Factors Affecting the Survival of Metastatic Breast Cancer Patients Treated With Cdk 4/6 Inhibitors

doi:10.21203/rs.3.rs-4965457/v1

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Factors Affecting the Survival of Metastatic Breast Cancer Patients Treated With Cdk 4/6 Inhibitors

https://doi.org/10.21203/rs.3.rs-4965457/v1

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Objective

We aim to determine the efficacy, and the factors associated with the effectiveness of first-line CDK4/6i (ribociclib or palbociclib) in HR-positive, HER2-negative MBC patients.

Material and method

This is a retrospective, cross-sectional, and descriptive study. Ninety patients with metastatic breast cancer receiving CDK 4/6i from three different oncology clinics were included in the study.

Results

Of the patients, 56 (62.2%) had received ribociclib, and 34 (37.8%) palbociclib. There was no significant difference between the groups regarding age, gender, comorbidities, ECOG performance status, and menopausal status (p>0.05). The cut-off values for ER, PR, and Ki-67 levels were determined by ROC curve analysis. It was found as 80% for ER level, 50% for PR level, and 30% for Ki-67 level. PFS was significantly longer in patients with ER-level greater than 80% and Ki-67 expression less than 30% in multivariate analysis. Among the patients included in our study, the median PFS was 22.41 months in the patients with only a Ki-67 level of 30% and above, while the median PFS was 17.24 months in the patients with only an ER level of 80% and below. In the patients with a combined ER of 80% or less, and a Ki-67 of 30% or more, the median PFS was 12.42 months (p<0.001).

Conclusion

This study demonstrated that CDK4/6i therapies had longer PFS in patients with ER levels greater than 80% and Ki-67 expression less than 30%. It is essential to determine which patient group benefits more from first-line CDK4/6is.

Metastatic breast cancer

CDK 4/6 inhibitors

Ribociclib

Palbociclib

Breast cancer is the most common malignancy diagnosed in women worldwide, and the leading cause of mortality (1). Approximately 70% of breast cancer is hormone-receptor (HR) positive and human epidermal growth factor receptor-2 (HER2) negative. HR-positive, HER2-negative breast cancers have better prognosis than other types (2). Although significant improvements in survival have been seen with current systemic therapies, metastatic breast cancer (MBC) remains incurable (3). The cornerstone of initial treatment for metastatic HR-positive, HER2-negative breast cancer is endocrine therapy (4).

Cyclin-dependent kinases (CDKs) play a critical role in regulating cell cycle. CDK4 and CDK6, in particular, are key regulators of the G1-S phase transition, driving cell proliferation. In HR-positive breast cancer, dysregulation of these CDKs contributes to uncontrolled tumor growth. CDK 4/6 inhibitors (CDK4/6i) function by binding to the ATP-binding pocket of CDK4 and CDK6, thereby preventing their interaction with cyclin D, and subsequent phosphorylation of the retinoblastoma protein (Rb). This ultimately leads to cell cycle arrest and inhibits tumor growth (5). Adding CDK4/6i (e.g., ribociclib, palbociclib, or abemaciclib) to endocrine therapy has proven clinically beneficial. Compared to endocrine therapy alone, the combination of CDK4/6i and endocrine therapy showed a significant improvement in progression-free survival (PFS) and overall survival (OS) (6). In the MONALEESA-2 study, ribociclib has demonstrated significant PFS and OS benefits when added to an aromatase inhibitor (AI) in postmenopausal patients with HR-positive, HER2-negative advanced breast cancer (7). Significant PFS and OS benefits were seen both in the MONALEESA-7 study that was performed in premenopausal patients and in the MONALEESA-3 study that was performed in postmenopausal patients (8, 9). Although palbociclib did not show an OS benefit in the PALOMA-2 trial, it showed a significant PFS benefit (10).

Patient characteristics, treatment factors, and tumor biology may play a role in the effectiveness of CDK4/6i. Understanding these factors is crucial to tailor treatment strategies and optimize outcomes in HR-positive, HER2-negative MBC patients (11, 12). Ki-67 is a proliferation marker indicating the percentage of actively dividing cells within a tumor. Higher Ki-67 scores and higher tumor grades generally correlate with aggressive disease, and in recent studies PFS was found significantly shorter in these patients (11, 13). The impact of estrogene receptor (ER) and progesterone receptor (PR) levels on CDK4/6i efficacy needs to be clarified. While some studies suggest no significant association, others indicate potential benefits in patients with higher ER and PR expression (12–14).

This study aims to determine the efficacy, and the factors associated with the effectiveness of first-line CDK4/6i (ribociclib or palbociclib) in HR-positive, HER2-negative MBC patients.

This is a retrospective, cross-sectional, and descriptive study. The study was performed in MBC patients who were referred to the medical oncology clinic between December 2019 and January 2024. Ninety patients admitted to three different oncology outpatient clinics in Turkey were included.

The inclusion criteria of the research were being diagnosed with MBC, having HR-positive and HER2-negative primary tumors, and who received first-line CDK4/6i (ribociclib or palbociclib) treatment for metastatic disease. The patients who received chemotherapy or endocrine therapy in the adjuvant and neoadjuvant setting were allowed to be included in the study. The patients under 18 years of age, who did not undergo treatment response evaluation or who had CDK4/6i-based treatment for less than three months were not included in the study. Data were collected by the researchers from patient files after obtaining written permission from the institutions where the research was conducted. The study complied in accordance with the Helsinki Declaration and approved by the Bezmialem Vakıf University ethic approval committee (2022/396).

The 8th edition TNM staging system was used for tumor staging. According to the patients' files, demographic characteristics, clinical and pathological features, treatment responses, the number of medications, and comorbid diseases were collected for each patient. Functional status was measured using the Eastern Cooperative Oncology Group (ECOG) scale.

PFS was defined as the time from initiation of CDK4/6i therapy to the progression of disease or the last day of follow-up. OS was defined as the time from initiation of CDK4/6i therapy to death or the last day of follow-up.

Statistical analysis

Statistical analysis was performed using Statistical Package for Social Sciences version 25 (SPSS, v25). Qualitative variables were described by frequencies and percentages, continuous variables by mean and standard deviation, or median and range. The normal distribution range was determined by the Kolmogorov–Smirnov test. T-test and Chi-square test were used to describe patient characteristics and to compare subgroups of patients. The factors associated with PFS were assessed using univariate and multivariate logistic regression analysis. Odds ratios were calculated to evaluate the magnitude of the impact of the significant variables with a 95% confidence interval (CI). Survival analysis was performed using the Kaplan–Meier method and log-rank test. The cut-off value for ER, PR, and Ki-67 levels was determined by ROC curve analysis. The statistical significance level was accepted as a p-value < 0.05.

The study included 90 patients with MBC who received first-line CDK4/6i. Of the patients, 56 (62.2%) had received ribociclib, and 34 (37.8%) palbociclib. There was no significant difference between the groups regarding age, gender, comorbidities, ECOG performance status, and menopausal status (p > 0.05) (Table 1).

Table 1

Baseline Characteristics of the Patients
Characteristics	All patients, n (%)	Luminal A, n (%)	Luminal B, n (%)	p-value
Age < 65 years ≥ 65 years	63 (70%) 27 (30%)	31 (70.5%) 13 (29.5%)	32 (69.6%) 14(30.4%)	0.927
Sex Women Men	87 (96.7%) 3 (3.3%)	43 (97.7%) 1 (2.3%)	44 (95.7%) 2 (4.3%)	0.584
Smoking Yes No	15 (16.7%) 75 (83.3%)	8 (18.2%) 36 (81.8%)	7 (15.2%) 39 (84.8%)	0.706
Comorbidities DM HT CAD	19 (21.1%) 29 (32.2%) 9 (10%)	10 (22.7%) 12 (27.3%) 4 (9.1%)	9 (19.6%) 17 (37%) 5 (10.9%)	0.713 0.326 0.779
ECOG-PS 0–1 2	79 (87.8%) 11 (12.2%)	39 (88.6%) 5 (11.4%)	40 (87%) 6 (13%)	0.808
Polypharmacy Yes No	19 (21.1%) 71 (78.9%)	11 (25%) 33 (75%)	8 (17.4%) 38 (82.6%)	0.337
Histology Ductal carcinoma Lobular carcinoma Others	74 (82.2%) 12 (13.3%) 4 (4.4%)	35 (79.5%) 7 (15.9%) 2 (4.5%)	39 (84.8%) 5 (10.9%) 2 (4.3%)	0.777
Grade 1–2 3	63 (70%) 27 (30%)	41 (93.2%) 3 (6.8%)	22 (47.8%) 24 (52.2%)	< 0.001
Menopausal Status Premenopause Postmenopause	41 (45.6%) 49 (54.4%)	22 (50%) 22 (50%)	19 (41.3%) 27 (58.7%)	0.408
Breast cancer De novo Recurrent	44 (48.9%) 46 (51.1%)	24 (54.5%) 20 (45.5%)	20 (43.5%) 26 (56.5%)	0.294
Metastatic sites Visceral Non-visceral	51 (56.7%) 39 (43.3%)	22 (50%) 22 (50%)	29 (63%) 17 (37%)	0.212
Metastatic sites Bone Liver Lung Cranial Lymph nodes, distant	79 (87.8%) 16 (17.8%) 29 (32.2%) 3 (3.3%) 23 (25.6%)	41 (93.2%) 7 (15.9%) 14 (31.8%) 0 9 (20.5%)	38 (82.6%) 9 (19.6%) 15 (32.6%) 3 (6.5%) 14 (30.4%)	0.126 0.650 0.936 0.085 0.278
Number of metastatic sites 1 2 ≥3	47 (52.2%) 22 (24.4%) 21 (23.3%)	24 (54.5%) 10 (22.7%) 10 (22.7%)	23 (50%) 12 (26.1%) 11 (23.9%)	0.902
Prior therapy for EBC Surgery Chemotherapy Endocrine therapy	54 (60%) 46 (51.1%) 46 (51.1%)	24 (54.5%) 20 (45.5%) 20 (45.5%)	30 (65.2%) 26 (56.5%) 26 (56.5%)	0.302 0.294 0.294
Endocrine therapy during CDK4/6i Aromatase inhibitors Fulvestrant	76 (84.4%) 14 (15.6%)	38 (86.4%) 6 (13.6%)	38 (82.6%) 8 (17.4%)	0.623
Dose Reduction Yes No	45 (50%) 45 (50%)	21 (47.7%) 23 (52.3%)	24 (52.2%) 22 (47.8%)	0.673
(CAD: Coronary Artery Disease, CDK 4/6i: Cyclin-Dependent Kinase 4/6 inhibitor, DM: Diabetes Mellitus, EBC: Early Breast Cancer, ECOG-PS: Eastern Cooperative Oncology Group-Performance Status, HT: Hypertension)

In the present study, the patients using fulvestrant (n = 14, 15.6%) with CDK4/6i were those who developed recurrence under adjuvant AI therapy. Among the patients in the study, 39 had non-visceral metastases, and 51 had visceral metastases. PFS was significantly shorter in patients with liver metastases compared with those without. However, no significant relationship was found between other metastasis sites and PFS. Forty-six patients (51.1%) had metastatic disease after undergoing curative treatment for primary breast cancer, while 44 patients were de-novo metastatic; there were no significant differences in PFS among these patients (p: 0.130) (Table 2).

Table 2

Univariate and multivariate analyses of PFS
	Univariate analysis			Multivariate analysis
Variables	HR	95%CI	p value	HR	95%CI	p value
Age < 65 years (R) ≥ 65 years	0.60	0.29–1.25	0.174
Menopausal Status Premenopause Postmenopause	1.08	0.60–1.94	0.787
Smoking Yes No (R)	0.65	0.28–1.56	0.342
Polypharmacy Yes No (R)	1.14	0.56–2.30	0.714
Grade 1–2 3	1.75	0.96–3.19	0.069
Luminal type Luminal A Luminal B	2.28	1.24–4.21	0.008	1.39	0.52–3.67	0.511
Breast cancer De novo Recurrent	1.57	0.87–2.83	0.130
Metastatic sites Non-visceral (R) Visceral	0.93	0.52–1.67	0.820
Bone metastasis Yes No (R)	1.50	0.59–3.80	0.392
Liver metastasis Yes No (R)	2.23	1.17–4.24	0.014	1.55	0.76–3.16	0.227
Lung metastasis Yes No (R)	0.62	0.31–1.22	0.163
Cranial metastasis Yes No (R)	1.87	0.45–7.75	0.387
Lymph nodes, distant Yes No (R)	0.95	0.48–1.87	0.878
Endocrine therapy during CDK 4/6i Aromatase inhibitors (R) Fulvestrant	2.05	1.01–4.15	0.045	1.98	0.96–4.08	0.064
CDK 4/6i adverse events Yes No (R)	1.71	0.41–7.06	0.458
Dose Reduction Yes No (R)	0.92	0.51–1.64	0.780
ER (ROC) ≤ 80 > 80 (R)	2.48	1.36–4.52	0.003	2.50	1.36–4.61	0.003
PR (ROC) ≤ 50 >50 (R)	1.80	1.0-3.25	0.05	1.69	0.92–3.11	0.088
Ki-67 (ROC) < 30 (R) ≥ 30	2.31	1.28–4.14	0.005	2.22	1.22–4.05	0.009
ECOG 1–2 (R) 3	1.20	0.47–3.06	0.696
Number of metastatic sites 1 (R) 2 ≥ 3	1.16 1.27	0.59–2.43 0.63–2.53	0.695 0.503
(CDK 4/6i: Cyclin-Dependent Kinase 4/6 inhibitor, ECOG-PS: Eastern Cooperative Oncology Group-Performance Status, ER: Estrogen receptor, HR: Hazard ratio, PR: Progesterone receptor)

The cut-off values for ER, PR, and Ki-67 levels were determined by ROC curve analysis. It was found as 80% for ER level [AUC:0.650 (0.537–0.763), p: 0.014], 50% for PR level [AUC: 0.624 (0.506–0.741), p: 0.044], and 30% for Ki-67 level [AUC:0.644 (0.529–0.758), p: 0.019]. Associations between PFS and patients' and tumors' characteristics were investigated using cox-regression analysis. In univariate analysis, PFS was significantly longer in patients with luminal A subtype, without liver metastases, receiving AI, with ER-level greater than 80%, PR-level greater than 50%, and Ki-67 expression less than 30%. In multivariate analysis, PFS was significantly longer in patients with ER-level greater than 80% and Ki-67 expression less than 30% (Table 2). The PFS of the patients according to ER level and ki-67 expression is shown in Figs. 1 and 2. Among the patients included in our study, the median PFS was 22.41 months (15.73–29.08, 95% CI) in the patients with only a Ki-67 level of 30% and above, while the median PFS was 17.24 months (14.86–19.62, 95% CI) in the patients with only an ER level of 80% and below. In the patients with a combined ER of 80% or less, and a Ki-67 of 30% or more, the median PFS was 12.42 months (8.12–16.72, 95% CI) (Fig. 3).

The median follow-up time was 30 months. The median PFS (mPFS) of all patients was 27.3 months (95%CI, 20.9–33.7). mPFS in patients with luminal-A type was not reached, and mPFS with luminal-B type was 19.2 months (95%CI, 13.1–25.3)(p:0.018). The median OS (mOS) of all patients was not reached. In addition, mOS in patients with luminal A type was not reached, and mOS in patients with luminal B type was 36.8 months (p:0.438). The survival rates of the patients with luminal A and luminal B types were 100% and 95.9% at 12 months, 82.8% and 85.3% at 24 months, and 76% and 59.3% at 36 months, respectively. The PFS of the patients with luminal A and luminal B types were 86.4% and 76.1% at 12 months, 63.8% and 43.1% at 24 months, and 51.8% and 27.4% at 36 months, respectively.

This study evaluated the predictive factors of pathological and clinical characteristics that can inform the prognosis of MBC patients treated with CDK4/6i. Our results demonstrated that CDK4/6i therapies had longer PFS in patients with ER levels greater than 80% and Ki-67 expression less than 30% (p < 0.05). In univariate analysis, PFS was significantly longer in patients with luminal A subtype and PR levels greater than 50%. However, multivariate analysis showed that PR levels and luminal subtypes are not associated with prolonged PFS. Similarly, the presence of liver metastases was significantly prognostic in the univariate analysis but not in the multivariate analysis. No significant OS difference was observed between luminal A and B subtypes (p:0.438).

CDK4/6is are now the standard first-line treatment for HR-positive and HER2-negative MBC. However, no strong predictor exists which tumors will respond better to CDK4/6i. It is known that the luminal subtype is not just sufficient to decide on treatment choice and predict CDK4/6i response (15). ER and PR positivity and HER2 status are widely accepted in breast cancer prognosis. It is known that higher levels of ER and PR are associated with longer PFS and OS in MBC (16). However, it is not clear to what extent ER and PR levels predict the response to CDK4/6i. ER positivity was the best predictor of CDK4/6i and hormone therapy in a large pooled US Food and Drug Administration (FDA) analysis. However, the relationship between ER level and response rate has not been investigated, and PR status was not considered as a predictive marker in this study (6). In our study, the patients with ER levels > 80% had significantly longer PFS than those with ER levels < 80% (33.7 vs 17.1 months, p: 0.002). The SONIA trial compared the patients who received first-line nonsteroidal AI (NSAI) plus a CDK4/6i and then received single-agent fulvestrant upon disease progression or the patients who received first-line NSAI and then received fulvestrant plus a CDK4/6i upon disease progression. No significant differences in PFS2 or OS emerged between treatment arms. In this case, it was discussed in which patients using CDK4/6is in the first-line setting should be preferred in terms of cost-effectiveness (17).

In an analysis of the MONARCH-2 and MONARCH-3 studies, shorter PFS was observed in patients receiving AI alone with either PR-negative or high-grade tumors. However, there was no significant relation between PFS and these factors in the group that received abemaciclib in combination with endocrine therapy (18). Cristofanilli et al. investigated the factors that predicted the long-term benefit of palbociclib and fulvestrant in their analysis of the PALOMA-3 study. They showed that a high level of PR expression was associated with a longer duration of benefit (19).

The choice of therapy in MBC is based on prognostic factors such as histological tumor type, tumor size, nodal status, grade, age, HR status, and the Ki-67 expression. Ki-67 is a nuclear protein identified in 1983 and expressed during all cell cycle phases except G0. Many studies have investigated the potential use of Ki-67 as a prognostic marker for breast cancer (16). Clinical and pathological responses to neoadjuvant chemotherapy in breast cancer patients were better in those with higher Ki-67 levels (20). The MonarchE study showed that the patients with high Ki-67 achieved a statistically significant improvement in invasive disease-free survival (iDFS) with abemaciclib in combination with adjuvant endocrine therapy (21). Although studies have shown that high Ki-67 levels are associated with better chemotherapy response in MBC, it is known that Ki-67 is a poor prognostic marker (15). Metaanalysis by Azambuja et al. confirmed that high Ki-67 levels confer a worse DFS and OS in breast cancer (22). Wang et al. identified Ki-67 as a significant predictor of PFS in patients with MBC receiving palbociclib, which is consistent with the findings of Lee et al. (23, 24). Our study showed that PFS was significantly shorter in the patients with Ki-67 expression ≥ 30%. mPFS was not reached in the patients with Ki-67 expression < 30%, while mPFS was 19.2 months in the patients with Ki-67 expression ≥ 30% (p:0.004). In the study that investigated treatment with CDK4/6i, similar to our research, PFS was negatively affected by high Ki-67 expression but not associated with PR levels (12).

The mPFS of all patients was 27.3 months, and 19.2 months in the patients with the luminal-B subtype. In the MONALEESA-7 study, mPFS reached 23.8 months in premenopausal patients with ribociclib, while in the MONALEESA-3 study, mPFS in postmenopausal patients was 20.5 months. In the MONALEESA-7 study, some of the patients had received chemotherapy before receiving CDK4/6i in the advanced stage, while in the MONALEESA-3 study, they had received hormone therapy (25, 26). The longer PFS in our study may be because of the first treatment of the patients in the study was CDK4/6i in the advanced stages. While liver metastasis is associated with poor prognosis in breast cancer patients, better PFS may be the result of small number of patients with liver metastasis in our study. Our data showed that PFS was shorter in patients with liver metastasis in univariate analysis. However, this was not statistically significant on multivariate analysis, possibly because of the small number of patients with liver metastasis.

In our study, PFS was significantly shorter in the patients using fulvestrant with CDK4/6i. The patients using fulvestrant consist who progressed while taking adjuvant AI therapies, and these patients are considered endocrine resistant. As shown in clinical studies, the contribution of CDK4/6i to PFS is less in endocrine-resistant patients than in endocrine-sensitive (23).

In the PALOMA-2 and MONALEESA-3 studies, dose was reduced in 36% and 37.9% of the patients, respectively, while this rate was 50% in our study (26, 27). Similar to the PALOMA-2 study, no significant difference in PFS was observed in patients with dose reduction in CDK4/6i treatment. The rate of all-grade adverse events in the PALOMA-2 study was 98.9%, whereas 99% in the MONALEESA-3 study. In our study, any grade adverse event occurred in 93.3% of the patients (26, 27).

This study has some limitations. Our research is a retrospective study with a limited sample size, and endocrine-resistant patients were also included. However, the present study has multiple strengths. The patients who were admitted to three different oncology outpatient clinics were included in the study, and our findings reflect real-world patient populations. The patients did not use any other treatment, such as chemotherapy or hormone therapy, before CDK4/6i treatment in the advanced stage.

CDK4/6is broke new ground in the treatment of HR-positive, HER2-negative MBC by providing significant contributions to PFS and OS. However, on the other hand, they are associated with both drug and financial toxicities. Therefore, it is essential to determine which patient group benefits more from first-line CDK4/6is. Comprehensive studies will ensure which cost-effective treatments may lead maximum benefit to the patients with minimum toxicity.

Conflict of interest disclosure: The authors declare that they have no conflict of interest.

Ethical approval: The study was approved by the local ethics committee (identifier: 2022/396).

Compliance with Ethical Standards: The study protocols in data collection were performed by the ethical standards of the 1964 Helsinki declaration and its later amendments.

Funding: None

Author contributions: Z.S.I, A.I.Y, M.S. and A.T. designed the study and wrote the main manucscript text, Z.S.I., H.M and Z.A.T collected the data, H.M.T, M.S. and, M.B have done the statistics. All authors reviewed the manuscript.

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No competing interests reported.

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Factors Affecting the Survival of Metastatic Breast Cancer Patients Treated With Cdk 4/6 Inhibitors

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Abstract

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INTRODUCTION

MATERIALS AND METHODS

Statistical analysis

RESULTS

DISCUSSION

Conclusion

Declarations

References

Additional Declarations

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