
==== Front
ESMO Open
ESMO Open
ESMO Open
2059-7029
Elsevier

S2059-7029(24)01460-1
10.1016/j.esmoop.2024.103691
103691
Original Research
Real-world treatment patterns and outcomes in patients with HR+/HER2− metastatic breast cancer treated with chemotherapy in the United States
Tolaney S.M. Sara_Tolaney@DFCI.HARVARD.EDU
1∗
Punie K. 2
Carey L.A. 3
Kurian A.W. 4
Ntalla I. 5
Sjekloca N. 5
Shah A. 6†
Rehnquist M.K. 6
Stokes M. 7
Fraeman K. 7
Verret W. 6
Jhaveri K. 89
1 Breast Oncology Program, Dana-Farber Cancer Institute, Harvard Medical School, Boston, USA
2 GZA Hospitals Sint-Augustinus, Wilrijk, Belgium
3 University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, USA
4 Stanford University School of Medicine, Stanford, USA
5 Gilead Sciences Europe Ltd., Stockley Park, UK
6 Gilead Sciences, Inc., Foster City, USA
7 Evidera, Bethesda, USA
8 Memorial Sloan Kettering Cancer Center (MSKCC), New York, USA
9 Weill Cornell Medical College, New York, USA
∗ Correspondence to: Dr Sara M. Tolaney, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA 02215, USA. Tel: +1-617-632-3800 Sara_Tolaney@DFCI.HARVARD.EDU
† Affiliation at the time the work was completed.

05 9 2024
9 2024
05 9 2024
9 9 103691© 2024 The Authors
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Background

Until recently, treatment options for patients with hormone receptor-positive/human epidermal growth factor 2-negative (HR+/HER2−) metastatic breast cancer (mBC) and resistance to endocrine therapy were limited to chemotherapy. This real-world study describes treatment patterns and outcomes in patients treated with chemotherapy in the United States before approval of antibody–drug conjugates.

Patients and methods

This retrospective, observational study included adults with HR+/HER2− mBC from the ConcertAI Patient360™ Breast Cancer dataset who initiated their first chemotherapy in the metastatic setting between January 2011 and June 2021. Treatment patterns were described; real-world overall survival, time to next treatment or death, and real-world progression-free survival were evaluated for all eligible patients and patients treated with subsequent chemotherapy. Index dates were the start date of each chemotherapy treatment.

Results

Among 1545 eligible patients, 76% were white, 12% had Eastern Cooperative Oncology Group performance status ≥2, 38% had de novo mBC, and median age was 61 years (range, 52-69 years). Within the index period, capecitabine was used the most as the first chemotherapy agent and decreased in later treatments, while the use of eribulin increased between first and fourth chemotherapies. Median (95% confidence interval) real-world overall survival was 23.3 months (21.3-25.4 months) from start of first chemotherapy, time to next treatment or death was 6.5 months (5.9-7.1 months), and real-world progression-free survival was 6.9 months (6.4-7.6 months); median times from second, third, and fourth chemotherapies decreased with each additional chemotherapy treatment.

Conclusions

This real-world study demonstrates that for patients with HR+/HER2− mBC, chemotherapy provides relatively limited survival benefit which decreases with each additional chemotherapy line, and highlights the need for improved treatment options.

Highlights

• Endocrine therapy ± CDK4/6i is initially effective in HR+/HER2− metastatic breast cancer but most patients will develop resistance.

• Before the recent approval of antibody–drug conjugates, treatment options for these patients were limited to chemotherapy.

• This study demonstrates the relatively limited survival benefit of chemotherapy in patients with pre-treated HR+/HER2− mBC.

Key words

antibody–drug conjugates
chemotherapy
HER2-negative
hormone receptor-positive
metastatic breast cancer
RWE
==== Body
pmcIntroduction

Hormone receptor-positive (HR+) and human epidermal growth factor 2-negative (HER2−) breast cancer (BC) is defined by tumor cells with estrogen and/or progesterone receptor-positive and HER2-immunohistochemistry (IHC) 0 (HER2 IHC0) or HER2-low [IHC1+ or IHC2+ confirmed by negative in situ hybridization (ISH−)].1 HR+/HER2− disease represents ∼70% of all BCs.2 The 5-year relative survival for locally advanced HR+/HER2− BC is 100%, and it declines to 35% for distant metastatic disease.2 All subtypes of metastatic BCs (mBCs), including HR+/HER2− mBCs, that relapse after therapy are characterized by more aggressive tumor biology and associated with worse survival outcomes compared with de novo mBCs, and ∼75% of all mBCs represent recurrent disease.3,4 In patients with HR+ and/or HER2− BC, recurrences may occur later in follow-up (beyond 5 years).5,6 Therefore, close follow-up and extended therapy may be needed in the subgroup of patients with a high risk of later recurrence.

Endocrine therapy (ET) in combination with cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) is the preferred first-line systemic therapy regimen for HR+/HER2− mBC in appropriate patients, which leads to median overall survival (OS) up to 64 months compared with 51 months with ET alone.3,7, 8, 9 Using various combinations of ET and CDK4/6i is initially effective in this patient population, after which most patients will develop resistance.10,11 Until recently, treatment options for these patients were limited to chemotherapy.3,12,13 Patients with HR+/HER2− mBC who became refractory to ET and/or experienced visceral crises and received first-line chemotherapy had a median progression-free survival (PFS) of ∼12 months and a median OS of ∼41 months; patients who received chemotherapy as a second line and later therapy after treatment with anthracycline and/or taxane, had a median PFS of ∼3 to 7 months and a median OS of ∼9 to 16 months.14,15 Real-world studies provide insight into the effectiveness of ET with or without CDK4/6i for mBC.16, 17, 18, 19 Similar data for chemotherapy are needed, including for patients whose disease progressed after CDK4/6i, as nearly half of patients receive chemotherapy at some point for HR+/HER2− mBC.20, 21, 22 This is becoming particularly important as treatment options are expanding with the use of antibody–drug conjugates (ADCs) in this setting.10,23 The impact of recent approvals of sacituzumab govitecan-hziy (sacituzumab govitecan; a Trop-2-directed ADC) for HR+/HER2− mBC (defined as IHC0, IHC1+, or IHC2+/ISH−) and fam-trastuzumab deruxtecan-nxki (trastuzumab deruxtecan; an HER2-directed ADC) for HER2-low mBC (defined as IHC1+ or IHC2+/ISH−) on the treatment landscape and real-world outcomes for patients with HR+/HER2− remains to be evaluated.24, 25, 26

The objective of this study was to describe treatment patterns and outcomes in chemotherapy-treated patients with HR+/HER2− mBC in routine clinical care settings in the United States before the approval of ADCs.

Methods

Data sources and study design

This retrospective, observational cohort study used the ConcertAI Patient360™ Breast Cancer dataset of electronic health record data from the United States (Supplementary Figure S1, available at https://doi.org/10.1016/j.esmoop.2024.103691). The primary study cohort included adults (aged ≥18 years) diagnosed with HR+/HER2− mBC who initiated their first chemotherapy or investigational agent (as described in the next section) between January 2011 and June 2021 (index period). The end-of-study date was 31 December 2021 (data cut-off) to allow for a minimum of a 6-month follow-up period. Patients who were treated with HER2-targeted therapies during the study period or who were diagnosed with any other primary cancer (except for nonmetastatic, nonmelanoma skin cancer) within 5 years before the index date were excluded. The index date was defined as the start date of first chemotherapy or investigational agent in the metastatic setting. Study objectives were to describe treatment patterns and clinical outcomes in patients who received their first chemotherapy/investigational agent during the index period and in those who were subsequently treated with a second, third, and fourth chemotherapy/investigational agent. Patient demographics, disease characteristics, and treatments received were extracted and summarized. Follow-up started on the index date and continued until death, loss to follow-up, or end of study period, whichever occurred first.

Treatment exposure

Treatments of interest (hereafter referred to as chemotherapy) for the primary cohort included taxanes (paclitaxel, docetaxel, albumin-bound paclitaxel), epothilones (ixabepilone), anthracyclines (doxorubicin, liposomal doxorubicin, epirubicin), platinum agents (cisplatin, carboplatin), pyrimidine analogues (capecitabine, gemcitabine), and other neoplastic agents (vinorelbine, eribulin). Investigational agents at the time of data collection (sacituzumab govitecan, trastuzumab deruxtecan if used for patients with HER2-low mBC) were also included as treatments of interest and referred to as chemotherapy for the purpose of this manuscript.

Treatment patterns

Treatment patterns included all systemic treatments received on or after mBC diagnosis. Lines of any systemic therapy were defined as one or more cycles (or continuous oral treatment) of a planned therapy regimen. A regimen-based line of therapy framework, rather than a progression-based one, was used to define start of therapy and advancement to next line of therapy as progression events may be underreported in real-world data.

Clinical outcomes

Real-world OS (rwOS) was defined as time from first, second, third, or fourth chemotherapy initiation until death from any cause; rwOS from the time of mBC diagnosis was also determined. Time to next treatment or death (TTNTD) was defined as time until the start of the next treatment or death, whichever occurred first. Real-world PFS (rwPFS) was defined as the time from first, second, third, or fourth chemotherapy initiation until progression or death, whichever occurred first.

Statistical analysis

All patients who met the eligibility criteria for the primary study cohort were included in the main analysis, and data were summarized using descriptive statistics. Continuous variables were reported as medians [interquartile range (IQR)]. Categorical variables were summarized as number and percentage of the total study population. For clinical outcomes (rwOS, TTNTD, and rwPFS), medians and 95% confidence intervals (CIs) were estimated using Kaplan–Meier methods. Patients were censored at the last confirmed activity date if they were still on treatment (for rwPFS and TTNTD only), had discontinued their treatment without disease progression (for rwPFS only), were still alive at the end of the study period, or were lost to follow-up. For rwPFS, patients were censored at treatment discontinuation if this occurred before the last activity date. Stratified analyses of the primary study cohort were carried out for subgroups with sufficient patient numbers and/or data availability. Subgroups of interest included HER2 expression status (HER2-IHC0 and HER2-low), treatment exposure (capecitabine, gemcitabine, eribulin, and vinorelbine), number of prior ETs (1, 2, and ≥3), cumulative duration of prior ET for mBC (<6 and ≥6 months), and cumulative duration of CDK4/6i therapy for mBC (<12 and ≥12 months). Missing data were not imputed but were reported as number (percentage) for categorical and continuous variables.

Analyses of treatment patterns and rwOS for a secondary study cohort of all patients with HR+/HER2− mBC initiating any first-line treatment (Figure 1A) were also carried out to contextualize findings from the main analysis.Figure 1 (A) Patient selection and (B) disposition. BC, breast cancer; CT, chemotherapy; ER+, estrogen receptor-positive; HER2−, human epidermal growth factor receptor 2-negative; HR+, hormone receptor-positive; mBC, metastatic BC; PR+, progesterone receptor-positive. aPatients were excluded if they did not receive next CT, or if they received next CT but it started after the end of the patient identification period, after censoring due to a change in follow-up biomarker status, or on the last activity date.

Ethics and integrity

This retrospective, observational study was carried out in accordance with ethical principles that are consistent with the Declaration of Helsinki, International Conference on Harmonisation (ICH) Good Clinical Practice (GCP), and the applicable legislation on non-interventional studies and/or observational studies.

Results

Patients

Out of the 34 281 adult patients with a BC diagnosis in the dataset, the primary cohort included 1545 patients diagnosed with HR+/HER2− mBC who started chemotherapy treatment within the index period (Figure 1A). Among these patients, 886 (57%) were subsequently treated with a second chemotherapy during the index period, 480 (31%) patients with a third chemotherapy, and 260 (17%) with a fourth chemotherapy; overall, 43%-46% of patients did not receive a subsequent chemotherapy treatment (Figure 1B).

Of these 1545 patients, 1530 (99%) were female, 1171 (76%) were white, and 205 (13%) were black, and median (IQR) age was 61 years (52-69 years) [1051 (68%) patients were aged ≥55 years]. Most patients [1228 (79%)] received treatment in the community setting (Table 1). In total, 580 (38%) patients were diagnosed with de novo mBC, 1096 (73%) had bone metastases, and 1054 (68%) had visceral metastases. The median (IQR) time from mBC diagnosis to first chemotherapy was 11.9 months (1.4-30.8 months) [the median time was 20.4 months (10.9-32.0 months) for patients with prior exposure to CDK4/6i and 1.3 months (0.7-4.1 months) for patients without prior exposure to CDK4/6i]. Use of ET (as monotherapy or in combination with CDK4/6i or other targeted therapies) and CDK4/6i in the mBC setting before first chemotherapy were recorded for 889 (58%) and 674 (44%) patients, respectively. Median (95% CI) follow-up time per chemotherapy treatment was 16.5 months (7.2-32.4 months) for first chemotherapy, 13.1 months (6.1-25.7 months) for second chemotherapy, 10.1 months (4.7-18.4 months) for third chemotherapy, and 8.0 months (4.0-14.0 months) for fourth chemotherapy.Table 1 Baseline demographics and disease characteristics in the primary cohort.

Characteristics	Patient population (N = 1545)	
Age, median (IQR), years	61 (52-69)	
 <65, n (%)	944 (61)	
 ≥65, n (%)	601 (39)	
Sex, n (%)		
 Male	15 (1)	
 Female	1530 (99)	
Race groups, n (%)		
 White	1171 (76)	
 Black	205 (13)	
 Asian	41 (3)	
 Other/unknown	128 (8)	
Ethnic groups, n (%)		
 Hispanic or Latino	91 (5.9)	
 Other/unknown	1454 (94.1)	
Treatment provider type, n (%)		
 Community	1228 (79)	
 Academic	273 (18)	
 Unknown	44 (3)	
Practice region, n (%)		
 Northeast	136 (9)	
 South	688 (45)	
 Midwest	404 (26)	
 West	309 (20)	
 Unknown	8 (1)	
ECOG performance status,an (%)		
 0-1	984 (64)	
 ≥2	192 (12)	
 Unknown	369 (24)	
De novo mBC, n (%)	580 (38)	
Time from mBC diagnosis to index date, median (IQR) (months)	11.9 (1.4-30.8)	
Number of metastasis sites, median (IQR)	3 (2-4)	
Metastasis sites,bn (%)	1054 (68)	
 Bone	1096 (73)	
 Brain	125 (8)	
 Liver	467 (31)	
 Lung	358 (24)	
 Lymph nodes	353 (23)	
 Unknown	35 (2)	
Visceral metastases at baseline, n (%)	1054 (68)	
Prior ET use in the metastatic setting, n (%)c	889 (58)	
 Prior ET use in the metastatic setting ≥6 months,dn (%)	698 (79)	
Prior CDK4/6i in the metastatic setting, n (%)	674 (44)	
 Prior CDK4/6i in the metastatic setting for mBC diagnosis in 2015 or later,en (%)	488 (54)	
 Prior CDK4/6i use in the metastatic setting ≥12 months,fn (%)	219 (45)	
CDK4/6i, cyclin dependent kinase 4/6 inhibitor; CT, chemotherapy; ECOG, Eastern Cooperative Oncology Group; ET, endocrine therapy; IQR, interquartile range; mBC, metastatic breast cancer.

a ECOG performance status records during the 6-month period before the index date until 2 months after the index date only were used. If ECOG performance status scores were not available during the 6-month period before the index date, Karnofsky scores were used instead (ECOG performance status 0-1 corresponds to Karnofsky scores 70-100 and ECOG performance status ≥2 to corresponds to Karnofsky scores ≤60).

b The proportion of patients may add up to >100% as the subgroups are not mutually exclusive.

c Number of patients with ET use before CT treatment initiation at any line. Patients who received ET + CT (± other are not included).

d Assessed among patients with prior ET use only.

e Assessed among patients with a first ever mBC diagnosis in 2015 or later only (n = 911).

f Assessed among patients with prior CDK4/6i use and mBC diagnosis in 2015 or later only (n = 488).

Treatment patterns

Among the 1545 patients in the primary cohort, 627 (41%) received chemotherapy as monotherapy or in combination [including 75 (5%) patients who received chemotherapy with ET], and 847 (55%) received an ET-based regimen without chemotherapy in the first-line metastatic setting (Figure 2); 418 (27%) received ET monotherapy, 404 (26%) received ET + CDK4/6i, and 25 (2%) received ET + other targeted therapy. When only considering patients with a diagnosis of mBC in 2015 or later (n = 911; approval year of CDK4/6i in the United States), 492 (54%) received an ET-based regimen without chemotherapy in the first-line metastatic setting; 130 (14%) received ET monotherapy, 353 (39%) received ET + CDK4/6i therapy, and 9 (1%) received ET + other targeted therapy. Among all patients with HR+/HER2− mBC initiating any first-line treatment (secondary cohort), 2286 (75%) were treated with an ET-based regimen without chemotherapy in the first-line setting (Supplementary Figure S2A, available at https://doi.org/10.1016/j.esmoop.2024.103691).Figure 2 Treatment patterns by line of metastatic treatment for patients in the primary cohort. ET-based regimen included ET monotherapy (aromatase inhibitor, fulvestrant, and SERM), ET + CDK4/6i, ET + other TT [ET combined with mTORi, PI3Ki, poly(ADP-ribose) polymerase inhibitor, or tyrosine kinase inhibitor], and ET + other [ET + ET combination therapy and ET + other combination therapy not included in ET + CDK4/6i, ET + other TT, and ET + CT (± other)]; ET + CT (± other) included ET combined with CT with or without targeted therapy; CT included CT monotherapy and CT combination therapy (defined as any combination of at least 2 CT and CT + TT); other included ADCs/investigational treatments, palbociclib, abemaciclib, olaparib, alpelisib, everolimus, and other monotherapy/combination therapy. ADC, antibody–drug conjugate; ADP, adenosine diphosphate; CDK4/6i, cyclin-dependent kinase 4/6 inhibitor; CT, chemotherapy; ET, endocrine therapy; L, line of treatment; mTORi, mammalian target of rapamycin inhibitor; PI3Ki, phosphoinositide 3-kinase inhibitor; SERM, selective estrogen receptor modulator; TT, targeted therapy.

With advancing lines of therapy, use of ET-based regimens decreased from 55% in first line to 26% in the 10th line, while chemotherapy use increased from 41% to 62%, respectively (Figure 2); a similar trend was observed in the subset of patients with mBC diagnosis after 2015 in the primary (Supplementary Figure S3, available at https://doi.org/10.1016/j.esmoop.2024.103691) and secondary (Supplementary Figure S2B, available at https://doi.org/10.1016/j.esmoop.2024.103691) cohorts.

In the primary cohort, on average, 63% of chemotherapy-treated patients received single-agent chemotherapy across their first four chemotherapy treatments. Single-agent capecitabine and paclitaxel (including albumin-bound paclitaxel, from now on referred to as paclitaxel) were the most commonly used as first chemotherapies. Capecitabine [first chemotherapy: 34% (520/1545), fourth chemotherapy: 10% (27/260)] and paclitaxel [first chemotherapy: 18% (284/1545), fourth chemotherapy: 7% (19/260)] use decreased in later chemotherapy treatments, while the use of eribulin [first chemotherapy: 2% (35/1545), fourth chemotherapy: 16% (41/260)], vinorelbine [first chemotherapy: 1% (14/1545), fourth chemotherapy: 8% (20/260)], and gemcitabine [first chemotherapy: 2% (29/1545), fourth chemotherapy: 12% (32/260)] increased from first to fourth chemotherapy treatments (Figure 3). On average, 37% of chemotherapy-treated patients received doublet or triplet combinations across their first four chemotherapy treatments. The most common combination partners as first chemotherapy included anthracycline [10% (148/1545)—mainly doxorubicin/cyclophosphamide] and paclitaxel [11% (166/1545)—common combinations observed included gemcitabine/paclitaxel and carboplatin/paclitaxel; 7% (102/1545) of patients were treated with platinum-based doublet chemotherapy, mainly as gemcitabine/carboplatin or carboplatin/paclitaxel].Figure 3 Single-agent chemotherapy use across the first four chemotherapy treatments received by patients in the primary cohort. Other includes epirubicin and investigational agents, paclitaxel includes paclitaxel and albumin-bound paclitaxel. Percentages are based on the total number of patients in each CT treatment group. CT, chemotherapy.

In the primary cohort, sacituzumab govitecan, an investigational agent at the time of data collection, was received by a very small number (<5) of patients in each line; no patients received trastuzumab deruxtecan.

Clinical outcomes

Among patients treated in the primary cohort, median rwOS (95% CI) was 23.3 months (21.3-25.4 months). The 12- and 24-month survival rates (95% CI) for patients receiving first chemotherapy were 70% (67%-72%) and 49% (46%-52%), respectively. In patients who subsequently received a second, third, and fourth chemotherapy during the index period, median rwOS (from initiation of that chemotherapy) decreased with each additional chemotherapy to 9.1 months (7.3-11.2 months) with the fourth chemotherapy (Figure 4A); rwOS rates for subsequent lines of therapy are reported in Supplementary Table S1, available at https://doi.org/10.1016/j.esmoop.2024.103691. A similar trend was observed for TTNTD [Figure 4B; median (95% CI) TTNTD from 6.5 months (5.9-7.1 months) for first chemotherapy to 3.9 months (3.5-4.3 months) for fourth chemotherapy] and median (95% CI) rwPFS [Figure 4C; from 6.9 months (6.4-7.6 months) for first chemotherapy to 3.7 months (3.2-4.6 months) for fourth chemotherapy].Figure 4 Kaplan–Meier curves for (A) rwOS, (B) TTNTD, and (C) rwPFS in the primary cohort. CT, chemotherapy; rwOS, real-world overall survival; rwPFS, real-world progression-free survival; TTNTD, time to next treatment or death.

Among all patients in the secondary cohort who received any type of first-line treatment in the metastatic setting, median rwOS (95% CI) was 43.1 months (41.3-45.5 months). For patients who received first-line ET monotherapy (n = 961), ET + CDK4/6i (n = 1122), or chemotherapy (n = 630), median rwOS (95% CI) from first-line initiation was 50.8 months (47.4-53.8 months), 41.9 months (39.3-45.5 months), and 34.2 months (29.9-37.2 months), respectively. Of note, the number of patients treated with first chemotherapy diverged between the primary and secondary cohorts due to differences in the selection criteria (Figure 1A).

Stratified analyses

In the primary cohort, stratified analyses by HER2 expression status, treatment exposure, number and duration of prior ET in the metastatic setting, and duration of prior CDK4/6i treatment in the metastatic setting for each chemotherapy treatment showed results similar to those of the overall population. rwOS, TTNTD, and rwPFS are shown in Supplementary Tables S2-S4, available at https://doi.org/10.1016/j.esmoop.2024.103691, respectively.

Discussion

This retrospective, observational cohort study investigated real-world treatment patterns and clinical outcomes for patients with HR+/HER2− mBC in the United States who started chemotherapy in the metastatic setting during the period before the approval of ADCs.

Patients included in the current study were mainly treated in the community setting, and their age and race/ethnicity did not differ substantially from HR+/HER2− mBC populations in other real-world studies using different databases.27, 28, 29, 30 The short duration between mBC diagnosis and first chemotherapy may reflect the high percentage of patients with visceral metastasis or aggressive disease. The distribution of metastatic sites in patients with HR+/HER2− mBC in this study was consistent with that observed in this patient population from other real-world studies using the Surveillance, Epidemiology, and End Results and CancerLinQ® databases.29,30

In agreement with current guidelines for the treatment of HR+/HER2− mBC,3,7,9 ET use decreased, whereas chemotherapy use increased, with increasing line of therapy. Capecitabine and paclitaxel were the most used treatments for first chemotherapy, which are among the recommended options in NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®).9 Use of eribulin and vinorelbine, two microtubule inhibitors that are also recommended in the NCCN Guidelines®, increased in later lines.9 In the primary cohort, 41% of patients received a chemotherapy-based regimen in the first-line metastatic setting; this may be an overestimate compared with other studies that reported lower overall rates of chemotherapy use (28%), as this analysis only included patients who had received at least one chemotherapy.20 In the secondary cohort including all patients with HR+/HER2− mBC, regardless of treatment received, the proportion of patients who received chemotherapy with or without ET as first-line treatment was lower (21%). Similarly, in a retrospective real-world study using the CancerLinQ® database and including all patients with HER2− mBC, 28% of patients with HR+/HER2− mBC received chemotherapy as their first treatment.30 The proportion of patients who received single-agent versus doublet or triplet chemotherapy combinations (63% and 37%, respectively) was similar to what has been reported previously in this patient population.31 While 44% of patients received CDK4/6i before starting their first chemotherapy in the current study, this percentage increased to 54% when considering only patients diagnosed with mBC in 2015 (approval year of CDK4/6i in the United States) or later; these post-approval data may be more representative of current guidelines that recommend the use of CDK4/6i with ET as the preferred first-line systemic therapy regimen for HR+/HER2− mBC in appropriate patients.3,7,9 Similarly, in a retrospective study using the Flatiron Health longitudinal database, 22% of patients received a CDK4/6i in combination with ET as first-line therapy in the metastatic setting in 2015, with an increase to 49% in 2018.32

The analysis of clinical outcomes in the primary cohort showed patients had a relatively limited survival benefit, which decreased with each additional chemotherapy. These findings were consistent with those of another real-world study reporting data for patients receiving their second to fifth lines of chemotherapy in the metastatic setting.33 In the current study, the attrition between each chemotherapy represented almost half of the patients, with a quarter to a third of these patients not surviving to the next chemotherapy. Of note, treatment of interest, referred to as chemotherapy, included <0.1% patients who received an ADC as investigational therapy and were unlikely to have affected the overall results. Furthermore, similar to other studies, TTNTD in the current analysis was consistent with rwPFS.34, 35, 36 Because progression is often not well captured in electronic health records,37 data reported here further support the use of TTNTD as a proxy for PFS in the real-world setting. In clinical trials of patients with any type of mBC who had received two or more lines of chemotherapy in the metastatic setting, the next line of chemotherapy yielded median PFS of ∼3 to 7 months and OS of ∼13 to 21 months.38, 39, 40 Additionally, in the registrational TROPiCS-02 trial of sacituzumab govitecan, median PFS was 4 months and median OS was 11 months in the control arm (physicians’ choice of chemotherapy) in patients with endocrine-resistant HR+/HER− mBC who had received two to four previous chemotherapy regimens for metastatic disease. In the registrational DESTINY-Breast04 trial of trastuzumab deruxtecan, the median PFS and OS in the control arm were 5 and 18 months, respectively, in patients with HR+/HER2-low mBC who had received one or two previous lines of chemotherapy for metastatic disease.10,41,42 While acknowledging the limitations of cross-study comparisons, including the fact that DESTINY-Breast04 recruited patients in earlier lines, these results are consistent with the rwPFS (∼4 to 7 months) and rwOS (∼9 to 23 months) findings from the current real-world study. Thus, consistent with prior literature, this real-world study demonstrates that outcomes are generally poor in patients with HR+/HER2− mBC who initiate chemotherapy.

Two novel ADCs have recently been approved in multiple countries for the treatment of patients with HR+ mBC, based on findings from two phase III clinical trials.10,23,42 Sacituzumab govitecan is approved for the treatment of patients with locally advanced or metastatic HR+/HER2− (defined as IHC0, IHC1+, or IHC2+/ISH−) BC after ET and two or more additional systemic therapies in the metastatic setting.24 In treatment guidelines, sacituzumab govitecan is recommended for patients who are not candidates for trastuzumab deruxtecan, and after prior treatments including ET, a CDK4/6i, and at least two lines of chemotherapy (including a taxane), one of which was in the metastatic setting and can be considered for later line if not used as second-line therapy.9,43 Trastuzumab deruxtecan is approved for patients with HER2-low mBC (defined as IHC1+, or IHC2+/ISH) after one line of chemotherapy in the metastatic setting or recurrence during or within 6 months of completing adjuvant therapy.25,26 In US treatment guidelines, it is recommended as second-line treatment in patients with HER2 IHC1+ or 2+/ISH− disease that are in visceral crisis or endocrine refractory, and may be considered in a later line if not used in second line.9 In recent studies, favorable real-world activity was observed with sacituzumab govitecan and trastuzumab deruxtecan in patients with HR+/HER2− and HR+/HER2-low mBC, respectively; however, these studies were limited by small sample sizes.44,45 Future studies with higher numbers of patients should assess the extent to which the benefits demonstrated with these agents in clinical trials are reflected in the real-world setting.

This study was based on data extracted from electronic health records; thus, data entry errors and missing data may have affected study outcomes, and results may not be generalizable to the overall population with HR+/HER2− mBC in the United States. Outcome definitions and censoring rules in this noninterventional study may differ from those defined in the protocols for interventional studies, which makes study comparisons difficult. The regimen-based line of therapy algorithm used in this study was based on the availability and nature of the data within the ConcertAI database and the list of treatments of interest used for data extraction; thus, treatment patterns may not fully reflect the true sequencing and specific combinations of treatments that occurred in patients with HR+/HER2− mBC. Moreover, with a regimen-based line of therapy algorithm, change in therapy may have reflected unacceptable toxicity rather than progression. The high percentage (38%) of patients reported to have de novo mBC might be explained by the definition of mBC used for this study (stage 4/M1 recorded within the index period). Generally, patients are not re-staged at the time of metastatic recurrence, and they would be described as recurrent metastatic rather than as stage 4/M1. Therefore, in this study, any record of stage 4/M1 disease was interpreted as de novo disease, when it might have been recurrent metastatic disease. This study also included patients who were treated during the COVID-19 pandemic, which may have affected treatment decisions and/or the routine clinical care. Additionally, geographic variation was observed with few patients from the Northeast and a large proportion of patients from the South included in the study, this may also have had an impact on study outcomes.

Conclusion

In summary, this study provides important real-world context regarding the characteristics, clinical outcomes, and treatment patterns among chemotherapy-treated patients with HR+/HER2− mBC in the United States in the era before the availability of ADCs. The results demonstrate the relatively limited survival benefit provided by chemotherapy and highlight the high unmet need for more effective treatment options. The impact of ADCs on outcomes in the real-world setting for this patient population is yet to be assessed, considering their recent approval and the resulting shift in the treatment landscape.

Supplementary data

Supplementary data

Acknowledgements

Medical writing assistance was provided by Christiane Dresch, PhD of Parexel, and was funded by Gilead Sciences, Inc. Evidera has received funding from Gilead Sciences, Inc. for conducting the analysis of this study. Patients treated at Memorial Sloan Kettering Cancer Center were supported in part by a Memorial Sloan Kettering Cancer Center support grant (P30 CA008748).

Funding

This work was supported by 10.13039/100005564 Gilead Sciences , Inc. (no grant number).

Disclosure

SMT reports consulting/advisory role for Novartis, Pfizer (SeaGen), Merck, Eli Lilly, AstraZeneca, Genentech/Roche, Eisai, Sanofi, Bristol Myers Squibb, CytomX Therapeutics, Daiichi Sankyo, Gilead Sciences, Inc., Zymeworks, Zentalis, Blueprint Medicines, Reveal Genomics, Umoja Biopharma, Artios Pharma, Menarini/Stemline, Aadi Bio, Bayer, Incyte Corp., Jazz Pharmaceuticals, Natera, Tango Therapeutics, Systimmune, eFFECTOR, Hengrui USA, Cullinan Oncology, Circle Pharma, Arvinas, BioNTech, and Johnson&Johnson; research funding from Genentech/Roche, Merck, Exelixis, Pfizer, Lilly, Novartis, Bristol Myers Squibb, Eisai, AstraZeneca, NanoString Technologies, Gilead Sciences, Inc., Seattle Genetics, OncoPep, and Jazz Pharmaceuticals; and travel support from Eli Lilly, Sanofi, Gilead, Jazz Pharmaceuticals, and Pfizer. KP reports research grants to institute from Merck Sharp & Dohme (MSD) and Sanofi; speaker fees and honoraria for consultancy and advisory board functions from AstraZeneca, Eli Lilly, Exact Sciences, Focus Patient, Gilead Sciences, Inc., Medimix, Medspace, MSD, Novartis, Pfizer, Roche, Sanofi, and Seagen; speaker fees and honoraria for consultancy and advisory board functions to institution from AstraZeneca, Eli Lilly, Exact Sciences, Gilead Sciences, Inc., MSD, Novartis, Pfizer, Roche, Seagen, and Teva; and travel grants from AstraZeneca, Gilead Sciences, Inc., Novartis, Pfizer, PharmaMar, and Roche. LAC reports uncompensated relationships with AstraZeneca, Genentech/Roche, GlaxoSmithKline, Novartis, and SeaGen, and research funding to institution from AstraZeneca, Genentech/Roche, Gilead Sciences, Inc., NanoString, Lilly, Novartis, and Veracyte. IN, NS, AS, MKR, and WV are employees of Gilead Sciences, Inc.; IN, NS, AS, and MKR own Gilead Sciences, Inc. stock options and AS owns Roche stock options. MS and KF are employees of Evidera; Evidera has received funding from Gilead Sciences, Inc. for conducting the analysis of this study. KJ reports consultant/advisory board fees from Novartis, AstraZeneca, Pfizer, Bristol Myers Squibb, Jounce Therapeutics, Taiho Oncology, Genentech/Roche, Lilly Pharmaceuticals/Loxo Oncology, AbbVie, Eisai, Blueprint Medicines, Seattle Genetics, Daiichi Sankyo, Gilead, Olema Pharmaceuticals, Sun Pharma Advanced Research Company Ltd, Menarini/Stemline, and Scorpion Therapeutics; and research funding from Novartis, Genentech/Roche, AstraZeneca, Debio Pharmaceuticals, Pfizer, Lilly Pharmaceuticals/Loxo Oncology, Zymeworks, Gilead Sciences, Inc., PUMA Biotechnology, Blueprint Medicines, Scorpion Therapeutics, and Merck Pharmaceuticals. AK has declared no conflicts of interest.

Data sharing

Data to support the findings of this study were derived from the ConcertAI Patient360™ Breast Cancer dataset, but restrictions apply to the availability of these data, which were used under license for the current study and are thus not publicly available.

Patient consent statement

This retrospective, observational study of de-identified data from an existing dataset of electronic health record data from the United States did not involve direct enrollment of any patients and personal identifiable data were not collected; informed consent forms were therefore not collected.
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