Real-world patient-reported outcomes of women receiving initial endocrine-based therapy for HR+/HER2− advanced breast cancer in five European countries

Breast cancer is the most common cancer in women across Europe and worldwide [1, 2]. In 2018, it was estimated there would be 523,000 new cases of breast cancer in women in Europe and that 138,000 women would die from breast cancer in the same year [1]. Advanced breast cancer is defined as locally advanced (stage IIIb/c) or metastatic (stage IV). An estimated 5–10% of all breast cancer patients have metastatic disease at initial presentation (de novo) [3], whereas approximately 30% of patients diagnosed with early-stage disease will progress to develop metastatic disease [4]. Hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2−) is the most common subtype of advanced breast cancer (66%) and incurs a median overall survival of 24.8 months after diagnosis of distant metastases [5, 6]. Patients with the HR+/HER2− subtype have a more favorable prognosis than those with other breast cancer subtypes [5, 7].

Treatment for HR+/HER2− advanced breast cancer is primarily palliative and aims to delay disease progression, prolong life, reduce disease- and/or treatment-related symptoms, improve daily functioning, and maintain/improve health-related quality of life (HRQoL) [8]. However, outcomes such as survival and HRQoL still need to be improved for patients with HR+/HER2− advanced breast cancer [6]. Patient-reported outcome (PRO) measures are often used in randomized clinical trials to evaluate symptoms and HRQoL, but there are concerns regarding the heterogeneity of the methodology used, analysis, and quality of reporting [9‐11]. It is important to capture real-world symptom and HRQoL data from patients living with advanced breast cancer, as patients enrolled in clinical trials are more homogeneous than the heterogeneous population in the real world.

PRO data on patients with advanced breast cancer in the real-world setting are limited, especially in those with HR+/HER2− disease [12‐17]. Evidence is also lacking from European settings. Much of the existing data come from Canada and the United States (US), which may differ from Europe with respect to healthcare systems and routine treatment practices [18].

The 4th European School of Oncology–European Society for Medical Oncology (ESO–ESMO) international consensus guidelines for advanced breast cancer recommend endocrine therapy (ET)-based regimens as the preferred first-line treatment option for women with HR+/HER− advanced breast cancer [8]. Because of the heterogeneous and incurable nature of the disease, most patients with HR+ advanced breast cancer will develop endocrine resistance, leading to relapse and disease progression. However, targeted therapies, such as inhibitors of cyclin-dependent kinases (CDK) 4 and 6 or the mammalian target of rapamycin (mTOR), can now be used in combination with ET to improve outcomes and delay the development of endocrine resistance [8]. This is a rapidly evolving therapeutic field, and three CDK4 & 6 inhibitors (palbociclib, ribociclib, and abemaciclib) have now been approved in the European Union (EU) for use in combination with ET as first-line advanced therapy for those naïve to systemic therapy in this setting. With the introduction of this new drug class, changes in treatment paradigms can be expected, with the goal of extending patients’ lives and maintaining/improving their HRQoL. Presently, questions to be addressed include the optimal initial therapy for advanced disease and the subsequent sequence of treatments for delaying disease progression and improving/maintaining the HRQoL of those living with HR+/HER− advanced breast cancer.

The aim of this study was to describe the characteristics, HRQoL, and symptoms of women with HR+/HER2− advanced breast cancer receiving their first ET-based regimen for advanced disease in real-world clinical practice across five European countries (EU5), using PRO data collected as part of the Adelphi Advanced Breast Cancer Disease Specific Programme™ (DSP). The survey was conducted in 2017 at the start of the change in the therapeutic landscape for such patients.

This single point-in-time real-world survey conducted in 2017 in five European countries shows the unmet needs of women receiving their initial ET-based regimen for HR+/HER2− advanced breast cancer.

The women in our survey who provided PRO data were predominantly older, post-menopausal, not working/retired, had stage IV disease (many with bone [66%] and/or visceral metastases [38%]), were considered by their oncologist to have stable disease (58%) or to be responding to treatment (35%), and had been on their current ET-based regimen for a mean of 6.7 months. The characteristics of this subset of women were similar to the overall EU5 sample with HR+/HER2− advanced breast cancer currently receiving their initial ET-based regimen. They reported a poor overall HRQoL, a high level of symptoms, especially fatigue, pain, and insomnia, and impaired activity and sexual functioning. Unexpectedly, 89% of the PRO subset of women in our survey had advanced disease (stage IIIb/IIIc/IV) at diagnosis. This is much higher than the estimated 28.5% of patients in the comparable de novo metastatic breast cancer cohort in the Epidemiological Strategy and Medical Economics (ESME) research program in France [37]. The reasons for the high percentage of patients with de novo advanced disease in our cohort are unclear, but it may be a methodological issue in that such patients are consulting more frequently in the real-world setting and are therefore more likely to be selected by physicians for the survey than patients who had disease recurrence. Some physicians may have deviated from the protocol and selected more patients with de novo metastatic disease and therefore less involved patient histories to reduce the time burden of completing the PRFs. It may also reflect that improved treatment in the adjuvant setting has caused a shift in stage distribution, such that fewer patients diagnosed with early-stage breast cancer progress to the advanced/metastatic stage [38].

The subset of women providing PRO data in our analyses were considered ET responsive, and 77% were on endocrine-only therapy as initial treatment for advanced disease at the time of the survey, which is consistent with current guideline recommendations [8]. At the time of the survey, only 7% of patients who provided PRO data were receiving a combination of ET plus a CDK4 & 6 inhibitor as their initial therapy for advanced disease. The most probable reason for this is that palbociclib was the only CDK 4 & 6 inhibitor available at the time and had only recently been approved in the EU (clinical trial participants were not included in the DSP), whereas three CDK4 & 6 inhibitors are now available (palbociclib, ribociclib, and abemaciclib). Future studies could determine whether increasing use of such treatments has a positive effect on the HRQoL of patients living with advanced breast cancer.

The development of novel treatments that are effective and well-tolerated, and their use in combination with ET as part of a first-line regimen for advanced disease in patients with HR+/HER2− advanced breast cancer, has led to improvements in progression-free survival [39]. It is important that this also translates into an improved or maintained HRQoL, especially during the time of stable disease. Further research in this area is needed.

In the absence of a cure, HRQoL is an important issue for patients with advanced breast cancer when the goal of treatment is to prolong life while maintaining the quality of survival [8]. HRQoL deteriorates as the disease progresses and can be affected by many patient-, disease-, and treatment-related factors [40, 41]. Not surprisingly, the women with advanced breast cancer in our real-world survey had poorer HRQoL than published general population norms for older women in Europe [36], in agreement with previous studies [42]. However, the mean EORTC QLQ-C30 global health/QoL scale score for our EU5 cohort of women with HR+/HER2− advanced breast cancer (50.9) was lower (worse) than the reference value published in 2008 for women with recurrent/metastatic breast cancer (60.2) [35]. The reason for this difference is unclear and may be due to many factors, including sociodemographic characteristics, disease characteristics, comorbidity, country, care setting, and treatment. Although 58% of the women providing PRO data in our survey were considered by their physician to have stable disease, their mean EORTC QLQ-C30 global health/QoL scale score (50.9) was similar to that reported for a group with progressive disease (52.9) in a real-world study in Canada of postmenopausal women with HR+/HER2− advanced breast cancer receiving first-line treatment [16].

Patients with advanced breast cancer experience a range of symptoms associated with the disease and its treatment that can impact their HRQoL. Fatigue, pain, and insomnia were the EORTC QLQ-C30 symptoms of greatest severity reported by our women with HR+/HER2− advanced breast cancer, consistent with other studies, including real-world surveys and qualitative interviews [12, 43, 44]. In our cohort, BPI “worst pain” was moderate/severe for 42% of patients, and “pain interference” was moderate/severe for 80% of patients. Increased pain severity has been associated with a worse HRQoL or health status in patients with advanced breast cancer [14, 40, 45]. However, patient-reported pain/discomfort was not an independent predictor of HRQoL in our regression analysis despite a high proportion (~ 70%) of the EU5 patients in our analysis reporting some/extreme problems in the EQ-5D-3L domain of pain/discomfort. Although 96% of patients currently experiencing pain reported taking analgesic medication, most of these patients took non-opioid analgesia (58%) or weak opioids (23%). Strong opioid analgesics were taken by only 15% of patients, which is consistent with the low use of strong opioids by patients with advanced breast cancer and bone metastases reported by Cleeland et al. [28]. Taken together, these findings suggest the potential for improved HRQoL with improved pain management. Delaying the onset of pain, reducing pain severity, and reducing pain interference with daily activities are important issues for patients with advanced breast cancer [46]. The patients in Germany had higher and/or more severe pain scores than patients in the other EU countries and this may be because the German patients were more likely to have multiple metastatic sites and lung metastases present at the time of data collection compared with women from EU4 combined.

Bone is the most common site of metastasis in patients with HR+/HER2− advanced breast cancer [7, 47]. Bone metastases were present in 66% of our cohort providing PRO data. Patients with bone metastases report worse pain and poorer HRQoL than those without bone metastases, as shown in previous real-world data from patients with advanced breast cancer in six European countries [48].

A recent analysis of unfavorable prognostic factors in an EU5 and US real-world population of patients with HR+/HER2− advanced breast cancer found that HRQoL was lowest among patients with liver metastases [Davie A, Carter GC, Rider A, Bailey A, Lewis K, Price G, Ostojic H, Ringeisen F, Pivot X: Real-world clinical profile, treatment patterns and outcomes of HR+/HER2− advanced breast cancer patients with unfavorable prognostic factors: data from an international study. submitted]. However, the presence of liver metastases (in 18% of EU5 women providing PRO data) was not an independent predictor of HRQoL in our regression analysis. Analyses of phase III studies aimed at identifying which subgroup of patients may benefit most from a combination of ET plus CDK4 & 6 inhibitor as initial therapy for advanced disease found that patients with indicators of a poor prognosis (liver metastases, progesterone receptor-negative tumors, high-grade tumors, or treatment-free interval < 36 months) benefited most from this combination therapy [49]. Thus, greater use of ET plus a CDK4 & 6 inhibitor as initial therapy for advanced disease in women with HR+/HER2− advanced breast cancer may have the potential to maintain/improve patient HRQoL. However, the poor HRQoL of the women in our survey may be more disease related than treatment related, as they were mostly considered to be stable on treatment.

Our EU5 cohort reported substantial (44%) activity impairment, which is consistent with a previous HR+/HER2− real-world study in the USA and Europe, which reported 57% activity impairment for the total sample [13]. Our regression analysis found that greater activity impairment due to breast cancer was independently associated with worse HRQoL in women with HR+/HER2− advanced breast cancer on their initial ET-based regimen for advanced disease. This agrees with data from the VIRGO observational cohort study in the USA, which reported a significant correlation between percent activity impairment on the WPAI and overall HRQoL in patients with advanced breast cancer [12]. In that study, symptom severity and interference were also strong predictors of activity impairment.

A strength of our study was that we assessed real-world patient outcomes of patients with advanced breast cancer (i.e., women with HR+/HER2− advanced breast cancer receiving an initial ET-based regimen for advanced disease) across five European countries using a variety of well-validated standard PRO instruments, including the frequently used EORTC QLQ-C30. Real-world data complement clinical trial data to help inform patient care [50]. PRO measures are increasingly being used in clinical trials and are broadly applicable in both clinical research and daily clinical practice; they can be used to support decision making by regulators, payers, healthcare providers, and patients [51]. However, the interpretation of EORTC QLQ-C30 scores can be challenging for clinicians [52] and various definitions of a clinically meaningful difference in these scores have been used [53‐57]. Nevertheless, for many of the QLQ-C30 and QLQ-BR23 scores, the difference in means between our EU5 sample and the reference value for patients with advanced breast cancer could be considered clinically meaningful. Moreover, there is a need for additional PRO questionnaires for use in patients with advanced breast cancer because the side effects of targeted therapies are not covered by existing instruments, including the EORTC QLQ-BR23 [10]. Symptomatic adverse events from the patient’s perspective can be captured using the PRO version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) [58], but there are no reports of studies using this tool during routine treatment of patients with breast cancer.

Several limitations of our study must be considered. There may be some selection bias of the physicians and patients included in the study, which may contribute to the high percentage of patients diagnosed with advanced disease. German physicians also had a higher workload than physicians in the other countries. As it was not a mandatory requirement for study participation, only 32% of patients with PRF data completed the PSC forms and provided PRO data. The small sample size of the subset of women reporting PROs should be considered when interpreting the findings. Non-response bias could affect the generalizability of the survey findings and many factors may be associated with non-completion of PRO measures in clinical care [59]. However, the subset of women providing PRO data and the overall sample had similar characteristics. Another factor that may limit the generalizability of the findings is that the data were collected at a single time point for each patient. This also means that causal inferences cannot be made regarding the relationships of interest. For example, although the regression analysis showed that poorer HRQoL (from the EORTC-QLQ-C30) was associated with greater activity impairment (from the WPAI), we do not know the direction of this association. Also, patient-reported symptoms and HRQoL and the factors influencing HRQoL are likely to change over time. As no adjustments for multiple testing were made, care must be taken when interpreting surprising or non-intuitive p-values. Although all patients had HR+/HER2− advanced breast cancer and were receiving an initial ET-based regimen for advanced disease, the mean duration of this treatment was only 6.7 months, and this short follow-up time must be considered when interpreting the results. These women were either newly diagnosed with advanced disease or had progressed to advanced disease after having a long disease-free interval (> 12 months) following the cessation of earlier adjuvant treatment. Both situations are likely to have an impact on their HRQoL. Our analyses were primarily descriptive and focused on the EU5; nevertheless, we did find between-country differences in some of the PROs measured. As 40% of the women providing PRO data were from Germany, the data were likely skewed and this must be taken into consideration when interpreting the results. In addition, country (especially Germany) was an independent predictor of HRQoL in the regression analysis. Numerous factors are likely to be associated with the differences between countries, but the higher prevalence of multiple metastatic sites and greater presence of lung metastases at the time of data collection among the German women who provided PRO data compared with the EU4 countries combined is likely to have contributed to their worse pain scores and lower HRQoL. Our study focused on the patient and not the entire burden of advanced breast cancer, which would include the impact on caregivers and on healthcare resource utilization and costs to give a societal perspective. Previous studies have shown that caregivers can experience low HRQoL and high productivity losses [16].

This real-world survey in 2017 at the start of the change in therapeutic landscape was conducted across the EU5 and demonstrated that women with HR+/HER− advanced breast cancer on an initial ET-based regimen for advanced disease were living with a high level of symptoms, pain, pain interference, activity impairment, and poor overall HRQoL. These findings underscore the need to reduce pain and preserve/improve health status/HRQoL in this patient population. HRQoL is adversely influenced by greater activity impairment, and new treatments that control symptoms, prolong a stable disease state with manageable toxicity, and reduce activity impairment may have a positive effect on the HRQoL of those living with advanced breast cancer. An update to this real-world analysis would be of interest to understand the impact of the CDK4 & 6 inhibitors in this clinical setting.