Validity, reliability, responsiveness, and clinically meaningful change threshold estimates of the National Comprehensive Cancer Network-Functional Assessment of Cancer Therapy-Breast Cancer Symptom Index (NFBSI-16)

Abstract

Background

Breast cancer is one of the most common cancers in women. Patient-reported outcome measures are used to evaluate patients’ health-related quality of life in clinical breast cancer studies. This study evaluated the structure, validity, reliability, and responsiveness of the National Comprehensive Cancer Network-Functional Assessment of Cancer Therapy-Breast Cancer Symptom Index (NFBSI-16) subscales in a clinical trial featuring patients with advanced/metastatic breast cancer (aBC), and estimated NFBSI-16 meaningful change thresholds.

Methods

Data from 101 patients with aBC enrolled in a phase II trial (Xenera-1) were included for psychometric evaluation of the NFBSI-16. Subscale structure was evaluated by assessing inter-item correlations, item-total correlations, and internal consistency (cycles 2 and 5). Validity was assessed using scale-level convergent validity (cycles 2 and 5) and known-groups (Baseline). Reliability was analysed via test-retest at cycles 3–4, and responsiveness to improvement and worsening was evaluated at cycles 5, 7, and 9. Meaningful change thresholds were estimated using anchor-based methods (supported by distribution-based methods) at cycles 5, 7, and 9.

Results

NFBSI-16 internal consistency was acceptable, but item-total correlations suggested that its subscales and the GP5 item (side-effect of treatment) scores may be preferred over a total score. Convergent and known-groups evidence supported NFBSI-16 validity. Test-retest reliability was good to excellent for Total and DRS-P (disease-related symptoms: physical) scales, and moderate for the GP5 item. Responsiveness to worsening was generally demonstrated, but responsiveness to improvement could not be demonstrated due to limited observed improvement. Anchor-based meaningful change thresholds were estimated for DRS-P and Total scores.

Conclusion

This study provides evidence that the NFBSI-16 has desirable psychometric properties for use in clinical studies in aBC. It also provides estimates of group- and individual-level meaningful change thresholds to facilitate score interpretation in future aBC research.

Background

Breast cancer is one of the most common cancers in women. More than 180,000 deaths due to breast cancer are expected annually in the United States and Europe combined, and more than 680,000 globally [1]. While early-stage disease is curable, median overall survival for advanced breast cancer (aBC) patients remains poor.

Patient-reported outcomes (PROs) are typically used to provide insight into a patient’s experience of living with cancer. Disease-specific PROs attempt to capture aspects that are most relevant to a condition, such as disease symptoms, treatment side effects, and daily functioning. One such measure for breast cancer is the National Comprehensive Cancer Network-Functional Assessment of Cancer Therapy-Breast Cancer Symptom Index (NFBSI-16) [2, 3].

The NFBSI-16 was developed using methods consistent with recent regulatory guidance [4,5,6] on PROs as endpoints in clinical trials, with emphasis on patient input during the development process. Conceptual relevance and content validity of the NFBSI-16 has been supported with cognitive debriefing interviews [2, 3]. However, to date, the psychometric properties of the NFBSI-16 have not been investigated.

The aim of this study was to undertake the first comprehensive psychometric evaluation of the NFBSI-16 in patients with aBC using clinical trial data. This included assessing the subscale structure, validity, reliability, and responsiveness of the NFBSI-16, as well as estimating thresholds for interpreting clinically meaningful change on the NFBSI-16 in patients with aBC.

Methods

Data source

Analyses were conducted using data from the phase II Xenera-1 clinical trial (NCT03659136). Xenera-1 was a multi-centre, double-blind, randomised trial assessing the efficacy of xentuzumab, a humanized IgG1 insulin-like growth factor monoclonal antibody, in combination with everolimus and exemestane compared to everolimus and exemestane alone in post-menopausal female patients with histologically confirmed hormone receptor positive (HR+)/human epidermal growth factor receptor 2 negative (HER2−) locally advanced or aBC and non-visceral disease. Results of the clinical trial outcomes were published in June 2023 [7].

Data were collected in 11 countries (Belgium, France, Germany, Greece, Italy, Portugal, Spain, UK, Canada, US, Australia) between January 2019 and September 2021. Xenera-1 was carried out in accordance with the principles of the Declaration of Helsinki, in accordance with the International Conference for Harmonisation clinical practice guidelines, in accordance with applicable regulatory requirements, and in compliance with the trial protocol. Informed consent was obtained from each study participant.

Study measures

PRO questionnaires administered in Xenera-1 included the NFBSI-16 (which includes the single GP5 item), Brief-Pain Inventory-Short Form (BPI-SF) [8], Euroqol 5-Dimension Health Status Self-Assessment (EQ-5D-5L) [9] and eight items from the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) library (difficulty swallowing, skin cracking at corners of the mouth, decreased appetite, vomiting, heartburn, diarrhoea, pain in the abdomen, rash) [10, 11]. Questionnaires were administered at Baseline, day 1 from cycles 2 to 20 (every 28 days), then day one of every second cycle (every 56 days) until end of treatment. Patients were treated in 28-day cycles until the end of cycle 20 (week 80) and in 56-day cycles from cycle 21 until they had progressive disease occurrence of intolerable AEs or withdrew consent. The following NFBSI-16 language versions were used for the 11 countries: Dutch, French, German, Greek, Italian, Portuguese, Spanish, English. Responses from the NFSBI-16 (including GP5 item) and EQ-5D-5L questionnaires were used in this psychometric analysis.

In addition to data from PRO questionnaires, the Eastern Cooperative Oncology Group (ECOG) performance status (PS) collected at clinical visits was used as an anchor measure. The Analgesic Quantification Algorithm (AQA) was completed by investigators to assess analgesic use [11].

Analysis set

The analysis sample for the Psychometric Evaluation Population consisted of patients in Xenera-1 who completed at least one item on either the NFBSI-16 or BPI-SF at any timepoint.

NFBSI-16

The NFBSI-16 is a 16-item assessment of disease related symptoms, treatment side effects, and general function and well-being. The instrument has four subscales: Disease-Related Symptom—Physical (DRS-P, 8 items; score range: 0–32), Disease-Related Symptoms—Emotional (DRS-E, 1 item; score range: 0–4); Treatment Side-Effect (TSE 4 items; score range: 0–16) (not analysed in this study); and Functional Well-Being (FWB, 3 items; score range: 0–12). A total score can be obtained for the NFBSI-16 (16 items; score range: 0–64). The GP5 item measures bother from side effects [12]. All items have a seven-day recall period and a five-point verbal descriptive response scale (0 = “not at all”, 1 = “a little bit”, 2 = “somewhat”, 3 = “quite a bit”, and 4 = “very much”). Reverse scoring is applied to negatively worded items, so that higher scores are better than lower ones, indicating less symptomatology and better functioning and health-related quality of life.

Analyses

Psychometric evaluation of the NFBSI-16 was performed in accordance with best practices, and consistent with European Medicine Agency (EMA) and US Food and Drug Administration (FDA) guidance relating to PROs [4, 13].

Scoring and missing item-level PRO data were managed in accordance with developer scoring documentation Version 2_0 [14]. Selection of timepoints was related to the intent of each analysis and expected timeframes for improvement/declines based on expected clinical responses for patients with aBC in the clinical trial, with timepoints selected from baseline and up to cycle 12 (week 44 post randomization) being considered for psychometric analysis.

Item responses

The completion rate and distribution of item responses, including evaluation of potential floor and ceiling effects were explored at baseline and each cycle up to cycle 9 using descriptive summaries.

Subscale structure of the NFBSI-16

Data at cycle 2 (week 4) and cycle 5 (week 16) were selected as supportive timepoints for assessment of subscale structure. It was expected the number of patients on treatment would still be high, but that patients would have experienced changes in disease-related symptoms and side effects due to treatment.

Inter-item correlation

Inter-item correlations for NFBSI-16 were assessed at cycle 2 and repeated at cycle 5 to evaluate potential item redundancy (i.e., items with a correlation > 0.9) [15].

Item-total correlation

For assessing item-total correlations in terms of item-level convergent and discriminant validity, multitrait analysis was used [16]. The analysis was completed at Cycle 2 and repeated at Cycle 5. All ordinal NFBSI-16 item responses were assessed using polyserial correlation coefficients with multi-item subscales scores (Total score, DRS-P and FWB, all assumed continuous); subscales were corrected for overlap (i.e., the subscale score was calculated with the removal of the item with which it was correlated). Items with a scaling success ≥ 0.4 were considered correlated [16], and problematic if the highest correlation was with a different subscale.

Internal consistency

Internal consistency was examined by calculating Cronbach’s alpha coefficient at Cycle 2 and repeated at Cycle 5 for NFBSI-16 Total, DRS-P, and FWB subscales. Internal consistency was considered acceptable if the alpha coefficient was ≥ 0.70 [15]. The impact of item removal on internal consistency reliability was also examined.

Validity

Scale-level convergent validity

A priori hypothesised relationships between NFBSI-16 scores and items of EQ-5D-5L were defined based on consideration of the concepts of the item; the EQ-5D-5L VAS, as a general measure of HRQoL was hypothesized to show convergent validity with all NFBSI-16 subscales. Polyserial correlations were estimated; correlation coefficients ≥|0.3|were considered supportive of convergent validity [17].

Known-groups comparisons (construct validity)

Known-groups based on clinical characteristics of patients were selected a priori. The baseline characteristics of ECOG PS (1 vs 0) was selected to identify clinically distinct groups of patients, where ECOG PS status 0 represents fully active patients and ECOG PS 1 represents some level of physical impairment. Additional known-groups were selected based on key study entry criteria of ‘bone metastases at screening’, ‘measurable disease at Baseline’, and ‘number of previous lines of therapy’.

For known-groups, score differences were tested using one-way analysis of variance (ANOVA), with p < 0.05 (not adjusted for multiple comparisons). The magnitude of differences was assessed using between-group effect size (ES; Cohen’s d) estimates, using the pooled standard deviation as the denominator. Between-group ES estimates were classified using conventional benchmarks of “small” (0.2), “medium” (0.5), and “large” (0.8) [17].

Reliability—test retest

Test-retest reliability of the NFBSI-16 was examined in subsets that were considered stable according to various anchor measures. Cycle 3 (week 8) and Cycle 4 (Week 12) were selected as timepoints most likely to reflect stable PRO outcomes (i.e., after initial response to treatment and prior to deterioration). The anchor measures selected were performance status (ECOG PS), and the widely used general HRQoL PRO EQ-5D-5L. Groups were defined as stable based on no change in response level (for ECOG PS and EQ-5D-5L items) or a change in EQ-5D-5L VAS score of < 7 points, aligning with a clinically meaningful change in VAS score [18] (see Supplementary Table 1 for overview of anchors). Test-retest reliability was investigated by calculating the intraclass correlation coefficient ICC_[2,1] [19]. The following threshold values were employed to interpret ICC values: values less than 0.5 are indicative of poor reliability, values between 0.5 and 0.75 indicate moderate reliability, values between 0.75 and 0.90 indicate good reliability, and values greater than 0.90 indicate excellent reliability [20].

Responsiveness—improvement/worsening

Change from baseline to cycle 5, cycle 7, and cycle 9 (weeks 16, 24, and 32) were selected as timepoints where improvement or deterioration may be expected, but before a high proportion of patients experienced disease progression. ECOG PS and EQ-5D-5L were defined as anchor measures for evaluation of responsiveness as both are well established measures known to show responsiveness to change in oncology patients. For ECOG PS changes of 1 level were considered as improvement/worsening. For EQ-5D-5L items changes in response of 1 level were considered as improvement/worsening. For EQ-5D-5L VAS a change in score ≥ 7 points was improvement and £ 7 points as worsening [18].

For each subscale, and the single GP5 item, mean change scores were assessed using within-group ES estimates [21] (mean change score divided by the SD_Baseline) and interpreted descriptively using typical benchmarks of “small” (0.2), “medium” (0.5), and “large” (0.8) [17]. One-way ANOVA F-tests were used to evaluate the statistical significance (p ≤ 0.05) of differences in change scores between groups.

Meaningful change

Timepoints for meaningful change analyses were selected to reflect longitudinal data for patients up to 32 weeks from randomisation. PRO assessments were collected at later timepoints, but it was expected that data would be missing over time as patients stopped treatment due to disease progression/death. Meaningful change in scores for the NFBSI-16 Total and subscales were evaluated at both the group- and individual-level. Anchor-based and distribution-based methods were used.

Three types of meaningful change threshold were considered. First, a clinically important change (CIC): a change over time within a group considered clinically relevant. Second, a clinically important difference (CID) between treatment groups considered clinically relevant [22]. The CID was defined as the difference between mean change scores for the Stable and Improved/Stable and Worsened groups. Third, a clinically important responder (CIR) (meaningful within-patient change): the amount of change a patient would have to report to indicate that a relevant treatment benefit has been experienced [22]. These thresholds were not necessarily minimal in nature (i.e., reflecting the smallest change that patients perceive as important) [22, 23], due to merging minimal and moderate anchor categories.

Anchor and NFBSI-16 score pairings exhibiting polyserial (NFBSI-16 Total, DRS-P, and FWB scores) and polychoric (NFBSI-16 DRS-E and GP5 item) correlation ≥|0.3| [24] for at least two of the three assessment timepoints were taken forward for further score analyses [25, 26].

Mixed models for repeated measures (MMRMs) were used to evaluate CIC and CID thresholds across multiple timepoints, all of which were incorporated into a single longitudinal [27] model, enabling an increased number of observations to contribute to estimates. Least squares (LS) mean estimates for the Minimal-to-Moderate Improved and Minimal-to-Moderate Worsened groups corresponded to estimates of the CIC for improvement/worsening. The CID was estimated as the difference in LS means between the Minimal-to-Moderate improvement/worsening and Stable groups.

Receiver operating characteristic (ROC) curve analysis was used to inform CIR estimates. Potential CIR estimates (i.e., all possible change scores) were evaluated by finding an optimal cut-point between stable and improved or worsened groups (collapsing Minimal/Moderate/Major improvement/worsened groups) according to ROC curves using the sum of squares method (i.e., Min[(1 − sensitivity)² + (1 − specificity)²]) [28].

Supportive empirical cumulative distribution function (eCDF) plots were also produced to evaluate the performance of proposed CIR thresholds, as per US FDA guidance [29].

A lower and upper standard error of measurement (SEM) was calculated, using two ICCs from test-retest reliability analyses as reliability coefficients (i.e., the lower SEM was calculated using the smallest ICC, the upper ICC was calculated using the largest). While the SEM was not intended as an estimate of importance thresholds [30], score changes beyond this threshold are more likely than not to be free from measurement error.

For triangulation, where multiple CIC, CID, or CIR threshold estimates were obtained, the largest of the estimated thresholds was selected to ensure that results were clinically meaningful. Additionally, the SEM of NFBSI-16 scores was taken into consideration to inform CIR estimates that exceeded measurement error.

Results

Baseline characteristics, item responses and completion rate

There were 101 patients included in the Psychometric Evaluation Population. The mean age of study patients was 60.56 years (SD = 10.59), with ages ranging from 29 to 84. Table 1 provides further detail regarding the demographic and clinical characteristics for the Psychometric Evaluation Population. The mean scores for NFBSI-16 subscales, EQ-5D-VAS, and proportion with GP5 item responses at baseline are presented in Table 2.

Table 1 Demographic and clinical characteristics at baseline

Table 2 Baseline NFBSI-16 and EQ-5D-5L VAS scores

For patients remaining on treatment from baseline to cycle 12, completion for the NFBSI-16 was high across items, with missing data rates for all items less than 8.2% across all visits except Item B5 (‘I am bothered by hair loss’) at Cycle 12 (missing = 15%). For the key timepoints of interest in this study (up to cycle 5) the available data included over 62 patients (out of 101 patients in the analysis Psychometric Evaluation Population). NFBSI-16 Total: Baseline n = 97 (96%), cycle 2 n = 93 (92%), cycle 3 n = 78 (77%) and cycle 5 n = 62 (61%). Across Baseline to Cycle 12 only a single individual had more than two NFBSI-16 items missing; 10 individuals (10.3%) were missing 2 items at baseline, with less than 3 individuals at all other timepoints.

At baseline, some patients reported responses of “Not at all” i.e., no level of problems at baseline and therefore the responses of these patients could not improve which could lead to a ceiling effect being observed in analysis at later timepoints: Items GP3 (‘I have trouble meeting family needs’, B1 (‘I have been short of breath’), BP1 (‘I have bone pain’), GP6 (‘I feel ill’), and HI7 (‘I feel fatigued’) within the DRS-P scale all showed patterns of having potential ceiling effects. Also, for GP5 (‘I am bothered by side effects of treatment’) 63% of patients reported “Not at all” at baseline.

Subscale structure of the NFBSI-16

Inter-item-correlations

No items were deemed redundant in terms of inter-item correlations (all correlations < 0.9).

Item-total correlation

Item-total correlations (corrected for overlap) at Cycle 2 for NFBSI-16 Total score were > 0.4, except for items B1 (‘I have been short of breath’; r = 0.36), GF5 (‘I am sleeping well’; r = 0.34), GE6 (‘I worry condition will get worse; r = 0.33), N6 (‘I have mouth sores’; r = 0.23), and B5 (‘I am bothered by hair loss’; r = 0.27). Regarding the DRS-P scale, all item-total correlations were > 0.4 except for item GF5 (‘I am sleeping well’; r = 0.32). Some items exhibited higher correlations with other subscales than their corrected subscale, including item GF5 (‘I am sleeping well’) correlating better with FWB (r = 0.42) than NFBSI-16 DRS-P (r = 0.32). Similar patterns were also seen at Cycle 5 (Supplementary Tables 2.1 and 2.2).

Internal consistency

At cycles 2 and 5, internal consistency was high (i.e., > 0.8) for all scales. At cycle 2, alpha for the NFBSI-16 Total was 0.844; for DRS-P it was 0.832. Following individual item deletion, changes to alpha values were negligible (NFBSI-16 Total range: 0.820–0.855; DRS-P range: 0.788–0.852).

Validity

Scale-level convergent validity

Scale-level convergent correlations for NFBSI-16 subscales were larger than the hypothesized convergent criteria (i.e., ≥ 0.3) (Table 3). This pattern was also seen at cycle 5 (data not presented).

Table 3 Scale-level convergent validity of NFBSI-16 with EQ-5D-5L hypothesized measures

Known-groups comparisons

For NFBSI-16 Total score (Table 4), NFBSI-16 DRS-P, and NFBSI-16 FWB there were statistically significant differences in scores for each of the baseline ECOG performance groups, with lowest mean NFBSI-16 scores being seen in the EOCG PS 0 status patients. The between group differences were large (i.e., effect sizes ≥ 0.80) and statistically significant (p < 0.001) for NFBSI-16 Total score and NFBSI-16 DRS-P and moderate for NFBSI-16 FWB. Other baseline characteristics of ‘bone metastases at screening’, ‘measurable disease at baseline’ and ‘number of previous lines of therapy were also considered as potentially identifying clinically distinct patients, although no strong evidence for differences in NFBSI-16 scores were noted for these groups.

Table 4 Known groups at baseline: ECOG PS vs NFBSI-16

Reliability

Test-retest reliability was assessed in stable patients between cycle 3 (Week 9) and cycle 4 (Week 12), resulting in subsets of between 37 to 54 patients. The ICCs for the anchors for each NFBSI-16 subscale (Table 5) were moderate to excellent across all scales and anchors (ICC > 0.6).

Table 5 NFBSI-16 test-retest reliability analysis between cycle 3 (week 8) and cycle 4 (week 12)

Responsiveness

Responsiveness to worsening was demonstrated with large within-group effect sizes between Baseline and Cycle 5 for the NFBSI-16 Total score (ES = −1.05; p = 0.043), DRS-P (ES = −0.53; p = 0.081), and GP5 item (ES = −2.81, p = 0.018). Responsiveness to worsening was also demonstrated for other NFBSI-16 scales (Data not presented).

Meaningful change

NFBSI-16 Total score, DRS-P, and DRS-E scales had anchors (EQ-5D-5L VAS, pain, usual activities) that reached acceptable thresholds (i.e., anchor correlation of ≥|0.3|for at least two of three timepoints assessed (cycle 5, 7, 9). Table 6 provides an overview of all available anchor-based estimates for these scales. The remaining NFBSI-16 scales were insufficiently correlated with potential anchors (Supplementary Table 3) and could only have meaningful change explored via distribution-based methods.

Table 6 Overview of anchor-based CIC, CID, and CIR estimates for NFBSI-16 scales

For NFBSI-16 Total score (with a range of 0–64 points), a single anchor (EQ-5D-5L VAS) was sufficiently correlated to derive score interpretation threshold estimates. For the improved group, the CIC was unevaluable because a change score of 0.0 was estimated (subsequently invalidating the CID); furthermore, no CIR threshold estimates provided better than chance discrimination (i.e., AUC CIs included 0.500). For the worsened group, estimates indicated that a CIC of −7, and CID of −4.8 were appropriate; as was a CIR threshold of −7, which would surpass the upper estimate of SEM (SEM = 4.1) and correctly classify most worsened patients as evidenced by eCDF plots and ROC curves (Supplementary Fig. 1.1.x.x (eCDFs) and Fig. 2.1.x.x. (ROC Improved) and Fig. 3.1.x.x (ROC Worsening) and Supplementary Table 4.1.x).

For DRS-P (with a range of 0–32 points), two anchors (EQ-5D-5L Pain and EQ-5D-5L Usual Activities) were sufficiently correlated to derive score interpretation threshold estimates. For the improved group, estimates indicated that a CIC of 1.2 and CID of 2 were appropriate; as was a CIR threshold of 6, which would surpass the upper estimate of SEM (SEM = 3.8). For the worsened group, estimates indicated that CICs of −2.6 to −2.9 and CIDs of −1.8 to −2.4 were appropriate, as was a CIR threshold of −4. eCDFs were generally considered supportive of proposed DRS-P thresholds (Supplementary Fig. 1.2.x.x (eCDFs) and Fig. 2.2.x.x (ROC Improved) and Fig. 3.2.x.x (ROC Worsening) and Supplementary Table 4.2.x).

For DRS-E (range 0–4 points), a single anchor (EQ-5D-5L VAS) was sufficiently correlated to derive score interpretation threshold estimates. For the improved group, estimates indicated that a CIC of 0.4, and CID of 0.1 were appropriate; no CIR was estimable because ROC curve AUC CIs included 0.500 (i.e., indicating no better than chance classification). For the worsened group, the CIC and CID were inadmissible because positive scores were estimated (representing an improved health state); for the CIR, an estimate of −1 was indicated, which would surpass the upper estimate of SEM (SEM = 0.812) and supported correctly classifying most worsened patients plots (Supplementary Fig. 1.3.x.x (eCDFs) and Fig. 2.3.x.x (ROC Improved) and Fig. 3.3.x.x (ROC Worsening) and Supplementary Table 4.3.x).

Discussion

This study evaluated the psychometric properties of the NFBSI-16 and provided estimates of meaningful change thresholds. It is the first study to provide evidence of the psychometric properties of the NFBSI-16 and its score interpretation in an aBC patient population.

Internal consistency was high for NFBSI-16 Total and DRS-P scales (i.e., > 0.8). Although inter-item correlations did not indicate redundancy of any NFBSI-16 items (i.e., all correlations were < 0.9), some items displayed low item-total correlations with their intended scales or larger correlations with other scales than those intended across cycles 2 and 5 (Supplementary Tables 2.1 and 2.2). These included items B1 (‘I have been short of breath’), GF5 (‘I am sleeping well’), GE6 (‘I worry condition will get worse’), N6 (‘I have mouth sores’), and B5 (‘I am bothered by hair loss’) with NFBSI-16 Total; and GF5 (‘I am sleeping well’) with NFBSI-16 DRS-P. These results suggest that scores from the NFBSI-16 subscales, not the Total score, may be the preferred focus in future clinical research. Future research may also explore the performance of the DRS-P scale without the inclusion of item GF5 (‘I am sleeping well’), which fit less-well within this subscale as indicated in the internal consistency reliability and multi-trait analyses. Similar issues concerning the inclusion of an item assessing sleep in a related ovarian cancer measure have been reported [31].

Test-retest reliability evidence was generally adequate, with good to excellent reliability for Total and DRS-P, and moderate reliability for the GP5 item. This provides supportive evidence of reliability of the GP5 item to assess overall treatment tolerability in patients with aBC, adding to work that has investigated its validity in a diverse sample of cancer patients [32].

A summary of proposed score interpretation thresholds for the NFBSI-16 is presented in Table 7, with indicated threshold estimates rounded to the nearest whole number for simplicity. A process of triangulation is generally recommended for multiple meaningful change threshold estimates [24, 33,34,35]; in this study, when multiple estimates were available, the largest of the available estimates was included as the proposed score. There were no anchor-based estimates for the GP5 Item scores due to a lack of acceptable correlations with anchor measures; therefore, distribution-based estimates (i.e., the SEM) form the basis of these proposed thresholds. SEM estimates also informed proposed thresholds in the absence of eligible estimates for specific improved (NFBSI-16 Total) and worsened (DRS-E).

Table 7 Summary of proposed CIC, CID, and CIR thresholds for NFBSI-16 scales

It should be noted that there are various issues in the score interpretation literature for which there is no consensus; these include consensus on terminology, optimal estimation methodology, and indices of likely change [36]. Subsequently, the proposed thresholds in this study represent a broader clinically meaningful change compared to a minimal threshold (as they are based on merged minimal and moderately changed groups). Meaningful change thresholds varied depending on the overall score range for the NFBSI-16; i.e., 5–7 points were indicated for the 0 to 64-point Total score, while a 1-point threshold was indicated for the 0 to 4- GP5 item score. From a patient perspective, a 1-point change in NFBSI-16 scores equates to a 1-category shift on an item.

The NFBSI-16 treatment side effect (TSE) scale is not presented in these results. The TSE scale contains three items on nausea, mouth sores, and hair loss, as well as an item reflecting global side effect burden (item GP5); however, the introduction of novel therapies since the original development of the NFBSI-16 means additional toxicities are now relevant to patients with aBC. Although we did not recommend removal of any NFSBI-16 items, this scale is not included in the analysis as it is no longer considered content valid in the current clinical setting. FACIT.org no longer recommends scoring the TSE items as a scale, preferring to focus on item GP5 (http://www.facit.org). Psychometric evidence has supported the validity of the GP5 single item across diverse cancer sites and various countries [12, 37,38,39]. Use of the GP5 single item to assess overall side effect impact alongside items assessing specific symptomatic adverse events, for example from the PRO-CTCAE library, is also aligned with recent FDA guidance [40].

A limitation of this study is the lack of anchor-derived meaningful change thresholds for every NFBSI-16 subscale. The FWB scale, and GP5 item lacked sufficiently correlated anchors for deriving meaningful change threshold estimates. Similarly, meaningful change estimates for improvement were not valid for the NFBSI-16 Total score (i.e., a score of 0 was estimated); therefore, only thresholds for worsening may be used in future applications. Generally, improved and worsened within-individual thresholds were estimated, as well as distribution-based scores that can be used as interpretative benchmarks (albeit do not directly target important change) [41].

It is noted that this is a relatively small sample size (n = 101) for psychometric analysis, particularly as oncology study patients experience disease progression and stop treatment; there were only 62 patients who completed the NFBSI-16 at the cycle 5 timepoint. This may have led to the slight inconsistencies observed for some results. Further studies in larger and broader patient populations should be conducted to gather additional psychometric evidence to confirm the scale structure and meaningful change thresholds of the NFBSI-16 in related populations, such as HR+, HER2− and visceral metastases [42], HER2 positive or triple negative breast cancer.

It would also be interesting to better understand how patients reflect on the PROs used and results of this study by undertaking qualitative interviews. Patient experience data like interviews could confirm and deepen the understanding of the results relating them to patients’ experiences of their disease and their treatment. In turn, this may facilitate further understanding of the results of this study. Moreover, qualitative interviews may provide important information that might enhance construction of hypotheses in future clinical cancer trials. For example, new treatments may delay worsening of disease-related symptoms but perhaps not improve the general burden and experience of the cancer disease which could influence the research question.

In summary, the NFBSI-16 has desirable psychometric properties for use in aBC studies given appropriate consideration of its intended use (i.e., given a focus on subscales in future clinical research, and worsening of breast cancer-related severity as the outcome of interest). Furthermore, psychometric properties of the NFBSI-16 may be improved in future studies by considering removal of items that were shown to fit poorly according to developer-recommended scoring (e.g., item GF5), or those with potential baseline ceiling effects that may limit scale responsiveness (e.g., item N6).

Conclusion

This study provides evidence that the NFBSI-16 has desirable psychometric properties for use in aBC studies given appropriate consideration of its intended use; the study also provides estimates of group- and individual-level meaningful change thresholds for use in future aBC research.