Evaluating the POWER Trial.

INTRODUCTION: Radiation therapy (RT) omission is acceptable in older women with early-stage estrogen receptor + breast cancer treated with breast-conserving surgery (BCS) and adjuvant endocrine therapy (AET). However, RT rates in this population remain high, causing concern for overtreatment. Conversely, patients who omit RT and do not complete a course of AET are at risk of undertreatment. In the Pre-Operative Window of Endocrine Therapy to Inform Radiation Therapy Decisions (POWER) trial, participants receive 90 days of preoperative endocrine therapy to assess tolerance before deciding about RT. This study aimed to determine the rates of undertreatment and overtreatment institutionally and among POWER trial participants. METHODS: Data were retrospectively collected from medical records of women aged ≥ 65 years diagnosed with invasive, estrogen receptor +/human epidermal growth factor receptor 2- breast cancer, ≤ 3 cm, who had BCS between 2012 and 2022. Patients were categorized as undertreated (BCS alone), overtreated (BCS + RT + AET), or appropriately treated (BCS + RT or BCS + AET). RESULTS: The cohort included 478 patients, of whom 62 (12.97%) were undertreated, 202 (42.26%) were overtreated, and 214 (44.77%) were appropriately treated. Appropriately treated patients were more likely to be aged 70-79 years (P < 0.0001) and have high health literacy (P = 0.0003). Of the 37 patients (7.71%) in the POWER trial, more were appropriately treated than patients not in the POWER trial (81.1% versus 44.8%) (P < 0.0001). CONCLUSIONS: Despite long-standing guideline changes, RT utilization remains high. This study highlights how a novel patient-centered approach to guide adjuvant therapy decisions may increase the number of appropriately treated patients.

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.

The Antioxidant and HDAC-Inhibitor α-Lipoic Acid Is Synergistic with Exemestane in Estrogen Receptor-Positive Breast Cancer Cells.

Anti-estrogenic therapy is established in the management of estrogen receptor (ER)-positive breast cancer. However, to overcome resistance and improve therapeutic outcome, novel strategies are needed such as targeting widely recognized aberrant epigenetics. The study aims to investigate the combination of the aromatase inhibitor exemestane and the histone deacetylase (HDAC) inhibitor and antioxidant α-lipoic acid in ER-positive breast cancer cells. First, the enantiomers and the racemic mixture of α-lipoic acid, and rac-dihydro-lipoic acid were investigated for HDAC inhibition. We found HDAC inhibitory activity in the 1-3-digit micromolar range with a preference for HDAC6. Rac-dihydro-lipoic acid is slightly more potent than rac-α-lipoic acid. The antiproliferative IC50 value of α-lipoic acid is in the 3-digit micromolar range. Notably, the combination of exemestane and α-lipoic acid resulted in synergistic behavior under various incubation times (24 h to 10 d) and readouts (MTT, live-cell fluorescence microscopy, caspase activation) analyzed by the Chou-Talalay method. α-lipoic acid increases mitochondrial fusion and the expression of apoptosis-related proteins p21, APAF-1, BIM, FOXO1, and decreases expression of anti-apoptotic proteins survivin, BCL-2, and c-myc. In conclusion, combining exemestane with α-lipoic acid is a promising novel treatment option for ER-positive breast cancer.

Initiation of Oral Endocrine Therapy and Survival Benefit Among Women with Early-Stage Breast Cancer.

Introduction: Endocrine therapy (ET) is the cornerstone of systemic treatment for patients with estrogen receptor positive breast cancer, but its uptake and adherence need further improvement. This observational study assessed ET initiation and 1-year adherence and its survival benefit among female Medicare beneficiaries with early-stage breast cancer. Materials and Methods: This retrospective cohort study analyzed the linked 2011-2019 Surveillance, Epidemiology, and End Results-Medicare data. Female beneficiaries newly diagnosed with hormone receptor positive, stage I-III breast cancer were included. Beneficiaries who initiated tamoxifen, anastrozole, letrozole, or exemestane within 3 months after cancer diagnosis were defined as initiators (n = 24,289), and those who never initiated these treatments were noninitiators (n = 8,899). Adherence was measured using proportion of days covered (PDC) in the continuous 12 months follow-up period. Multivariable logistic regression models were used to assess factors associated with ET initiation and adherence (PDC ≥ 80%), controlling for covariates. Weighted Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of all-cause and breast cancer related mortality between initiators and noninitiators and by adherence status. Results: Among eligible female beneficiaries (n = 55,893), 43% initiated ET within 3 months of cancer diagnosis. Among initiators, 77% had PDC ≥ 80% during the first year. Patient's demographics (e.g., older age, race/ethnicity) and baseline health services utilization (e.g., mammography) were associated with ET initiation and adherence. ET initiation and adherence was associated with reduced risk of all-cause (adjusted HR = 0.62, 0.59-0.66; HR = 0.55, 0.53-0.59; respectively) and breast cancer related (adjusted HR = 0.57, 0.50-0.64; HR = 0.41, 0.36-0.47; respectively) mortality compared with noninitiators. Conclusion: Women with early-stage breast cancer who initiate ET and are adherent to treatment may achieve survival benefits compared with noninitiators.

Expanded Indications for Neoadjuvant Endocrine Therapy in Early-Stage Breast Cancer During the COVID-19 Pandemic.

BACKGROUND: In response to the COVID-19 pandemic, the Pandemic Breast Cancer Consortium (PBCC) published recommendations for triage of breast cancer patients. The recommendations included neoadjuvant treatment of early-stage breast cancer patients experiencing delays in surgery. This study evaluated national patterns of neoadjuvant treatment according to triage guidelines. METHODS: Patients treated with surgery (upfront or post-neoadjuvant) in 2018-2020 were collected from the National Cancer Database. The proportions of patients treated according to the PBCC triage guidelines were calculated in 2020 and compared with similar cohorts in 2018-2019. Patient and hospital factors were evaluated for association with treatment. RESULTS: Among cT1N0 ER+/PR+/HER2- patients, those treated in 2020 were more likely to receive neoadjuvant endocrine therapy (NET) compared with those before that time (odds ratio [OR], 3.08; range, 2.93-3.24). Among the patients with cT2N0 or cT1N1 disease, NET was more common in 2020 (OR, 1.76; range, 1.65-1.88). Academic facility, black or Asian race, more comorbidities, and the New England/Middle Atlantic region were associated with NET use. CONCLUSIONS: During the COVID-19 pandemic, expanded utilization of neoadjuvant therapy for surgical breast cancer patients was observed. Health care system limitations during the pandemic contributed to expanded adoption of neoadjuvant therapy for early breast cancer, contrary to usual practice. Long-term outcomes for patients treated according to PBCC recommendations should be closely monitored.

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.

CDK4/6 inhibitors plus endocrine therapy vs. placebo plus endocrine therapy for HR+/HER2- advanced breast cancer: a phase III RCTs based meta-analysis.

BACKGROUND: Does incorporating Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors into endocrine therapy (ET) effectively enhance survival outcomes, notably overall survival (OS), among individuals with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer? This remains a clinical controversy. We compared the antitumor efficacy and adverse effects (AEs) between CDK4/6 inhibitors + ET (CET) and placebo + ET (PET) by conducting a phase III randomized controlled trials (RCTs) based meta-analysis. METHODS: Seven databases were searched to identify eligible studies, comprising Phase III RCTs comparing CET to PET. The primary endpoints were OS and progression-free survival (PFS), with secondary endpoints including responses and adverse events (AEs). RESULTS: Seven RCTs (DAWNA-2, MONALEESA-2, MONALEESA-3, MONALEESA-7, MONARCH-3, PALOMA-2, and PALOMA-4) were included. The CET group exhibited significantly improved OS (HR: 0.81 [0.74, 0.88]), PFS (HR: 0.57 [0.52, 0.63]), objective response rate (RR: 1.31 [1.20, 1.43]), and clinical benefit rate (RR: 1.11 [1.07, 1.15]). These benefits were consistent across almost all subgroups. Additionally, the CET group showed better overall survival rates (OSR) from 24 to 60 months (OSR 24-60 m) and progression-free survival rates (PFSR) from 6 to 60 months (PFSR 6-60 m). However, more total AEs, grade 3-5 AEs, and serious AEs were found in CET group. The top 5 grade 3-5 AEs in the CET group were neutropenia (59.39%), leukopenia (24.11%), decreased white blood cell count (12.99%), hypertension (7.03%), and increased alanine aminotransferase (5.91%). CONCLUSIONS: The superiority of CET over PET in HR+/HER2- advanced breast cancer is evident, showing improved survival and responses. Nonetheless, the higher incidence of AEs, specifically hematologic AEs, requires cautious attention.

A Randomized Trial Comparing Concurrent versus Sequential Radiation and Endocrine Therapy in Early-Stage, Hormone-Responsive Breast Cancer.

Concerns exist regarding increased toxicities, including endocrine therapy toxicity, with concurrent radiation and endocrine therapy in early breast cancer (EBC). We present a pragmatic, randomized trial comparing concurrent versus sequential endocrine and radiotherapy in hormone-responsive EBC. In this multicenter trial, patients were randomized to receive adjuvant endocrine therapy concurrent with, or sequential to, radiotherapy. The primary outcome was change in endocrine therapy toxicity from baseline to 3 months post radiotherapy using the Functional Assessment of Cancer Therapy-Endocrine Symptom (FACT-ES) score. From September 2019 to January 2021, 133 patients were randomized to concurrent endocrine and radiotherapy, and 127 to sequential treatment. Most patients were post-menopausal (72.7%, 189/260) with stage 1 disease (65.8%, 171/260). Tamoxifen was the endocrine therapy of choice for 69.6% (181/260) of patients, and an aromatase inhibitor for the remainder. The median total radiation dose and fractions were 40.1 Gray (range 26-50) and 15 fractions (range 5-25), respectively. For the primary outcome of change in endocrine therapy toxicity per FACT-ES scores from baseline to 3 months post radiotherapy, no significant difference was found between the groups (median [range] = -4.9 (-82, 38.8) for concurrent and -5.1 (-42, 40) for sequential, p = 0.87). This is the first trial to investigate the impact of concurrent versus sequential adjuvant endocrine and radiotherapy on endocrine therapy-related toxicities. The findings provide further support to allow the optimal timing of radiation and endocrine therapy to be tailored for the individual patient.

Pharmacogenetics of Toxicities Related to Endocrine Treatment in Breast Cancer: A Systematic Review and Meta-analysis.

BACKGROUND/AIM: Endocrine therapy is the standard treatment for hormone receptor-positive (HR+) breast cancer (BC). Yet, it is accompanied by treatment-related toxicities, leading to poor treatment adherence, high relapse, and low rates of survival. While pharmacogenomic variants have the potential to guide personalized treatment, their predictive value is inconsistent across published studies. MATERIALS AND METHODS: To systematically assess the literature's current landscape of pharmacogenomics of endocrine therapy-related adverse drug effects, systematic searches in MEDLINE, Embase, Cochrane CENTRAL, Google Scholar and PharmGKB databases were conducted. RESULTS: We identified 87 articles. Substantial heterogeneity and variability in pharmacogenomic effects were evident across studies, with many using data from the same cohorts and predominantly focusing on the Caucasian population and postmenopausal women. Meta-analyses revealed Factor V Leiden mutation as a predictor of thromboembolic events in tamoxifen-treated women (p<0.0001). Meta-analyses also found that rs7984870 and rs2234693 were associated with musculoskeletal toxicities in postmenopausal women receiving aromatase inhibitors (p<0.0001 and p<0.0001, respectively). CONCLUSION: Overall, the current body of evidence regarding the potential role of pharmacogenomics in endocrine therapy-related toxicity in BC remains largely inconclusive. Key concerns include the heterogeneity in toxicity definitions, lack of consideration for genotype-treatment interactions, and the failure to account for multiple testing. The review underscores the necessity for larger and well-designed studies, particularly with the inclusion of premenopausal women and non-Caucasian populations.

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.

Associations between HIV infection status, psychosocial factors, and adjuvant endocrine therapy adherence among South African women with early-stage breast cancer.

Purpose: We aimed to evaluate for associations between HIV status, psychosocial factors, and adjuvant endocrine therapy (AET) adherence in South African (SA) women with estrogen receptor positive (ER+) breast cancer (BC). Methods: We enrolled South African women with early-stage ER + BC in remission and prescribed tamoxifen or an aromatase inhibitor to the prospective observational study. We performed AET pill counts at enrollment, 12 weeks, and 24 weeks, and calculated adherence ratios of pills consumed between visits to days between visits. Women completed questionnaires on social support, attitude towards medication, health literacy, self-efficacy, mental health, and AET toxicity. We collected household wealth data. We used hierarchical linear (HLM) and structural equation modelling (SEM) to compare adherence ratios between women with and without HIV while adjusting for psychosocial factors. Results: We collected adherence data from 239 women, 63 (26.4%) with co-morbid HIV. Comparing women with and without HIV, median AET adherence ratio was 0.88 vs 0.89, respectively (HLM p = 0.31). In our SEM model for the full cohort, mental health, healthcare savvy, and side effect burden latent variables were not significantly associated with adherence. In the subgroup of women living with HIV, lower SES quintile (ß 0.04, SE 0.02, p = 0.08) and poorer mental health (ß -0.02, SE 0.01, p = 0.10) showed trends toward association with adherence. Conclusions: HIV status is not predictive of AET adherence among SA women with ER + BC, though decreasing SES status and increasing mental health symptoms are marginally associated with adherence in women with BC and HIV.