Simple Summary
This retrospective study evaluates the safety of combining CDK4/6 inhibitors with palliative radiotherapy in metastatic hormone receptor-positive, HER2-negative breast cancer. CDK4/6 inhibitors are essential in managing this disease but are associated with hematologic toxicities. Palliative radiotherapy, often used for bone metastases, shares similar side effects, raising concerns about their concurrent use. Involving 188 patients, the study revealed no significant increase in grade ≥ 3 hematologic toxicities, such as anemia or neutropenia, among patients receiving both treatments compared to those treated with CDK4/6 inhibitors alone. Ribociclib was linked to lower rates of severe hematologic toxicity, neutropenia, and fewer treatment interruptions and dose reductions compared to palbociclib. These findings suggest that palliative radiotherapy can be safely integrated with CDK4/6 inhibitors, providing critical insights into optimizing treatment strategies for patients with metastatic breast cancer. The study highlight the need for further prospective trials to confirm these observations and refine clinical guidelines.
Abstract
Purpose: CDK4/6 inhibitors require meticulous monitoring due to their potential to cause hematological toxicities and hepatotoxicity. This study evaluates the safety of combining CDK4/6 inhibitors with palliative radiotherapy in patients with metastatic hormone receptor-positive and HER2-negative breast cancer. Patients and Methods: This study included 188 patients treated with CDK4/6 inhibitors between January 2021 and June 2024. Data on patient demographics, tumor characteristics, and treatment interventions were extracted from medical records. The primary focus was on the incidence of grade ≥ 3 hematologic toxicities and hepatotoxicity, assessed according to CTCAE 5.0 criteria, in those receiving concurrent palliative radiotherapy. Results: With a median follow-up of 18.5 months, the 18-month PFS and OS rates were 67% and 85%, respectively. The median age was 57.5 years, and 79% of patients were post-menopausal. Bone and liver metastases were present in 66% and 23% of patients, respectively. Concurrent palliative radiotherapy was administered in 25% of the cohort. The incidence of grade ≥ 3 hematologic toxicity was comparable between those who received radiotherapy and those who did not. Ribociclib use was associated with lower rates of grade 3 hematologic toxicity (OR: 0.37), neutropenia (OR: 0.41), dose interruptions (OR: 0.30), and dose reductions (OR: 0.37). Pre-menopausal status was linked to fewer dose reductions (OR: 0.17). Rates of treatment interruption, dose reduction, and withdrawal were 55%, 24%, and 2%, respectively. Conclusions: The concurrent use of CDK4/6 inhibitors and palliative radiotherapy does not increase the incidence of hematological adverse events in patients with metastatic breast cancer.
1. Introduction
The use of cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6 inhibitors) (palbociclib, ribociclib, and abemaciclib) in combination with endocrine therapy is the current standard of care for the first- or second-line treatment of hormone receptor-positive, HER2-negative metastatic breast cancer [1,2,3]; also, abemaciclib and ribociclib plus endocrine therapy have demonstrated an improvement in invasive disease-free survival in patients with HR+/HER2- early breast cancer whose tumors had a high risk of recurrence [4,5].
The widespread use of CDK4/6 inhibitors highlights the critical need to effectively understand and manage their associated side effects. The toxicity profiles of CDK4/6 inhibitors (palbociclib, ribociclib, and abemaciclib) can differ based on their selective inhibition of CDK4 and CDK6 [6]. Palbociclib exhibits similar selectivity for CDK4 and CDK6, leading to a predominantly hematologic toxicity profile. Ribociclib, with a slightly higher selectivity for CDK4 than palbociclib, shares a similar toxicity profile. In contrast, abemaciclib, which has a much more potent inhibition of CDK4 than CDK6, is associated with a higher incidence of non-hematologic toxicities, such as gastrointestinal side effects, and a comparatively lower incidence of hematologic toxicity [7,8]. Fatigue, nausea, liver function abnormalities, skin toxicity, and thromboembolism are other commonly observed adverse effects.
Radiotherapy can be used in early-stage disease to prevent local recurrence after surgery, as well as in the metastatic stage for palliative purposes. The risk of cytopenia increases when radiotherapy is applied to bone structures where hematopoiesis is commonly observed. There are conflicting results in studies evaluating whether radiotherapy increases hematologic toxicity when using CDK4/6 inhibitors [9,10,11]. These studies are retrospective and involve a small number of patients. Although interruption of palbociclib during radiotherapy is recommended in the PALOMA trial, no prospective randomized trials evaluate the safety of combined use of radiotherapy and CDK4/6 inhibitors.
We aimed to evaluate the impact of palliative radiotherapy on the adverse effect profile of CDK4/6 inhibitors.
2. Patients and Methods
2.1. Patient Selection
Patients with hormone-positive HER2-negative metastatic breast cancer who received CDK4/6 inhibitors in Ankara Bilkent City Hospital between January 2021 and June 2024 were retrospectively reviewed. Patients whose radiotherapy status was unknown were not included in the study. The study was designed as a retrospective, single-center study. Data on demographic and clinical characteristics, progression-free survival (PFS), and overall survival (OS) were extracted from medical records. Follow-up duration was calculated using the reverse Kaplan–Meier method. The primary endpoint was the incidence of grade ≥ 3 hematologic toxicity associated with palliative radiotherapy in patients receiving CDK 4/6 inhibitors. Secondary endpoints included identifying factors influencing the occurrence of grade ≥ 3 hematologic and non-hematologic toxicities, such as liver function abnormalities and acute kidney injury, as well as PFS and OS. The study focused on palliative radiotherapy administered to bone structures for pain relief and fracture prevention. Extensive bone metastasis was defined as 5 or more bone metastases.
2.2. Evaluation of Adverse Effects
Toxicity was evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 5.0, for patients undergoing treatment with CDK4/6 inhibitors. Blood samples collected throughout the treatment were analyzed, and examination findings, hemograms, and biochemistry test results were meticulously recorded. The highest recorded values were used for the toxicity assessment. An interruption in CDK4/6 inhibitor therapy was defined as temporarily discontinuing the medication until the subsequent scheduled follow-up. Dose reduction was characterized as decreasing the dosage to 400 mg/day or 200 mg/day for ribociclib and 100 mg/day or 75 mg/day for palbociclib. Withdrawal refers to the permanent cessation of the medication. PFS was defined as the time from the initiation of CDK4/6 inhibitor therapy to either disease progression, the last recorded follow-up, or death. OS was defined as the time from the initiation of CDK4/6 inhibitor therapy to death or the last recorded follow-up.
2.3. Statistics
Descriptive statistics were reported as mean with standard deviation or median with interquartile range, depending on the distribution of the variables. For comparisons of numerical variables, Student’s t-test was employed for normally distributed data, while the Mann–Whitney U test was utilized for non-normally distributed data. The Chi-Square test was used to compare proportions in categorical variables. Progression-free survival (PFS) and overall survival (OS) were analyzed using the Kaplan–Meier method, with group comparisons made using the log-rank test. Cox regression analysis was performed to identify independent predictors of survival, and logistic regression analysis was used to determine independent predictors of hematological toxicity, drug interruption, and withdrawal. All statistical analyses were conducted using SPSS version 26.0 (SPSS Inc., Chicago, IL, USA). A p-value of less than 0.05 was considered statistically significant.
This study received approval from the institutional ethics review board of Ankara Bilkent City Hospital and was conducted according to the principles of the Declaration of Helsinki.
3. Results
Patient and Tumor Characteristics
The study included 188 patients, with a median follow-up time of 18.5 months. The 18-month PFS and OS rates were 67% and 85%, respectively. Detailed patient and tumor characteristics are presented in Table 1. The cohort’s median age was 57.5 years, with 79% of patients being post-menopausal. Most patients had a PS of 0/1. The most common sites of metastasis were bone (66%), liver (23%), and lymph nodes (22%). Extensive bone metastases were observed in 46% of patients, and vertebral bone metastases were observed in 47% of patients. The rate of de novo metastasis was 63%. Among those treated with CDK4/6 inhibitors, 76% received them as first-line therapy, while 22% were treated in the second line. Aromatase inhibitors were used in 70% of patients and fulvestrant in 30%. Concurrent radiotherapy and CDK4/6 inhibitor therapy were administered to 25% of patients (n = 47). Patient characteristics were generally comparable between those who received radiotherapy and those who did not, with the exception of a higher rate of de novo metastases (70% vs. 46%, p = 0.003) and first-line CDK4/6 inhibitor use (82% vs. 57%, p = 0.006) in the non-radiotherapy group (Supplementary Table S2).
Table 1.
Tumor and patient characteristics and adverse events.
Of the 47 patients receiving concomitant radiotherapy, 44 underwent treatment with 20Gy delivered in 5 fractions, while 3 patients received 30Gy in 10 fractions. Regarding the timing of radiotherapy relative to CDK4/6 inhibitor therapy, 32 patients received radiotherapy within the first 3 months of treatment, 6 patients during the second 3 months, and 9 patients after 6 months. The choice of fractionation and dose was determined by the treating clinician and was guided by standard palliative radiotherapy guidelines [12]. A total of 30Gy was administered to the sternum and lumbar vertebrae. Palliative radiotherapy was administered to a single bone metastatic site per patient, with the treatment site selected based on clinical assessment of the most symptomatic or high-risk lesion requiring intervention. The most common sites treated with radiotherapy were the spine (29), femur (9), pelvis (4), sternum (2), humerus (2), and skull (1), respectively. Twenty-three patients (12%) had received chemotherapy within one year before initiating CDK4/6 inhibitors.
Kaplan–Meier survival curves comparing progression-free survival and overall survival between patients receiving CDK4/6 inhibitors with concomitant palliative radiotherapy and those receiving CDK4/6 inhibitors alone were included and analyzed in Supplementary Figures S1 and S2. PFS and OS were comparable between groups.
Grade ≥ 1 hematologic toxicity was reported in 92% of patients receiving CDK4/6 inhibitors. The incidences of anemia, neutropenia, and thrombocytopenia were 65%, 90%, and 23%, respectively. Grade ≥ 3 hematologic toxicity occurred in 52% of patients, with the rates of grade ≥ 3 anemia, neutropenia, and thrombocytopenia being 10%, 47%, and 7%, respectively. Elevated ALT levels were observed in 23% of patients, with a 1% incidence of grade ≥ 3 ALT elevation. Additionally, grade 2 QT prolongation was reported in two patients, and grade 3 dermatitis was observed in one patient.
Table 2 summarizes the frequency of adverse effects according to treatment, patient, and tumor characteristics. The frequency of grade ≥ 3 hematologic toxicity (52% vs. 47%, p = 0.677) and grade ≥ 3 neutropenia (48% vs. 47%, p = 0.985) was comparable between patients with ECOG PS 0/1 and those with ECOG PS 2/3. Patients receiving fulvestrant experienced a higher incidence of grade ≥ 3 hematologic adverse events (59% vs. 48%, p = 0.174) and grade ≥ 3 neutropenia (57% vs. 43%, p = 0.071) compared to those receiving aromatase inhibitors (AIs). In patients aged 60 and older, the frequency of grade ≥ 3 hematologic adverse events (58% vs. 46%, p = 0.097) and grade ≥ 3 neutropenia (54% vs. 42%, p = 0.124) was higher compared to those under 60. Patients receiving palbociclib exhibited significantly more grade ≥ 3 hematologic adverse events (68% vs. 42%, p < 0.001), grade ≥ 3 anemia (16% vs. 7%, p = 0.056), and grade ≥ 3 neutropenia (61% vs. 39%, p = 0.005) compared to those receiving palbociclib. Furthermore, patients treated with CDK4/6 inhibitors in the first-line setting had fewer grade ≥ 3 hematologic adverse events (47% vs. 67%, p = 0.020), grade ≥ 3 anemia (8% vs. 16%, p = 0.167), and grade ≥ 3 neutropenia (43% vs. 60%, p = 0.051) compared to those receiving these inhibitors in subsequent lines of therapy.
Table 2.
Frequency of hematological and liver toxicity.
Treatment interruption, dose reduction, and discontinuation rates were 55%, 24%, and 2%, respectively. There was no significant difference in the rates of CDK4/6 inhibitor interruption (53% vs. 56%, p = 0.735) and dose reduction (28% vs. 23%, p = 0.490) between patients who received palliative radiotherapy and those who did not.
Detailed results regarding drug interruption, dose reduction, and discontinuation are provided in Table 3. Drug interruption was less frequent among patients using aromatase inhibitors compared to those on fulvestrant (51% vs. 64%, p = 0.098), younger patients under 60 compared to those 60 years and older (48% vs. 64%, p = 0.026), those treated with ribociclib versus palbociclib (44% vs. 73%, p < 0.001), and those receiving first-line treatment compared to those on second or subsequent lines of therapy (53% vs. 67%, p = 0.079).
Table 3.
Frequency of interruption and dose reduction for CDK4/6 inhibitors.
Dose reduction was less common in patients treated with ribociclib compared to palbociclib (16% vs. 37%, p = 0.001), in younger patients under 60 compared to older patients (17% vs. 32%, p = 0.018), in pre-menopausal compared to post-menopausal patients (8% vs. 28%, p = 0.010), and in those receiving LHRH therapy compared to those who did not (9% vs. 26%, p = 0.080). Drug discontinuation was less frequently observed in patients with ECOG PS 0/1 compared to those with ECOG PS 2/3 (1% vs. 11%, p = 0.028).
Multivariate analysis revealed that ribociclib was significantly associated with a lower incidence of grade ≥ 3 hematologic toxicity (OR: 0.37, 95% CI: 0.20–0.70, p = 0.002; Supplementary Table S1). Similarly, ribociclib use was linked to a lower incidence of grade ≥ 3 neutropenia (OR: 0.41, 95% CI: 0.22–0.76, p = 0.004; Table 4). In the analysis of treatment interruptions, ribociclib use was associated with fewer interruptions (OR: 0.30, 95% CI: 0.16–0.58, p < 0.001; Table 5). Finally, the multivariate analysis for dose reduction identified ribociclib use (OR: 0.37, 95% CI: 0.18–0.76, p = 0.007) and pre-menopausal status (OR: 0.17, 95% CI: 0.04–0.74, p = 0.018) as factors associated with fewer dose reductions (Table 6).
Table 4.
Univariate and multivariate analysis results on grade ≥ 3 neutropenia.
Table 5.
Univariate and multivariate analysis results on interruption.
Table 6.
Univariate and multivariate analysis results on dose reduction.
4. Discussion
In this study, we demonstrated that the frequency of grade ≥ 3 hematologic toxicities, including anemia, neutropenia, and thrombocytopenia, did not increase in HR+ HER2-negative metastatic breast cancer patients receiving CDK4/6 inhibitors in combination with palliative radiotherapy compared to those not receiving radiotherapy. An inverse relationship was observed between the use of ribociclib and the incidence of grade ≥ 3 hematologic toxicity, grade ≥ 3 neutropenia, drug interruptions, and drug withdrawal. Additionally, menopausal status was identified as a significant factor associated with the likelihood of dose reduction.
CDK4/6 inhibitors are frequently associated with grade ≥ 3 hematologic adverse events. Bone metastases are common in patients with HR+ HER2-negative metastatic breast cancer treated with these agents. In cases of bone metastases, palliative radiotherapy may be necessary to prevent fractures and manage pain. Therefore, it is crucial to understand the impact of palliative radiotherapy on the incidence of hematologic adverse events in patients undergoing treatment with CDK4/6 inhibitors.
The efficacy of concurrent or sequential use of CDK4/6 inhibitors and radiotherapy is currently being evaluated in both preclinical and clinical studies, including the NCT03691493 (ASPIRE) and NCT03870919 (PALATINE) trials [13]. The most significant adverse effects of both treatment modalities are hematologic. Our study examined the impact of concurrently using these two modalities, which have overlapping side effects, on the incidence of hematologic and non-hematologic toxicities.
Ionizing radiation induces double-strand breaks and single-strand lesions in DNA, leading to significant genomic instability and potential cell death [14,15]. When DNA sustains irreparable damage, a signaling cascade involving critical proteins like ATM, Chk2, and p53 is triggered. This cascade results in the cell cycle arrest at the G1/S phase, providing an opportunity for DNA repair or, if the damage is too severe, initiating apoptosis [16]. When single-strand breaks occur, the cell cycle is arrested at the G2/M phase via a pathway involving ATR and Chk1. In cancer cells, which often lose p53 function, the ability to halt the cell cycle at the G1/S phase is compromised, leaving the G2/M phase as the primary checkpoint for arrest [17]. Cyclin-dependent kinases (CDKs) are serine/threonine protein kinases that regulate cell cycle progression by interacting with cyclin D, retinoblastoma protein (Rb), and E2F. CDK4/6 inhibitors act by binding to the ATP-binding domain of CDK4/6, but they differ in their specific cyclin-D targets. Ribociclib primarily targets D1-CDK4 and D3-CDK6, and palbociclib inhibits D1-CDK4, D2-CDK6, and D3-CDK4, while abemaciclib targets D1-CDK4 and D1-CDK6 [18]. CDK4/6 inhibitors impede cell cycle progression by inhibiting the phosphorylation of the Rb protein, effectively arresting the cell cycle at the G1/S phase transition [19,20]. CDK4/6 inhibitors are believed to potentially diminish the effectiveness of radiotherapy by arresting the cell cycle at the G1/S phase, thereby preventing cells from progressing to more radiosensitive phases [21]. The ideal treatment combination and timing to achieve synergistic effects of these two treatment modalities are not yet clear.
In our study, during the 18-month follow-up period, the median PFS and OS were not reached, which is consistent with the literature [1,22,23,24]. Our study included patients who were using palbociclib or ribociclib as CDK4/6 inhibitors. Abemaciclib was not included due to the lack of reimbursement in our country’s healthcare system.
Our study observed that the rates of grade ≥ 3 hematologic toxicities, including anemia, neutropenia, and thrombocytopenia, did not increase in patients receiving CDK4/6 inhibitors who also underwent palliative radiotherapy compared to those who did not receive radiotherapy. Most studies that report contrasting results are retrospective and involve small patient cohorts. Our findings align with the meta-analysis conducted by Kubeczko and colleagues, which included data from 1133 patients [25].
In our study, grade ≥ 3 neutropenia was observed in 47% of patients. This is lower than the incidences reported in clinical trials for ribociclib, where grade ≥ 3 neutropenia was seen in 64% of patients in both the MONALEESA-2 [2] and MONALEESA-7 [26] trials and 54% in the MONALEESA-3 trial [23]. Similarly, palbociclib trials reported higher rates of grade ≥ 3 neutropenia, with 54% in PALOMA-4 [27], 70% in PALOMA-3 [24], and 66% in PALOMA-2 [1].
The lower incidence in our study may be explained by the younger age of our patient cohort, their lower tumor burden, and fewer instances of extensive bone metastases. The rates of grade ≥ 3 anemia and thrombocytopenia in our study were consistent with those reported in the literature. Additionally, while 23% of patients experienced elevated ALT levels, only 1% had grade ≥ 3 ALT elevation.
In our study, treatment interruption, dose reduction, and discontinuation rates of CDK4/6 inhibitors were 55%, 24%, and 2%, respectively. These findings are consistent with those reported in the PALOMA-2 [1] study, which observed interruption and dose reduction rates of 67% and 36%, and the MONALEESA-3 [23] trial, which reported a 38% dose reduction rate. The similarity between our results and previous safety data reinforces the consistency of these outcomes. Furthermore, the interruption and dose reduction rates were similar between patients who received radiotherapy and those who did not. The rate of CDK4/6 inhibitor discontinuation in our study was also in line with that in the established literature.
Kubeczko et al. conducted a study investigating the safety of both concurrent and sequential radiotherapy [28]. In this study, the frequency of early-onset neutropenia after radiotherapy in CDK4/6 inhibitor users was similar between those who received radiotherapy and those who did not. However, the incidence of neutropenia increased in patients who received radiotherapy starting from the second half of the second cycle. Our study did not evaluate the timing between radiotherapy and grade ≥ 3 hematologic toxicity onset. Additionally, the dose reduction rate was consistent between patients who received radiotherapy and those who did not.
Our study revealed that ribociclib use was associated with lower incidences of grade ≥ 3 hematologic toxicity, grade ≥ 3 neutropenia, drug interruption, and drug discontinuation compared to palbociclib. Although these findings are consistent with those reported in clinical trials, it is important to highlight that no studies have directly compared these two drugs head to head [29].
The primary limitation of our study is its retrospective nature. Furthermore, we did not assess the interval between radiotherapy and the onset of grade ≥ 3 hematological adverse events. Despite these challenges, our study stands out as one of the most extensive single-center experiences reported to date.
5. Conclusions
In conclusion, the administration of concomitant palliative radiotherapy during CDK4/6 inhibitor therapy does not elevate the risk of grade ≥ 3 hematologic adverse events. Moreover, ribociclib is associated with a lower incidence of grade ≥ 3 hematologic toxicity, grade ≥ 3 neutropenia, drug interruptions, and dose reductions, suggesting a more favorable safety profile than other CDK4/6 inhibitors.
Supplementary Materials
The following supporting information can be downloaded at https://www.mdpi.com/article/10.3390/cancers17030424/s1: Figure S1: Kaplan-Meier Survival Analysis of Overall Survival in Patients Treated With CDK4/6 Inhibitors With or Without Concomitant Palliative Radiotherapy. Figure S2: Kaplan-Meier Survival Analysis of Progression-Free Survival in Patients Treated With CDK4/6 Inhibitors With or Without Concomitant Palliative Radiotherapy; Table S1: Univariate and multivariate analysis results on grade ≥ 3 hematologic toxicity; Table S2: Comparison of Patient Characteristics Between the Combined Treatment Group (CDK4/6 Inhibi-tors with Radiotherapy) and the CDK4/6 Inhibitor-Only Group.
Author Contributions
F.C., M.M., B.B., A.K.T., B.Y., M.B.A., D.Ş.D., M.A.N.Ş., E.A. and Ş.Y. contributed equally to all aspects of the study, including conceptualization, data collection, analysis, manuscript preparation, and revisions. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
This study was conducted in strict adherence to the ethical principles outlined in the Declaration of Helsinki. Ethical approval was obtained from the institutional review board of Ankara Bilkent City Hospital (TABED 1-24-456 07/08/2024). In accordance with hospital policy, all patients provide general consent at the time of admission, allowing the use of their anonymized medical data for research purposes. Consequently, no additional informed consent was required for this study.
Informed Consent Statement
In accordance with hospital policy, all patients provided general consent at the time of admission, allowing the use of their anonymized medical data for research purposes. Consequently, no additional informed consent was required for this study.
Data Availability Statement
The data supporting the findings of this study are available from the corresponding author upon reasonable request. In adherence to ethical standards and institutional policies, only fully anonymized datasets will be shared to protect patient confidentiality. Data access will be granted exclusively for legitimate academic and non-commercial research purposes, following a formal request and subject to approval in line with institutional and ethical regulations.
Conflicts of Interest
The authors declare no conflicts of interest.
References
- Finn, R.S.; Martin, M.; Rugo, H.S.; Jones, S.; Im, S.A.; Gelmon, K.; Harbeck, N.; Lipatov, O.N.; Walshe, J.M.; Moulder, S. Palbociclib and letrozole in advanced breast cancer. N. Engl. J. Med. 2016, 375, 1925–1936. [Google Scholar] [CrossRef] [PubMed]
- Hortobagyi, G.N.; Stemmer, S.M.; Burris, H.A.; Yap, Y.S.; Sonke, G.S.; Paluch-Shimon, S.; Campone, M.; Petrakova, K.; Blackwell, K.L.; Winer, E.P.; et al. Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive, HER2-negative advanced breast cancer. Ann. Oncol. 2018, 29, 1541–1547. [Google Scholar] [CrossRef] [PubMed]
- Sledge, G.W.; Toi, M., Jr.; Neven, P.; Sohn, J.; Inoue, K.; Pivot, X.; Burdaeva, O.; Okera, M.; Masuda, N.; Kaufman, P.A.; et al. The Effect of Abemaciclib Plus Fulvestrant on Overall Survival in Hormone Receptor-Positive, ERBB2-Negative Breast Cancer That Progressed on Endocrine Therapy-MONARCH 2: A Randomized Clinical Trial. JAMA Oncol. 2020, 6, 116–124. [Google Scholar] [CrossRef]
- Slamon, D.; Lipatov, O.; Nowecki, Z.; McAndrew, N.; Kukielka-Budny, B.; Stroyakovskiy, D.; Yardley, D.A.; Huang, C.S.; Fasching, P.A.; Crown, J.; et al. Ribociclib plus Endocrine Therapy in Early Breast Cancer. N. Engl. J. Med. 2024, 390, 1080–1091. [Google Scholar] [CrossRef]
- Johnston, S.R.D.; Toi, M.; O’Shaughnessy, J.; Rastogi, P.; Campone, M.; Neven, P.; Huang, C.S.; Huober, J.; Jaliffe, G.G.; Cicin, I.; et al. Abemaciclib plus endocrine therapy for hormone receptor-positive, HER2-negative, node-positive, high-risk early breast cancer (monarchE): Results from a preplanned interim analysis of a randomised, open-label, phase 3 trial. Lancet Oncol. 2023, 24, 77–90. [Google Scholar] [CrossRef] [PubMed]
- George, M.A.; Qureshi, S.; Omene, C.; Toppmeyer, D.L.; Ganesan, S. Clinical and Pharmacologic Differences of CDK4/6 Inhibitors in Breast Cancer. Front. Oncol. 2021, 11, 693104. [Google Scholar] [CrossRef]
- Thill, M.; Schmidt, M. Management of adverse events during cyclin-dependent kinase 4/6 (CDK4/6) inhibitor-based treatment in breast cancer. Ther. Adv. Med. Oncol. 2018, 10, 1758835918793326. [Google Scholar] [CrossRef] [PubMed]
- Wekking, D.; Lambertini, M.; Dessì, M.; Denaro, N.; Bardanzellu, F.; Garrone, O.; Scartozzi, M.; Solinas, C. CDK4/6 inhibitors in the treatment of metastatic breast cancer: Focus on toxicity and safety. Semin. Oncol. 2023, 50, 131–139. [Google Scholar] [CrossRef] [PubMed]
- Chowdhary, M.; Sen, N.; Chowdhary, A.; Usha, L.; Cobleigh, M.A.; Wang, D.; Patel, K.R.; Barry, P.N.; Rao, R.D. Safety and Efficacy of Palbociclib and Radiation Therapy in Patients With Metastatic Breast Cancer: Initial Results of a Novel Combination. Adv. Radiat. Oncol. 2019, 4, 453–457. [Google Scholar] [CrossRef] [PubMed]
- Figura, N.B.; Potluri, T.K.; Mohammadi, H.; Oliver, D.E.; Arrington, J.A.; Robinson, T.J.; Etame, A.B.; Tran, N.D.; Liu, J.K.; Soliman, H.; et al. CDK 4/6 inhibitors and stereotactic radiation in the management of hormone receptor positive breast cancer brain metastases. J. Neurooncol. 2019, 144, 583–589. [Google Scholar] [CrossRef] [PubMed]
- Al-Rashdan, A.; Quirk, S.; Roumeliotis, M.; Abedin, T.; Amaro, C.P.; Barbera, L.; Lupichuk, S.; Cao, J.Q. Radiation Therapy With Cyclin-Dependent Kinase 4/6 Inhibitors: A Multi-institutional Safety and Toxicity Study. Int. J. Radiat. Oncol. Biol. Phys. 2022, 114, 399–408. [Google Scholar] [CrossRef] [PubMed]
- Lutz, S.; Balboni, T.; Jones, J.; Lo, S.; Petit, J.; Rich, S.E.; Wong, R.; Hahn, C. Palliative radiation therapy for bone metastases: Update of an ASTRO Evidence-Based Guideline. Pract. Radiat. Oncol. 2017, 7, 4–12. [Google Scholar] [CrossRef] [PubMed]
- Petroni, G.; Buqué, A.; Yamazaki, T.; Bloy, N.; Liberto, M.D.; Chen-Kiang, S.; Formenti, S.C.; Galluzzi, L. Radiotherapy delivered before CDK4/6 inhibitors mediates superior therapeutic effects in ER+ breast cancer. Clin. Cancer Res. 2021, 27, 1855–1863. [Google Scholar] [CrossRef]
- Yokoya, A.; Shikazono, N.; Fujii, K.; Urushibara, A.; Akamatsu, K.; Watanabe, R. DNA damage induced by the direct effect of radiation. Radiat. Phys. Chem. 2008, 77, 1280–1285. [Google Scholar] [CrossRef]
- O’neill, P.; Fielden, E.M. Primary free radical processes in DNA. In Advances in Radiation Biology; Elsevier: Amsterdam, The Netherlands, 1993; Volume 17, pp. 53–120. [Google Scholar]
- Abraham, R.T. Checkpoint signalling: Focusing on 53BP1. Nat. Cell Biol. 2002, 4, E277–E279. [Google Scholar] [CrossRef]
- Lin, Y.; Raj, J.; Li, J.; Ha, A.; Hossain, M.A.; Richardson, C.; Mukherjee, P.; Yan, S. APE1 senses DNA single-strand breaks for repair and signaling. Nucleic Acids Res. 2020, 48, 1925–1940. [Google Scholar] [CrossRef]
- Yang, Y.; Luo, J.; Chen, X.; Yang, Z.; Mei, X.; Ma, J.; Zhang, Z.; Guo, X.; Yu, X. CDK4/6 inhibitors: A novel strategy for tumor radiosensitization. J. Exp. Clin. Cancer Res. 2020, 39, 188. [Google Scholar] [CrossRef]
- Pesch, A.M.; Hirsh, N.H.; Michmerhuizen, A.R.; Jungles, K.M.; Wilder-Romans, K.; Chandler, B.C.; Liu, M.; Lerner, L.M.; Nino, C.A.; Ward, C. RB expression confers sensitivity to CDK4/6 inhibitor–mediated radiosensitization across breast cancer subtypes. JCI Insight 2022, 7, e154402. [Google Scholar] [CrossRef]
- Watt, A.C.; Goel, S. Cellular mechanisms underlying response and resistance to CDK4/6 inhibitors in the treatment of hormone receptor-positive breast cancer. Breast Cancer Res. 2022, 24, 17. [Google Scholar] [CrossRef]
- Tornyi, I.; Árkosy, P.; Horváth, I.; Furka, A. A new perspective on the proper timing of radiotherapy during CDK4/6 inhibitor therapy in patients with “bone-only” metastatic breast cancer. Pathol. Oncol. Res. 2023, 29, 1611369. [Google Scholar] [CrossRef]
- Hortobagyi, G.N.; Stemmer, S.M.; Burris, H.A.; Yap, Y.S.; Sonke, G.S.; Hart, L.; Campone, M.; Petrakova, K.; Winer, E.P.; Janni, W.; et al. Overall Survival with Ribociclib plus Letrozole in Advanced Breast Cancer. N. Engl. J. Med. 2022, 386, 942–950. [Google Scholar] [CrossRef] [PubMed]
- Slamon, D.J.; Neven, P.; Chia, S.; Fasching, P.A.; Laurentiis, M.D.; Im, S.A.; Petrakova, K.; Bianchi, G.V.; Esteva, F.J.; Martín, M.; et al. Overall Survival with Ribociclib plus Fulvestrant in Advanced Breast Cancer. N. Engl. J. Med. 2020, 382, 514–524. [Google Scholar] [CrossRef] [PubMed]
- Turner, N.C.; Slamon, D.J.; Ro, J.; Bondarenko, I.; Im, S.A.; Masuda, N.; Colleoni, M.; DeMichele, A.; Loi, S.; Verma, S.; et al. Overall Survival with Palbociclib and Fulvestrant in Advanced Breast Cancer. N. Engl. J. Med. 2018, 379, 1926–1936. [Google Scholar] [CrossRef] [PubMed]
- Kubeczko, M.; Jarząb, M.; Gabryś, D.; Krzywon, A.; Cortez, A.J.; Xu, A.J. Safety and feasibility of CDK4/6 inhibitors treatment combined with radiotherapy in patients with HR-positive/HER2-negative breast cancer. A systematic review and meta-analysis. Radiother. Oncol. 2023, 187, 109839. [Google Scholar] [CrossRef]
- Im, S.-A.; Lu, Y.-S.; Bardia, A.; Harbeck, N.; Colleoni, M.; Franke, F.; Chow, L.; Sohn, J.; Lee, K.S.; Gomes, S.C.; et al. Overall Survival with Ribociclib plus Endocrine Therapy in Breast Cancer. N. Engl. J. Med. 2019, 381, 307–316. [Google Scholar] [CrossRef]
- Xu, B.; Hu, X.; Li, W.; Sun, T.; Shen, K.; Wang, S.; Cheng, Y.; Zhank, Q.; Cui, S.; Tong, Z.; et al. Palbociclib plus letrozole versus placebo plus letrozole in Asian postmenopausal women with oestrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer: Primary results from PALOMA-4. Eur. J. Cancer 2022, 175, 236–245. [Google Scholar] [CrossRef]
- Kubeczko, M.; Gabryś, D.; Gawkowska, M.; Gilowska, A.P.; Cortez, A.J.; Krzywon, A.; Woźniak, G.; Latusek, T.; Leśniak, A.; Świderska, K.; et al. Safety and Feasibility of Radiation Therapy Combined with CDK 4/6 Inhibitors in the Management of Advanced Breast Cancer. Cancers 2023, 15, 690. [Google Scholar] [CrossRef] [PubMed]
- Kappel, C.; Elliott, M.J.; Kumar, V.; Nadler, M.B.; Desnoyers, A.; Amir, E. Comparative overall survival of CDK4/6 inhibitors in combination with endocrine therapy in advanced breast cancer. Sci. Rep. 2024, 14, 3129. [Google Scholar] [CrossRef]
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