Background
Breast cancer is the most common malignancy worldwide and the largest cause of cancer-related death in women [
1]. With advancements across screening and treatment modalities over the past 3 decades, evidence from institutional databases and clinical trials [
2,
3] suggests that patients with metastatic breast cancer (MBC) are surviving longer than the median of 18–24 months that has been traditionally reported [
4]. However, it unfortunately still remains an incurable disease in nearly all instances, and the goal of treatment is to palliate or prevent symptoms, delay disease progression, and prolong survival [
4]. Patients living with advanced disease can experience diminished health-related quality of life (HRQOL) due to cancer- and treatment-related symptoms, such as pain, fatigue, cognitive dysfunction, sleep disturbances, arm morbidity, neuropathy, and menopausal symptoms [
5,
6].
Self- report from cancer patients provides a unique perspective that addresses aspects of wellbeing, feelings, and functioning, which may not be otherwise captured with standard clinical assessments [
7]. Patients who have reported worsening of symptoms and HRQOL have also experienced deterioration in their clinical condition [
7,
8]. Research has shown that HRQOL-related information can serve as a useful adjunct to conventional clinical assessments for oncology patients by improving patient-clinician communication and, in particular, helping clinicians understand patient challenges from a psychosocial perspective [
7,
9‐
16]. Understanding all of these factors is increasingly important in oncology in order to optimize the care of patients [
17‐
20].
Patient-reported outcome data obtained from validated instrumentation have demonstrated consistency and reliability in association with clinical outcomes for cancer and non-cancer conditions [
21,
22]. Given the increasing potential for such data to be clinically informative [
23,
24], patient-reported outcomes and symptoms have emerged as important measures of cancer treatment in clinical trials. Stratifying patients in clinical trials by baseline HRQOL can result in more homogeneous treatment groups and allow for better understanding of study results [
25].
Patient-reported outcomes, assessed via a variety of different instruments, have shown independent prognostic value for survival in post hoc analyses of clinical trials [
26‐
29] and in observational studies of MBC patients undergoing cancer treatment [
30,
31]. The prognostic value of HRQOL and associated domains has also been demonstrated in an exploratory fashion across other solid-tumor-specific studies, [
7,
32‐
39] as well as in systematic reviews and meta-analyses [
7,
25]. A recent analysis of 7417 patients examined the relative value of different HRQOL domains for multiple cancer types using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30). Results demonstrated that HRQOL parameters of greatest prognostic value differed by cancer type, and the effect size of each parameter varied according to tumor site. For breast cancer as well as other cancer types, at least one domain provided additional prognostic information to that obtained from clinical and sociodemographic variables [
23].
The current report is an exploratory, post hoc analysis of clinical and HRQOL outcomes from a phase III trial comparing gemcitabine plus paclitaxel with paclitaxel alone in patients with advanced breast cancer. As previously reported [
40], patients receiving doublet therapy experienced significantly improved survival versus paclitaxel alone and were also more likely to have improved HRQOL over time as measured by the Brief Pain Inventory-Short Form (BPI-SF) and Rotterdam Symptom Checklist (RSCL). Here we evaluate the prognostic effect of BPI-SF and RSCL baseline scores on survival. The BPI-SF is used extensively in clinical practice [
41] and it has been used across many studies in breast cancer to assess pain. To our knowledge, however, this is the first exploratory report evaluating the prognostic significance of baseline pain and the relationship to survival utilizing this instrument. Other studies in advanced breast cancer to date have utilized the RSCL [
42‐
44] although none have reported the prognostic significance of baseline scores. The current analysis therefore adds to the body of research by evaluating the prognostic effect of baseline scores for pain and other HRQOL domains on survival in advanced breast cancer utilizing the BPI-SF and the RSCL.
Discussion
We have shown in this post hoc analysis that baseline patient-reported outcomes and symptoms, as measured by the BPI-SF and RSCL, were prognostic for survival in patients with locally recurrent or metastatic breast carcinoma who received gemcitabine with or without paclitaxel. The use of two different, validated instruments was informative when exploring this prognostic effect in that they measure distinct aspects of HRQOL in cancer patients [
57], and the present study allowed for a model-dependent sensitivity analysis.
In this study, the worst pain and pain interference measures of the BPI-SF as well as activity level, physical distress, and HRQOL scores of the RSCL were all prognostic for survival in the univariate analysis. The BPI-SF worst pain and RSCL activity subscales retained a statistically significant effect in the multivariate analysis, which incorporated clinical, and sociodemographic variables commonly used as prognostic indicators in advanced breast cancer (Table
4). Clinical factors previously reported as prognostic via multivariate analysis for this study cohort included time from diagnosis to randomization, number of tumor sites, estrogen receptor status, and KPS [
40].
The RSCL activity subscale had the greatest effect on survival, as reflected by the hazard ratio in the univariate analysis (Table
4). In addition, it was the only subscale to retain a statistically significant effect in the multivariate analysis that considered the other RSCL subscales as well as baseline clinical or demographic characteristics. The RSCL psychological distress subscale had no relationship with survival based on 10-point increments in a Cox proportional hazards model (Table
4). However, the dichotomous comparison (above and below median scores) did reveal a significant difference in survival curves (log-rank
p = 0.0109; Fig.
2). It is important to note that systematic literature reviews have found only minimal evidence for prognostic effects of psychosocial HRQOL domains on cancer survival [
7,
58].
The most commonly utilized instruments in MBC trials include the Functional Assessment of Cancer Therapy-Breast (FACT-B) and the EORTC QLQ-C30 with or without the EORTC breast cancer-specific module, QLQ-BR23 [
59]; positive prognostic results have been demonstrated in previously reported analyses of advanced breast cancer that used baseline EORTC QLC-C30 assessments [
27‐
29].
The current exploratory analysis of a clinical study population further adds to the body of evidence that patient-reported outcomes and symptoms can be prognostic indicators in patients with advanced breast cancer and as such, a useful adjunct for informing the routine care of patients. It is important to note that because patient-reported responses can be subject to social and environmental factors, this information is best used as an added tool to all other demographic and clinical considerations that are part of patient care [
9]. The reasons for the relationship between patient-reported outcomes and symptoms, and survival have not been completely elucidated. However, it is thought that patient-reported outcomes may be sensitive to disease progression or markers of patient behaviors or other characteristics, such as treatment adherence or healthy lifestyles [
7]. In addition, the inclusion of multiple items in patient survey instruments may enhance their diagnostic sensitivity whether in clinical management or in oncology drug trials [
7].
It is important to reiterate that the current study was a post hoc analysis of HRQOL data originally recorded as secondary outcomes in a prospective clinical trial [
46]. Although not all randomized patients were included in the analyses due to limited availability of translations of the BPI-SF and RSCL, a high percentage of the patients with translations available to them completed the questionnaires; furthermore because only baseline questionnaire responses were used, there was less potential for nonrandom missing data. Prognostic factors in the current study were not defined prior to study enrollment, and no adjustments were made for multiplicity. Therefore, it would be worthwhile to evaluate the hypothesis prospectively in order to further support the utility of patient-survey instruments for the added benefit of assessing patient prognosis both in clinical trials as well as in routine clinical practice. If confirmed, these data could be used to potentially identify appropriate cut points for the purposes of prognostic evaluation and study stratification. It is important to reiterate that these findings are specific to first-line advanced disease and cannot be generalized to other lines of therapy. Furthermore, results discordant with those of other studies may have been due to differences in statistical techniques or instrumentation.
Acknowledgements
The study, the development of this manuscript, and article processing charge were supported by Eli Lilly and Company. We thank Zhanglin Lin Cui and Jiaying Guo of Eli Lilly and Company for their assistance in statistical analysis. We also thank David Hartree of ClinGenuity, LLC, Cincinnati, USA, for writing assistance, which was supported by Eli Lilly and Company.
Competing interests
ENS, WS, LB, PP, WJ, AM, and AML are employees and shareholders at Eli Lilly and Company.
Authors’ contributions
WS and LB originated the concept and design of the study; WS performed data acquisition; WS, PP, LB, and ENS were responsible for statistical analyses/interpretation; ENS and WS drafted the manuscript. All authors revised the manuscript for important intellectual content and approved the final version.