Cyclin-dependent kinase 4/6 inhibitors combined with stereotactic ablative radiotherapy in oligometastatic HR-positive/HER2-negative breast cancer patients.

BACKGROUND: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) have significantly improved the survival of patients with hormone receptor-positive HER2-negative advanced breast cancer (ABC). Although stereotactic ablative radiotherapy (SABR) is used more often in routine clinical practice, data on the safety and efficacy of combining SABR with CDK4/6i are lacking. Herein, we present the results of SABR combined with CDK4/6i in ABC. MATERIALS AND METHODS: Patients with ABC who received CDK4/6i and SABR between 2018-2023 were analyzed. RESULTS: Among 384 patients treated with CDK4/6i, 34 patients received 44 courses of SABR. 2-year PFS was 63.6% (95%CI : 45.8-88.3), and the median PFS was 32 months. 3-year OS was 88.9% (95%CI : 77.7-100). 2-year local control was 92.7% [95%CI : 83.4-100]. Median OS and LC were not reached. The subgroup analysis showed the difference in survival between oligometastatic patients (OMD) and non-OMD subgroup. 2-year PFS was 69.2%(95%CI : 44.5-100) in OMD compared with 57.4% (95%CI : 36-91.7) in the non-OMD (p = 0.042). 3-year OS was 90%(95%CI : 73.2-100) in OMD compared with 86.2%(95%CI : 70-100) in the non-OMD (p = 0.67). Median PFS and OS in the non-OMD were 26 and 56 months, respectively, and were not reached in OMD. Fifteen patients required CDK4/6i dose reduction, and two discontinued treatment due to toxicity. No difference in high-grade toxicity was observed between the sequential and concurrent SABR. CONCLUSION: The addition of SABR to CDK4/6i seems to be safe and effective, especially in patients with oligometastatic disease. ADVANCES IN KNOWLEDGE: In advanced breast cancer patients treated with CDK4/6i, SABR provides a high local control and may provide additional benefit in an oligometastatic setting.

Treatment outcomes and prognostic factors in nonmetastatic metaplastic breast cancer patients: a multicenter retrospective cohort study.

BACKGROUND AND PURPOSE: Metaplastic breast carcinoma (BC-Mp) is an uncommon subtype that poses unique challenges. The limited information on patient prognosis and therapeutic strategies motivated our research initiative. We aimed to assess disease-free survival (DFS), overall survival (OS), and influential factors in patients with nonmetastatic BC-Mp. MATERIALS AND METHODS: In this multicenter retrospective cohort study, clinicopathological data for nonmetastatic BC-Mp patients treated at four oncology units in Poland (2012-2022) were gathered. RESULTS: Among 115 women (median age 61, range: 28-91), the median tumor size was 40 mm (range 20-130); 30% of patients exhibited positive local lymph nodes. The majority of patients presented with stage II (46%) and triple-negative breast cancer (TNBC) (84%). Radiotherapy was administered to 61% of patients. Surgical procedures included breast-conserving surgery in 31% of patients and mastectomy in 68%. Eighty-three per cent of patients received chemotherapy. The median estimated DFS and OS were 59 and 68 months, respectively. Multivariable analysis revealed that tumor size influenced DFS and OS (Hazard ratios [HR] = 1.02, 95%CI 0.01-0.03 for both endpoints) and taxanes application improved DFS (HR = 0.47, 95%CI 0.24-0.93), but other factors did not. For patients receiving neoadjuvant systemic therapy (N = 51), taxanes improved DFS and OS according to univariable analysis. INTERPRETATION: Our findings highlight poor DFS and OS regardless of receiving optimal treatment, emphasizing the need for tailored therapeutic strategies for BC-Mp patients. Taxanes appear promising in a neoadjuvant setting, particularly within the current standard of care for the TNBC subtype.

Locoregional Radiotherapy in Patients with Advanced Breast Cancer Treated with Cyclin-Dependent Kinase 4/6 Inhibitors Based on Real-World Data.

BACKGROUND: The use of locoregional radiotherapy (RT) in patients with advanced ER-positive, HER2-negative breast cancer remains a topic of ongoing debate. In this study, we aimed to evaluate the efficacy of locoregional RT in advanced breast cancer patients treated with cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in a first-line setting. METHODS: We conducted a retrospective analysis of patients diagnosed with advanced breast cancer between 2018 and 2023 who received treatment with CDK4/6i and underwent locoregional radiotherapy. RESULTS: Among the 371 patients treated with CDK4/6i as part of their first-line therapy, 23 received locoregional RT either concurrently or sequentially with CDK4/6 inhibitors. Disease progression within the breast occurred in 19 patients (5.1%). Among these cases, five patients had previously undergone breast RT (5/23, 21.7%), while 14 did not (14/348, 4.0%, p = 0.004). All cases of local progression after RT followed palliative doses and were accompanied by early systemic progression. The 2-year PFS in the entire cohort of patients treated with locoregional RT was 65.7% (95% CI: 40.5-82.3%). Notably, patients who received higher RT doses had longer 2-year PFS (83.3%, 95% CI: 27.3-97.5%) than those with palliative RT doses (59.3%, 95% CI: 30.7-79.3%); however, the results were not statistically significant (p = 0.58). Furthermore, the 2-year local control in the entire cohort with locoregional RT was 73.0% (95% CI: 46.5-87.9%). Importantly, no local progression was observed after RT when using high doses. CONCLUSIONS: The addition of locoregional radiotherapy to first-line CDK4/6 inhibitors warrants further investigation across various clinical scenarios in advanced breast cancer. Palliative radiation regimens delivered early in breast oligoprogression may not always suffice, emphasizing the need for comprehensive studies in this context.

Tailoring advanced breast cancer treatment after cyclin-dependent kinase 4/6 inhibitors progression - real-world data analysis.

Background: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) represent the gold standard of the hormone receptor positive human epidermal growth factor receptor 2 (HER-2) negative advanced breast cancer. However, optimal treatment after disease progression is a matter of debate. We aimed to assess predictive and prognostic factors associated with the treatment outcome following CDK4/6i progression. Methods: We retrospectively analyzed patients who progressed on CDK4/6i treatment between 2018 and 2024. Treatment based on molecular findings (PIK3CA mutation), genetic findings (BRCA1/2 germline mutation), or adapted to the change in the tumor phenotype in rebiopsy (anti-HER2 therapy in the transformation to HER-2-positive disease) was grouped into tailored treatment and compared to the endocrine-based therapy and chemotherapy alone. Results: Five hundred twelve patients were treated with CDK4/6i. Two hundred patients with disease progression were enrolled in the study. Duration of response to CDK4/6i was not predictive of the response to subsequent treatment, whereas the progression in the central nervous system was the worst prognostic factor. Thirty patients were ineligible for subsequent treatment. Survival after CDK4/6i progression was significantly longer in patients eligible for tailored treatment. The median PFS in patients with tailored treatment (n=19) was 13.5 months vs. 4.9 months in patients with non-tailored therapy (n=151; p=0.045). 12-month PFS was 54.1% with tailored treatment [95% CI 24.1-76.7%] compared to 18.5% with non-tailored therapy [95% CI 11.6-26.6%]. The median OS for patients treated with a tailored approach was not reached compared to 11.5 months with non-tailored treatment (p=0.016). The 24-month OS for patients treated with a tailored approach was 80.2% [95% CI 40.3-94.8%] compared to 21.1% [95% CI 12.2-31.7%] for patients with non-tailored treatment. Conclusions: Tailoring of subsequent treatment strategy seems to be essential for achieving long-term benefit. Further studies are required, as the prognosis after CDK4/6i progression remains dismal, especially in cases affecting the central nervous system.

Liquid biopsy utilizing miRNA in patients with advanced breast cancer treated with cyclin­dependent kinase 4/6 inhibitors.

Cyclin-dependent kinase 4/6 inhibitors (CDK4/6is) are the mainstay of treatment of hormone receptor+/human epidermal growth factor receptor 2-patients with advanced breast cancer (ABC). Despite improvements in overall survival, most patients experience disease progression. Biomarkers derived from a liquid biopsy are appealing for their potential to detect resistance to treatment earlier than computed tomography imaging. However, clinical data concerning microRNAs (miRNAs/miRs) in the context of CDK4/6is are lacking. Thus, the present study assessed the use of miRNAs in patients with ABC treated with CDK4/6is. Patients treated for ABC with CDK4/6is between June and August 2022 were eligible. miRNA expression analyses were performed using a TaqMan™ low-density miRNA array. A total of 80 consecutive patients with ABC treated with CDK4/6is at Maria Sklodowska-Curie National Research Institute of Oncology (Gliwice, Poland) were assessed, with 14 patients diagnosed with progressive disease at the time of sampling, 55 patients exhibited clinical benefit from CDK4/6i treatment and 11 patients were at the beginning of CDK4/6i treatment. Patients with disease progression had significantly higher levels of miR-21 (P=0.027), miR-34a (P=0.011), miR-193b (P=0.032), miR-200a (P=0.027) and miR-200b (P=0.003) compared with patients who benefitted from CDK4/6i treatment. Significantly higher levels of miR-34a expression were observed in patients with progressive disease than in patients beginning treatment (P=0.031). The present study demonstrated the potential innovative role of circulating miRNAs during CDK4/6i treatment. Plasma-based expression of miR-21, -34a, -193b, -200a and -200b effectively distinguished patients with ABC who responded to CDK4/6i treatment from patients who were resistant. However, longitudinal studies are required to verify the predictive and prognostic potential of miRNA.

Clinical analysis of metaplastic breast carcinoma with distant metastases: A multi­centre experience.

Metaplastic breast cancer (BC-Mp), which includes a range of epithelial and mixed epithelial-mesenchymal tumours, are rare malignancies with an unfavourable prognosis. The limited literature on BC-Mp focuses mainly on retrospective data for radically treated patients. Notably absent are studies dedicated to the palliative treatment of BC-Mp with distant metastases. The present retrospective study investigated treatment modalities and prognosis in a multi-centre cohort of 31 female participants diagnosed with distant metastatic BC-Mp, including 7 patients with de novo metastatic disease. The median age of the patients was 61 years (range, 33-87 years), with 38.7% presenting local lymph node involvement. Lungs were the most common site for the metastatic disease (61.3%). Median Ki-67 index was 50% (range, 35-70%), and 80.7% of cases were classified as grade 3. Human epidermal growth factor receptor 2 (HER2)+ and estrogen receptor+ were detected in 12.9 and 6.5% of cases, respectively. A total of 62.4% of patients received first-line palliative systemic treatment. The 1- and 2-year overall survival (OS) were 38.5 and 19.2%, respectively. Receiving ≥1 line of palliative treatment was significantly associated with improved OS (P<0.001). Factors such as age, Ki-67 index, HER2 or hormonal status, presence of specific epithelial or mesenchymal components, location of metastases or chemotherapy regimen type did not influence OS. The present study provided insights into the clinicopathological profile, systemic treatment experience, prognostic factors and OS data of BC-Mp with distant metastases, emphasizing the imperative for clinical trials in this population.

Discrepancy between Tumor Size Assessed by Full-Field Digital Mammography or Ultrasonography (cT) and Pathology (pT) in a Multicenter Series of Breast Metaplastic Carcinoma Patients.

Metaplastic breast cancer (BC-Mp) presents diagnostic and therapeutic complexities, with scant literature available. Correct assessment of tumor size by ultrasound (US) and full-field digital mammography (FFDM) is crucial for treatment planning. METHODS: A retrospective cohort study was conducted on databases encompassing records of BC patients (2012-2022) at the National Research Institutes of Oncology (Warsaw, Gliwice and Krakow Branches). Inclusion criteria comprised confirmed diagnosis in postsurgical pathology reports with tumor size details (pT) and availability of tumor size from preoperative US and/or FFDM. Patients subjected to neoadjuvant systemic treatment were excluded. Demographics and clinicopathological data were gathered. RESULTS: Forty-five females were included. A total of 86.7% were triple-negative. The median age was 66 years (range: 33-89). The median pT was 41.63 mm (6-130), and eight patients were N-positive. Median tumor size assessed by US and FFDM was 31.81 mm (9-100) and 34.14 mm (0-120), respectively. Neither technique demonstrated superiority (p > 0.05), but they both underestimated the tumor size (p = 0.002 for US and p = 0.018 for FFDM). Smaller tumors (pT1-2) were statistically more accurately assessed by any technique (p < 0.001). Only pT correlated with overall survival. CONCLUSION: The risk of underestimation in tumor size assessment with US and FFDM has to be taken into consideration while planning surgical procedures for BC-Mp.