Introduction

Breast cancer is the most prevalent and leading cause of cancer-related deaths in women [1]. Hormone receptor-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer makes up around 66% of all malignant neoplasms in the breast [2-4]. Adjuvant endocrine treatment can effectively treat hormone-receptor positive breast cancer in its early stages. However, a few individuals experienced recurrence or distant metastases due to endocrine treatment resistance. According to the ESMO 5^th worldwide consensus recommendations for advanced breast cancer in 2020, primary endocrine resistance (De novo resistance) is defined as recurrence during the first two years of adjuvant ET or Progressive Disease (PD) within the first six months of first-line ET for MBC while on ET. Secondary endocrine resistance is defined as relapse during adjuvant ET but beyond the first 2 years, relapse within 12 months after finishing adjuvant ET, or PD ≥6 months after commencing ET for MBC while on ET [5].

Three CDK4/6 inhibitors have shown promising effects in clinical trials: Palbociclib [6-8], Ribociclib [9-12], and Abemaciclib [13,14]. Clinical trials show that combining CDK4/6 inhibitors with endocrine treatment increases Progression-Free Survival (PFS) over endocrine therapy alone. These drugs are intended to treat hormone receptor-positive, HER2-negative metastatic breast tumors. Palbociclib is utilized as a first-line therapy for postmenopausal women, in conjunction with an aromatase inhibitor [1517].

It is also used in combination with fulvestrant in premenopausal and postmenopausal women who have disease progression after endocrine therapy. Fulvestrant exerts its impact by downregulating and degrading the estrogen receptor. Premenopausal women should have their ovarian function suppressed or ablation during endocrine treatment [8,9].

Ribociclib is used as the initial endocrine treatment in premenopausal and postmenopausal women, with an AI. It is also used in conjunction with fulvestrant as the first endocrine treatment in postmenopausal women, as well as in postmenopausal patients who progress after endocrine therapy [10-12].

Abemaciclib is used as the initial endocrine medicine in postmenopausal women, in combination with an AI. It is also used in conjunction with fulvestrant to treat premenopausal and postmenopausal women whose illness progresses despite endocrine therapy. If the illness continues despite endocrine and chemotherapy treatment, Abemaciclib may be used as a monotherapy if disease progresses on endocrine therapy and chemotherapy [13,14].

These CDK inhibitors are usually well tolerated, while they can have some side effects, as reported here [15,16]. For example, typical adverse effects include tiredness, nausea, neutropenia, and infection, although interstitial lung disease is less prevalent. Ribociclib can also produce QTc prolongation and hepatotoxicity, whereas Abemaciclib can result in hepatotoxicity, increased blood creatinine, and grade 3 diarrhea [17,18].

Although the development and licensure of CDK inhibitors have revolutionized the treatment of metastatic breast cancer, resistance to these drugs has also emerged. As a result, more research into the underlying mechanism of acquired resistance to these drugs is required, as is the development of novel CDK inhibitors. This trial will compare the effect of CDK4/6 plus hormonal treatment on progression-free survival to hormonal treatment alone, as well as the tolerance, effectiveness, and safety profile of CDK4/6 inhibitors when combined with hormonal therapy.

Research methodology & design

Study design

This was a comparative, record-based retrospective cohort study aiming to compare the effectiveness of CDK4/6 with hormonal treatment on progression-free survival to hormonal treatment alone, as well as the tolerance and toxicity profile of CDK4/6 after hormonal therapy.

Study setting

This study was conducted at Suez Canal University Hospital’s (SCUH) Clinical Oncology and Nuclear Medicine Department in Ismailia, Egypt. The patients were identified via the department registry, and data was retrieved from their medical records using a predetermined form.

Patient selection and data collection

The sample size was computed. We gathered all eligible patients from their records within the appropriate timeframe (1/2022 to 6/2024) depending on sample size and monitored them to record disease outcome and clinicopathological features.

Patients are classified into two groups:

• Group A got CDK 4/6 plus hormonal therapy.

• Group B: received hormonal treatment only.

The data for this study came from the Clinical Oncology Department’s patient file recording system. The data obtained included:

• Personal data:

- Age at the time of diagnosis

- Family history of breast cancer.

- Chronic illness is defined as diseases that persist one year or more and need continuing medical treatment, impede everyday activities, or both (according to the Center for Disease Control).

• Clinical data:

- ECOG performance status.

- Menopausal stages include premenopausal, perimenopausal, and postmenopausal.

• Radiological findings

• Pathological data:

- Receptors at the metastatic tumor site (ER and PR receptors)

- Progesterone receptor status.

- Metastatic luminal categorization (Luminal A & B), with Luminal A tumors having the presence of ER and/or PR but no HER2, as well as a low expression of the cell proliferation marker Ki67 (less than 20%). Luminal B tumors are of higher grade and worse prognosis compared to Luminal A. They are ER positive, can be PR negative, and have a high expression of Ki67 (greater than 20%).

- Ki 67 proliferation index.

- Tumor stage at the time of diagnosis.

• First line treatment received:

- First-line adjuvant/neoadjuvant chemotherapy (in case received).

- Type of chemotherapy.

- Adjuvant radiotherapy.

• Adjuvant endocrine therapy:

- First-line hormonal treatment in an adjuvant setting.

- Period of adjuvant endocrine therapy in months.

- Primary endocrine resistance (De novo resistance) is defined as: relapse while on the first 2 years of adjuvant ET. Secondary (acquired) endocrine resistance is defined as: relapse while on adjuvant ET but after the first 2 years.

• Metastasis:

- Timing of metastasis (period of disease-free) indicating number of months from time of presentation till development of metastasis.

- Pattern of metastasis (bone metastasis only, bone and visceral metastasis, bone and non-visceral metastasis, visceral metastasis only (lung, liver, brain), non-visceral only (lymph nodes, skin, other breast), visceral and non-visceral metastasis, bone visceral non-visceral.

- Visceral metastasis defined as lung, liver, and brain metastasis, while non-visceral only (lymph nodes, skin, other breast).

• Number of sites/organs of metastasis.

• Endocrine therapy at the time of metastasis.

• Type of CDK 4/6 inhibitor received (Ribociclib, Abemaciclib, Palbociclib) in Group A.

• Adverse events occurred according to common terminology criteria for adverse events.

• Whether discontinuation of drug due to toxicity occurs & mean time in months, in addition post discontinuation therapy.

• Assessment of treatment response after 6 months of starting treatment. This is according to RECIST criteria.

• Progression-free survival on a CDK4/6 inhibitor or hormonal treatment.

• Status at the date cutoff (alive or dead).

• Overall survival (from date of diagnosis till date cutoff June 2024).

• Compliance on treatment arm either CDK 4/6 inhibitor or hormonal treatment. Patient may be shifted due to toxicity to another CDK 4/6 inhibitor, progressed and shifted to another line, or stay on the same line of treatment at the date cutoff.

• Follow-up data for every patient recorded.

Inclusion criteria:

• Female patients only.

• Age is more than or equal to 20 years old.

• Immunohistochemistry proved metastatic luminal breast cancer patients.

• Radiologically confirmed skeletal, visceral, or non-visceral metastasis.

Exclusion criteria:

• Multiple primary tumors or double pathological lesions.

• Triple-negative breast cancer.

• Her2neu-enriched breast cancer.

• Non-metastatic luminal breast cancer.

• Male breast cancer.

Sample size and sampling technique:

From January 2022 to June 2024, a simple random sample of patients attended the Clinical Oncology and Nuclear Medicine department at Suez Canal University Hospital. We included patients who were diagnosed with metastatic luminal breast cancer using pathology, immunohistochemistry, and radiography. Patients must fulfill the inclusion and exclusion criteria.

Sample size:

The sample size was determined using the following equation [19]:

n = (Z_α/2+Z_β)^2* (p₁ (1-p₁) +p₂ (1-p₂)) / (p₁-p₂)²

where Z_α/2 is the critical value of the Normal distribution at α/2 (e.g. for a confidence level of 95%, α is 0.05 and the critical value is 1.96),

Z_β is the critical value of the Normal distribution at β (e.g. for a power of 80%, β is 0.2 and the critical value is 0.84).

P₁ and p₂ are the expected sample proportions of the two groups.

P₁ was 63% and p₂ was 42.2% [20]

The calculated sample size is 174 participants.

Ethical considerations

The research ethics committee of the Faculty of Medicine Suez Canal University (FOMSCU) has approved the final protocol.

Clinical data will be collected with the agreement of FOMSCU’s research ethics council.

The study data will be collected from the patient’s files. To safeguard patient confidentiality and privacy, no personally identifiable information will be released.

The data will only be used for that research; moreover, patient contact will be required to decrease the challenges associated with inaccurate recording and follow-up.

The data analysis will be displayed in a covert way, with no mention of patient identities.

Statistical analysis

The statistical analysis was carried out using SPSS software for Windows, version 28 (IBM Co., Armonk, NY, USA). The MannWhitney or Kruskal-Wallis tests were used to analyze numerical data in the form of median and Interquartile Range (IQR). Categorical data were presented as frequency and percentage, then analyzed using the chi-square or exact test, as appropriate.

The Kaplan-Meier curve with log-rank test was used for survival analysis, and Cox regression was used to investigate various survival factors. A two-tailed P value<0.05 indicates statistical significance.

Results

Baseline patient characteristics

From January 2022 to June 2024, 174 people were tested for eligibility at the Clinical Oncology and Nuclear Medicine departments at Suez Canal University Hospital. Each of these individuals had metastatic luminal breast cancer. Of those, 89 patients received Cdk 4/6 inhibitors in addition to endocrine therapy and were assigned to Group A, whereas 85 patients received just endocrine therapy and were assigned to Group B. (Table 1) provides a complete description of the baseline patient characteristics. There was no significant difference in baseline patients between the two therapy groups in terms of age, family history, comorbidities, menopausal state, or ki-67 proliferation index. There was only a difference in tumor stage and ECOG PS at the time of diagnosis (P value=0.030 and 0.001, respectively). Metastatic luminal categorization at the time of metastasis differs between the two groups (p value=0.007).

Table 1: Baseline characteristics of the studied groups.

First-line treatment details

In group A, 66 patients (74.2%) were given first-line chemotherapy (59.6% anthracycline and taxanes, 14.6% taxanes alone) in the adjuvant/neoadjuvant setting. In group B, 62 patients got first-line chemotherapy, with 48.2% receiving anthracycline plus taxanes and 24.7% receiving taxanes alone, with a statistically insignificant P value.

The duration of adjuvant endocrine treatment (in months) was considerably shorter in group A than in group B (P=0.002), with a median of 60 (IQR 24, 67.5) versus 60 (IQR 60, 84). The majority of patients in groups A and B got aromatase inhibitors as their first line hormonal therapy in the adjuvant context (44.9% and 47.1%, respectively), followed by LHRH with AI (16.9% and 30.6%). 27.3% of the study population was metastatic from the start and did not receive adjuvant endocrine therapy, while 3.5% presented with primary triple negative breast cancer at the primary tumor site and were later diagnosed with metastatic luminal breast cancer via immunohistochemistry (this is why they did not receive adjuvant hormonal therapy). Table 2 illustrates the first line of therapy received.

Table 2: First line treatment of the studied groups.

Metastasis

Time to metastasis (months) was considerably shorter in group A compared to group B (P<0.001), with a median of 72 (IQR 36, 96) versus 108 (IQR 72, 123) months. The majority of patients (52.8% of group A vs. 76.5% of group B) acquired secondary endocrine treatment resistance, with a statistically significant difference (P value=0.004). 26 individuals were metastatic from the beginning and did not get adjuvant endocrine therapy. Three individuals tested triple negative at the initial tumor location and did not receive adjuvant hormone treatment.

The majority of patients in groups A and B received aromatase inhibitors as their first-line hormonal treatment in the adjuvant setting (44.9% and 47.1%, respectively), followed by LHRH with AI (16.9% and 30.6%). 27.3% of the study population was metastatic from the start and did not receive adjuvant endocrine therapy, while 3.5% had primary triple negative breast cancer at the primary tumor site but were later diagnosed with metastatic luminal breast cancer via immunohistochemistry. Table 2 illustrates this in detail.

Cdk 4/6 inhibitor plus hormonal treatment versus hormonal alone: In group A, 75.3% received a CDK 4/6 inhibitor in addition to fulvestrant, whereas 24.7% received a CDK 4/6 inhibitor plus aromatase inhibitors. Regarding Cdk 4/6 inhibitors, 48.3% of patients took Ribociclib, 30.3% received Abemaciclib, and 21.3% received Palbociclib.

In group B, patients only got hormonal therapy. 52.9% of patients received both an aromatase inhibitor and LHRH analogues. Others received an aromatase inhibitor with fulvestrant (36.5%) or only fulvestrant (10. 6%). Table 2 illustrates this in detail.

Group A had significantly higher rates of diarrhea (18% vs. 0%, P<0.001), neutropenia (28.1% vs. 0%, P<0.001), easy fatigability (27% vs. 1.2%, P<0.001), abdominal pain (12.4% vs. 0%, P=0.001), anemia (7.9% vs. 0%, P=0.014), arthralgia (33.7% vs. 8.2%, P<0.001), and muscle weakness (6.7% vs. 0%, P=0.029). In contrast, no patients in group A had osteoporosis, but 7.1% of those in group B did, indicating a statistically significant difference between groups (P=0.012). In terms of increased liver enzymes, 4.5% of group A had levels 3 to 5 times higher than normal, whereas 7.1% of group B had levels less than 3 times normal, indicating a statistically significant difference (P=0.002) (Table 3).

Table 3: Adverse events in the studied groups.

Table 4: Discontinuation to therapy and response of the studied groups.

After 6-month treatment, patients in group A shown a considerably greater treatment response than those in group B (P<0.001), with 23.6% showing CR, 52.8% showing PR, 14.6% showing SD, and 9% showing PD compared to 5.9% of the latter (Table 4 & Figure 2).

In group A, 19.1% of patients stopped CDK 4/6 owing to toxicity. The average period of discontinuance was 5 months. Furthermore, 16.9% of group A switched to a different line of treatment due to toxicity, whereas 61.2% of group B suffered disease progression and 66.3% remained on the same line of treatment. The difference in proportions between groups was statistically significant (P<0.001) (Table 4 & Figures 3,4).

In terms of post-discontinuation therapy, in group A, 16.9% shifted to another CDK 4/6 inhibitor and hormonal therapy with an acceptable toxicity profile, 11.2% of patients developed a visceral crisis and received chemotherapy, and 5.6% received Everolimus-based therapy, whereas in group B, 47.1% were on hormonal therapy and shifted to the other treatment arm, 9.4% received chemotherapy, 3.5% had the best supportive care, and 1.2% had Everolimus-based therapy, indicating Patients in group A got post-discontinuation medication for a median of 4 (IQR 3, 22.25) months, which was significantly less than the time in group B (12 (IQR 6, 23.5) months); P=0.003 (Table 4 & Figure 5).

Table 5: PFS analysis of patients according to treatment method.

Survival analysis

The Kaplan-Meier analysis with log-rank test revealed a statistically significant difference in PFS between the two treatment arms (P<0.001). Patients who received CDK 4/6 inhibitors in combination with endocrine therapy had a longer PFS than those who received endocrine therapy alone, with an estimated mean of 65.53 months (95% CI: 54.73 to 76.34) vs. 24.52 months (95% CI: 18.96 to 30.07), resulting in an incidence rate of 16.9% vs. 61.2%, with an HR of 0.24 (95% CI: 0.14 to 0.4) (Table 5 & Figure 6).

Table 6: OS analysis of patients according to treatment method.

In terms of OS, there was no statistically significant difference between patients in both treatment groups, with death rates of 2.2% and 3.5%, respectively (Table 6 & Figure 7).

In univariate Cox regression analysis, metastasis luminal classification, CDK 4/6 subtype, adverse event exposure, and drug discontinuation due to high toxicity profile were significant predictors of longer PFS, with women with luminal B cancers having a lower risk than those with luminal A subtype (HR=0.53; 95% CI: 0.32 to 0.87, P=0.011). Upon analysis, patients in group A had a substantially decreased risk of tumor progression, with HR (95% CI) of 0.34 (0.17 to 0.68, P=0.002), 0.1 (0.02 to 0.39, P=0.001), and 0.19 (0.05 to 0.79, P=0.023).

Furthermore, individuals who encountered adverse events had a decreased risk of tumor progression compared to those who did not (HR=0.56, 95% CI: 0.34 to 0.92, P=0.021).

Patients who terminated medication owing to toxicity had a substantially reduced risk of progression than others (HR=0.1, 95% CI: 0.01-0.76, P=0.026). Furthermore, patients who received Ribociclib and Abemaciclib had a significantly lower risk of tumor progression than those who received Palbociclib, with HR (95% CI) of 0.26 (0.12 to 0.6, P=0.002) and 0.1 (0.02 to 0.47, P=0.003), respectively (Table 7).

Table 7: Cox-regression analysis for factors associated with PFS of patients.

CDK 4/6 inhibitor subtypes

In group A, there was a statistically significant difference in adverse events between the CDK 4/6 inhibitor subtypes. Diarrhea was more common with Abemaciclib, with 34.6% experiencing grade 3 diarrhea with a statistically significant p-value (P-value<0.001). Neutropenia emerged in 36.3% of patients on Ribociclib, followed by Palbociclib (31.6%) and Abemaciclib (11.5%), with a statistically significant difference (P=0.029). 23.1% of Abemaciclib-treated patients had anemia with a hemoglobin level of less than or equal to 9 gm/dL (P=0.003).

Serum creatinine levels increased in 15.4% of Abemaciclib patients (P=0.031). Abemaciclib and Ribociclib caused bone pains in 19.2% and 4.5% of patients, respectively, with a significant P value (P=0.026). Table 8 shows adverse outcomes for CDK 4/6 subtypes.

In terms of medication adherence in Group A, therapy was discontinued due to toxicity in an identical percentage across CDK 4/6 inhibitor subtypes (15.9% with Ribociclib, 15.4% with Abemaciclib, and 21.1% with Palbociclib). The mean time to cessation in months for Ribociclib, Abemaciclib, and Palbociclib was 5.5, 4, and 5 months, respectively.

After 6 months on CDK 4/6 inhibitors, 15 patients had disease progression and failure, whereas 59 stayed on the same treatment group. Patients in Group A were switched to a different treatment line due to unacceptable toxicity or disease progression, as judged by RECIST criteria. Following discontinuation, another CDK 4/6 and hormonal treatment (52.4%) was taken, followed by chemotherapy for a visceral crisis (28.7%) and Everolimus-based therapy (16%). There were no significant differences between CDK 4/6 inhibitor subtypes in terms of therapy response evaluation using RECIST criteria. This is seen in Table 9.

Table 8: Adverse events in group A according to CDK 4/6 inhibitors subtype.

Table 9: Discontinuation to therapy and response of group A according to CDK 4/6 inhibitors subtype.

The Kaplan-Meier analysis using the log-rank test revealed that CDK 4/6 inhibitor subtypes had no statistically significant effect on PFS, with progression rates of 22.7%, 11.5%, and 10.5% for Ribociclib, Abemaciclib, and Palbociclib, respectively (Figure 8).

Analysis of the operating system at the date cutoff found no statistically significant difference in mortality rates between CDK 4/6 inhibitor subtypes, with 2.3% getting Ribociclib and 5.3% receiving Palbociclib (Figure 9).

Discussion

Approximately 66% of all breast cancers are hormone-receptor positive, HER2-negative malignant breast neoplasms [2-4]. Adjuvant endocrine treatment can cure the majority of hormone-receptor positive breast tumors in their early stages. However, the number of patients who had recurrence and distant metastases as a result of endocrine therapy resistance is still small.

Three CDK4/6 inhibitors have demonstrated encouraging results in clinical trials: Palbociclib [6-8], Ribociclib [9-12], and Abemaciclib [13,14]. Several clinical studies have shown that combining CDK4/6 inhibitors with endocrine therapy improves Progression-Free Survival (PFS) compared to endocrine treatment alone.

This study’s findings provide supporting evidence that treatment had a statistically significant impact on patients’ PFS, as patients receiving CDK 4/6 inhibitors in combination with endocrine therapy remained free of progression for a longer period of time than those receiving endocrine therapy alone, with an estimated mean of 65.53 months vs. 24.52 months. This pattern of results is consistent with previous study, which found that adding CDK4/6 inhibitors to endocrine treatment significantly improved PFS in persons with hormone receptor-positive, HER2-negative metastatic breast cancer [6,8-11,13].

The current study’s findings confirm the notion that there is no statistically significant difference in overall survival between individuals receiving CDK 4/6 inhibitors in conjunction with endocrine treatment and those getting endocrine therapy alone. These findings support the argument that OS data are only available for PALOMA 1 [7,8], PALOMA 3 [8], and MONALEESA 2 [9].

Two previous meta-analyses [21-23] were insufficient to identify the overall survival advantage, which accounts for the majority of survival. The outcomes of the included RCTs are pending. The US Food and Drug Administration pooled study [24] revealed a non-statistically significant OS benefit across all pooled studies. Because the efficacy data were obtained on April 30, 2018, the overall survival rates for all pooled studies are now incomplete.

Li et al. [25] revealed that CDK4/6 inhibitors improved overall survival (HR 0.79, 95% CI). 0.67–0.93), despite the fact that there were just three randomized controlled trials. Schettini et al. [26] completed a meta-analysis. CDK4/6 inhibitors were proven to improve OS, although they did not include PALOMA-1’s most recent operating system data, which was published in 2017 [7,8]. The latest OS findings from the phase III investigations MONARCH2, MONALEESA 3, and 6 have been revealed [13,14]. A recent meta-analysis extensively examined all six trials, randomized clinical investigations, and updated OS data.

We found that CDK4/6 inhibitors with endocrine therapy significantly improved OS in patients with metastatic luminal breast cancer compared to endocrine therapy alone. We hypothesize that the difference in OS and PFS is attributable to the varied subsequent treatment regimens and the switch from control to CDK4/6 inhibitor therapy. In this example, the increase in PFS was insufficient to justify an OS extension.

The findings clearly suggest that diarrhea, neutropenia, easy fatigability, stomach discomfort, anemia, arthralgia, and muscular weakness occurred in much greater proportions in group A than in group B. Previous studies have shown that adding CDK4/6 inhibitors increased the number of grade 3 and 4 adverse events. The majority of adverse effects impact the blood system, including neutropenia, leucopenia, and anemia. There is a significant difference in the frequency of grade 3 digestive system adverse events, such as diarrhea and vomiting [7,8,21-26].

In our study, CDK 4/6 inhibitors delivered to group A had no statistically significant effect on PFS, with progression rates of 22.7%, 11.5%, and 10.5% for Ribociclib, Abemaciclib, and Palbociclib, respectively. There was no statistically significant difference in OS between the three CDK 4/6 groups, with death rates of 2.3% and 5.3% in patients on Ribociclib and Palbociclib, respectively. This pattern of results is comparable with previous research, which shows that all CDK4/6 inhibitor trials exhibited consistent PFS effects (HRs ranging from 0.50 to 0.59). Meta-analyses revealed no significant differences in PFS across medicines [7,8,22-27].

As a consequence, OS has determined the most essential indicators of pharmacological effectiveness. A network meta-analysis was used to indirectly evaluate the differences in OS and safety profiles across diverse medicines. Their findings reveal that there are no substantial effectiveness differences in OS among the three medications and that effect sizes are clinically important in the majority of cases, independent of statistical significance. However, as expected, there were significant disparities in safety and tolerability [22-27].

Previous studies found significant differences in the safety and tolerability of several CDK4/6 inhibitors. Our study found a strong relationship between the CDK 4/6 subtype and the occurrence of diarrhea, neutropenia, nausea and vomiting, easy fatigability, anemia, renal impairment, and bone pains. Abemaciclib was associated with diarrhea, accounting for 34.6% of cases. Neutropenia is 36.3%, 31.6%, and 11.5% with Ribociclib, Palbociclib, and Abemaciclib, respectively. This conclusion is consistent with recent studies indicating that the most common adverse effects of CDK4/6 inhibitors are hematologic toxicity, which causes a decrease in blood cell counts across many lineages.

Notably, the RORs for Palbociclib and Ribociclib were higher than those for Abemaciclib, and serious systemic infections were uncommon, in line with an earlier study [27]. Hematologic toxicity, the most prominent adverse effect of CDK4/6 inhibitors, is primarily caused by their capacity to inhibit CDK6, a critical regulator of hematopoietic precursor proliferation [28,29]. Palbociclib is similarly effective against both CDK4 and CDK6, but Abemaciclib has a higher affinity for CDK4, resulting in less hematologic damage [28,30].

Furthermore, CDK4/6 inhibitors produce neutropenia primarily through cell cycle suppression rather than chemotherapy-induced DNA damage and consequent death in hematopoietic cells [31].

Study limitations and strengths

Our study has various limitations due to its retrospective nature; a selection bias cannot be totally removed. Another drawback was that our investigation was conducted in a single site with a small number of patients, preventing accurate matching between study groups in terms of comparable staging and hence proper comparison. Furthermore, this study included all patients who came in during this time period, whether they were newly diagnosed or had previously been diagnosed with metastatic luminal breast cancer, resulting in some disparities across study groups.

We suggest more research with a bigger sample size to support or refute our findings. Furthermore, this was the first research to compare the efficacy and safety of three currently available CDK 4/6 inhibitors. Furthermore, this study was carried out in Egypt, where patients and tumors differ from those found in Western nations.

Conclusion

Compared to endocrine therapy alone, CDK4/6 inhibitors significantly improved PFS and OS in patients with hormone receptor-positive, HER2-negative metastatic breast cancer. CDK4/6 inhibitors provided consistent benefits in patients with a variety of patient and tumor characteristics. However, CDK4/6 inhibitors have a higher risk of negative side effects. According to our findings, the kinds of CDK 4/6 inhibitors used showed no statistically significant difference in PFS or OS.

Declarations

Acknowledgements: I’d want to thank everyone who contributed to the work’s creation. This information includes the writers’ opinions, findings, and conclusions.

Authors contributions: SHS and MMA collaborated on the piece’s conception and development. SHS, MMM helped collect data from the filling system. SHS and MMA helped collect, analyze, and interpret the data. SHS and MMA assessed and oversaw the work. SHS and MMA authored the first draft of the text. SHS, MMA perform editing of final draft of the manuscript. All authors contributed to the manuscript editing. All writers agreed on the final version of the manuscript.

Availability of data and materials: Upon reasonable request, the relevant author will provide the data supporting the results of this investigation.

Ethics, approval, and consent to participate: The final protocol was accepted by the research ethics committee of Suez Canal University’s Faculty of Medicine (FOMSCU). Clinical data was obtained with permission from the patients’ filling system.

The confidentiality of the information and patient privacy were taken into account, and no personal information was published.

The data will only be utilized for that specific study; also, patients’ contact information was requested to reduce the chance of erroneous recording and follow-up visits.

Competing interests: The authors stated that they had no competing interests.

Abbreviations: AI: Aromatase Inhibitor; CDK: Cycline-Dependent Kinase; CR: Complete Reaction; ECOG: Eastern Cooperation Oncology Group; ER: Estrogen Receptor; ESMO: European Society for Medical Oncology; ET: Endocrine Treatment; FOMSCU: Faculty of Medicine, Suez Canal University; HER2: Human Epidermal Growth Factor Receptor 2; HR: Hazard Ratio; IQR: Interquartile Range; LHRH: Luteinizing Hormone-Releasing Hormone; MBC: Metastatic Breast Cancer. OS: Overall Survival; PD: Progressive Disease; PFS: Progression-Free Survival; PR: Partial Response; PR Receptor: The Progesterone Receptor; PS: Performance Status; QTc: The Corrected QT Interval; RCT: Randomized Controlled Trials; RECIST: Response Evaluation Criteria in Solid Tumors; ROR: Reporting Odds Ratio; SCUH: Suez Canal University Hospital; SD: Stable Disease; vs.: Versus.

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