Risk of neutropenia and healthcare resource utilization in patients with metastatic breast cancer treated with CDK4/6 inhibitors in real-world setting

Örebro University School of Medical Sciences Degree project, 15 ECTS

January 2020

Risk of neutropenia and healthcare resource utilization in patients with metastatic breast cancer treated with CDK4/6 inhibitors in real-world setting

Author:

Anna Bergkvist

Supervisor:

Antonios Valachis, docent and senior consultant at the Department of Oncology,

Abstract

Introduction: In patients with metastatic estrogen-receptor (ER) positive breast cancer, the

current standard of care as first or second line treatment is a combination of endocrine therapy with a CDK 4/6-inhibitor. Neutropenia is a dose-limiting toxicity of CDK 4/6 inhibitors leading to dose adjustment and treatment discontinuation in a considerable number of

patients. The healthcare resource utilization pattern due to neutropenia in patients treated with CDK 4/6 inhibitors has not been studied in real-world setting.

Aim: To identify the rate of neutropenia in breast cancer patients treated with CDK4/6

inhibitors palbociclib or ribociclib in clinical practice, and investigate the healthcare resource utilization between the two types of CDK 4/6 inhibitors as well as between patients with neutropenia versus those without neutropenia.

Method: A retrospective cohort study based on electronic medical records of all patients with

ER-positive breast cancer patients treated with CDK 4/6 inhibitors at the Department of Oncology at Örebro University Hospital, between January 2018 and June 2020 was performed.

Results: Sixty-nine patients were included in the study cohort. The rate of grade III-IV

neutropenia was 65%. No statistically significant difference between palbociclib and

ribociclib was observed regarding rate of neutropenia or healthcare resource utilization. The mean number of extra blood analyses (2.04 vs. 0.13; p-value < 0.001) and the mean number of extra telephone contacts (1.69 vs. 0.83; p-value = 0.013) were higher among patients who developed neutropenia compared to patients without neutropenia. No increased risk for in-person visits or hospitalization in patients with neutropenia was observed.

Conclusion: The rate of neutropenia is high among patients treated with CDK 4/6 inhibitors

in daily clinical practice but in accordance with the evidence from randomized trials. Some aspects of healthcare resource utilization are increased due to neutropenia. Healthcare providers need to organize their clinical practice based on the potential need to allocate specific healthcare resources for patients treated with CDK 4/6 inhibitors.

Abbreviations

AI: Aromatase inhibitor

ANC: Absolute neutrophil count CDK: Cyclin dependent kinase ER: Estrogen receptor

HER-2: Human epidermal growth factor receptor 2 MBC: Metastatic breast cancer

NHG: Nottingham Histologic Grade PR: Progesterone receptor

pRB: Protein RB

Index

1. Introduction ... 1

1.1 Epidemiology ... 1

1.2 Histological and anatomical classification of breast cancer ... 1

1.3 Treatment of metastatic breast cancer (MBC) ... 1

1.4 CDK 4/6 inhibitors ... 2

1.5 Neutropenia as dose-limiting toxicity of CDK 4/6 inhibitors ... 3

1.6 Health care resource utilizations ... 3

2. Aim ... 4

2.1 Questions at issue ... 4

3. Material and methods ... 4

3.1 Study design and settings ... 4

3.1.2 Data collection process ... 4

3.1.3 Definitions ... 5 3.2 Statistical methods ... 6 3.3 Ethical considerations ... 6 4. Results ... 6 4.1 Study cohort ... 6 4.2 Patient characteristics ... 7 4.3 Rate of neutropenia ... 8

4.4 Healthcare resource utilization ... 8

5. Discussion ... 10

5.1 Limitations ... 12

6. Conclusion ... 12

1. Introduction

Breast cancer is the most common type of cancer amongst females in Sweden and globally [1– 3]. Every tenth woman will some time in her life be diagnosed with breast cancer [4]. In Sweden, 10 126 individuals were diagnosed with breast cancer during 2018, including 10 063 women and 63 men. [5]. The relative 5- and 10-year breast cancer survival is high, corresponding to

approximately 92% for 5-year and 86% 10-year survival, respectively [4]. Despite the high survival rate, approximately 1400 individuals die from breast cancer each year in Sweden. [6]. 1.2 Histological and anatomical classification of breast cancer

Morphologically, breast cancer is classified based on tubule formation, nuclear pleomorphism and mitotic activity into three grades according to the NHG (Nottingham Histologic Grade) [7]. The anatomical classification of breast cancer is performed according to the TNM classification system. T is the determination of the primary tumor size, N assesses whether regional lymph nodes are invaded or not, and to which extent they are invaded, and M shows the occurrence of distant metastases. The TNM classification is used as prognostic indicator but is also a useful guide for treatment decision making. The TNM classification can be translated into an anatomical tumor stage that classifies breast cancer into four stages, namely from I to IV [8]. Several immunohistochemical factors are also used as prognostic and predictive factors in breast cancer patients. The most common is the ER (estrogen receptor), which is expressed in

approximately 80% of all breast tumors. ER-status is correlated to how well the tumor will respond to endocrine treatment. Expression of the PR (progesterone receptor) is an additional immunohistochemical marker with prognostic value. HER-2 (human epidermal growth factor receptor 2) is a transmembrane growth factor receptor that is overexpressed in approximately 15% of breast cancer patients and its overexpression is associated with worse prognosis but it is also a predictive factor for response to specific treatment against HER2. Finally, Ki67 is a proliferation marker [4] and is associated with negative prognosis when it is high [9]. 1.3 Treatment of metastatic breast cancer (MBC)

In general, the goals of treatment in patients with MBC are to prolong survival without compromising the quality of life and, if possible, to improve the quality of life. The choice of treatment is depending on patients’ health status, comorbidities, metastatic pattern, subtype of breast cancer, and patients’ preferences [10].

Regarding breast cancer subtype, three different subtypes should be considered before treatment decision making in metastatic setting, namely luminal (ER-positive) breast cancer, HER2-positive breast cancer, or triple negative breast cancer. To distinguish among these three

subtypes, immunohistochemical analyses are necessary. When the cancer metastasizes, there is a risk that the metastatic disease is different in some characteristics from the primary tumor. The ER- and PR-status can be changed in around every third patient whereas the HER2 status can be changed in every tenth patient. It is, therefore, important to re-analyze these markers by taking biopsy from metastatic lesion in order to be able to choose the most adequate treatment strategy in MBC [4,10].

Treatment with aromatase inhibitors (AI) has been the standard of care as first line treatment strategy in postmenopausal women with MBC of luminal type [4,11,12]. Chemotherapy could also be given to this breast cancer subtype as first line treatment strategy but only in cases of visceral crisis [4]. However, recent randomized trials have shown that the addition of a CDK 4/6 inhibitor to endocrine therapy leads to a statistically significant and clinically meaningful

improvement in both progression-free and overall survival compared to endocrine therapy alone [4,13]. For premenopausal women with luminal MBC, the addition of CDK 4/6 inhibitors along with GnRH-analogue and endocrine therapy with AI has also shown a survival benefit [4,14]. CDK 4/6 inhibitor combined with fulvestrant, which is another type of endocrine therapy, has also been associated with improved survival as second line treatment in patients with luminal MBC who received endocrine therapy alone as first line treatment [4].

1.4 CDK 4/6 inhibitors

Palbociclib (Ibrance) and ribociclib (Kisqali) are two different pharmaceutical agents within the same drug class, CDK 4/6 inhibitors, with similar chemical structure and similar potencies [13]. CDK (cyclin dependent kinase) are important enzymes to the cells, facilitating the progress during the cell cycle. CDK 4/6 takes the cell from G1 to S-phase [4,13,15]. CDK 4 or CDK 6 need to be a complex with cyclin D to be activated. This complex will then initiate

phosphorylation of pRB (protein RB), and other proteins in the RB family [16] that will lead to the release of E2F transcription factors which are essential for DNA synthesis by allowing the cell to move from G1 to S-phase of the cell cycle [12,13].

CDK 4 and 6, leading to inactivation of the cyclin D and CDK4/6 complex. This leads to an increased activity of pRB and an arrest of the cell cycle in G1 phase. The results of this

inhibition is an increased apoptosis of the tumor cells [13,15,17]. A recent study has shown that the CDK 4/6 inhibitors might also have some immunologic effects, where they most likely increase the tumors antigen presenting skills. At the same time, the inhibitors seem to reduce the T regulator lymphocytes which are immunosuppressive and in turn could enhance activation of the cytotoxic T cells [12].

1.5 Neutropenia as dose-limiting toxicity of CDK 4/6 inhibitors

Neutropenia is defined by the ANC (absolute neutrophil count), which refers to the product of the total leucocyte count and the percentage of neutrophils in the peripheral blood by a

differential leucocyte count. Neutropenia is defined as ANC < 1500 cells/mm³ and it can be graded as mild (1000-1500 cells/mm3) , moderate (500-1000 cells/mm3) and severe (< 500 cells/mm3) [18].

Neutropenia is the most common adverse event to these two types of drugs [13,19]. In the randomized PALOMA-1, -2 and -3 trials grade III-IV neutropenia has been reported as the most common adverse event, affecting between 54-70% of all patients receiving palbociclib [20–22]. For ribociclib similar results has been seen in the randomized MONALEESA-2, -3 and -7 trials, where the incidence of grade III-IV neutropenia was between 53.4-63.5% [14,23,24]. In spite this being such a common adverse event, the neutropenia due to CDK 4/6 inhibitors can most often be treated with temporary treatment breaks or a dose reduction and it is rarely the cause for discontinuation of treatment [19,21,23–27].

The mechanism for neutropenia induced by CDK 4/6 inhibitors is through bone marrow

suppression due to the cell cycle arrest, therefore the proliferation of the hematopoetic stem cells is decreased. This process is reversible [28]. The presence of neutropenia increases the risk of infection and infectious complications [29]. Febrile neutropenia is a condition with both

neutropenia and a body temperature of > 38.5°C at one instance or >38.0°C for at least one hour. Only the suspicion of a febrile neutropenia require a quick administration since the condition fast could turn in to a life threatening septic condition [30].

1.6 Health care resource utilizations

Since breast cancer is one of the most common types of cancer, it is relevant to investigate the burden of this disease on the healthcare systems in terms of healthcare resource utilization and

cost. Neutropenia is a common adverse event of CDK 4/6 inhibitors that might result in increased healthcare resource utilization with more blood analyses, in-person visits, or

hospitalizations. The healthcare resource utilization due to neutropenia among patients treated with CDK 4/6 inhibitors in real-world setting has not been studied [18].

2. Aim

The purpose of this study was to identify the rate of neutropenia in breast cancer patients treated with palbociclib or ribociclib in clinical practice and investigate the healthcare resource

utilization between patients treated with the two CDK 4/6 inhibitors and between patients with neutropenia versus those without neutropenia.

2.1 Questions at issue

How many breast cancer patients treated with CDK4/6 inhibitors palbociclib and ribociclib develop grade III or IV neutropenia? Are there differences in healthcare resource utilization between patients treated with palbociclib and ribociclib or between patients with neutropenia and those without neutropenia?

3. Material and methods

This was a retrospective cohort study. The cohort consisted of all patients that received CDK 4/6 inhibitors palbociclib or ribociclib due to MBC at the Department of Oncology, Örebro

University Hospital between January 2018 and June 2020. The patients have been identified through the Swedish National Database for new cancer therapy. We excluded patients without metastatic disease, patients treated with CDK 4/6 inhibitors due to other type of cancer than breast cancer. For patients treated with both CDK 4/6 inhibitors subsequently, we included only the period of first exposure to a CDK 4/6 inhibitor.

3.1.2 Data collection process

The data have been extracted from the patients’ electronic medical records in a structured manner.

Following data has been extracted from the medical records: age at diagnosis, date of diagnosis. Charlson comorbidity index, ER-status, PgR-status, NHG, Ki-67, pT and pN stage, tumor stage; information on treatment strategies at primary diagnosis including surgical procedures,

date for discontinuation; data on recurrence including date of recurrence, age at recurrence, metastatic location; line of treatment when CDK 4/6 inhibitors were given, type of CDK 4/6 inhibitor, treatment combination with CDK 4/6 inhibitor – aromatase inhibitor or fulvestrant, chemotherapy use in metastatic setting before CDK 4/6 inhibitor, performance status at start of CDK 4/6 inhibitor, date for discontinuing CDK 4/6 inhibitor, reason for discontinuing CDK 4/6 inhibitor, development of neutropenia grade III-IV, dose adjustments due to toxicity, liver toxicity due to ribociclib.

The outcomes of interest regarding healthcare resource utilization were: the number of extra blood tests performed considering as standard blood tests on cycle 1 day 1, cycle 1 day 15, cycle 2 day 1, cycle 2 day 15, and then day 1 for each cycle; any extra telephone contact considering as standard contact one telephone contact after each blood test; the number of extra in-person visits to the nurse considering as standard visit one visit on day 1 for each cycle; extra in-person visit to oncologist considering as standard one visit every three months; number of hospitalizations due to any cause during the exposure time to CDK 4/6 inhibitors.

3.1.3 Definitions

The presence of comorbidity was assessed by Charlson Comorbidity index which is a well-established tool for comorbidities that predicts the 10-years survival in patients based on comorbidities [31].

Performance status according to the Eastern Cooperative Oncology Group was used to measure how the cancer disease impacts a patient’s daily living abilities. The patients can be categorized into four categories (0 to 4) according to their performance status. [32].

The distinction between Luminal A and luminal B breast cancer was done using the following definition: Luminal A-like tumors are ER-positive, HER2-negative and have a low (<14%) or

intermediate (14-19%) Ki-67 expression and high (>20%) PR levels. Luminal B-like tumors are ER-positive, ER-negative, have an intermediate or low (<20%) PR level or a high (>20%) Ki-67 expression [33].

Neutropenia grade III-IV was defined according to the Common Terminology Criteria for Adverse Events version 4 as grade III in case of ANC between 500 and 1000/mm3 _{and grade IV}

3.2 Statistical methods

Data were extracted to an excel file Microsoft Excel (version 16.42) and later were processed in the statistical program SPSS (version 27.0).

Categorical variables were expressed as numbers and percentages whereas continuous variables as median and interquartile range. For comparisons between categorical variables, chi-square test was performed. For comparisons between presence of neutropenia (yes vs. no) or type of CDK 4/6 inhibitor (palbociclib vs. ribociclib) and healthcare resource utilization outcomes, the non-parametric Mann-Whitney test (due to non-normally distributed variables) was used to compare the potential differences in mean ranks.

3.3 Ethical considerations

The study was an internal quality assurance for the Department’s treatment strategies and not a research for publication, hence no ethical approval was required. An approval from the Head of the Department was given to ensure that the process would be in accordance to the GDPR practice. Each patient’s Swedish personal identification number and name was coded for the collection of data so that patients’ identities cannot be revealed. The code key has been stored in a secure and locked room at the Department of Oncology.

4. Results

In total, the study cohort consisted of 69 patients (Fig. 1).

Patients treated with CDK 4/6 inhibitors according to the National Swedish Database for

new cancer therapy.

n = 75

Patients included

n = 69

Patients treated with CDK 4/6 inhibitors at two time periods

n = 4 No breast cancer diagnosis

n = 1 Adjuvant therapy

Figure 1. Flowchart of study cohort selection process.

4.2 Patient characteristics

The patients’ characteristics are presented in Table 1. Within the study cohort, 57 patients (83%) were treated with palbociclib whereas 12 patients (17%) with ribociclib. The CDK 4/6 inhibitors were used as first line treatment in 28 patients (40%), as second line in 15 patients (22%), and as third or more advanced lines in 26 patients (38%). The reason for discontinuing the treatment was related to progression of the disease for 43 patients (62%) whereas 7 patients (10%) ended the treatment due to toxicity. Thirteen patients still had an ongoing treatment at the time for the last follow-up date.

Table 1. Baseline patient- and tumor characteristics

Characteristics median (range)

Age at diagnosis 53 (34-83)

Charlson Comorbidity Index 1 (0-9)

Age at recurrence 62 (37-83)

n (%)

Molecular subtype (primary diagnosis) Luminal A Luminal B Missing 27 (39) 26 (38) 16 (23) Stage (primary diagnosis)

I II III IV Missing 13 (19) 13 (19) 22 (32) 10 (14) 11 (16) Surgical procedure No surgery

Breast conserving surgery Mastectomy Missing 9 (13) 30 (44) 27 (39) 3 (4)

Neoadjuvant / adjuvant Chemotherapy 33 (48)

Adjuvant Radiotherapy: No radiotherapy Local radiotherapy Locoregional radiotherapy Missing 14 (20) 24 (35) 28 (41) 3 (4)

Adjuvant Endocrine therapy 23 (33)

Line of treatment for CDK 4/6-inhibitor 1 2 3+ 28 (40) 15 (22) 26 (38)

Type CDK 4/6 inhibitor: Palbociclib

Ribociclib 57 (83) 12 (17)

Backbone endocrine therapy with CDK 4/6 inhibitor: Aromatase inhibitors

Fulvestrant 37 (54) 32 (46)

Chemotherapy against metastatic disease before CDK

4/6 inhibitor 8 (12)

Performance status (at the time of CDK 4/6-inhibitor initiation) 0 1 2 Missing 16 (23) 27 (39) 8 (12) 18 (26) Reason for discontinuation of CDK 4/6-inhibitor

Disease progression Toxicity

Patient’s choice Physician’s choice Impaired health status Death

Ongoing treatment at the time of last follow-up date

43 (62) 7 (10) 2 (3) 1 (1.5) 1 (1.5) 2 (3) 13 (19) 4.3 Rate of neutropenia

The rate of neutropenia within the study cohort was 65%. Among the patients who developed neutropenia, 29 patients (42%) needed dose adjustment. The hospitalization rate due to any reason during treatment with CDK 4/6 inhibitors was 9%. There was no statistically significant difference regarding rate of neutropenia, need for dose adjustments and hospital admissions between palbociclib and ribociclib (Table 2).

Table 2. Outcomes regarding toxicity in patients treated with palbociclib and ribociclib.

Outcome Total N = 69 n (%) Palbociclib N = 57 n (%) Ribociclib N = 12 n (%) P-value

Neutropenia grade III-IV 45 (65) 38 (67) 7 (58) 0.582

Dose adjustment due to

neutropenia 29 (42) 25 (44) 4 (33) 0.749

Hospital admissions 6 (9) 5 (9) 1 (8) 1.000

4.4 Healthcare resource utilization

Patients who developed neutropenia had an increased healthcare resource utilization in terms of extra blood analyses and extra telephone contact compared to those without neutropenia (Table

3; Fig. 2 and 3). No difference between patients with and without neutropenia was observed regarding extra in-person visits to nurse or physician, and hospitalization rate (Table 3). No difference in the different aspects of healthcare resource utilization was observed between patients treated with palbociclib and those treated with ribociclib (Table 4).

Table 3. Healthcare resource utilization between patients with and without neutropenia due to

CDK 4/6-inhibitors Presence of neutropenia N = 45 Absence of neutropenia N = 24 P-value

Extra blood analyses performed, mean (SD) 2.04 (1.55) 0.13 (0.45) <0.001

Extra telephone contact, mean (SD) 1.69 (1.56) 0.83 (1.20) 0.013

Extra in-person visits to the nurse, mean (SD) 0.13 (0.41) 0.42 (0.93) 0.125

Extra in-person visits to the doctor, mean (SD)

0.09 (0.29) 0.33 (0.76) 0.140

Hospital admission, n (%) 2 (4) 4 (17) 0.173

Figure 2. Distribution of frequencies of extra blood analyses between patients with neutropenia

Figure 3. Distribution of frequencies of extra telephone contacts between patients with

neutropenia compared to those without neutropenia.

Table 4. Healthcare resource utilization between neutropenic patients receiving palbociclib and

ribociclib. Palbociclib N = 57 Ribociclib N = 12 P-value

Extra blood analyses performed, mean (SD) 1.33 (1.57) 1.58 (1.62) 0.539

Extra telephone contact, mean (SD) 1.26 (1.45) 2.00 (1.65) 0.117

Extra in-person visits to the nurse, mean (SD) 0.25 (0.69) 0.17 (0.39) 1.000

Extra in-person visits to the doctor, mean (SD)

0.14 (0.48) 0.33 (0.65) 0.171

Hospital admission, n (%) 5 (9) 1 (8) 1.000

5. Discussion

In our study cohort, including consecutive patients treated with CDK 4/6 inhibitors in a real-world setting, we found a considerable rate of grade III-IV neutropenia. The type of CDK 4/6 inhibitor (palbociclib or ribociclib) did not seem to influence the rate of neutropenia or the healthcare resource utilization. However, an increased healthcare resource utilization for patients who developed neutropenia compared to those without neutropenia was observed with a mean of

two extra blood analyses for each patient and a mean of one extra telephone contact. The high rate of neutropenia due to palbociclib and ribociclib has been shown in both

randomized trials and studies of real-world setting [13,19,25,35]. As a result, our study results showing that more than half of our patients developed neutropenic were expected. Although there are no published studies directly comparing the rate of neutropenia between palbociclib and ribociclib, there are studies investigating each of the CDK 4/6 inhibitors’ rate of grade 3/4

neutropenia. In the randomized PALOMA-1, -2 and -3 trials grade III-IV neutropenia was seen in 54%, 66.4% and 70% of all patients receiving palbociclib, respectively [20–22]. Similar rates have been presented in real-world studies for palbociclib, where grade III-IV neutropenia was developed in 55-60% of the study cohort [25,26,36,37]. Similar results were seen for ribociclib in the randomized MONALEESA-2, -3 and -7 trials, with the incidence of grade III-IV

neutropenia to be ranged between 53.4% and 63.5% [14,23,24]. Limited evidence is published on the toxicity of ribociclib in real-world setting with only one recent study that showed a rate for grade III-IV neutropenia of 69.5% [25]. Our results of neutropenia are, therefore, comparable with the current randomized and non-randomized evidence. Furthermore, the results from the direct comparison between palbociclib and ribociclib in our study cohort are comparable with the indirect comparison from the current evidence between the two drugs. The comparable results between the two CDK 4/6 inhibitors regarding neutropenia can be explained by the similar pharmacological mechanism of action between palbociclib and ribociclib that leads to similar toxicity profile [13,19,25,35]. The number of patients needed dose adjustment due to neutropenia in our study cohort was comparable to previous studies [13,14,19–26,35–37]. Considering the low treatment discontinuation rate in this study as well as in previous ones, it seems that the neutropenia due to CDK 4/6 inhibitors can more often be treated with temporary treatment breaks or a dose reduction and it is rarely the cause for treatment discontinuation [19,21,23–27].

Regarding the healthcare resource utilization, the results showed that the neutropenic patients demanded a mean of 2 extra blood analyses and 1 extra telephone contact to nurse or physician. There was, however, no difference between the two patient groups (neutropenic vs.

non-neutropenic) in healthcare resource aspects with higher cost such as hospital admissions and extra in-person visits to nurse or physician. No previous studies investigating the healthcare resource utilization based on the presence of neutropenia in patients treated with CDK 4/6 inhibitors have been published. When the exploitation of healthcare resource utilization is compared for patients treated with palbociclib or ribociclib, no difference was found. One could

argue that the present study investigates some aspects of healthcare resource utilization and not all the potential aspects. However, our selection process was based on choosing the most common healthcare resource aspects [38] along with those that are relevant considering the expected adverse events of CDK 4/6 inhibitors. As a result, the selected healthcare resource aspects for this study can be considered the most relevant for treatment with CDK 4/6 inhibitors. An interesting observation from our study cohort is the fact that more than one third of the patients received CDK 4/6 inhibitor as third or later line of treatment. This is not in line with the current Swedish National Guidelines where CDK 4/6 inhibitors are recommended as first or second line treatment strategy in patients with luminal MBC [4] but it might reflect the pattern of how a new cancer treatment is introduced into clinical practice.

5.1 Limitations

The study has several limitations that need to be considered when interpreting the results. First, this was a retrospective study and thus prone to information and selection bias due to the

retrospective nature of the study design. In addition, the limited number of patients included into the study cohort makes the generalizability of the results questionable. Furthermore, we did not consider the costs associated with healthcare resource utilization, an aspect of importance when the burden of a specific treatment to the healthcare system is investigated.

6. Conclusion

Our study results confirm the high rate of grade III-IV neutropenia in patients treated with CDK 4/6 inhibitors as it has been evident in randomized trials and studies in real-world settings. We could not reveal any difference regarding the rate of neutropenia or healthcare resource

utilization between palbociclib and ribociclib but further studies with larger cohorts are necessary to investigate this issue. Considering the higher number of extra blood analyses and telephone contacts for patients with neutropenia due to CDK 4/6 inhibitors compared to patients without neutropenia, the healthcare providers need to organize their clinical practice based on the potential need to allocate specific healthcare resources for patients treated with CDK 4/6

inhibitors. Future research should include not only healthcare resource utilization but also the cost attributed to adverse events due to CDK 4/6 inhibitors to present a more reliable model on the burden of treatment with CDK 4/6 inhibitors to the healthcare system.

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