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Association of treatment-emergent symptoms identified by patient-reported outcomes with adjuvant endocrine therapy discontinuation

Association of treatment-emergent symptoms identified by patient-reported outcomes with adjuvant... www.nature.com/npjbcancer ARTICLE OPEN Association of treatment-emergent symptoms identified by patient-reported outcomes with adjuvant endocrine therapy discontinuation 1 2 3 1 1,7 3 1 Karen Lisa Smith , Neha Verma , Amanda L. Blackford , Jennifer Lehman , Kelly Westbrook , David Lim , John Fetting , 1 1 1,8 1,9 1 1 Antonio C. Wolff , Daniela Jelovac , Robert S. Miller , Roisin Connolly , Deborah K. Armstrong , Raquel Nunes , 1,4 1 1 1 1 2,5,6 1 Kala Visvanathan , Carol Riley , Katie Papathakis , Nelli Zafman , Jennifer Y. Sheng , Claire Snyder and Vered Stearns Many patients discontinue endocrine therapy for breast cancer due to intolerance. Identification of patients at risk for discontinuation is challenging. The minimal important difference (MID) is the smallest change in a score on a patient-reported outcome (PRO) that is clinically significant. We evaluated the association between treatment-emergent symptoms detected by worsening PRO scores in units equal to the MID with discontinuation. We enrolled females with stage 0-III breast cancer initiating endocrine therapy in a prospective cohort. Participants completed PROs at baseline, 3, 6, 12, 24, 36, 48, and 60 months. Measures included PROMIS pain interference, fatigue, depression, anxiety, physical function, and sleep disturbance; Endocrine Subscale of the FACT-ES; and MOS-Sexual Problems (MOS-SP). We evaluated associations between continuous PRO scores in units corresponding to MIDs (PROMIS: 4-points; FACT-ES: 5-points; MOS-SP: 8-points) with time to endocrine therapy discontinuation using Cox proportional hazards models. Among 321 participants, 140 (43.6%) initiated tamoxifen and 181 (56.4%) initiated aromatase inhibitor (AI). The cumulative probability of discontinuation was 23% (95% CI 18–27%) at 48 months. For every 5- and 4-point worsening in endocrine symptoms and sleep disturbance respectively, participants were 13 and 14% more likely to discontinue endocrine therapy respectively (endocrine symptoms HR 1.13, 95% CI 1.02–1.25, p = 0.02; sleep disturbance HR 1.14, 95% CI 1.01–1.29, p = 0.03). AI treatment was associated with greater likelihood of discontinuation than tamoxifen. Treatment-emergent endocrine symptoms and sleep disturbance are associated with endocrine therapy discontinuation. Monitoring for worsening scores meeting or exceeding the MID on PROs may identify patients at risk for discontinuation. npj Breast Cancer (2022) 8:53 ; https://doi.org/10.1038/s41523-022-00414-0 INTRODUCTION Symptoms experienced by patients during endocrine therapy are often under-appreciated by clinicians . Patient-reported Although 5–10 years of adjuvant endocrine therapy reduces outcomes (PRO) are assessments from patients about their health recurrence and death after early hormone receptor-positive (HR+ ) status without interpretation by a clinician . The minimal breast cancer, approximately 50% of patients are non-adherent (do important difference (MID) is the smallest change in a score on not take endocrine therapy as prescribed) or non-persistent 1–14 a PRO measure that patients perceive as beneficial or harmful and (discontinue endocrine therapy early) . While some patients that would affect management . Prior studies evaluating the discontinue shortly after initiation, others do so later, with 15,16 association of symptoms with endocrine therapy discontinuation persistence overall declining with time . Risks of recurrence have not used changes in PRO scores meeting or exceeding the and death are higher among those who are non-adherent or who 8,17–19 MID to identify clinically important symptoms. discontinue endocrine therapy early . We report findings from a clinic-based cohort of women receiving Common symptoms during endocrine therapy include musculos- endocrine therapy for early HR+ breast cancer who completed PRO keletal discomfort, sleep disturbance, fatigue, anxiety, depression, measures over 5 years. We aimed to evaluate the association of and endocrine symptoms, such as vaginal dryness and hot 10,12,20–30 treatment-emergent symptoms, defined as worsening scores com- flashes . Side effects are frequently cited as a reason for pared to baseline in increments equal to the MID for each PRO early endocrine therapy discontinuation and multiple studies have measure, with discontinuation of endocrine therapy prior to demonstrated associations between symptoms and non-adherence 9,10,12,16,23,24,26,27,29,31–45 completing 5 years of treatment. We hypothesized that patient- or discontinuation . However, prospective reported new or worsening symptoms could identify individuals at identification of patients at risk for early discontinuation due to risk for early discontinuation. intolerance remains a clinical challenge. 1 2 Johns Hopkins Women’s Malignancies Program, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Johns Hopkins Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Division of Biostatistics and Bioinformatics, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA. 4 5 Division of Cancer Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA. Department of Health Policy and Management, Johns Hopkins 6 7 Bloomberg School of Public Health, Baltimore, MD, USA. Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Present address: Duke 8 9 Cancer Institute, Duke University Medical Center, Durham, NC, USA. Present address: CancerLinQ, American Society of Clinical Oncology, Alexandria, VA, USA. Present address: Cancer Research @UCC, College of Medicine and Health, University College Cork, Cork, Ireland. email: ksmith60@jhmi.edu Published in partnership with the Breast Cancer Research Foundation 1234567890():,; K.L. Smith et al. RESULTS Scores on PRO measures Participant characteristics Mean scores for all PRO measures were within one SD of published population means at all time points. The proportion Of 321 participants, 140 (43.6%) initiated tamoxifen and 181 of participants who completed the PROs declined over time (Table 2). (56.4%) an aromatase inhibitor (AI). Seventeen (5.3%) participants Mean changes in PRO scores during the first 24 months were received ovarian function suppression (OFS) and 6 (1.9%) enrolled small, and, while statistically significant for worsening endocrine upon switching endocrine therapy agents. The median age at symptoms (p < 0.001), the mean (SD) change in the FACT-ES score enrollment was 63 years and 65.4% were post-menopausal. The from baseline to 24 months was −2.9 (8.3), which is less than 1 majority of participants were White (83.5%) and lived in zip codes MID (Fig. 1). Despite small mean changes, the worst change in the with low neighborhood poverty (85.9%). Participants who initiated score at any time up to 60 months met or exceeded the MID for tamoxifen were younger than those who initiated an AI (Table 1). each measure in over one-third of participants. Symptom domains with the greatest proportions of participants with score worsening meeting or exceeding the MID at any time up to 60 months were Table 1. Characteristics of study population according to type of sleep disturbance (54%), endocrine symptoms (53%), sexual endocrine therapy initiated at study enrollment. problems (48%), and fatigue (46%) (Fig. 2). Treatment-emergent symptoms often developed soon after endocrine therapy initia- Characteristic Overall Study Tamoxifen Aromatase tion (Fig. 3). For example, worsening compared to baseline by at Population N = 140 Inhibitor N = 321 N = 181 least the MID for sleep disturbance, endocrine symptoms, sexual problems, and fatigue was already observed at 3 months in 27.1%, Median (Q1-Q3) age 63 (56–71) 54 (49–59) 69 (64–74) 26.3%, 23.3%, and 20.3% of participants respectively (Table 3). in years Due to the decline in PRO completion rates over time, we Post-menopausal – N (%) 210 (65.4) 34 (24.3) 176 (97.2) performed a sensitivity analysis comparing participants who Ovarian Function 17 (5.3) 16 (11.4) 1 (0.6) completed all measures during the first 24 months to those with Suppression – N (%) at least one missing measure during that timeframe. With the Switching Endocrine 6 (1.9) 0 (0) 6 (3.3) exception of differences in the number of concomitant medica- Therapy – N (%) tions and mean baseline fatigue and physical function scores, those with and without missing measures had similar key baseline Race – N (%) characteristics. The differences in mean baseline fatigue and White 268 (83.5) 112 (80) 156 (86.2) physical function between these groups were less than the MID Black 33 (10.3) 16 (11.4) 17 (9.4) (Table 4). Other 20 (6.2) 12 (8.6) 8 (4.4) Neighborhood Poverty Rate – N (%) Cumulative probability of discontinuation 0–15% 274 (85.9) 116 (82.9) 158 (88.3) Median follow-up was 56.1 months and 204 (63.6%) participants >15% 45 (14.1) 24 (17.1) 21 (11.7) remained on endocrine therapy at the time of data cut-off. Median number of 4(0–29) 3 (0–29) 5 (0–22) Twenty-six (8.1%) participants had discontinued after completing concomitant the planned course and 13 (4.0%) due to recurrence. Five (1.6%) medications at switched from the endocrine therapy initiated at enrollment to enrollment (range) another agent with less than 6 weeks interruption. Sixty-three Stage – N (%) (19.6%) participants had stopped endocrine therapy due to side 0 28 (8.7) 18 (12.9) 10 (5.5) effects/intolerance and 10 (3.1%) due to other reasons besides recurrence, new primary breast cancer, completion of at least 5 I 191 (59.5) 80 (57.1) 111 (61.3) years of endocrine therapy or switching agents. Among the 73 II 79 (24.6) 39 (27.9) 40 (22.1) participants who discontinued due to side effects/intolerance or III 23 (7.2) 3 (2.1) 20 (11) other reasons besides recurrence, new primary breast cancer, ER-positive – N (%) 320 (100) 139 (100) 181 (100) completion of at least 5 years of endocrine therapy or switching PR-positive – N (%) 282 (88.7) 128 (93.4) 154 (85.1) agents, the times at which they discontinued were distributed HER2-positive – N (%) 26 (8.9) 10 (8.2) 16 (9.4) across the follow-up period. Ten discontinued in the first 3 months (13.7%), 10 in months 3–6 (13.7%), 6 in months 6–9 (8.2%), 9 in Mastectomy – N (%) 143 (44.5) 76 (54.3) 67 (37) months 9–12 (12.3%), 9 in months 12–18 (12.3%), 8 in months Radiation – N (%) 215 (67) 85 (60.7) 130 (71.8) 18–24 (11%), and 21 after 24 months (28.8%). Among participants Chemotherapy – N (%) 90 (28.2) 43 (30.9) 47 (26.1) with and without missing PRO measures in the first 24 months, Median duration of 56.1 (6.9–87.7) 57.9 (9.1–87.7) 54.4 (6.9–87.3) 25.4% and 11.4% respectively discontinued due to side effects/ follow-up in months intolerance (Table 4). The cumulative probabilities of discontinua- (range) tion at 3, 6, 12, 24, 36, and 48 months were 3% [95% confidence Q1-Q3 interquartile range, ER estrogen receptor, PR progesterone receptor, interval (CI): 1–5%], 6% (95% CI: 4–9%), 11% (95% CI: 7–14%), 17% HER2 human epidermal growth factor receptor-2, SD standard deviation. (95% CI: 12–21%), 19% (95% CI: 14–23%), and 23% (95% CI: Participants were eligible to enroll at the time they first initiated adjuvant 18–27%), respectively. Figure 4 depicts the time to discontinuation endocrine therapy or at the time of switching from one type of adjuvant of endocrine therapy for the entire cohort and according to the endocrine therapy to another. type of endocrine therapy. Neighborhood poverty rate is the percentage of persons living in a zip code with a family income below the federal poverty line based on United States census data. Neighborhood poverty rate was missing for Association of patient-reported outcomes and clinico- two participants. demographic factors with endocrine therapy discontinuation ER status was missing for one participant. PR status was missing for 3 Of the 73 study participants who discontinued endocrine therapy participants. due to side effects/intolerance or due to other reasons besides Follow-up was calculated as the time from study entry to last clinic visit or recurrence, completion of at least 5 years of endocrine therapy or last PRO survey completion, whichever came last. switching agents, 63 completed the PRO measures at the time npj Breast Cancer (2022) 53 Published in partnership with the Breast Cancer Research Foundation 1234567890():,; K.L. Smith et al. Table 2. Mean scores on patient-reported outcome measures at each study time point. Domain Baseline 3 months 6 months 12 months 24 months 36 months 48 months 60 months a a a a a a a a N N N N N N N N Mean (SD) Mean (SD) Mean (SD) Mean (SD) Mean (SD) Mean (SD) Mean (SD) Mean (SD) Physical Function 320 282 253 214 144 91 52 24 51.5 (8.3) 52 (8.1) 53.3 (7.9) 53.2 (8.1) 53.9 (8.1) 54.5 (7.6) 54.3 (7.3) 56.8 (8.1) Endocrine Symptoms 319 281 252 214 143 90 52 24 65.1 (8.6) 63.7 (8.8) 63.7 (8.4) 62.5 (9.4) 62.9 (8.9) 63.4 (8.1) 63.4 (8.2) 67.2 (7.5) Sexual Problems 315 277 248 210 141 90 51 23 27.4 (32.0) 27.9 (33.7) 25.8 (31.4) 27.1 (31.1) 25.2 (30.2) 21.6 (28) 25.3 (30.1) 20.4 (29.8) Depression 319 280 250 212 142 91 52 24 45.4 (7.8) 44.9 (8.1) 44.6 (8) 45.2 (8.1) 44.2 (8.2) 43.5 (7.8) 44.9 (6.3) 43.0 (7.6) Anxiety 320 281 253 214 144 91 52 24 49.0 (9.4) 47.9 (9.1) 47.5 (8.7) 48.1 (8.6) 47.4 (8.4) 47.3 (8.5) 47.6 (7.5) 43.8 (7.5) Sleep Disturbance 320 282 253 215 144 91 52 24 49.0 (8.1) 49.8 (8.7) 48.8 (8.3) 49.1 (8.65) 47.6 (8.3) 49 (7.8) 46.8 (9) 43.8 (7.5) Fatigue 319 281 252 215 146 90 52 24 48.7 (7.7) 48.3 (7.9) 48 (8.5) 47.3 (8.3) 46.4 (8.9) 46.6 (7.5) 46.1 (7.9) 43.3 (5.9) Pain Interference 319 281 252 214 143 90 52 24 48.4 (8.2) 47.7 (8.2) 46.8 (7.6) 47.4 (7.5) 47.3 (7.7) 46 (6.7) 45.8 (7.4) 44.4 (5.6) SD standard deviation. N at each time point for each domain represents the number of participants who completed the patient-reported outcome measure. point immediately before their discontinuation. And, among the are a key driver of this decision . To date, interventions to support 248 participants who did not discontinue endocrine therapy, 190 adherence and persistence have largely focused on educational or 7,50 completed the PRO measures at the time point immediately behavioral strategies and have had limited success . We argue before they completed follow-up. Therefore, we had complete that early intervention to mitigate side effects has the potential to data for evaluation of the association of PROs with time to enhance endocrine therapy adherence and persistence. The discontinuation on 253 (79%) of patients. cornerstone to this strategy, however, is comprehensive detection In univariate analyses, worsening of multiple symptoms of treatment-emergent symptoms that may drive patients to (endocrine symptoms, fatigue, sleep disturbance, and pain discontinue therapy. Unfortunately, in routine clinical care, interference) plus receipt of AI were associated with endocrine clinicians often underappreciate side effects patients experience therapy discontinuation. In the final multivariate model, during endocrine therapy, and the symptom burden reported by 22,46 treatment-emergent endocrine symptoms (adjusted HR 1.13, patients often exceeds that detected by clinicians . Our data 95% CI 1.02 – 1.25, p = 0.02) and sleep disturbance (adjusted HR demonstrate that clinically relevant treatment-emergent symp- 1.14, 95% CI 1.01–1.29, p = 0.03) remained significantly associated toms are common during endocrine therapy and that use of PRO with endocrine therapy discontinuation. Additionally, patients measures as an adjunct to routine clinical care can identify receiving AI were twice as likely to discontinue compared to those symptoms associated with early discontinuation. on tamoxifen (adjusted HR 1.98, 95% CI 1.17–3.33, p = 0.01). When utilizing PRO measures in clinical care, the optimal score Higher stage was associated with lower likelihood of discontinua- thresholds beyond which clinical action should be taken are tion (adjusted HR 0.61, 95% CI: 0.43 – 0.87, p = 0.006) (Table 5). uncertain and may vary depending on the clinical scenario, symptoms, specific measures, and clinical outcomes to which 51,52 score thresholds are anchored . It is possible that MIDs may DISCUSSION vary by factors such as age, race, ethnicity, socioeconomic status, In this real-world prospective clinic-based cohort of women with stage, treatment duration or intervention and, moreover, that early HR + breast cancer receiving endocrine therapy who MIDs may change over time. Although severity thresholds can completed PRO measures over 5 years, we demonstrated that identify particularly bothersome symptoms and absolute scores treatment-emergent symptoms, defined as worsening scores at on PROs during the course of endocrine therapy have been any time during follow-up compared to baseline, was associated associated with discontinuation, worsening of scores over time with risk for discontinuing endocrine therapy prior to completing can indicate changes in supportive care needs and thus present a 9,53–56 5 years of treatment. Specifically, new or worsening endocrine clinical opportunity to provide symptom management . Our symptoms and sleep disturbance were associated with endocrine findings demonstrate that treatment-emergent symptoms, therapy discontinuation. As the severity of the treatment- defined by score worsening compared to baseline meeting or emergent symptoms worsened, the risk of discontinuation exceeding the MID for the selected measure, can identify clinically increased. For every 5-point worsening on the Endocrine Subscale significant symptoms associated with endocrine therapy disconti- of the FACT-ES measure, the risk of discontinuation was 13% nuation. Patients in whom these symptoms are identified should higher, and for every 4-point worsening on the PROMIS sleep be targeted for enhanced symptom management with the dual disturbance measure, the risk of discontinuation was 14% higher. goals of improving symptoms and supporting persistence. Worsening of scores meeting or exceeding the MID of on these Our findings build on previous work demonstrating that measures was common, each occurring in approximately half the treatment-emergent symptoms often present soon after endo- study population, with approximately half of these participants crine therapy initiation, indicating that symptom monitoring with experiencing worsening by more than twice the MID. PROs has the potential to identify patients at risk for discontinua- Although multiple factors may contribute to an individual tion early during the course of therapy to whom interventions 12,26,31 patient’s decision to discontinue endocrine therapy, side effects could be targeted . However, as has also previously been Published in partnership with the Breast Cancer Research Foundation npj Breast Cancer (2022) 53 K.L. Smith et al. Fig. 1 Change in patient-reported outcome scores over time. Line graphs display median PRO scores at each time point. The size of each dot is proportional to the number of participants who completed the PRO measure at that time point. The numbers of participants who completed the PRO measure at baseline and at 12, 24, 36, 48, and 60 months point are noted under the X-axis at the corresponding time points. The Y-axis denotes the score range for each PRO measure. Bars represent interquartile ranges. P-values summarize overall mean change in PRO scores during the first 24 months compared to baseline with a four-degree-of-freedom test. PRO patient-reported outcomes. reported, endocrine therapy discontinuation in our cohort supporting ongoing PRO monitoring throughout the course of increased over time and worsening of symptoms meeting or therapy. exceeding the MID at any time during 5 years of follow-up was In our study, the cumulative probabilities of endocrine therapy 15,16,33,45 associated with discontinuation . Most prior studies have discontinuation at 6, 12, 24, 36, and 48 months, respectively were focused on associations between baseline symptoms or those that 6, 11, 17, 19, and 23%. These observed discontinuation rates are 8,11 emerge early during endocrine therapy with discontinua- lower than reported in many prior studies . It is possible that 9,10,12,24,26,27,31,32,37,42 tion . Our study is unique in that it demon- completing PRO measures motivated patients to continue strates that treatment-emergent symptoms at any time over 5 endocrine therapy. Alternatively, although we did not mandate years are associated with endocrine therapy discontinuation, that clinicians review scores nor implement symptom npj Breast Cancer (2022) 53 Published in partnership with the Breast Cancer Research Foundation K.L. Smith et al. Physical Function Endocrine Symptoms Sexual Problems Depression 40% Worsened by 1 MID 35% Worsened by 2 MID 29% 30% Worsened by 3 or more MID 24% 25% 19% 20% 16% 15% 14% 15% 13% 12% 11% 10% 9% 10% 7% 5% 0% ≥ 3 MID ≥ 3 MID ≥ 3 MID ≥ 3 MID 1 MID 2 MID 1 MID 2 MID 1 MID 2 MID 1 MID 2 MID Anxiety Sleep Disturbance Fatigue Pain Interference 40% 35% 30% 26% 25% 23% 20% 16% 15% 15% 14% 15% 13% 13% 13% 11% 10% 10% 10% 5% 0% 1 MID 2 MID ≥ 3 MID 1 MID 2 MID ≥ 3 MID 1 MID 2 MID ≥ 3 MID 1 MID 2 MID ≥ 3 MID Fig. 2 Proportion of participants who experienced worsening of patient-reported outcome scores exceeding the minimal important difference at any time point through 60 months. Bar plots display worst change in PRO scores at any time point in follow-up through 60 months. Worst changes are categorized as at least the MID but less than twice the MID, at least twice the MID but less than three times the MID and at least three times the MID for each measure. Only participants with baseline values and at least one follow-up measure are included. The proportions of participants whose worst changes in each PRO scores were less than the MID (i.e. who experienced improvement, no change or worsening less than the MID) are not displayed. The MID was considered to be 4 points for the physical function, depression, anxiety, sleep disturbance, fatigue, and pain interference measures; 8 points for the sexual problems measure; and 5 points for the endocrine symptoms measure. MID minimal important difference, 1 MID at least the MID but less than twice the MID, 2 MID twice the MID but less than three times the MID, 3 MID at least three times the MID, PRO patient-reported outcomes. management interventions, it is possible that greater patient and that were prospective, many did not use validated measures, clinician awareness of symptoms due to the PROs led to better assessed fewer symptoms or limited symptom assessment to early 10,12,16,23,26,27,31–33,37,40–42,57,72 symptom management and, in turn, to enhanced persistence. during the course of therapy . Our findings are consistent with prior studies linking symptoms A key limitation of our study is that the proportion of prior to or during receipt of tamoxifen or an AI such as endocrine participants who completed the PROs declined over time. In our symptoms and sleep disturbance with non-adherence and early sensitivity analysis, baseline characteristics of participants with 10,23,26,27,31,40,42,57 treatment discontinuation . Endocrine symptoms and without missing measures were similar with the exception of include vasomotor symptoms, weight changes, vaginal or sexual the number of baseline concomitant medications. Some literature symptoms, mood changes and joint pain . In patients with breast demonstrates an association between polypharmacy and endo- cancer, endocrine symptoms, such as hot flashes and night crine therapy discontinuation, however, this association has not 58,59 sweats, can disrupt sleep . Evidence-based strategies can been consistently demonstrated and no prior literature indicates mitigate the treatment-emergent symptoms that were associated that a difference in one drug (the difference we observed in the with early discontinuation of endocrine therapy in our cohort. For median number of concomitant medications for those with and example, improved sleep hygiene, exercise, and cognitive 73–75 without missing PROs in the first 24 months) is meaningful . behavioral therapy can support patients with sleep distur- Thus, we believe our sensitivity analysis indicates patients with 60–67 bance . For patients with hot flashes or sweats, medications and without missing PRO measures are similar and that our such as anti-depressants or gabapentin may improve both findings are robust despite missing data. Of note, however, the 68,69 daytime symptoms and sleep . proportion of participants who discontinued endocrine therapy As has been previously reported, endocrine therapy disconti- due to side effects/intolerance was higher among participants nuation was more frequent among participants in our study taking with missing measures suggesting that patients with greater an AI than tamoxifen, a finding potentially attributable to frequent 32,70,71 symptom burden may have been less likely to complete the PROs. musculoskeletal discomfort during AI therapy . We also If participants with greater symptoms did not complete the PROs, confirmed previous findings demonstrating that individuals with it is possible that the association between treatment-emergent higher stage disease are less likely to discontinue endocrine symptoms and endocrine therapy discontinuation is even stronger therapy, a finding potentially explained by greater motivation to 33,35,44 than we estimated. But, the fact that PRO data was complete for take therapy in light of higher recurrence risk . In addition to assessing the time to discontinuation for 79% of study participants PRO scores, these factors may guide identification of patients at supports our findings regarding the association between risk for endocrine therapy discontinuation for interventions to treatment-emergent symptoms and endocrine therapy disconti- support persistence. nuation. The extent of missing PRO data in our study speaks to the Strengths of our study are that we comprehensively assessed need for strategies to further engage patients in incorporating common symptoms during endocrine therapy prospectively over 5 years with validated PRO measures in a real-world population. PROs into their care. Considerations may include reducing the Many previous studies evaluating symptoms during endocrine length or frequency of assessments to limit respondent burden therapy used cross-sectional or retrospective designs and, of those and assessing PROs in conjunction with clinic visits. Published in partnership with the Breast Cancer Research Foundation npj Breast Cancer (2022) 53 Percent of Participants with Worsening Percent of Participants with Worsening K.L. Smith et al. Physical Function Endocrine Symptoms 35 35 1 MID 30 2 MID 30 3+ MID 25 25 20 20 15 15 10 10 5 5 0 0 36 12 36 12 Months From Enrollment Months From Enrollment No. P No. Pa ar rt ticipants icipants 282 253 214 No. P No. Pa ar rt ticipants icipants 281 252 214 Sexual Problems Depression 35 35 30 30 25 25 20 20 15 15 10 10 5 5 0 0 36 12 36 12 Months From Enrollment Months From Enrollment No. P No. Pa ar rt ticipants icipants 277 248 210 No. P No. Pa ar rt ticipants icipants 280 250 212 Anxiety Sleep Disturbance 35 35 30 30 25 25 20 20 15 15 10 10 5 5 0 0 36 12 36 12 Months From Enrollment Months From Enrollment No. P No. Pa ar rt ticipants icipants 281 253 214 No. P No. Pa ar rt ticipants icipants 282 253 215 Fatigue Pain Interference 35 35 30 30 25 25 20 20 15 15 10 10 5 5 0 0 36 12 36 12 Months From Enrollment Months From Enrollment No. P No. Pa ar rt ticipants icipants 281 252 215 No. P No. Pa ar rt ticipants icipants 281 252 214 Fig. 3 Proportion of participants who experienced worsening of patient-reported outcome scores meeting or exceeding the minimal important difference at 3, 6, and 12 months. Line graphs display percentage of participants with worsening of PRO scores compared to baseline at 3, 6, and 12 months after enrollment. Worsening of PRO scores is categorized as at least the MID but less than twice the MID, at least twice the MID but less than three times the MID and at least three times the MID for each measure. Only participants with baseline values and at least one follow-up measure are included. The percentage of participants whose PRO scores worsened by less than the MID (i.e. who experienced improvement, no change or worsening less than the MID) are not displayed. The MID was considered to be 4 points for the physical function, depression, anxiety, sleep disturbance, fatigue, and pain interference measures; 8 points for the sexual problems measure; and 5 points for the endocrine symptoms measure. MID minimal important difference, 1 MID at least the MID but less than twice the MID, 2 MID twice the MID but less than three times the MID, 3+ MID at least three times the MID, PRO patient-reported outcomes. npj Breast Cancer (2022) 53 Published in partnership with the Breast Cancer Research Foundation Percent of Participants with Worsening Percent of Participants with Worsening Percent of Participants with Worsening Percent of Participants with Worsening Percent of Participants with Worsening Percent of Participants with Worsening Percent of Participants with Worsening Percent of Participants with Worsening K.L. Smith et al. Table 3. Change in symptoms compared to baseline at each time point through 12 months. Symptom Domain 3 months 6 months 12 months N (%) N (%) N (%) Physical Function No change or improvement 189 (58.9) 184 (57.3) 150 (46.7) Worsening by less than the MID 44 (13.7) 28 (8.7) 22 (6.9) Worsening by at least the MID but less than twice the MID 28 (8.7) 26 (8.1) 19 (5.9) Worsening by at least twice the MID but less than three times the MID 13 (4) 9 (2.8) 16 (5) Worsening by at least three times the MID 8 (2.5) 6 (1.9) 7 (2.2) PRO not completed 38 (11.8) 67 (20.9) 106 (33) Endocrine Symptoms No change or improvement 123 (38.3) 106 (33) 79 (24.6) Worsening by less than the MID 74 (23.1) 74 (23.1) 57 (17.8) Worsening by at least the MID but less than twice the MID 48 (15) 40 (12.5) 42 (13.1) Worsening by at least twice the MID but less than three times the MID 22 (6.9) 17 (5.3) 19 (5.9) Worsening by at least three times the MID 14 (4.4) 15 (4.7) 17 (5.3) PRO not completed 39 (12.1) 68 (21.2) 106 (33) Sexual Problems No change or improvement 201 (62.6) 187 (58.3) 114 (44.9) Worsening by less than the MID 1 (0.3) 0 (0) 0 (0) Worsening by at least the MID but less than twice the MID 18 (5.6) 15 (4.7) 19 (5.9) Worsening by at least twice the MID but less than three times the MID 19 (5.9) 15 (4.7) 14 (4.4) Worsening by at least three times the MID 38 (11.8) 31 (9.7) 33 (10.3) PRO not completed 43 (13.4) 72 (22.4) 110 (34.3) Depression No change or improvement 192 (59.8) 175 (54.5) 139 (43.3) Worsening by less than the MID 31 (9.7) 17 (5.3) 22 (6.9) Worsening by at least the MID but less than twice the MID 37 (11.5) 28 (8.7) 24 (7.5) Worsening by at least twice the MID but less than three times the MID 12 (3.7) 20 (6.2) 15 (4.7) Worsening by at least three times the MID 8 (2.5) 10 (3.1) 12 (3.7) PRO not completed 40 (12.5) 70 (21.8) 108 (33.6) Anxiety No change or improvement 180 (56.1) 170 (53) 136 (42.4) Worsening by less than the MID 39 (12.1) 34 (10.6) 31 (9.7) Worsening by at least the MID but less than twice the MID 29 (9) 19 (5.9) 23 (7.2) Worsening by at least twice the MID but less than three times the MID 22 (6.9) 16 (5) 9 (2.8) Worsening by at least three times the MID 11 (3.4) 14 (4.4) 15 (4.7) PRO not completed 39 (12.1) 67 (20.9) 106 (33) Sleep Disturbance No change or improvement 146 (45.5) 139 (43.3) 120 (37.4) Worsening by less than the MID 49 (15.3) 40 (12.5) 34 (10.6) Worsening by at least the MID but less than twice the MID 50 (15.6) 40 (12.5) 27 (8.4) Worsening by at least twice the MID but less than three times the MID 17 (5.3) 18 (5.6) 18 (5.6) Worsening by at least three times the MID 20 (6.2) 16 (5) 16 (5) PRO not completed 38 (11.8) 67 (20.9) 105 (32.7) Fatigue No change or improvement 158 (49.2) 130 (40.5) 116 (36.1) Worsening by less than the MID 58 (18.1) 53 (16.5) 40 (12.5) Worsening by at least the MID but less than twice the MID 33 (10.3) 44 (13.7) 38 (11.8) Worsening by at least twice the MID but less than three times the MID 18 (5.6) 14 (4.4) 11 (3.4) Worsening by at least three times the MID 14 (4.4) 11 (3.4) 10 (3.1) PRO not completed 39 (12.1) 68 (21.2) 105 (32.7) Pain Interference No change or improvement 209 (65.1) 193 (60.1) 153 (47.7) Worsening by less than the MID 22 (6.9) 17 (5.3) 16 (5) Worsening by at least the MID but less than twice the MID 23 (7.2) 17 (5.3) 26 (8.1) Worsening by at least twice the MID but less than three times the MID 11 (3.4) 11 (3.4) 9 (2.8) Worsening by at least three times the MID 16 (5) 14 (4.4) 10 (3.1) PRO not completed 39 (12.1) 68 (21.2) 106 (33) MID minimal important difference, PRO patient-reported outcome. MID = 4 points; MID = 5 points; MID = 8 points. Published in partnership with the Breast Cancer Research Foundation npj Breast Cancer (2022) 53 K.L. Smith et al. Table 4. Characteristics of participants with and without missing patient-reported outcome measures during the first 24 months of study participation. Characteristic No Missing PRO Measures During First 24 ≥1 Missing PRO Measure During First 24 p value Months (N = 132) Months (N = 189) Mean age in years (SD) 63.0 (10.5) 62.2 (11.3) 0.51 Post-menopausal – N (%) 85 (64.4) 125 (66.1) 0.81 Ovarian Function Suppression – N (%) 6 (4.5) 11 (5.8) 0.80 Endocrine Therapy Tamoxifen 64 (48.5) 76 (40.2) 0.17 AI 68 (51.5) 113 (59.8) Switching Endocrine Therapy – N (%) 0 (0) 6 (3.2) 0.05 Race – N (%) White 117 (88.6) 151 (79.9) 0.12 Black 9 (6.8) 24 (12.7) Other 6 (4.5) 14 (7.4) Neighborhood Poverty Rate – N (%) 0–15% 117 (89.3) 157 (83.5) 0.19 >15% 14 (10.7) 31 (16.5) Median number of concomitant medications at 4(0–13) 5 (0–29) 0.006 enrollment (range) Stage – N (%) 0 15 (11.4) 13 (6.9) 0.13 I 78 (59.1) 113 (59.8) II 34 (25.8) 45 (23.8) III 5 (3.8) 18 (9.5) ER-positive – N (%) 132 (100) 189 (100) PR-positive – N (%) 110 (83.8) 172 (92.5) 0.02 HER2-positive – N (%) 8 (6.8) 18 (10.2) 0.40 Mastectomy – N (%) 59 (44.7) 84 (44.4) >0.99 Radiation – N (%) 85 (64.4) 130 (63.8) 0.47 Chemotherapy – N (%) 36 (27.5) 54 (28.7) 0.90 Mean Baseline Depression Score (SD) 44.6 (7.5) 46.0 (8.1) 0.12 Mean Baseline Physical Function Score (SD) 52.7 (8.3) 50.0 (8.1) 0.005 Mean Baseline Endocrine Symptoms Score (SD) 65.8 (7.7) 64.6 (9.2) 0.21 Mean Baseline Sexual Problems Score (SD) 25.3 (29.7) 29.0 (33.6) 0.30 Mean Baseline Depression Score (SD) 44.6 (7.5) 46.0 (8.1) 0.12 Mean Baseline Anxiety Score (SD) 48.5 (9.2) 49.4 (9.5) 0.41 Mean Baseline Sleep Disturbance Score (SD) 48.2 (7.7) 49.6 (8.3) 0.13 Mean Baseline Fatigue Score (SD) 47.3 (8.0) 49.6 (7.4) 0.01 Mean Baseline Pain Interference Score (SD) 47.5 (7.9) 49.0 (8.3) 0.09 Discontinuation Status Completed Treatment – N (%) 24 (18.2) 2 (1.1) <0.001 Discontinued due to Distant Metastases – N (%) 3 (2.3) 8 (4.2) Discontinued due to Locoregional Recurrence– N (%) 2 (1.5) 0 (0) Discontinued due to Side effects/Intolerance – N (%) 15 (11.4) 48 (25.4) Discontinued Tamoxifen to Transition to AI – N (%) 2 (1.5) 3 (1.6) Discontinued due to Other reasons – N (%) 2 (1.5) 8 (4.2) Still on Endocrine Therapy – N (%) 84 (63.6) 120 (63.5) ER estrogen receptor, PR progesterone receptor, HER2 human epidermal growth factor receptor-2, SD standard deviation, AI aromatase inhibitor. Participants were eligible to enroll at the time they first initiated adjuvant endocrine therapy or at the time of switching from one type of adjuvant endocrine therapy to another. Neighborhood poverty rate is the percentage of persons living in a zip code with a family income below the federal poverty line based on United States census data. Neighborhood poverty rate was unknown for one participant with no missing PRO measures during the first 24 months and for one participant with at least one missing PRO measure during the first 24 months. PR status was unknown for 3 participants with missing PRO measures during the first 24 months. HER2 status was unknown for 15 participants with no missing PRO measures during the first 24 months and for 13 participants with at least one missing PRO measure during the first 24 months. Receipt of chemotherapy was unknown for 1 participant with no missing PRO measures during the first 24 months and for 1 participant with at least one missing PRO measure during the first 24 months. P-values are for Fisher’s exact test for categorical measures, t-tests for comparison of means and Wilcoxon rank sum tests for comparison of medians npj Breast Cancer (2022) 53 Published in partnership with the Breast Cancer Research Foundation K.L. Smith et al. Cumulative Probability of Stopping By 12 Months Whole Cohort: 11% Participants on Tam: 5% Participants on AI: 15% AI Whole Cohort Tam 012 24 36 48 60 MONTHS FROM STUDY START NNNNNN Events Rate Events Rate Events Rate Events Rate Events Rate Whole Cohort 321 35 3.55 278 17 1.96 252 7 0.89 224 9 1.42 162 4 0.94 83 Tam 14075451 1.59 127 1.24 118 1.13 98 1.75 77 0.47 47 AI 181 28 5.13 151 12 2.58 134 3 0.7 126 4 1.16 85 3 1.43 36 Fig. 4 Cumulative probability of endocrine therapy discontinuation. Curves depict time to discontinuation of endocrine therapy for the entire cohort and according to type of endocrine therapy. AI aromatase inhibitor, Tam tamoxifen. Table 5. Univariate and multivariate associations of new or worsening symptoms and clinico-demographic variables with time to discontinuation of adjuvant endocrine therapy. Variable Univariate Hazard Ratio (95% CI) p-value Multivariate Adjusted Hazard Ratio (95% CI) p-value Physical Function (4-point worsening) 1.06 (0.95–1.19) 0.30 Endocrine Symptoms (5-point worsening) 1.15 (1.06–1.26) 0.001 1.13 (1.02–1.25) 0.02 Fatigue (4-point worsening) 1.15 (1.02–1.29) 0.02 Depression (4-point worsening) 1.03 (0.93–1.15) 0.55 Anxiety (4-point worsening) 1.05 (0.95–1.16) 0.33 Sleep Disturbance (4-point worsening) 1.18 (1.06–1.32) 0.002 1.14 (1.01–1.29) 0.03 Sexual Problems (8-point worsening) 1.05 (1.00–1.11) 0.06 Pain Interference (4-point worsening) 1.11 (1.00–1.24) 0.05 Age in years 1.02 (1.00–1.04) 0.09 Race (White vs. Other) 1.30 (0.67–2.53) 0.44 High neighborhood poverty rate 1.10 (0.58–2.09) 0.78 Adjuvant endocrine therapy (AI vs. Tamoxifen) 1.93 (1.17–3.19) 0.01 1.98 (1.17–3.33) 0.01 Number of baseline concomitant medications 1.05 (1.00–1.11) 0.07 Higher Stage 0.71 (0.51–1.00) 0.05 0.61 (0.43–0.87) 0.006 HER2-positive 0.53 (0.17–1.70) 0.29 Mastectomy 0.91 (0.57–1.45) 0.69 Radiation 0.98 (0.60–1.59) 0.93 Chemotherapy 0.47 (0.25–0.88) 0.02 AI aromatase inhibitor, CI confidence interval, HER2 human epidermal growth factor receptor-2. Multivariable HR only shown for variables included in final model. Another limitation of our study is that few pre-menopausal evaluated the association between each individual treatment- participants received OFS and an AI, potentially limiting general- emergent symptom with discontinuation, but we did not evaluate izability of our findings to the many young patients who may whether the overall symptom burden affected the risk of receive this therapy in light of recently published survival data. discontinuation. Another limitation of our study is that we Additionally, few participants enrolled upon switching endocrine assessed pain with the PROMIS pain interference measure, a tool therapies. Although some patients who switch due to side effects not specific to joint pain that may not have been sensitive enough tolerate the second agent, our findings cannot fully address to detect AI-associated musculoskeletal symptoms. It is possible tolerance after switching . Additionally, we grouped patients that had we used a more sensitive and specific measure, we would taking tamoxifen and an AI, however, the treatment-emergent have identified an association between treatment-emergent symptoms that identify those at risk for discontinuation may differ musculoskeletal pain and endocrine therapy discontinuation as by drug. It is also possible that we misclassified discontinuation has been reported previously. Additionally, we did not collect any status and reasons for discontinuation based on chart review. We data regarding comorbidities and, for concomitant medications, did not confirm endocrine therapy administration dates with we only collected the number of medications (including both over pharmacy records or pill diaries, nor did we confirm reasons for the counter and prescribed medications) at baseline in our study, discontinuation by patient report. Additionally, our analysis thus we cannot address any potential associations between Published in partnership with the Breast Cancer Research Foundation npj Breast Cancer (2022) 53 Cumulative Probability of Discontinuation (%) K.L. Smith et al. specific medication classes and their side effects, nor the reason for discontinuation were determined by chart review. Reasons for discontinuation were classified as: completed treatment, discontinued due associations of any changes in concomitant medications during to distant metastases, discontinued due to loco-regional recurrence, study participation or of any comorbidities, with time-to- discontinued due to side effects/intolerance, discontinued tamoxifen to discontinuation of endocrine therapy. Furthermore, our study transition to AI and discontinued due to other reasons. No patient population was predominantly white and high socioeconomic discontinued due to a new primary breast cancer. status which may limit generalizability of our findings to other populations. Patient-reported outcomes Finally, it must be noted that while a change in a score of at PROs were collected at baseline and 3, 6, 12, 24, 36, 48, and 60 months using least the MID is considered clinically significant, it is not certain 77–79 the online PatientViewpoint website . Measures included the Patient- that a change of this degree is truly the minimal change that is Reported Outcome Measurement Information System (PROMIS) Version 1.0 significant . If anchored to endocrine therapy discontinuation, it pain interference, fatigue, depression, anxiety, physical function, and sleep is possible that smaller changes in scores would be clinically disturbance short forms; the Endocrine Subscale of the Functional significant and had we looked at smaller changes, we may have Assessment of Cancer Therapy - Endocrine Symptom (FACT-ES) measure; identified associations between discontinuation and worsening of 30,80–87 and the Medical Outcomes Study Sexual Problems (MOS-SP) scale . other symptoms as have previously been reported such as Treatment-emergent symptoms were defined as worsening of scores at any musculoskeletal discomfort, depression, and anxi- time compared to baseline in increments meeting or exceeding the MID for 10,12,23,24,26,32,37,40–42 ety . Further study is needed to determine each measure. PROMIS measures are scored with a T-score metric for which the optimal PRO measures for symptom assessment during 50 represents the mean in the United States (US) population and 10 is the endocrine therapy and the score thresholds to best identify standard deviation (SD). Higher scores on PROMIS measures indicate more of the outcome measured. PROMIS measures have been validated in early-stage treatment-emergent symptoms associated with discontinuation in 80–83,88 cancer patients with a MID of 3–5points . We considered the midpoint diverse populations. of this range (4 points) to be the MID. Endocrine Subscale FACT-ES scores The use of PROs to assess symptoms improves clinical range from 0–76 with lower scores indicating more endocrine symptoms. outcomes including hospitalization rates, emergency room The mean and SD on the Endocrine Subscale of the FACT-ES in women with utilization, chemotherapy delivery and quality of life, effects likely early breast cancer are 59 and 9.7 respectively .In accordance withthe mediated by enhanced symptom detection and subsequent distribution-based, Effect Size method of identifying a MID for a PRO 54,76 symptom management . To date, whether use of PROs impacts measure, we used 0.5 SD to define a medium effect size as a conservative oral cancer therapy persistence has not been prospectively estimate of the MID on the Endocrine Subscale of the FACT-ES and rounded determined. In this real-world cohort of patients taking adjuvant this estimate to 5 points . MOS-SP scores range from 0–100 with higher endocrine therapy for early HR + breast cancer, we found that scores indicating more sexual problems. The reported mean MOS-SP score for women with early breast cancer ranges from approximately 20–36 with treatment-emergent endocrine symptoms and sleep disturbance 28,85,87 SD approximately 27–31 . As has previously been done, due to some detected via PRO measures were associated with early endocrine uncertainty about the mean and SD on the MOS-SP in the literature, we used therapy discontinuation. This finding is proof of the principle that the distribution-based, Empirical Rule Effect Size method to guide the collecting serial PROs during routine clinical care can identify identification of the MID for the MOS-SP. Based on this method, the SD was patients at risk for endocrine therapy discontinuation due to side assumed to be one-sixth of 100 and the estimated MID was calculated by effects who may benefit from symptom management interven- 28,89 dividing this number by half, yielding an estimated MID of 8 points . tions. To this end, we are prospectively evaluating the feasibility of A summary of PRO scores was available to clinicians at the time of follow-up using recommended symptom management pathways for clinic visits. patients receiving endocrine therapy who have symptoms identified on PROs. Future studies will also be needed to clarify Statistical analysis the optimal timing, the optimal PRO domains and MIDs to use Clinico-demographic characteristics of the participants and PRO scores when implementing PRO collection to identify patients receiving over time are presented descriptively using mean (SD), median (range or endocrine therapy at risk for treatment discontinuation. Better interquartile range), and proportions. We used Fisher’s exact test to symptom detection and management has the potential not only compare categorical measures, t-test to compare means and Wilcoxon to help patients feel better, but also to enhance endocrine therapy rank-sum test to compare medians between subgroups of the study persistence, an effect that could ultimately reduce breast cancer population as appropriate. Mean changes in PRO scores in the first recurrence and mortality. 24 months compared to baseline were estimated using a linear mixed- effects modeling approach with the PRO as the outcome, fixed effects for each time point, and a random intercept for each participant. A METHODS corresponding four-degree-of-freedom test was used to summarize the overall change in the first 24 months. Study population The time to discontinuation of endocrine therapy was calculated as the We enrolled women with HR+ stage 0-III breast cancer-initiating adjuvant time from study enrollment to endocrine therapy discontinuation. endocrine therapy with tamoxifen or an AI to a clinic-based prospective Participants who stopped the endocrine therapy initiated at enrollment cohort between March 2012 and December 2016 at Johns Hopkins due to recurrence, new primary breast cancer, completion of at least 5 (ClinicalTrials.gov Identifier: NCT01937052, registered September 3, 2013). years of endocrine therapy or who switched to another type of endocrine The study cohort was a convenience sample with candidate participants therapy after less than 6 weeks interruption were censored. All other identified by screening medical oncology provider clinic schedules and by participants were censored at the date of the last clinic visit before the provider referral. Pre-menopausal women could receive concurrent OFS. database was locked May 15, 2020. Time to discontinuation was estimated Participants could enroll when first initiating endocrine therapy or upon for the entire cohort and according to type of endocrine therapy (AI versus switching from one agent to another. All participants signed written Tamoxifen) using the Kaplan-Meier method. informed consent. The study was approved by the Johns Hopkins IRB. To assess how variables measured at baseline and during follow-up were associated with time to discontinuation, we fit Cox proportional hazards Discontinuation models using a time-dependent covariate structure. Non-time dependent demographic variables considered in the models included age at Endocrine therapy discontinuation was defined as stopping the endocrine enrollment, neighborhood poverty rate, and race. Neighborhood poverty therapy initiated at enrollment prior to completing 5 years of treatment for rate, the percentage of persons living in a zip code with a family income at least 6 weeks due to side effects/intolerance or other reasons besides recurrence, new primary breast cancer, completion of at least 5 years of below the federal poverty line based on US census data, was used as a endocrine therapy or switching to another type of endocrine therapy after surrogate for socioeconomic status (SES) with >15% considered indicative less than 6 weeks off therapy. Participants were allowed to continue of low SES . Clinical characteristics in the models included stage, endocrine therapy beyond 5 years. Endocrine therapy discontinuation and HER2 status, type of surgery, receipt of chemotherapy, receipt of radiation, npj Breast Cancer (2022) 53 Published in partnership with the Breast Cancer Research Foundation K.L. 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R Foundation for Sta- Armstrong, Raquel Nunes, Kala Visvanathan, Carol Riley, Katie Papathakis, Nelli tistical Computing. (R Core Team, R Foundation for Statistical Computing, Vienna, Zafman. Austria, 2020). ADDITIONAL INFORMATION ACKNOWLEDGEMENTS Supplementary information The online version contains supplementary material This work was supported by Susan G. Komen Foundation and National Institutes of available at https://doi.org/10.1038/s41523-022-00414-0. Health [P30 CA006973] Correspondence and requests for materials should be addressed to Karen Lisa Smith. Reprints and permission information is available at http://www.nature.com/ AUTHOR CONTRIBUTIONS reprints Conceptualization/Design: K.L.S., V.S., K.W., C.S. Funding Acquisition: V.S. Resources: C.S. Data Acquisition: K.L.S., J.F., A.C.W., D.J., R.S.M., R.C., D.K.A., R.N., K.V., C.R., K.P., N.Z., V.S. Data Curation: Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims J.L.,N.V.Analysis: D.L.,A.B.Interpretation ofData: Allauthors.Writing-original draft: K.L.S.,N.V. in published maps and institutional affiliations. Writing-review and editing: All authors. Approval of final manuscript: All authors. Agreement to be accountable for all aspects of work: All authors. Accountability for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved: All authors. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative COMPETING INTERESTS Commons license, and indicate if changes were made. The images or other third party Karen Lisa Smith has received research support (to institution) from Pfizer. Karen Lisa material in this article are included in the article’s Creative Commons license, unless Smith’s spouse has stock ownership in ABT Labs and Abbvie. Jennifer Y. Sheng has indicated otherwise in a credit line to the material. If material is not included in the received research support (to institution) from Pfizer. Roisin Connolly has received an article’s Creative Commons license and your intended use is not permitted by statutory unrestricted educational grant to her institution from Pfizer. Vered Stearns has regulation or exceeds the permitted use, you will need to obtain permission directly received research grants (to institution) from Pfizer and Novartis Claire Snyder has from the copyright holder. To view a copy of this license, visit http://creativecommons. research funding (to institution) from Pfizer and Genentech. The following authors org/licenses/by/4.0/. declare that they have no conflicts of interest related to the work presented in this manuscript: Neha Verma, Amanda Blackford, Jennifer Lehman, Kelly Westbrook, David Lim, John Fetting, Antonio Wolff, Danijela Jelovac, Robert Miller, Deborah © The Author(s) 2022 Published in partnership with the Breast Cancer Research Foundation npj Breast Cancer (2022) 53 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png npj Breast Cancer Springer Journals

Association of treatment-emergent symptoms identified by patient-reported outcomes with adjuvant endocrine therapy discontinuation

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www.nature.com/npjbcancer ARTICLE OPEN Association of treatment-emergent symptoms identified by patient-reported outcomes with adjuvant endocrine therapy discontinuation 1 2 3 1 1,7 3 1 Karen Lisa Smith , Neha Verma , Amanda L. Blackford , Jennifer Lehman , Kelly Westbrook , David Lim , John Fetting , 1 1 1,8 1,9 1 1 Antonio C. Wolff , Daniela Jelovac , Robert S. Miller , Roisin Connolly , Deborah K. Armstrong , Raquel Nunes , 1,4 1 1 1 1 2,5,6 1 Kala Visvanathan , Carol Riley , Katie Papathakis , Nelli Zafman , Jennifer Y. Sheng , Claire Snyder and Vered Stearns Many patients discontinue endocrine therapy for breast cancer due to intolerance. Identification of patients at risk for discontinuation is challenging. The minimal important difference (MID) is the smallest change in a score on a patient-reported outcome (PRO) that is clinically significant. We evaluated the association between treatment-emergent symptoms detected by worsening PRO scores in units equal to the MID with discontinuation. We enrolled females with stage 0-III breast cancer initiating endocrine therapy in a prospective cohort. Participants completed PROs at baseline, 3, 6, 12, 24, 36, 48, and 60 months. Measures included PROMIS pain interference, fatigue, depression, anxiety, physical function, and sleep disturbance; Endocrine Subscale of the FACT-ES; and MOS-Sexual Problems (MOS-SP). We evaluated associations between continuous PRO scores in units corresponding to MIDs (PROMIS: 4-points; FACT-ES: 5-points; MOS-SP: 8-points) with time to endocrine therapy discontinuation using Cox proportional hazards models. Among 321 participants, 140 (43.6%) initiated tamoxifen and 181 (56.4%) initiated aromatase inhibitor (AI). The cumulative probability of discontinuation was 23% (95% CI 18–27%) at 48 months. For every 5- and 4-point worsening in endocrine symptoms and sleep disturbance respectively, participants were 13 and 14% more likely to discontinue endocrine therapy respectively (endocrine symptoms HR 1.13, 95% CI 1.02–1.25, p = 0.02; sleep disturbance HR 1.14, 95% CI 1.01–1.29, p = 0.03). AI treatment was associated with greater likelihood of discontinuation than tamoxifen. Treatment-emergent endocrine symptoms and sleep disturbance are associated with endocrine therapy discontinuation. Monitoring for worsening scores meeting or exceeding the MID on PROs may identify patients at risk for discontinuation. npj Breast Cancer (2022) 8:53 ; https://doi.org/10.1038/s41523-022-00414-0 INTRODUCTION Symptoms experienced by patients during endocrine therapy are often under-appreciated by clinicians . Patient-reported Although 5–10 years of adjuvant endocrine therapy reduces outcomes (PRO) are assessments from patients about their health recurrence and death after early hormone receptor-positive (HR+ ) status without interpretation by a clinician . The minimal breast cancer, approximately 50% of patients are non-adherent (do important difference (MID) is the smallest change in a score on not take endocrine therapy as prescribed) or non-persistent 1–14 a PRO measure that patients perceive as beneficial or harmful and (discontinue endocrine therapy early) . While some patients that would affect management . Prior studies evaluating the discontinue shortly after initiation, others do so later, with 15,16 association of symptoms with endocrine therapy discontinuation persistence overall declining with time . Risks of recurrence have not used changes in PRO scores meeting or exceeding the and death are higher among those who are non-adherent or who 8,17–19 MID to identify clinically important symptoms. discontinue endocrine therapy early . We report findings from a clinic-based cohort of women receiving Common symptoms during endocrine therapy include musculos- endocrine therapy for early HR+ breast cancer who completed PRO keletal discomfort, sleep disturbance, fatigue, anxiety, depression, measures over 5 years. We aimed to evaluate the association of and endocrine symptoms, such as vaginal dryness and hot 10,12,20–30 treatment-emergent symptoms, defined as worsening scores com- flashes . Side effects are frequently cited as a reason for pared to baseline in increments equal to the MID for each PRO early endocrine therapy discontinuation and multiple studies have measure, with discontinuation of endocrine therapy prior to demonstrated associations between symptoms and non-adherence 9,10,12,16,23,24,26,27,29,31–45 completing 5 years of treatment. We hypothesized that patient- or discontinuation . However, prospective reported new or worsening symptoms could identify individuals at identification of patients at risk for early discontinuation due to risk for early discontinuation. intolerance remains a clinical challenge. 1 2 Johns Hopkins Women’s Malignancies Program, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Johns Hopkins Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Division of Biostatistics and Bioinformatics, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA. 4 5 Division of Cancer Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA. Department of Health Policy and Management, Johns Hopkins 6 7 Bloomberg School of Public Health, Baltimore, MD, USA. Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Present address: Duke 8 9 Cancer Institute, Duke University Medical Center, Durham, NC, USA. Present address: CancerLinQ, American Society of Clinical Oncology, Alexandria, VA, USA. Present address: Cancer Research @UCC, College of Medicine and Health, University College Cork, Cork, Ireland. email: ksmith60@jhmi.edu Published in partnership with the Breast Cancer Research Foundation 1234567890():,; K.L. Smith et al. RESULTS Scores on PRO measures Participant characteristics Mean scores for all PRO measures were within one SD of published population means at all time points. The proportion Of 321 participants, 140 (43.6%) initiated tamoxifen and 181 of participants who completed the PROs declined over time (Table 2). (56.4%) an aromatase inhibitor (AI). Seventeen (5.3%) participants Mean changes in PRO scores during the first 24 months were received ovarian function suppression (OFS) and 6 (1.9%) enrolled small, and, while statistically significant for worsening endocrine upon switching endocrine therapy agents. The median age at symptoms (p < 0.001), the mean (SD) change in the FACT-ES score enrollment was 63 years and 65.4% were post-menopausal. The from baseline to 24 months was −2.9 (8.3), which is less than 1 majority of participants were White (83.5%) and lived in zip codes MID (Fig. 1). Despite small mean changes, the worst change in the with low neighborhood poverty (85.9%). Participants who initiated score at any time up to 60 months met or exceeded the MID for tamoxifen were younger than those who initiated an AI (Table 1). each measure in over one-third of participants. Symptom domains with the greatest proportions of participants with score worsening meeting or exceeding the MID at any time up to 60 months were Table 1. Characteristics of study population according to type of sleep disturbance (54%), endocrine symptoms (53%), sexual endocrine therapy initiated at study enrollment. problems (48%), and fatigue (46%) (Fig. 2). Treatment-emergent symptoms often developed soon after endocrine therapy initia- Characteristic Overall Study Tamoxifen Aromatase tion (Fig. 3). For example, worsening compared to baseline by at Population N = 140 Inhibitor N = 321 N = 181 least the MID for sleep disturbance, endocrine symptoms, sexual problems, and fatigue was already observed at 3 months in 27.1%, Median (Q1-Q3) age 63 (56–71) 54 (49–59) 69 (64–74) 26.3%, 23.3%, and 20.3% of participants respectively (Table 3). in years Due to the decline in PRO completion rates over time, we Post-menopausal – N (%) 210 (65.4) 34 (24.3) 176 (97.2) performed a sensitivity analysis comparing participants who Ovarian Function 17 (5.3) 16 (11.4) 1 (0.6) completed all measures during the first 24 months to those with Suppression – N (%) at least one missing measure during that timeframe. With the Switching Endocrine 6 (1.9) 0 (0) 6 (3.3) exception of differences in the number of concomitant medica- Therapy – N (%) tions and mean baseline fatigue and physical function scores, those with and without missing measures had similar key baseline Race – N (%) characteristics. The differences in mean baseline fatigue and White 268 (83.5) 112 (80) 156 (86.2) physical function between these groups were less than the MID Black 33 (10.3) 16 (11.4) 17 (9.4) (Table 4). Other 20 (6.2) 12 (8.6) 8 (4.4) Neighborhood Poverty Rate – N (%) Cumulative probability of discontinuation 0–15% 274 (85.9) 116 (82.9) 158 (88.3) Median follow-up was 56.1 months and 204 (63.6%) participants >15% 45 (14.1) 24 (17.1) 21 (11.7) remained on endocrine therapy at the time of data cut-off. Median number of 4(0–29) 3 (0–29) 5 (0–22) Twenty-six (8.1%) participants had discontinued after completing concomitant the planned course and 13 (4.0%) due to recurrence. Five (1.6%) medications at switched from the endocrine therapy initiated at enrollment to enrollment (range) another agent with less than 6 weeks interruption. Sixty-three Stage – N (%) (19.6%) participants had stopped endocrine therapy due to side 0 28 (8.7) 18 (12.9) 10 (5.5) effects/intolerance and 10 (3.1%) due to other reasons besides recurrence, new primary breast cancer, completion of at least 5 I 191 (59.5) 80 (57.1) 111 (61.3) years of endocrine therapy or switching agents. Among the 73 II 79 (24.6) 39 (27.9) 40 (22.1) participants who discontinued due to side effects/intolerance or III 23 (7.2) 3 (2.1) 20 (11) other reasons besides recurrence, new primary breast cancer, ER-positive – N (%) 320 (100) 139 (100) 181 (100) completion of at least 5 years of endocrine therapy or switching PR-positive – N (%) 282 (88.7) 128 (93.4) 154 (85.1) agents, the times at which they discontinued were distributed HER2-positive – N (%) 26 (8.9) 10 (8.2) 16 (9.4) across the follow-up period. Ten discontinued in the first 3 months (13.7%), 10 in months 3–6 (13.7%), 6 in months 6–9 (8.2%), 9 in Mastectomy – N (%) 143 (44.5) 76 (54.3) 67 (37) months 9–12 (12.3%), 9 in months 12–18 (12.3%), 8 in months Radiation – N (%) 215 (67) 85 (60.7) 130 (71.8) 18–24 (11%), and 21 after 24 months (28.8%). Among participants Chemotherapy – N (%) 90 (28.2) 43 (30.9) 47 (26.1) with and without missing PRO measures in the first 24 months, Median duration of 56.1 (6.9–87.7) 57.9 (9.1–87.7) 54.4 (6.9–87.3) 25.4% and 11.4% respectively discontinued due to side effects/ follow-up in months intolerance (Table 4). The cumulative probabilities of discontinua- (range) tion at 3, 6, 12, 24, 36, and 48 months were 3% [95% confidence Q1-Q3 interquartile range, ER estrogen receptor, PR progesterone receptor, interval (CI): 1–5%], 6% (95% CI: 4–9%), 11% (95% CI: 7–14%), 17% HER2 human epidermal growth factor receptor-2, SD standard deviation. (95% CI: 12–21%), 19% (95% CI: 14–23%), and 23% (95% CI: Participants were eligible to enroll at the time they first initiated adjuvant 18–27%), respectively. Figure 4 depicts the time to discontinuation endocrine therapy or at the time of switching from one type of adjuvant of endocrine therapy for the entire cohort and according to the endocrine therapy to another. type of endocrine therapy. Neighborhood poverty rate is the percentage of persons living in a zip code with a family income below the federal poverty line based on United States census data. Neighborhood poverty rate was missing for Association of patient-reported outcomes and clinico- two participants. demographic factors with endocrine therapy discontinuation ER status was missing for one participant. PR status was missing for 3 Of the 73 study participants who discontinued endocrine therapy participants. due to side effects/intolerance or due to other reasons besides Follow-up was calculated as the time from study entry to last clinic visit or recurrence, completion of at least 5 years of endocrine therapy or last PRO survey completion, whichever came last. switching agents, 63 completed the PRO measures at the time npj Breast Cancer (2022) 53 Published in partnership with the Breast Cancer Research Foundation 1234567890():,; K.L. Smith et al. Table 2. Mean scores on patient-reported outcome measures at each study time point. Domain Baseline 3 months 6 months 12 months 24 months 36 months 48 months 60 months a a a a a a a a N N N N N N N N Mean (SD) Mean (SD) Mean (SD) Mean (SD) Mean (SD) Mean (SD) Mean (SD) Mean (SD) Physical Function 320 282 253 214 144 91 52 24 51.5 (8.3) 52 (8.1) 53.3 (7.9) 53.2 (8.1) 53.9 (8.1) 54.5 (7.6) 54.3 (7.3) 56.8 (8.1) Endocrine Symptoms 319 281 252 214 143 90 52 24 65.1 (8.6) 63.7 (8.8) 63.7 (8.4) 62.5 (9.4) 62.9 (8.9) 63.4 (8.1) 63.4 (8.2) 67.2 (7.5) Sexual Problems 315 277 248 210 141 90 51 23 27.4 (32.0) 27.9 (33.7) 25.8 (31.4) 27.1 (31.1) 25.2 (30.2) 21.6 (28) 25.3 (30.1) 20.4 (29.8) Depression 319 280 250 212 142 91 52 24 45.4 (7.8) 44.9 (8.1) 44.6 (8) 45.2 (8.1) 44.2 (8.2) 43.5 (7.8) 44.9 (6.3) 43.0 (7.6) Anxiety 320 281 253 214 144 91 52 24 49.0 (9.4) 47.9 (9.1) 47.5 (8.7) 48.1 (8.6) 47.4 (8.4) 47.3 (8.5) 47.6 (7.5) 43.8 (7.5) Sleep Disturbance 320 282 253 215 144 91 52 24 49.0 (8.1) 49.8 (8.7) 48.8 (8.3) 49.1 (8.65) 47.6 (8.3) 49 (7.8) 46.8 (9) 43.8 (7.5) Fatigue 319 281 252 215 146 90 52 24 48.7 (7.7) 48.3 (7.9) 48 (8.5) 47.3 (8.3) 46.4 (8.9) 46.6 (7.5) 46.1 (7.9) 43.3 (5.9) Pain Interference 319 281 252 214 143 90 52 24 48.4 (8.2) 47.7 (8.2) 46.8 (7.6) 47.4 (7.5) 47.3 (7.7) 46 (6.7) 45.8 (7.4) 44.4 (5.6) SD standard deviation. N at each time point for each domain represents the number of participants who completed the patient-reported outcome measure. point immediately before their discontinuation. And, among the are a key driver of this decision . To date, interventions to support 248 participants who did not discontinue endocrine therapy, 190 adherence and persistence have largely focused on educational or 7,50 completed the PRO measures at the time point immediately behavioral strategies and have had limited success . We argue before they completed follow-up. Therefore, we had complete that early intervention to mitigate side effects has the potential to data for evaluation of the association of PROs with time to enhance endocrine therapy adherence and persistence. The discontinuation on 253 (79%) of patients. cornerstone to this strategy, however, is comprehensive detection In univariate analyses, worsening of multiple symptoms of treatment-emergent symptoms that may drive patients to (endocrine symptoms, fatigue, sleep disturbance, and pain discontinue therapy. Unfortunately, in routine clinical care, interference) plus receipt of AI were associated with endocrine clinicians often underappreciate side effects patients experience therapy discontinuation. In the final multivariate model, during endocrine therapy, and the symptom burden reported by 22,46 treatment-emergent endocrine symptoms (adjusted HR 1.13, patients often exceeds that detected by clinicians . Our data 95% CI 1.02 – 1.25, p = 0.02) and sleep disturbance (adjusted HR demonstrate that clinically relevant treatment-emergent symp- 1.14, 95% CI 1.01–1.29, p = 0.03) remained significantly associated toms are common during endocrine therapy and that use of PRO with endocrine therapy discontinuation. Additionally, patients measures as an adjunct to routine clinical care can identify receiving AI were twice as likely to discontinue compared to those symptoms associated with early discontinuation. on tamoxifen (adjusted HR 1.98, 95% CI 1.17–3.33, p = 0.01). When utilizing PRO measures in clinical care, the optimal score Higher stage was associated with lower likelihood of discontinua- thresholds beyond which clinical action should be taken are tion (adjusted HR 0.61, 95% CI: 0.43 – 0.87, p = 0.006) (Table 5). uncertain and may vary depending on the clinical scenario, symptoms, specific measures, and clinical outcomes to which 51,52 score thresholds are anchored . It is possible that MIDs may DISCUSSION vary by factors such as age, race, ethnicity, socioeconomic status, In this real-world prospective clinic-based cohort of women with stage, treatment duration or intervention and, moreover, that early HR + breast cancer receiving endocrine therapy who MIDs may change over time. Although severity thresholds can completed PRO measures over 5 years, we demonstrated that identify particularly bothersome symptoms and absolute scores treatment-emergent symptoms, defined as worsening scores at on PROs during the course of endocrine therapy have been any time during follow-up compared to baseline, was associated associated with discontinuation, worsening of scores over time with risk for discontinuing endocrine therapy prior to completing can indicate changes in supportive care needs and thus present a 9,53–56 5 years of treatment. Specifically, new or worsening endocrine clinical opportunity to provide symptom management . Our symptoms and sleep disturbance were associated with endocrine findings demonstrate that treatment-emergent symptoms, therapy discontinuation. As the severity of the treatment- defined by score worsening compared to baseline meeting or emergent symptoms worsened, the risk of discontinuation exceeding the MID for the selected measure, can identify clinically increased. For every 5-point worsening on the Endocrine Subscale significant symptoms associated with endocrine therapy disconti- of the FACT-ES measure, the risk of discontinuation was 13% nuation. Patients in whom these symptoms are identified should higher, and for every 4-point worsening on the PROMIS sleep be targeted for enhanced symptom management with the dual disturbance measure, the risk of discontinuation was 14% higher. goals of improving symptoms and supporting persistence. Worsening of scores meeting or exceeding the MID of on these Our findings build on previous work demonstrating that measures was common, each occurring in approximately half the treatment-emergent symptoms often present soon after endo- study population, with approximately half of these participants crine therapy initiation, indicating that symptom monitoring with experiencing worsening by more than twice the MID. PROs has the potential to identify patients at risk for discontinua- Although multiple factors may contribute to an individual tion early during the course of therapy to whom interventions 12,26,31 patient’s decision to discontinue endocrine therapy, side effects could be targeted . However, as has also previously been Published in partnership with the Breast Cancer Research Foundation npj Breast Cancer (2022) 53 K.L. Smith et al. Fig. 1 Change in patient-reported outcome scores over time. Line graphs display median PRO scores at each time point. The size of each dot is proportional to the number of participants who completed the PRO measure at that time point. The numbers of participants who completed the PRO measure at baseline and at 12, 24, 36, 48, and 60 months point are noted under the X-axis at the corresponding time points. The Y-axis denotes the score range for each PRO measure. Bars represent interquartile ranges. P-values summarize overall mean change in PRO scores during the first 24 months compared to baseline with a four-degree-of-freedom test. PRO patient-reported outcomes. reported, endocrine therapy discontinuation in our cohort supporting ongoing PRO monitoring throughout the course of increased over time and worsening of symptoms meeting or therapy. exceeding the MID at any time during 5 years of follow-up was In our study, the cumulative probabilities of endocrine therapy 15,16,33,45 associated with discontinuation . Most prior studies have discontinuation at 6, 12, 24, 36, and 48 months, respectively were focused on associations between baseline symptoms or those that 6, 11, 17, 19, and 23%. These observed discontinuation rates are 8,11 emerge early during endocrine therapy with discontinua- lower than reported in many prior studies . It is possible that 9,10,12,24,26,27,31,32,37,42 tion . Our study is unique in that it demon- completing PRO measures motivated patients to continue strates that treatment-emergent symptoms at any time over 5 endocrine therapy. Alternatively, although we did not mandate years are associated with endocrine therapy discontinuation, that clinicians review scores nor implement symptom npj Breast Cancer (2022) 53 Published in partnership with the Breast Cancer Research Foundation K.L. Smith et al. Physical Function Endocrine Symptoms Sexual Problems Depression 40% Worsened by 1 MID 35% Worsened by 2 MID 29% 30% Worsened by 3 or more MID 24% 25% 19% 20% 16% 15% 14% 15% 13% 12% 11% 10% 9% 10% 7% 5% 0% ≥ 3 MID ≥ 3 MID ≥ 3 MID ≥ 3 MID 1 MID 2 MID 1 MID 2 MID 1 MID 2 MID 1 MID 2 MID Anxiety Sleep Disturbance Fatigue Pain Interference 40% 35% 30% 26% 25% 23% 20% 16% 15% 15% 14% 15% 13% 13% 13% 11% 10% 10% 10% 5% 0% 1 MID 2 MID ≥ 3 MID 1 MID 2 MID ≥ 3 MID 1 MID 2 MID ≥ 3 MID 1 MID 2 MID ≥ 3 MID Fig. 2 Proportion of participants who experienced worsening of patient-reported outcome scores exceeding the minimal important difference at any time point through 60 months. Bar plots display worst change in PRO scores at any time point in follow-up through 60 months. Worst changes are categorized as at least the MID but less than twice the MID, at least twice the MID but less than three times the MID and at least three times the MID for each measure. Only participants with baseline values and at least one follow-up measure are included. The proportions of participants whose worst changes in each PRO scores were less than the MID (i.e. who experienced improvement, no change or worsening less than the MID) are not displayed. The MID was considered to be 4 points for the physical function, depression, anxiety, sleep disturbance, fatigue, and pain interference measures; 8 points for the sexual problems measure; and 5 points for the endocrine symptoms measure. MID minimal important difference, 1 MID at least the MID but less than twice the MID, 2 MID twice the MID but less than three times the MID, 3 MID at least three times the MID, PRO patient-reported outcomes. management interventions, it is possible that greater patient and that were prospective, many did not use validated measures, clinician awareness of symptoms due to the PROs led to better assessed fewer symptoms or limited symptom assessment to early 10,12,16,23,26,27,31–33,37,40–42,57,72 symptom management and, in turn, to enhanced persistence. during the course of therapy . Our findings are consistent with prior studies linking symptoms A key limitation of our study is that the proportion of prior to or during receipt of tamoxifen or an AI such as endocrine participants who completed the PROs declined over time. In our symptoms and sleep disturbance with non-adherence and early sensitivity analysis, baseline characteristics of participants with 10,23,26,27,31,40,42,57 treatment discontinuation . Endocrine symptoms and without missing measures were similar with the exception of include vasomotor symptoms, weight changes, vaginal or sexual the number of baseline concomitant medications. Some literature symptoms, mood changes and joint pain . In patients with breast demonstrates an association between polypharmacy and endo- cancer, endocrine symptoms, such as hot flashes and night crine therapy discontinuation, however, this association has not 58,59 sweats, can disrupt sleep . Evidence-based strategies can been consistently demonstrated and no prior literature indicates mitigate the treatment-emergent symptoms that were associated that a difference in one drug (the difference we observed in the with early discontinuation of endocrine therapy in our cohort. For median number of concomitant medications for those with and example, improved sleep hygiene, exercise, and cognitive 73–75 without missing PROs in the first 24 months) is meaningful . behavioral therapy can support patients with sleep distur- Thus, we believe our sensitivity analysis indicates patients with 60–67 bance . For patients with hot flashes or sweats, medications and without missing PRO measures are similar and that our such as anti-depressants or gabapentin may improve both findings are robust despite missing data. Of note, however, the 68,69 daytime symptoms and sleep . proportion of participants who discontinued endocrine therapy As has been previously reported, endocrine therapy disconti- due to side effects/intolerance was higher among participants nuation was more frequent among participants in our study taking with missing measures suggesting that patients with greater an AI than tamoxifen, a finding potentially attributable to frequent 32,70,71 symptom burden may have been less likely to complete the PROs. musculoskeletal discomfort during AI therapy . We also If participants with greater symptoms did not complete the PROs, confirmed previous findings demonstrating that individuals with it is possible that the association between treatment-emergent higher stage disease are less likely to discontinue endocrine symptoms and endocrine therapy discontinuation is even stronger therapy, a finding potentially explained by greater motivation to 33,35,44 than we estimated. But, the fact that PRO data was complete for take therapy in light of higher recurrence risk . In addition to assessing the time to discontinuation for 79% of study participants PRO scores, these factors may guide identification of patients at supports our findings regarding the association between risk for endocrine therapy discontinuation for interventions to treatment-emergent symptoms and endocrine therapy disconti- support persistence. nuation. The extent of missing PRO data in our study speaks to the Strengths of our study are that we comprehensively assessed need for strategies to further engage patients in incorporating common symptoms during endocrine therapy prospectively over 5 years with validated PRO measures in a real-world population. PROs into their care. Considerations may include reducing the Many previous studies evaluating symptoms during endocrine length or frequency of assessments to limit respondent burden therapy used cross-sectional or retrospective designs and, of those and assessing PROs in conjunction with clinic visits. Published in partnership with the Breast Cancer Research Foundation npj Breast Cancer (2022) 53 Percent of Participants with Worsening Percent of Participants with Worsening K.L. Smith et al. Physical Function Endocrine Symptoms 35 35 1 MID 30 2 MID 30 3+ MID 25 25 20 20 15 15 10 10 5 5 0 0 36 12 36 12 Months From Enrollment Months From Enrollment No. P No. Pa ar rt ticipants icipants 282 253 214 No. P No. Pa ar rt ticipants icipants 281 252 214 Sexual Problems Depression 35 35 30 30 25 25 20 20 15 15 10 10 5 5 0 0 36 12 36 12 Months From Enrollment Months From Enrollment No. P No. Pa ar rt ticipants icipants 277 248 210 No. P No. Pa ar rt ticipants icipants 280 250 212 Anxiety Sleep Disturbance 35 35 30 30 25 25 20 20 15 15 10 10 5 5 0 0 36 12 36 12 Months From Enrollment Months From Enrollment No. P No. Pa ar rt ticipants icipants 281 253 214 No. P No. Pa ar rt ticipants icipants 282 253 215 Fatigue Pain Interference 35 35 30 30 25 25 20 20 15 15 10 10 5 5 0 0 36 12 36 12 Months From Enrollment Months From Enrollment No. P No. Pa ar rt ticipants icipants 281 252 215 No. P No. Pa ar rt ticipants icipants 281 252 214 Fig. 3 Proportion of participants who experienced worsening of patient-reported outcome scores meeting or exceeding the minimal important difference at 3, 6, and 12 months. Line graphs display percentage of participants with worsening of PRO scores compared to baseline at 3, 6, and 12 months after enrollment. Worsening of PRO scores is categorized as at least the MID but less than twice the MID, at least twice the MID but less than three times the MID and at least three times the MID for each measure. Only participants with baseline values and at least one follow-up measure are included. The percentage of participants whose PRO scores worsened by less than the MID (i.e. who experienced improvement, no change or worsening less than the MID) are not displayed. The MID was considered to be 4 points for the physical function, depression, anxiety, sleep disturbance, fatigue, and pain interference measures; 8 points for the sexual problems measure; and 5 points for the endocrine symptoms measure. MID minimal important difference, 1 MID at least the MID but less than twice the MID, 2 MID twice the MID but less than three times the MID, 3+ MID at least three times the MID, PRO patient-reported outcomes. npj Breast Cancer (2022) 53 Published in partnership with the Breast Cancer Research Foundation Percent of Participants with Worsening Percent of Participants with Worsening Percent of Participants with Worsening Percent of Participants with Worsening Percent of Participants with Worsening Percent of Participants with Worsening Percent of Participants with Worsening Percent of Participants with Worsening K.L. Smith et al. Table 3. Change in symptoms compared to baseline at each time point through 12 months. Symptom Domain 3 months 6 months 12 months N (%) N (%) N (%) Physical Function No change or improvement 189 (58.9) 184 (57.3) 150 (46.7) Worsening by less than the MID 44 (13.7) 28 (8.7) 22 (6.9) Worsening by at least the MID but less than twice the MID 28 (8.7) 26 (8.1) 19 (5.9) Worsening by at least twice the MID but less than three times the MID 13 (4) 9 (2.8) 16 (5) Worsening by at least three times the MID 8 (2.5) 6 (1.9) 7 (2.2) PRO not completed 38 (11.8) 67 (20.9) 106 (33) Endocrine Symptoms No change or improvement 123 (38.3) 106 (33) 79 (24.6) Worsening by less than the MID 74 (23.1) 74 (23.1) 57 (17.8) Worsening by at least the MID but less than twice the MID 48 (15) 40 (12.5) 42 (13.1) Worsening by at least twice the MID but less than three times the MID 22 (6.9) 17 (5.3) 19 (5.9) Worsening by at least three times the MID 14 (4.4) 15 (4.7) 17 (5.3) PRO not completed 39 (12.1) 68 (21.2) 106 (33) Sexual Problems No change or improvement 201 (62.6) 187 (58.3) 114 (44.9) Worsening by less than the MID 1 (0.3) 0 (0) 0 (0) Worsening by at least the MID but less than twice the MID 18 (5.6) 15 (4.7) 19 (5.9) Worsening by at least twice the MID but less than three times the MID 19 (5.9) 15 (4.7) 14 (4.4) Worsening by at least three times the MID 38 (11.8) 31 (9.7) 33 (10.3) PRO not completed 43 (13.4) 72 (22.4) 110 (34.3) Depression No change or improvement 192 (59.8) 175 (54.5) 139 (43.3) Worsening by less than the MID 31 (9.7) 17 (5.3) 22 (6.9) Worsening by at least the MID but less than twice the MID 37 (11.5) 28 (8.7) 24 (7.5) Worsening by at least twice the MID but less than three times the MID 12 (3.7) 20 (6.2) 15 (4.7) Worsening by at least three times the MID 8 (2.5) 10 (3.1) 12 (3.7) PRO not completed 40 (12.5) 70 (21.8) 108 (33.6) Anxiety No change or improvement 180 (56.1) 170 (53) 136 (42.4) Worsening by less than the MID 39 (12.1) 34 (10.6) 31 (9.7) Worsening by at least the MID but less than twice the MID 29 (9) 19 (5.9) 23 (7.2) Worsening by at least twice the MID but less than three times the MID 22 (6.9) 16 (5) 9 (2.8) Worsening by at least three times the MID 11 (3.4) 14 (4.4) 15 (4.7) PRO not completed 39 (12.1) 67 (20.9) 106 (33) Sleep Disturbance No change or improvement 146 (45.5) 139 (43.3) 120 (37.4) Worsening by less than the MID 49 (15.3) 40 (12.5) 34 (10.6) Worsening by at least the MID but less than twice the MID 50 (15.6) 40 (12.5) 27 (8.4) Worsening by at least twice the MID but less than three times the MID 17 (5.3) 18 (5.6) 18 (5.6) Worsening by at least three times the MID 20 (6.2) 16 (5) 16 (5) PRO not completed 38 (11.8) 67 (20.9) 105 (32.7) Fatigue No change or improvement 158 (49.2) 130 (40.5) 116 (36.1) Worsening by less than the MID 58 (18.1) 53 (16.5) 40 (12.5) Worsening by at least the MID but less than twice the MID 33 (10.3) 44 (13.7) 38 (11.8) Worsening by at least twice the MID but less than three times the MID 18 (5.6) 14 (4.4) 11 (3.4) Worsening by at least three times the MID 14 (4.4) 11 (3.4) 10 (3.1) PRO not completed 39 (12.1) 68 (21.2) 105 (32.7) Pain Interference No change or improvement 209 (65.1) 193 (60.1) 153 (47.7) Worsening by less than the MID 22 (6.9) 17 (5.3) 16 (5) Worsening by at least the MID but less than twice the MID 23 (7.2) 17 (5.3) 26 (8.1) Worsening by at least twice the MID but less than three times the MID 11 (3.4) 11 (3.4) 9 (2.8) Worsening by at least three times the MID 16 (5) 14 (4.4) 10 (3.1) PRO not completed 39 (12.1) 68 (21.2) 106 (33) MID minimal important difference, PRO patient-reported outcome. MID = 4 points; MID = 5 points; MID = 8 points. Published in partnership with the Breast Cancer Research Foundation npj Breast Cancer (2022) 53 K.L. Smith et al. Table 4. Characteristics of participants with and without missing patient-reported outcome measures during the first 24 months of study participation. Characteristic No Missing PRO Measures During First 24 ≥1 Missing PRO Measure During First 24 p value Months (N = 132) Months (N = 189) Mean age in years (SD) 63.0 (10.5) 62.2 (11.3) 0.51 Post-menopausal – N (%) 85 (64.4) 125 (66.1) 0.81 Ovarian Function Suppression – N (%) 6 (4.5) 11 (5.8) 0.80 Endocrine Therapy Tamoxifen 64 (48.5) 76 (40.2) 0.17 AI 68 (51.5) 113 (59.8) Switching Endocrine Therapy – N (%) 0 (0) 6 (3.2) 0.05 Race – N (%) White 117 (88.6) 151 (79.9) 0.12 Black 9 (6.8) 24 (12.7) Other 6 (4.5) 14 (7.4) Neighborhood Poverty Rate – N (%) 0–15% 117 (89.3) 157 (83.5) 0.19 >15% 14 (10.7) 31 (16.5) Median number of concomitant medications at 4(0–13) 5 (0–29) 0.006 enrollment (range) Stage – N (%) 0 15 (11.4) 13 (6.9) 0.13 I 78 (59.1) 113 (59.8) II 34 (25.8) 45 (23.8) III 5 (3.8) 18 (9.5) ER-positive – N (%) 132 (100) 189 (100) PR-positive – N (%) 110 (83.8) 172 (92.5) 0.02 HER2-positive – N (%) 8 (6.8) 18 (10.2) 0.40 Mastectomy – N (%) 59 (44.7) 84 (44.4) >0.99 Radiation – N (%) 85 (64.4) 130 (63.8) 0.47 Chemotherapy – N (%) 36 (27.5) 54 (28.7) 0.90 Mean Baseline Depression Score (SD) 44.6 (7.5) 46.0 (8.1) 0.12 Mean Baseline Physical Function Score (SD) 52.7 (8.3) 50.0 (8.1) 0.005 Mean Baseline Endocrine Symptoms Score (SD) 65.8 (7.7) 64.6 (9.2) 0.21 Mean Baseline Sexual Problems Score (SD) 25.3 (29.7) 29.0 (33.6) 0.30 Mean Baseline Depression Score (SD) 44.6 (7.5) 46.0 (8.1) 0.12 Mean Baseline Anxiety Score (SD) 48.5 (9.2) 49.4 (9.5) 0.41 Mean Baseline Sleep Disturbance Score (SD) 48.2 (7.7) 49.6 (8.3) 0.13 Mean Baseline Fatigue Score (SD) 47.3 (8.0) 49.6 (7.4) 0.01 Mean Baseline Pain Interference Score (SD) 47.5 (7.9) 49.0 (8.3) 0.09 Discontinuation Status Completed Treatment – N (%) 24 (18.2) 2 (1.1) <0.001 Discontinued due to Distant Metastases – N (%) 3 (2.3) 8 (4.2) Discontinued due to Locoregional Recurrence– N (%) 2 (1.5) 0 (0) Discontinued due to Side effects/Intolerance – N (%) 15 (11.4) 48 (25.4) Discontinued Tamoxifen to Transition to AI – N (%) 2 (1.5) 3 (1.6) Discontinued due to Other reasons – N (%) 2 (1.5) 8 (4.2) Still on Endocrine Therapy – N (%) 84 (63.6) 120 (63.5) ER estrogen receptor, PR progesterone receptor, HER2 human epidermal growth factor receptor-2, SD standard deviation, AI aromatase inhibitor. Participants were eligible to enroll at the time they first initiated adjuvant endocrine therapy or at the time of switching from one type of adjuvant endocrine therapy to another. Neighborhood poverty rate is the percentage of persons living in a zip code with a family income below the federal poverty line based on United States census data. Neighborhood poverty rate was unknown for one participant with no missing PRO measures during the first 24 months and for one participant with at least one missing PRO measure during the first 24 months. PR status was unknown for 3 participants with missing PRO measures during the first 24 months. HER2 status was unknown for 15 participants with no missing PRO measures during the first 24 months and for 13 participants with at least one missing PRO measure during the first 24 months. Receipt of chemotherapy was unknown for 1 participant with no missing PRO measures during the first 24 months and for 1 participant with at least one missing PRO measure during the first 24 months. P-values are for Fisher’s exact test for categorical measures, t-tests for comparison of means and Wilcoxon rank sum tests for comparison of medians npj Breast Cancer (2022) 53 Published in partnership with the Breast Cancer Research Foundation K.L. Smith et al. Cumulative Probability of Stopping By 12 Months Whole Cohort: 11% Participants on Tam: 5% Participants on AI: 15% AI Whole Cohort Tam 012 24 36 48 60 MONTHS FROM STUDY START NNNNNN Events Rate Events Rate Events Rate Events Rate Events Rate Whole Cohort 321 35 3.55 278 17 1.96 252 7 0.89 224 9 1.42 162 4 0.94 83 Tam 14075451 1.59 127 1.24 118 1.13 98 1.75 77 0.47 47 AI 181 28 5.13 151 12 2.58 134 3 0.7 126 4 1.16 85 3 1.43 36 Fig. 4 Cumulative probability of endocrine therapy discontinuation. Curves depict time to discontinuation of endocrine therapy for the entire cohort and according to type of endocrine therapy. AI aromatase inhibitor, Tam tamoxifen. Table 5. Univariate and multivariate associations of new or worsening symptoms and clinico-demographic variables with time to discontinuation of adjuvant endocrine therapy. Variable Univariate Hazard Ratio (95% CI) p-value Multivariate Adjusted Hazard Ratio (95% CI) p-value Physical Function (4-point worsening) 1.06 (0.95–1.19) 0.30 Endocrine Symptoms (5-point worsening) 1.15 (1.06–1.26) 0.001 1.13 (1.02–1.25) 0.02 Fatigue (4-point worsening) 1.15 (1.02–1.29) 0.02 Depression (4-point worsening) 1.03 (0.93–1.15) 0.55 Anxiety (4-point worsening) 1.05 (0.95–1.16) 0.33 Sleep Disturbance (4-point worsening) 1.18 (1.06–1.32) 0.002 1.14 (1.01–1.29) 0.03 Sexual Problems (8-point worsening) 1.05 (1.00–1.11) 0.06 Pain Interference (4-point worsening) 1.11 (1.00–1.24) 0.05 Age in years 1.02 (1.00–1.04) 0.09 Race (White vs. Other) 1.30 (0.67–2.53) 0.44 High neighborhood poverty rate 1.10 (0.58–2.09) 0.78 Adjuvant endocrine therapy (AI vs. Tamoxifen) 1.93 (1.17–3.19) 0.01 1.98 (1.17–3.33) 0.01 Number of baseline concomitant medications 1.05 (1.00–1.11) 0.07 Higher Stage 0.71 (0.51–1.00) 0.05 0.61 (0.43–0.87) 0.006 HER2-positive 0.53 (0.17–1.70) 0.29 Mastectomy 0.91 (0.57–1.45) 0.69 Radiation 0.98 (0.60–1.59) 0.93 Chemotherapy 0.47 (0.25–0.88) 0.02 AI aromatase inhibitor, CI confidence interval, HER2 human epidermal growth factor receptor-2. Multivariable HR only shown for variables included in final model. Another limitation of our study is that few pre-menopausal evaluated the association between each individual treatment- participants received OFS and an AI, potentially limiting general- emergent symptom with discontinuation, but we did not evaluate izability of our findings to the many young patients who may whether the overall symptom burden affected the risk of receive this therapy in light of recently published survival data. discontinuation. Another limitation of our study is that we Additionally, few participants enrolled upon switching endocrine assessed pain with the PROMIS pain interference measure, a tool therapies. Although some patients who switch due to side effects not specific to joint pain that may not have been sensitive enough tolerate the second agent, our findings cannot fully address to detect AI-associated musculoskeletal symptoms. It is possible tolerance after switching . Additionally, we grouped patients that had we used a more sensitive and specific measure, we would taking tamoxifen and an AI, however, the treatment-emergent have identified an association between treatment-emergent symptoms that identify those at risk for discontinuation may differ musculoskeletal pain and endocrine therapy discontinuation as by drug. It is also possible that we misclassified discontinuation has been reported previously. Additionally, we did not collect any status and reasons for discontinuation based on chart review. We data regarding comorbidities and, for concomitant medications, did not confirm endocrine therapy administration dates with we only collected the number of medications (including both over pharmacy records or pill diaries, nor did we confirm reasons for the counter and prescribed medications) at baseline in our study, discontinuation by patient report. Additionally, our analysis thus we cannot address any potential associations between Published in partnership with the Breast Cancer Research Foundation npj Breast Cancer (2022) 53 Cumulative Probability of Discontinuation (%) K.L. Smith et al. specific medication classes and their side effects, nor the reason for discontinuation were determined by chart review. Reasons for discontinuation were classified as: completed treatment, discontinued due associations of any changes in concomitant medications during to distant metastases, discontinued due to loco-regional recurrence, study participation or of any comorbidities, with time-to- discontinued due to side effects/intolerance, discontinued tamoxifen to discontinuation of endocrine therapy. Furthermore, our study transition to AI and discontinued due to other reasons. No patient population was predominantly white and high socioeconomic discontinued due to a new primary breast cancer. status which may limit generalizability of our findings to other populations. Patient-reported outcomes Finally, it must be noted that while a change in a score of at PROs were collected at baseline and 3, 6, 12, 24, 36, 48, and 60 months using least the MID is considered clinically significant, it is not certain 77–79 the online PatientViewpoint website . Measures included the Patient- that a change of this degree is truly the minimal change that is Reported Outcome Measurement Information System (PROMIS) Version 1.0 significant . If anchored to endocrine therapy discontinuation, it pain interference, fatigue, depression, anxiety, physical function, and sleep is possible that smaller changes in scores would be clinically disturbance short forms; the Endocrine Subscale of the Functional significant and had we looked at smaller changes, we may have Assessment of Cancer Therapy - Endocrine Symptom (FACT-ES) measure; identified associations between discontinuation and worsening of 30,80–87 and the Medical Outcomes Study Sexual Problems (MOS-SP) scale . other symptoms as have previously been reported such as Treatment-emergent symptoms were defined as worsening of scores at any musculoskeletal discomfort, depression, and anxi- time compared to baseline in increments meeting or exceeding the MID for 10,12,23,24,26,32,37,40–42 ety . Further study is needed to determine each measure. PROMIS measures are scored with a T-score metric for which the optimal PRO measures for symptom assessment during 50 represents the mean in the United States (US) population and 10 is the endocrine therapy and the score thresholds to best identify standard deviation (SD). Higher scores on PROMIS measures indicate more of the outcome measured. PROMIS measures have been validated in early-stage treatment-emergent symptoms associated with discontinuation in 80–83,88 cancer patients with a MID of 3–5points . We considered the midpoint diverse populations. of this range (4 points) to be the MID. Endocrine Subscale FACT-ES scores The use of PROs to assess symptoms improves clinical range from 0–76 with lower scores indicating more endocrine symptoms. outcomes including hospitalization rates, emergency room The mean and SD on the Endocrine Subscale of the FACT-ES in women with utilization, chemotherapy delivery and quality of life, effects likely early breast cancer are 59 and 9.7 respectively .In accordance withthe mediated by enhanced symptom detection and subsequent distribution-based, Effect Size method of identifying a MID for a PRO 54,76 symptom management . To date, whether use of PROs impacts measure, we used 0.5 SD to define a medium effect size as a conservative oral cancer therapy persistence has not been prospectively estimate of the MID on the Endocrine Subscale of the FACT-ES and rounded determined. In this real-world cohort of patients taking adjuvant this estimate to 5 points . MOS-SP scores range from 0–100 with higher endocrine therapy for early HR + breast cancer, we found that scores indicating more sexual problems. The reported mean MOS-SP score for women with early breast cancer ranges from approximately 20–36 with treatment-emergent endocrine symptoms and sleep disturbance 28,85,87 SD approximately 27–31 . As has previously been done, due to some detected via PRO measures were associated with early endocrine uncertainty about the mean and SD on the MOS-SP in the literature, we used therapy discontinuation. This finding is proof of the principle that the distribution-based, Empirical Rule Effect Size method to guide the collecting serial PROs during routine clinical care can identify identification of the MID for the MOS-SP. Based on this method, the SD was patients at risk for endocrine therapy discontinuation due to side assumed to be one-sixth of 100 and the estimated MID was calculated by effects who may benefit from symptom management interven- 28,89 dividing this number by half, yielding an estimated MID of 8 points . tions. To this end, we are prospectively evaluating the feasibility of A summary of PRO scores was available to clinicians at the time of follow-up using recommended symptom management pathways for clinic visits. patients receiving endocrine therapy who have symptoms identified on PROs. Future studies will also be needed to clarify Statistical analysis the optimal timing, the optimal PRO domains and MIDs to use Clinico-demographic characteristics of the participants and PRO scores when implementing PRO collection to identify patients receiving over time are presented descriptively using mean (SD), median (range or endocrine therapy at risk for treatment discontinuation. Better interquartile range), and proportions. We used Fisher’s exact test to symptom detection and management has the potential not only compare categorical measures, t-test to compare means and Wilcoxon to help patients feel better, but also to enhance endocrine therapy rank-sum test to compare medians between subgroups of the study persistence, an effect that could ultimately reduce breast cancer population as appropriate. Mean changes in PRO scores in the first recurrence and mortality. 24 months compared to baseline were estimated using a linear mixed- effects modeling approach with the PRO as the outcome, fixed effects for each time point, and a random intercept for each participant. A METHODS corresponding four-degree-of-freedom test was used to summarize the overall change in the first 24 months. Study population The time to discontinuation of endocrine therapy was calculated as the We enrolled women with HR+ stage 0-III breast cancer-initiating adjuvant time from study enrollment to endocrine therapy discontinuation. endocrine therapy with tamoxifen or an AI to a clinic-based prospective Participants who stopped the endocrine therapy initiated at enrollment cohort between March 2012 and December 2016 at Johns Hopkins due to recurrence, new primary breast cancer, completion of at least 5 (ClinicalTrials.gov Identifier: NCT01937052, registered September 3, 2013). years of endocrine therapy or who switched to another type of endocrine The study cohort was a convenience sample with candidate participants therapy after less than 6 weeks interruption were censored. All other identified by screening medical oncology provider clinic schedules and by participants were censored at the date of the last clinic visit before the provider referral. Pre-menopausal women could receive concurrent OFS. database was locked May 15, 2020. Time to discontinuation was estimated Participants could enroll when first initiating endocrine therapy or upon for the entire cohort and according to type of endocrine therapy (AI versus switching from one agent to another. All participants signed written Tamoxifen) using the Kaplan-Meier method. informed consent. The study was approved by the Johns Hopkins IRB. To assess how variables measured at baseline and during follow-up were associated with time to discontinuation, we fit Cox proportional hazards Discontinuation models using a time-dependent covariate structure. Non-time dependent demographic variables considered in the models included age at Endocrine therapy discontinuation was defined as stopping the endocrine enrollment, neighborhood poverty rate, and race. Neighborhood poverty therapy initiated at enrollment prior to completing 5 years of treatment for rate, the percentage of persons living in a zip code with a family income at least 6 weeks due to side effects/intolerance or other reasons besides recurrence, new primary breast cancer, completion of at least 5 years of below the federal poverty line based on US census data, was used as a endocrine therapy or switching to another type of endocrine therapy after surrogate for socioeconomic status (SES) with >15% considered indicative less than 6 weeks off therapy. Participants were allowed to continue of low SES . Clinical characteristics in the models included stage, endocrine therapy beyond 5 years. Endocrine therapy discontinuation and HER2 status, type of surgery, receipt of chemotherapy, receipt of radiation, npj Breast Cancer (2022) 53 Published in partnership with the Breast Cancer Research Foundation K.L. 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R Foundation for Sta- Armstrong, Raquel Nunes, Kala Visvanathan, Carol Riley, Katie Papathakis, Nelli tistical Computing. (R Core Team, R Foundation for Statistical Computing, Vienna, Zafman. Austria, 2020). ADDITIONAL INFORMATION ACKNOWLEDGEMENTS Supplementary information The online version contains supplementary material This work was supported by Susan G. Komen Foundation and National Institutes of available at https://doi.org/10.1038/s41523-022-00414-0. Health [P30 CA006973] Correspondence and requests for materials should be addressed to Karen Lisa Smith. Reprints and permission information is available at http://www.nature.com/ AUTHOR CONTRIBUTIONS reprints Conceptualization/Design: K.L.S., V.S., K.W., C.S. Funding Acquisition: V.S. Resources: C.S. Data Acquisition: K.L.S., J.F., A.C.W., D.J., R.S.M., R.C., D.K.A., R.N., K.V., C.R., K.P., N.Z., V.S. Data Curation: Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims J.L.,N.V.Analysis: D.L.,A.B.Interpretation ofData: Allauthors.Writing-original draft: K.L.S.,N.V. in published maps and institutional affiliations. Writing-review and editing: All authors. Approval of final manuscript: All authors. Agreement to be accountable for all aspects of work: All authors. Accountability for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved: All authors. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative COMPETING INTERESTS Commons license, and indicate if changes were made. The images or other third party Karen Lisa Smith has received research support (to institution) from Pfizer. Karen Lisa material in this article are included in the article’s Creative Commons license, unless Smith’s spouse has stock ownership in ABT Labs and Abbvie. Jennifer Y. Sheng has indicated otherwise in a credit line to the material. If material is not included in the received research support (to institution) from Pfizer. Roisin Connolly has received an article’s Creative Commons license and your intended use is not permitted by statutory unrestricted educational grant to her institution from Pfizer. Vered Stearns has regulation or exceeds the permitted use, you will need to obtain permission directly received research grants (to institution) from Pfizer and Novartis Claire Snyder has from the copyright holder. To view a copy of this license, visit http://creativecommons. research funding (to institution) from Pfizer and Genentech. The following authors org/licenses/by/4.0/. declare that they have no conflicts of interest related to the work presented in this manuscript: Neha Verma, Amanda Blackford, Jennifer Lehman, Kelly Westbrook, David Lim, John Fetting, Antonio Wolff, Danijela Jelovac, Robert Miller, Deborah © The Author(s) 2022 Published in partnership with the Breast Cancer Research Foundation npj Breast Cancer (2022) 53

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