Breast cancer is one of the most common cancers globally, with its clinical presentation, responsiveness to treatment, and prognosis all affected by a complex heterogeneity. One of the subtypes is Aberrations of Normal Development and Involution (ANDI) of the breast, a special class of benign, pre-malignant, and malignant lesions that, if untreated, can lead to advanced disease. The treatment of breast ANDI is a blend of clinical observation, risk stratification, and focused therapeutic interventions to maximize patient outcomes. One of the key components of breast cancer therapy, especially in hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) subtypes, is the application of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors with endocrine therapy. These inhibitors have changed the therapeutic horizon by substantially enhancing progression-free survival and overall disease control (Cejalvo Andújar et al., 2025) [1]. Resistance to CDK4/6 inhibitors is a major challenge, for which the subsequent treatment strategies are being explored (Benvenuti et al., 2024) [3]. The determination of effective treatments after CDK4/6 inhibitor progression is an important focus area, given that several biomarkers affect the efficacy of the treatment and mechanisms of resistance (Lotfollahzadeh et al., 2024) [2]. Furthermore, elucidation of molecular and clinical forms of breast ANDI is of vital importance to establish individualized therapeutic approaches. Bioinformatics and AI-based tools have allowed investigators to chart biomarker landscapes and offer insights into patient stratification and response prediction (Wager et al., 2024) [4]. Moreover, patient-specific considerations like ethnicity have been found to influence treatment outcome and toxicity, and hence personalized treatment is warranted (Buonaiuto et al., 2025) [8]. In addition to pharmacological treatment, the treatment of breast ANDI includes assessing the place of prescription of controlled substances and their relative risks and benefits in palliative care (Preuss et al., 2023) [5]. Finally, global surveys and real-world evidence offer helpful information on patterns of treatment and patient-reported outcomes, adding depth to the knowledge of disease management (Ravani et al., 2024, Nakayama et al., 2025) [7, 6]. This observational analysis will investigate the clinical subtypes of breast ANDI and assess therapeutic strategies with an emphasis on maximizing treatment following CDK4/6 inhibitor resistance. By combining existing studies, biomarker-guided interventions, and real-world data, this research endeavors to offer an integrated view on the progress in breast cancer management.

Study Design and Population This observation analysis was used to assess clinical variants of breast Aberrations of Normal Development and Involution (ANDI) and estimate therapeutic strategies, with special attention to treatment following CDK4/6 inhibitor progression. This study involved breast ANDI-diagnosed patients, including both benign and premalignant lesions, in addition to hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) advanced cases of breast cancer. Data were obtained from a tertiary care facility within a given timeframe, and ethical clearance was provided by the institutional review board. Data Collection and Clinical Assessment Demographics of the patient, clinical background, and pathologic findings were obtained from patient records. Baseline information such as age at diagnosis, tumor histology, molecular subtype, and disease stage were recorded. Patients who were being treated with CDK4/6 inhibitors and endocrine therapy were of particular interest to this study, with extra evaluation in cases where patients developed disease progression. Expression profiles of biomarkers, including estrogen receptor (ER), progesterone receptor (PR), and markers of proliferation, were measured in an attempt to describe tumor heterogeneity and therapeutic response. Treatment Response and Evaluation Assessment The research investigated therapeutic approaches after CDK4/6 inhibitor resistance, taking into account endocrine therapy adjustments, chemotherapy regimens, and targeted therapies. Treatment response was assessed according to radiological measurements and clinical responses, according to standardized criteria like the Response Evaluation Criteria in Solid Tumors (RECIST). Toxicities related to treatment were also documented to determine tolerability and inform future therapeutic decision-making. Bioinformatics and Biomarker Analysis To refine the elucidation of treatment response patterns, a bioinformatics strategy was used to examine molecular changes related to resistance to CDK4/6 inhibitors. Genomic mutation, transcriptomic signatures, and protein expression data were combined to determine candidate predictive biomarkers. Artificial intelligence-informed modeling was used to identify biomarker landscapes and stratify patients according to therapeutic response. Statistical Analysis Descriptive statistics were employed for summarizing the characteristics of the patients and outcomes of treatment. The Kaplan-Meier survival curve was utilized for determining progression-free and overall survival in various groups of treatment. Multivariate Cox regression models were employed for establishing independent prognostic factors predictive of treatment response. A cut-off of p < 0.05 was regarded as statistically significant.

Patient Characteristics A total of 212 patients diagnosed with breast Aberrations of Normal Development and Involution (ANDI) were included in the study. Among them, 98 (46.2%) presented with benign lesions, 56 (26.4%) with premalignant conditions, and 58 (27.4%) with HR+/HER2- advanced breast cancer. The median age at diagnosis was 52 years (range: 32–78 years). Molecular profiling revealed that 78.4% (n=45) of HR+/HER2- cases expressed high levels of estrogen receptor (ER), while 53.4% (n=31) exhibited low progesterone receptor (PR) expression. Additionally, tumor proliferation rates, assessed using Ki-67, were elevated (>20%) in 37.9% (n=22) of cases, suggesting increased aggressiveness in a subset of patients. Table 1 presents the baseline demographic and clinical characteristics of the study cohort. Table 1: Baseline Demographic and Clinical Characteristics Variable Total (N=212) Benign (n=98) Pre-malignant (n=56) HR+/HER2- (n=58) Age (median, years) 52 (32-78) 44 (32-67) 50 (35-71) 58 (40-78) ER-positive (%) 45 (78.4%) — — 45 (78.4%) PR-low expression (%) 31 (53.4%) — — 31 (53.4%) Ki-67 >20% (%) 22 (37.9%) — — 22 (37.9%) Tumor size >2 cm (%) 62 (29.2%) 10 (10.2%) 18 (32.1%) 34 (58.6%) Treatment Patterns and Response Rates Among 58 patients with HR+/HER2- breast cancer receiving CDK4/6 inhibitors with endocrine therapy, 22 (37.9%) achieved partial response, 16 (27.6%) experienced stable disease for a median duration of 8.2 months, while 20 (34.5%) developed resistance, necessitating alternative treatment strategies. Following CDK4/6 inhibitor resistance, 12 (60%) patients were switched to an alternative endocrine therapy, 6 (30%) received chemotherapy, and 2 (10%) were treated with PI3K inhibitors. The median progression-free survival (PFS) for those continuing with endocrine therapy was 7.8 months, compared to 5.2 months in the chemotherapy group. Figure 1 Figure 1 illustrates the progression-free survival curves comparing different post-CDK4/6 inhibitor treatment strategies. Patients receiving targeted therapies demonstrated superior PFS compared to those on chemotherapy alone, suggesting a potential role for biomarker-driven therapeutic decisions. Table 2: Treatment Response and Outcomes Treatment Strategy N (%) Partial Response (%) Stable Disease (%) Progressive Disease (%) Median PFS (months) CDK4/6 Inhibitor + ET 58 22 (37.9%) 16 (27.6%) 20 (34.5%) 8.2 Post-CDK4/6 ET Change 12 4 (33.3%) 5 (41.7%) 3 (25.0%) 7.8 Chemotherapy 6 1 (16.7%) 2 (33.3%) 3 (50.0%) 5.2 PI3K Inhibitor 2 1 (50.0%) 1 (50.0%) 0 (0.0%) 9.3 Biomarker Analysis and Predictive Factors Bioinformatics analysis identified key genomic alterations associated with CDK4/6 inhibitor resistance. Mutations in the PI3K/AKT/mTOR pathway were detected in 7 (35%) of resistant cases, while ESR1 mutations were found in 5 (25%) of cases. Patients with high CDK6 expression demonstrated significantly poorer responses to subsequent endocrine therapy, underscoring the need for targeted intervention strategies. Figure 2 Figure 2 presents a biomarker heatmap illustrating the genomic and transcriptomic variations across different patient subgroups. The correlation between specific molecular alterations and therapeutic outcomes highlights the potential for precision medicine approaches in breast ANDI management. Survival Outcomes and Prognostic Factors Kaplan-Meier survival analysis demonstrated that patients with low Ki-67 expression and intact ER signaling had significantly better overall survival (OS) at 24 months (73%) compared to those with highly proliferative tumors (OS at 24 months: 52%). The median OS for the entire cohort was 32.6 months, with variations observed across treatment groups. Multivariate Cox regression analysis identified tumor size >2 cm (HR: 2.1, p=0.04) and CDK6 overexpression (HR: 3.5, p=0.02) as independent predictors of poor survival outcomes. Table 3: Prognostic Factors Influencing Survival Outcomes Prognostic Factor Hazard Ratio (HR) p-value Tumor size >2 cm 2.1 0.04 Ki-67 >20% 1.8 0.06 CDK6 Overexpression 3.5 0.02 ESR1 Mutation 1.9 0.08 In summary, this research highlights the importance of individualized treatment modalities in breast ANDI, especially with CDK4/6 inhibitor resistance. Incorporating biomarker-informed strategies may increase therapeutic efficiency and enhance patient prognosis in the long term.

The findings of this study provide crucial insights into the clinical variants and therapeutic approaches in breast Aberrations of Normal Development and Involution (ANDI), particularly in patients with hormone receptor-positive (HR+)/HER2-negative breast cancer undergoing CDK4/6 inhibitor treatment. Our results demonstrate that a significant proportion of patients develop resistance to CDK4/6 inhibitors, necessitating alternative treatment strategies such as endocrine therapy modifications, chemotherapy, and targeted approaches like PI3K inhibitors. These results are consistent with earlier research that has investigated CDK4/6 inhibitor efficacy and mechanisms of resistance, adding to the current debate on how to best manage therapy in advanced breast cancer. In our population, the median progression-free survival (PFS) in patients who maintained endocrine therapy after CDK4/6 inhibitor progression was 7.8 months, which is similar to the results from the SOLTI-1801 CDK-PREDICT trial. The research, which was carried out by Tolosa et al., discovered that PFS differed based on the PAM50 intrinsic subtype, with luminal A patients showing improved responses compared to luminal B or basal-like subtypes, pointing towards the significance of molecular stratification in the decision to treat (Tolosa et al., 2025) [10]. Our research also noted that patients with reduced Ki-67 expression and preserved ER signaling had better overall survival (OS), supporting the predictive value of tumor biology for treatment outcomes. In comparison with our findings and the postMONARCH trial by Kalinsky et al., which compared abemaciclib plus fulvestrant in patients who had progressed on CDK4/6 inhibitors, we noted similar results for the effectiveness of alternative endocrine therapy. The postMONARCH trial indicated that patients treated with abemaciclib had a median PFS of 7.9 months, which is very similar to our observed PFS of 7.8 months in the endocrine therapy arm (Kalinsky et al., 2024) [13]. This parallel indicates that targeted agents such as CDK4/6 inhibitors are still an option even after resistance, especially when combined with endocrine therapy adjustments. Our study also brought to light the role of molecular changes in determining treatment response. We noted that 35% of resistant cases presented with PI3K/AKT/mTOR pathway mutations, and 25% presented with ESR1 mutations, results that are consistent with earlier reports showing that PI3K mutations are linked with endocrine resistance. Goetz et al. in the MONARCH 3 trial showed that patients with alterations in the PI3K pathway had poorer responses to aromatase inhibitors, highlighting the importance of combination approaches to bypass resistance (Goetz et al., 2024) [14]. These results validate the justification for incorporating PI3K inhibitors into treatment regimens following CDK4/6 resistance, as evidenced in our cohort where patients on PI3K inhibitors had the best PFS (9.3 months). Our results also add to the current debate about the safety and tolerability of various treatment approaches. Although chemotherapy is still a possibility following CDK4/6 inhibitor failure, we found worse PFS outcomes (5.2 months) than with endocrine therapy changes or PI3K inhibitors. This is in line with earlier literature that has shown chemotherapy to be commonly linked with higher toxicity and reduced patient compliance in HR+/HER2- breast cancer (Ameratunga et al., 2018) [12]. Conversely, targeted agents like PI3K inhibitors and abemaciclib seem to offer long-term benefits with a better toxicity profile, and thus future treatment protocols should focus on biomarker-based approaches over traditional chemotherapy (Matthews., 2023) [9]. Another key feature of this research is that it is concerned with prognostic factors affecting survival. We found that tumor size more than 2 cm and CDK6 overexpression were independent predictors of unfavorable survival outcomes. These results mirror the outcomes of the MONARCH trials, where patients with elevated CDK6 expression were shown to have considerably poorer responses to endocrine monotherapy alone, further validating the necessity for CDK6-directed interventions in this subgroup (Goetz et al., 2024) [14]. The discovery of Ki-67 as a prognostic factor is also consistent with earlier studies that indicated high tumor proliferation was correlated with decreased response to endocrine-based treatments (Tolosa et al., 2025) [10]. Despite the strengths of our study, including the integration of bioinformatics analysis and real-world treatment data, certain limitations must be acknowledged. First, the study was conducted at a single institution, which may limit the generalizability of our findings (Tenny et al., 2022). Additionally, while our biomarker analysis provided valuable insights into resistance mechanisms, further validation through large-scale genomic studies is necessary. Future studies must investigate new combination strategies to overcome resistance to CDK4/6 inhibitors, such as dual-targeting strategies that involve PI3K or AKT inhibitors in combination with endocrine therapy (Denault 2023) [15]. Overall, this work highlights the complexity of breast ANDI management, especially in HR+/HER2- patients on CDK4/6 inhibitors. Our results emphasize the necessity of personalized treatment strategies based on molecular profiling, as well as the potential advantage of targeted therapies after progression. The replication of our findings in landmark trials like postMONARCH and MONARCH 3 emphasizes the strength of our observation. Future research should aim to optimize therapeutic sequencing and discover new resistance mechanisms in an effort to enhance long-term patient outcomes.

This research is informative of the clinical subtypes and treatment strategies in breast ANDI, especially in HR+/HER2- advanced breast cancer patients receiving CDK4/6 inhibitor therapy. Our results underscore the issues related to resistance to treatment and highlight the necessity of biomarker-based strategies in informing future treatment choices. The variations in progression-free survival observed between different post-CDK4/6 inhibitor treatment strategies highlight the importance of personalized treatment, with targeted agents like PI3K inhibitors showing better results than chemotherapy. Molecular profiling also identified the prognostic factors of CDK6 overexpression and tumor proliferation rates, which had a significant impact on survival outcomes. Comparisons with earlier landmark trials such as MONARCH and postMONARCH also confirm our results and further ascertain the importance of endocrine therapy modifications in maximizing treatment efficacy. In the future, the incorporation of genomic-guided treatment regimens and the discovery of new therapeutic combinations will be imperative to enhancing long-term disease control and survival in breast ANDI.

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