The impact of CDK4/6 inhibitors on the quality of life of working-age women with metastatic breast cancer: a population-based cohort study from Portugal

Ethical considerations

The study was performed in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. The study protocol was submitted to the ethics committee of Portuguese Institute of Oncology (IPO) of Coimbra and approved on January 24, 2022 (TI 33/2021). Participants written and signed Informed Consent Form was obtained prior to any study-related activity.

Study design and participants

This is a unicentric prospective observational cohort study assessing the PROs on QoL and work activity of working-age women with HR+/HER2- metastatic breast cancer who started treatment with a CDK4/6i combined with AI or fulvestrant. We also intended to evaluate the patient-reported adverse events.

The recruitment period of the study occurred from April 2022 to March 2023, and patients were enrolled from the IPO of Coimbra, in Portugal. All patients that were about to start treatment with a CDK4/6i combined with AI or fulvestrant, irrespective of the line of treatment, were identified by the clinical research team as potential eligible participants.

To be enrolled in the study, participants must meet all the following inclusion criteria and none of the exclusion criteria. Inclusion criteria: i) Women aged 18 years old or older; ii) any menopausal status; iii) working-age women, including homemakers, unemployed, students or women on sick leave; and iv) histologically confirmed diagnosis of HR+/HER2- metastatic breast cancer and be followed in Medical Oncology consultation of the IPO of Coimbra were eligible to enroll the study. Exclusion criteria included: i) Male patients; ii) retired women; and iii) patients already undergoing treatment with CDK4/6is.

The study cohort included 35 women with ages ranging between 26 and 67 years old.

PRO assessment and data collection

After signing the informed consent form, participants were asked to complete three questionnaires concerning their health-related quality of life (HRQOL) at four different time points: at baseline (C0), on day 1 of cycles 2 (C2), 3 (C3), and 7 (C7). In addition, questionnaires were filled out whenever there was disease progression, or the treatment was discontinued. PROs were analyzed using the validated European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire C30 version 3 (QLQ-C30)^18,19 and the breast cancer-specific Questionnaire (EORTC QLQ - BR23),^20,21 and the translated version of the Work Productivity and Activity Impairment questionnaire - General Health (WPAI:GH).²²

The EORTC QLQ-C30 version 3 is a 30-item questionnaire composed of a global QoL subscale, five multi-item functional subscales (physical, role, emotional, cognitive, and social functioning), three multi-item symptom scales (fatigue, nausea/vomiting, and pain), and five single-item symptom scales assessing other cancer-related symptoms (dyspnea, sleep disturbance, appetite loss, constipation, and diarrhea).²³ The questionnaire consists of 28 4-point Likert scale items, with options from “not at all” to “very much”, to assess functioning and symptoms, and two 7-point Likert scale items for global health and overall QoL.

The EORTC QLQ-BR23 is a 23-item breast cancer-specific companion module to the EORTC QLQ-C30. It consists of four functional scales (body image, sexual functioning, sexual enjoyment, future perspective) and four symptom scales (systemic side-effects, breast symptoms, arm symptoms, upset by hair loss).

Responses to all items of EORTC QLQ-C30 and EORTC QLQ-BR23 were converted into a 0–100 scale, using a standard scoring algorithm. For functional and global QoL scales, higher scores represent a better level of functioning/QoL than lower scores. On the other hand, for symptom-oriented scales, higher scores represent greater symptom severity.

The WPAI:GH is a 6-item questionnaire composed of the following questions: Q1 = currently employed; Q2 = working hours missed due to health problems; Q3 = working hours missed due to other reasons; Q4 = hours worked; Q5 = health condition affected productivity during work and Q6 = health condition affected daily activities. WPAI outcomes are expressed as impairment percentages, with higher numbers indicating greater impairment and less productivity, reflecting worse outcomes. Absenteeism is defined as the percentage of time absent from work, in the last week, due to health conditions. It is calculated as Q2/(Q2 + Q4) × 100%. Presenteeism is measured by the how health problems affected work productivity, over the last 7 days, on a rating scale ranging from 0 to 10, with 0 indicating that health problems had “no effect on my work” and 10 indicating that “health problems completely forbid me from working”. The outcome is expressed as a percentage of impairment due to health issues, during work. Higher scores indicate greater impairment and, consequently, less productivity. This is calculated as (Q5/10) × 100%. Overall percentage of work impairment due to health conditions is calculated as follows Q2/(Q2 + Q4) + [(1-(Q2/(Q2 + Q4))) × (Q5/10)]. The percentage of activity impairment due to health problems is calculated as Q6/10.

Adverse Events were also evaluated based on data collected from medical records, according to the Common Terminology Criteria for Adverse Events (CTCAE), version 5. This evaluation was carried out on baseline, day 1 of cycles 2, 3, and 7, and whenever disease progression was observed, or when the treatment was discontinued.

Additionally, demographic, and clinical data were collected from medical records from Department of Medical Oncology. Those including age, employment status, comorbidities, ECOG performance status, menopausal status, stage at initial diagnosis, hormone receptor status, prior endocrine therapy and chemotherapy, as well as metastatic sites.

The participants were informed that no personal, health, or genetic information would be provided to third parties unless required by law, health authorities, or ethics committees in order to verify the information obtained in this study. As predicted by Portuguese Law 58/2019, implementing the General Data Protection Regulation (GDPR), all personal data will be considered confidential. To ensure the anonymization of participants personal data and identity, questionnaires were de-identified with a code. The association between the code and the identity was protected by an authorized person of the research team; strict measures were taken to make such information available only to authorized personnel, who will not be able to disclose the participant identity to third parties.

Statistical analysis

Sample size was calculated using the t-test for paired samples (two-sided), assuming a moderate effect with a Cohen’s d of 0.5, a 0.05 significance level and a power of 80%. From this, sample size was calculated as n = 34.

Data analysis was performed using RStudio (RRID:SCR_000432) with R Project for Statistical Computing (RRID:SCR_001905), version 4.2.2. Descriptive analysis of the variables was performed using mean (standard deviation) and median (interquartile range, minimum, and maximum) for quantitative variables and counts (percentages) for qualitative variables. For all analyses, a confidence interval (CI) of 95% was used. Longitudinal analysis was performed using linear mixed models using the glmer function from the R package: lme4 (RRID:SCR_015654).

Cohort characterization

Between April 2022 and March 2023, 35 patients were enrolled in the study, with ages ranging from 26 to 67 years old and a median age of 47 years. All participants presented with advanced metastatic disease at baseline. Of these, a total of 13 individuals (37%) presented with initial stage IV disease.

Regarding employment status, only 10 patients were actively working (either full-time or part-time employed). The remaining participants were homemakers, unemployed, students or on sick leave.

Most patients were previously submitted to endocrine therapy (74.3%) and/or chemotherapy (57.1%). Patient demographic, clinical and pathological characteristics at baseline, are summarized in Table 1.⁴³

In total, 32 patients (91.4%) received ribociclib, two (5.7%) received palbociclib and one patient (2.9%) received abemaciclib. CDK4/6i therapy was combined with fulvestrant in 12 patients (34%) and with letrozole in 23 patients (66%). Most patients received a CDK4/6i combined therapy as first-line treatment (29 patients, 82.9%), whereas six (17.1%) received CDK4/6i combined therapy as second-line treatment.

The questionnaire completion rates for the three questionnaires during the treatment period were 100% at baseline (C0), about 83% at cycle 2 (C2), 74% at cycle 3 (C3), and approximately 49% at cycle 7 (C7) of treatment with the CDK4/6i combined therapy (Table 2).

At the data cut off, 04/30/2023, stable disease (SD) was presented in 24 (69%) patients, seven (20%) had a partial response (PR) and four (11%) patients had disease progression (DP). From the four patients who presented DP, only two have responded to the questionnaires at the time of DP. Therefore, data from those participants were not included in the analysis.

EORTC QLQ-C30

Throughout the duration of the study, mean global QoL scores among participants receiving CDK4/6i combined therapy were maintained when compared to the baseline assessment.

Regarding the five QLQ-C30 functional scales (physical, role, cognitive, emotional, and social functioning) assessed at baseline, significant differences were identified. A significant enhancement from baseline to C2 and C7, and only to C7 in emotional functioning [10 (95% CI 3.3 to 17); P = 0.004] and social functioning [11 (95% CI 3.4 to 19); P = 0.005], respectively, were evident for participants receiving CDK4/6i combined therapy (Table 3; Figure 1). Contrarily, overall changes from baseline scores for physical, role, and cognitive functions did not attain statistical significance.

Figure 1. Graphical visualization of the variation in scores of European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire C30 version 3 (QLQ-C30) over the treatment cycles.

Relative to the QLQ-C30 symptom scale, a significant decrease from baseline in pain and in dyspnea related to pulmonary metastasis were observed at C3 [−8.6 (95% CI −16 to −1.3); P = 0.021 and -5.3 (95% CI -9.7 to -0.83; P = 0.020, respectively] (Table 3; Figure 1). Furthermore, a significant decrease in both insomnia [-11 (95% CI -21 to -0.54); P = 0.039] and financial difficulties [-19 (95% CI -30 to -9.2); P < 0.001] were also observed at C7 when compared to baseline values (Table 3; Figure 1). However, there was a significant worsening in diarrhea at C3 [7.6 (95% CI 1.8 to 13); P = 0.010] (Table 3; Figure 1). No significant differences were observed for the other EORTC QLQ-C30 symptoms.

EORTC QLQ-BR23

Regarding QLQ-BR23 functional scales, the sample size for sexual enjoyment parameter was smaller when compared to other scales (Table 2), as only sexually active participants respond to this parameter (48 vs. 107 answers, in total of the scale). A statistically significant improvement in future perspective was observed at C3 of CDK4/6i combined therapy [12 (95% CI 3.7 to 21), P = 0.005] (Table 3; Figure 2). Comparative evaluations of other breast cancer-specific functional scales to the baseline values did not yield statistically significant results.

Figure 2. Graphical visualization of the variation in scores of European Organization for Research and Treatment of Cancer (EORTC) Quality of Life breast cancer-specific Questionnaire (EORTC QLQ-BR23) over the treatment cycles.

With respect to the QLQ-BR23 symptom scale, it is important to clarify that the item hair loss was exclusively addressed to patients who effectively experienced hair loss, resulting in a considerably diminished cohort size (53) for the symptom scale “upset by hair loss” relative to other scales (Table 2). A statistically significant decrease from baseline to C2 and C7 in this parameter was observed [-17 (95% CI 33 to -1.9); P = 0.028] (Table 3; Figure 2). Conversely, a statistically significant deterioration from baseline to the same time points was observed for systemic therapy side effects [6.7 (95% CI 2.1 to 11); P = 0.005] (Table 3; Figure 2). Furthermore, on C2 of CDK4/6i combined therapy heralded a statistically significant improvement in breast symptoms [-6.6 (95% CI -11 to -1.9); P = 0.006] (Table 3; Figure 2).

WPAI:GH scores

Within the study cohort, it was observed that two participants, initially classified as “not currently employed” prior to the initiation of CDK4/6i combined therapy, resumed occupational activities during the course of treatment. Conversely, two participants, categorized as “currently employed” at baseline, ceased their occupational activities at C3 assessments. Analysis of the WPAI-GH metrics revealed a statistically significant increase in the number of working hours lost by C3 [17 (95% CI 0.54 to 33); P 0.043] (Table 3; Figure 3). Comparative evaluations of the other WPAI:GH parameters from baseline values did not yield any statistically significant variations.

Figure 3. Graphical visualization of the variation in scores of Work Productivity and Activity Impairment questionnaire - General Health (WPAI:GH) over the treatment cycles.

Adverse events

Adverse events, as classified per CTCAE version 5, were documented in 34 participants (representing 97% of the cohort) for the duration of this study. The most common adverse events encompassed hematological disorders, namely neutropenia (82%) and anemia (19%), accompanied by gastrointestinal disturbances, such as nausea and vomiting (13%). From the 29 patients presenting with neutropenia of any grade, 14 participants (comprising 40% of the cohort) experienced grade 3 neutropenia, while 15 experienced grade 1-2 neutropenia. No other adverse events reaching grade 3 severity were recorded. Importantly, it is not clear whether the underlying cause of the AEs observed can be attributed to CDK4/6i combined treatment or not. A detailed list of adverse events is shown in Table 4.