Patient characteristics and treatment patterns of patients with locally advanced or metastatic HER2-low breast cancer, a single site descriptive study

Abstract

Purpose

To evaluate the prevalence and characteristics of different HER2 categories among patients with advanced breast cancer (aBC) and describe treatment patterns and outcomes of those with HER2-low disease.

Methods

A retrospective cohort study was conducted via chart review at the Huntsman Cancer Institute, including patients diagnosed with aBC (stages IIIB, IIIC and IV) between 2010 and 2019. All patients with IHC1+ were considered HER2-low unless FISH was positive. Patients with IHC2+ were only classified as HER2-low if a negative FISH was documented. The prevalence and characteristics of each HER2 category were reported. Treatment patterns and survival outcomes of HER2-low patients who received first line treatment in 2017 or later were presented.

Results

A total of 240 of 414 patients (58%) with aBC were HER2-low, with the majority of patients (83%) classified as hormone receptor (HR)-positive. In first line, most HR-positive patients received endocrine therapy with chemotherapy for stage IIIB/IIIC (47%) and with CDK4/6 inhibitors for stage IV breast cancer (50%) Most HR-negative patients received chemotherapy alone (92% for stage IIIB/IIIC, 60% for stage IV). In second line, chemotherapy alone was the most common modality (21.4% for HR-positive; 45.5% for HR-negative). Median overall survival was 37.7 months while median progression-free survival from first line was 18.0 months, decreasing to 8.0 months in second line.

Conclusion

A substantial proportion of patients previously classified as HER2-negative have low but detectable HER2 expression and may benefit from novel HER2-directed agents, which have demonstrated clinical benefit in this population post-chemotherapy.

Supplementary Information

The online version contains supplementary material available at 10.1007/s10549-024-07458-9.

Introduction

Breast cancer is the most frequent cancer diagnosed and one of the leading causes of cancer-related mortality among women in the United States [1]. It is estimated that 287,850 women were diagnosed and 43,250 women died of breast cancer in 2022 [1, 2]. Breast cancer is a heterogeneous disease, which can be further stratified based on pathology assessment, including by estrogen receptor (ER) status, progesterone receptor (PR) status, and human epidermal growth factor receptor 2 (HER2) status [3].

HER2-positive breast cancer accounts for approximately 15–20% of breast cancer cases [4]. Although HER2 overexpression is associated with a more aggressive clinical course and poorer prognosis, the introduction of HER2-directed agents, such as trastuzumab, have transformed the treatment landscape for HER2-positive breast cancers. In both the adjuvant and metastatic settings, the addition of HER2-directed agents to conventional chemotherapy has led to improved response rates and extended survival among patients [5]. HER2 tumor testing is guided by immunohistochemistry (IHC) and fluorescence in-situ hybridization (FISH) tests which evaluate HER2 protein expression and detect HER2 gene amplification, respectively [6]. Based on current guidelines, tumors are classified as HER2-positive and patients are eligible for treatment with conventional HER2-directed agents if tumor samples stain with an IHC intensity score of 3+ or an IHC score 2+ with a positive result on FISH [6].

The pathology standards to determine HER2 receptor status were first established based on tumor responses in the initial trials of trastuzumab, the first HER2-directed monoclonal antibody developed [7]. Until recently, patients with IHC scores of 1+ and 2+ coupled with negative FISH results were classified as HER2-negative and did not receive HER2-targeted therapy despite expressing low levels of HER2 protein. Following the demonstration of clinical benefit from novel HER2-directed therapies in this patient population [8], tumor classification has evolved to describe this level of HER2 expression as HER2-low. Data is conflicting on whether patients with HER2-low disease are clinically different from those with no detectable HER2 expression (IHC0). Some studies have shown a higher expression of hormone receptors in the HER2-low subgroup compared to HER2 IHC0 with marginally longer or similar long-term survival [9–12]. Genetic differences have also been observed where HER2-low tumors were more likely to present with mutations in the PI3K-Akt signaling pathway [13].

Whether HER2-low breast cancer represents a distinct biological or clinical entity remains unclear but given that patients with HER2-low disease now have an actionable level of HER2-expression, it is critical to elucidate the characteristics of this patient population compared to other HER2 categories, the treatment trajectory and standard-of-care outcomes to better understand potential unmet medical needs. To this end, we conducted a real-world assessment at an academic cancer center to evaluate the prevalence and characteristics of different HER2 categories among patients with advanced breast cancer, and describe treatment patterns and outcomes of those with HER2-low status. Patients with advanced breast cancer include those who have locally advanced disease, who may be given neoadjuvant therapy followed by surgery if response is adequate or treated upfront similarly to patients with distant metastasis [14].

Methods

Study design and setting

This was a retrospective cohort study conducted via chart review at the Huntsman Cancer Institute (HCI), which is part of the University of Utah Healthcare System and the only National Cancer Institute (NCI)-designated Comprehensive Cancer Center serving Utah, Idaho, Montana, Nevada, and Wyoming within the Intermountain West region in the United States of America.

Data sources

Data sources that were utilized for this study include the University of Utah Clinical Enterprise Data Warehouse (EDW), the Utah Cancer Registry (UCR) and Huntsman Cancer Institute Tumor Registry (HCI-TR). The EDW is a database encompassing medical, financial, and administrative data of patients across the University of Utah Healthcare System and HCI with records dating back to 1993. The UCR and HCI-TR track cancer cases in Utah and HCI, respectively, and collect information on diagnosis, follow-up, and mortality. UCR is also part of the Surveillance, Epidemiology, and End Results (SEER) Program of the NCI.

Study population

The population of interest was patients with advanced breast cancer (stages IIIB, IIIC and IV) who were tested for HER2 receptor status. The inclusion criteria were (i) aged 18 years and older at the time of advanced breast cancer diagnosis; (ii) diagnosis of breast cancer reported to the HCI-TR between January 1, 2010 and December 31, 2019; (iii) at least 2 encounters with relevant ICD-9 or ICD-10 codes for breast cancer (174.x, C50.x) on two dates separated by ≥30 days between January 1, 2010 and December 31, 2019 in EDW; (iv) stages IIIB, IIIC, and IV documented in the HCI-TR based on pathologic classification or if unavailable, clinical classification. Patient eligibility was based on staging at advanced diagnosis regardless of whether the tumor was potentially resectable. Patients were excluded if a diagnosis of a primary cancer other than breast cancer was reported to the HCI-TR between January 1, 2010 and December 31, 2019. Patients were followed up from the date of advanced diagnosis to death, last documented follow-up or December 31, 2021, whichever occurring earlier.

Study procedures

Eligible patients were identified from the HCI-TR using a combination of ICD-9 and ICD-10 codes for breast cancer (174.x, 233.0; C50.x, D05.x) and staging information. HER2 testing was identified using Current Procedural Terminology (CPT) codes (2007332, 0049178, 0049174, 2008603) and HER2 status was ascertained through chart review of laboratory reports and clinical notes using an electronic text-searching tool. Patient data was extracted from electronic health records via chart review.

Outcomes of interest

Prevalence of HER2 categories

Pathology reports post advanced stage diagnosis were reviewed chronologically to collect data on pathology assessment. All study subjects were categorized based on the results of pathological assessments between the date of advanced disease diagnosis and prior to first line treatment initiation. If multiple assessments were conducted prior to treatment initiation, the highest HER2 expression or copy number was utilized. Patients with an IHC score of 0 were classified as HER2 IHC0; patients with an IHC score of 3+ or an IHC score of 1+/2+ and a positive FISH result were classified as HER2 positive; while patients with an IHC score of 1+ and a negative or unknown FISH result or an IHC score of 2+ and a negative FISH result were classified as HER2-low. Patients with an IHC score of 2+ but no FISH results documented were considered to have insufficient pathology results to be classified based on our study algorithm and excluded from analysis (Supplementary Information 1). Guidelines by the American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) to interpret IHC and FISH have slightly changed in 2013 and 2018. IHC. However, IHC and FISH interpretation in our study was based on contemporary guidelines at the time of HER2 testing, which would have guided decisions on the use of HER2-directed therapy for our study participants. All pathology testing was also performed by accredited laboratories with appropriately reactive controls and adhered to the necessary standards.

Baseline demographic and clinical characteristics

Baseline demographic characteristics of interest included: Age, ethnicity, insurance type, region of residence and smoking status. Baseline clinical characteristics of interest included: menopausal status, TNM staging at advanced diagnosis, histological type and grade, site of metastasis, hormone receptor (HR) status, performance status and prevalence of individual comorbidities within the Charlson Comorbidity Score. Characteristics were reported by HER2 category. Patients were HR positive if IHC results indicate at least 1% of tumor nuclei stain positive for either ER and/or PR.

Treatment patterns

To examine contemporary treatment patterns, first and second line treatment patterns relative to diagnosis of advanced disease were assessed for patients with HER2-low disease and received treatment for advanced disease in the last five years of the study period, from January 1, 2017 onwards. The period for analysis was limited to account for major changes in the standard of care for advanced breast cancer patients with HER2-negative, HR-positive disease where by 2017, two CDK4/6 inhibitors had been approved for use in this patient subpopulation. A new line of therapy was defined as a distinct change of an entire regimen due to intolerance, adverse events or disease progression based on documentation in the medical records. Maintenance therapy was not considered a new line of therapy. Among patients who were diagnosed with locally advanced (stage IIIB or IIIC) disease, some patients presented with potentially resectable tumors and were managed with neoadjuvant therapy, followed by surgery if response was deemed adequate. However, as surgery data was not collected in our study, it was not feasible to isolate these patients. Therefore, treatment patterns were reported by staging at diagnosis of advanced breast cancer (IIIB or IIIC vs IV) in addition to hormone receptor status. Treatment patterns of the full patient cohort is also included in Supplementary Information 2.

Survival outcomes

Overall survival (OS) and progression-free survival (PFS) of patients with HER2-low disease and received treatment for advanced disease in 2017 or later were evaluated. OS was defined as the time from initiation of first line treatment after diagnosis of advanced disease to death, with censoring performed at date of last follow-up or the end of study (December 31, 2021), whichever occurring earlier. PFS was defined as the time from initiation of treatment (first or second line after diagnosis of advanced disease) to death or disease progression, with censoring performed at the date of last follow-up or the end of study, whichever occurring earlier. Assessment of disease progression was based on clinician documentation in clinical notes. Survival outcomes of the full patient cohort is also included in Supplementary Information 3.

Statistical analysis

The baseline characteristics and prevalence of HER2 categories of all advanced breast cancer patients were summarized with descriptive statistics, including means and standard deviations for continuous variables and counts and percentages for categorical variables. The baseline demographic and clinical characteristics of patients with HER2-low disease were compared against those who were HER2 IHC0 using t-tests, Wilcoxon rank-sum tests, Chi-squared and Fisher’s exact tests depending on the type of variable evaluated. Treatment patterns of patients with HER2-low disease were also presented descriptively with Sankey diagrams illustrating treatment pathways from first line to second line settings, stratified by stage IIIB/IIIC vs stage IV disease and hormone receptor status. Kaplan-Meier analysis was conducted to quantify OS and PFS of patients with HER2-low disease and had first line treatment initiated in 2017 or later. Median survival time and OS and PFS rate at 1, 2 and 3 years, stratified by staging and hormone receptor status, were presented.

Results

Prevalence of HER2 categories

A total of 4626 patients with a diagnosis of breast cancer between 2010 and 2019 were identified from the HCI-TR, of which 522 had a confirmed diagnosis of locally advanced or metastatic breast cancer (stages IIIB, IIIC or IV) (Fig. 1). Among these patients, 103 (19.7%) did not have IHC results documented while 5 (1.0%) had an HER2 expression level of 2+ as measured by IHC but no FISH results, leaving 414 patients (79.3%) with sufficient pathology results for classification of HER2 categories based on our study algorithm. A patient flow chart detailing the categorization of HER2 categories by IHC and FISH results among patients with sufficient pathology results for classification is presented in Fig. 2. Most of these patients were determined to be HER2-low (n = 240, 58.0%), followed by HER2-positive (n =127, 30.6%) and HER2 IHC0 (n = 47, 11.4%) (Fig. 1). The HER2-low patient cohort consisted of 160 (66.7%) with IHC1+ and negative or no FISH results and 80 (33.3%) with IHC2+ with negative FISH results.

Fig. 1.

Patient flow chart and prevalence of HER2 categories among patients with advanced breast cancer (Stage IIIB, IIIC and IV)

Fig. 2.

Classification of HER2-low patients based on IHC and FISH pathology results. FISH fluorescence in situ hybridization, IHC immunohistochemistry

Patient characteristics

The demographic and clinical characteristics of patients are presented in Table 1. The majority of HER2-low patients were between the ages of 46 and 64 years old (n = 106, 44.2%), identified as white/Caucasian (n = 206, 85.8%), and had never smoked (n = 177, 73.8%). Most patients were enrolled in commercial insurance plans (n = 116, 48.3%), followed by Medicare (n = 77, 32.1%) while a higher proportion of patients were postmenopausal (n = 177, 74.1%) than premenopausal (n = 57, 23.8%). Similar demographic trends were observed across HER2 categories with no significant differences noted between HER2-low and IHC0 patients (Table 1).

Table 1.

Patient characteristics of overall cohort and by HER2 category

Variables	HER2-low		HER2 IHC0		HER2+ve		HER2-low vs HER2 IHC0
	n	%	n	%	n	%
N	240	58.0%	47	11.3%	127	30.7%
Demographic characteristics
Age at advanced diagnosis
18–30	5	2.1	1	2.1	3	2.4	0.24
31–45	38	15.8	10	21.3	30	23.6
46–64	106	44.2	23	48.9	61	48.0
65–79	70	29.2	7	14.9	22	17.3
≥80	16	6.7	6	12.8	6	4.7
Unknown	5	2.1	0	0	5	3.9
Ethnicity
Caucasian/white	206	85.8	39	83.0	113	89.0	0.11
African American	2	0.8	1	2.1	1	0.8
Hispanic/Latino	7	2.9	4	8.5	3	2.4
Native American	3	1.3	0	0.0	2	1.6
Asian/Pacific Islander	13	5.4	0	0.0	5	3.9
Other	4	1.7	0	0.0	2	1.6
Unknown	5	2.1	3	6.4	1	0.8
Plan Type
Commercial	116	48.3	22	46.8	63	49.6	0.29
Medicare	77	32.1	10	21.3	42	33.1
Medicaid	17	7.1	7	14.9	9	7.1
Other	26	10.8	7	14.9	13	10.2
Unknown	4	1.7	1	2.1	0	0.0
Region
Utah	193	80.4	36	76.6	94	74	0.55
Non-Utah	47	19.6	11	23.4	33	26
Unknown	0	0.0	0	0.0	0	0.0
Smoking status
Current Smoker	13	5.4	1	2.1	7	5.5	0.34
Former Smoker	47	19.6	14	29.8	26	20.5
Never Smoked	177	73.8	31	66	92	72.4
Unknown	3	1.3	1	2.1	2	1.6
Clinical characteristics
Menopausal status
Premenopausal	57	23.8	17	36.2	26	20.5	0.21
Postmenopausal	177	74.1	29	61.7	55	43.3
Unknown	6	2.5	1	2.1	46	36.2
Staging at advanced diagnosis
IIIB	31	12.9	4	8.5	18	14.2	0.33
IIIC	52	21.7	7	14.9	23	18.1
IV	157	65.4	36	76.6	86	67.7
Histological Type
Lobular	28	11.7	8	17	3	2.4	0.22
Ductal	181	75.4	33	70.2	108	85
Other	12	5.0	0	0.0	2	1.6
Unknown	19	7.9	6	12.8	14	11
Tumor histologic grade
1	13	5.4	2	4.3	4	3.1	0.40
2	103	42.9	16	34.0	33	26.0
3	82	34.2	16	34.0	66	52.0
Unknown	42	17.5	13	27.7	24	18.9
Site of metastasisa
Brain	11	7.0%	5	13.9%	19	22.1%	0.19
Lung	29	18.5%	6	16.7%	24	27.9%	1.00
Liver	37	23.6%	14	38.9%	35	40.7%	0.09
Bone	116	73.9%	24	66.7%	44	51.2%	0.25
(Bone as only site)	76	48.4%	12	33.3%	17	19.8%	0.07
Other	32	20.4%	12	33.3%	23	26.7%	0.08
Unknown	2	1.3%	1	2.8%	3	3.5%	0.46
Hormone receptor status
Positive	198	82.5	32	68.1	90	70.9	0.08
Negative	40	16.7	14	29.8	37	29.1
Unknown	2	0.8	1	2.1	0	0.0
ECOG Performance
0	65	27.1	13	27.7	44	34.6	0.07
1	76	31.7	7	14.9	21	16.5
2	10	4.2	2	4.3	8	6.3
3	4	1.7	3	6.4	5	3.9
Unknown	85	35.4	22	46.8	49	38.6
Comorbidities
Myocardial infarction	0	0.0	1	2.1	0	0.0	0.02
Congestive heart failure	5	2.1	2	4.3	4	3.1	0.38
Peripheral vascular disease	1	0.4	0	0.0	2	1.6	0.66
Cerebrovascular disease	6	2.5	0	0.0	2	1.6	0.27
Chronic pulmonary disease	18	7.5	6	12.8	7	5.5	0.23
Dementia	0	0.0	0	0.0	0	0.0	NA
Diabetes	25	10.4	4	8.5	16	12.6	0.69
Diabetes with complications	0	0.0	0	0.0	2	1.6	NA
Hemiplegia or paraplegia	0	0.0	0	0.0	0	0.0	NA
Renal disease	9	3.8	4	8.5	2	1.6	0.15
Mild liver disease	0	0.0	1	2.1	4	3.1	0.02
Moderate/severe liver disease	2	0.8	0	0.0	1	0.8	0.53
Peptic ulcer disease	4	1.7	0	0.0	0	0.0	0.37
Rheumatologic disease	1	0.4	0	0.0	0	0.0	0.66
AIDS	0	0.0	0	0.0	1	0.8	NA
None of the above	171	71.3	33	70.2	89	70.1	0.89

^aProportions of patients with specific sites of metastasis were calculated using the number of patients with stage IV disease as the denominator

In terms of disease characteristics, most HER2-low patients presented at Stage IV when diagnosed with advanced disease (n = 157, 65.4%), among which bone was the most common site of metastasis (n = 116, 73.9%) and approximately half had bone as the only site of metastasis (n = 76, 48.4%). The most prevalent histological type and grade were ductal type (n = 181, 75.4%) and grade 2 disease (n = 103, 42.9%), respectively among HER2-low patients. Most HER2-low patients presented with hormone receptor-positive disease (n = 198, 82.5%), which was higher than that observed among IHC0 patients (n = 90, 70.9%) but statistical significance was not achieved (p = 0.08) (Table 1).

Among patients with performance scores reported, most were evaluated to have a good performance status (Eastern Cooperative Oncology Group performance status of 0 and 1; n = 141, 58.8%). Comorbidities that were reported among HER2-low patients include diabetes (n = 25, 10.4%), chronic pulmonary disease (n = 18, 7.5%), renal disease (n = 9, 3.8%), cerebrovascular disease (n = 6, 2.5%), congestive heart failure (n = 5, 2.1%) and peptic ulcer disease (n = 4, 1.7%) (Table 1).

Treatment patterns following diagnosis of advanced breast cancer

Details on the proportion of HER2-low patients on each type of treatment regimen in the first line and second line setting are provided in Table 2 while the corresponding treatment pathways are illustrated in Fig. 3. Among HER2-low patients, 122 received first line treatment for advanced breast cancer in 2017 or later, out of which 46 were determined to be locally advanced (stage IIIB or IIIC) at diagnosis of advanced disease. The most common treatment regimen received by stage IIIB or IIIC patients with HR-positive (n = 32) and HR-negative (n = 12) disease was chemotherapy sequenced with endocrine therapy (n = 15, 46.9%) and chemotherapy alone (n = 11, 91.7%), respectively. Approximately half of these patients (n = 15, 46.9% for HR-positive, n = 6, 50.0% of HR-negative) experienced disease progression or intolerable side effects and proceeded to second line therapy during the study period. In the second line setting HR-positive patients were most likely to receive either chemotherapy alone (n = 7, 21.9%) or endocrine therapy alone (n = 6, 18.8%) while chemotherapy alone remained the most likely treatment regimen for HR-negative patients (n = 5, 41.7%) (Table 2). Notably, among stage IIIB or IIIC HR-positive patients who received endocrine therapy in the first line setting, most who required second line treatment continued to receive endocrine therapy as part of their therapy (Fig. 3A) while HR-negative patients who received chemotherapy alone continued to receive only chemotherapy in the event of second line therapy (Fig. 3B).

Table 2.

Treatment regimens received at first and second line by HER2-low patients with treatment initiation from 2017 onwards (n = 122)

Treatment	Overall	HR positive	HR negative
	n (%)	n (%)	n (%)
Stage IIIB, IIIC	46a	32	12
First lineb
Chemo alone	20 (43.5%)	8 (25.0%)	11 (91.7%)
Chemo + Endocrine	16 (34.8%)	15 (46.9%)	0 (0%)
Chemo + Targeted	1 (2.2%)	0 (0%)	1 (8.3%)
Endocrine alone	6 (13.0%)	6 (18.8%)	0 (0%)
Endocrine + CDK 4/6i	3 (6.5%)	3 (9.4%)	0 (0%)
Second lineb
Chemo alone	13 (28.3%)	7 (21.9%)	5 (41.7%)
Chemo + Immuno	1 (2.2%)	0 (0%)	1 (8.3%)
Endocrine alone	6 (13.0%)	6 (18.8%)	0 (0%)
CDK 4/6i alone	1 (2.2%)	1 (3.1%)	0 (0%)
Targeted alone	1 (2.2%)	1 (3.1%)	0 (0%)
Progression but no treatment	2 (4.3%)	1 (3.1%)	1 (8.3%)
No progression	22 (47.8%)	16 (50.0%)	5 (41.7%)
Stage IV	76	66	10
First lineb
Chemo alone	18 (23.7%)	12 (18.2%)	6 (60.0%)
Chemo + Endocrine	7 (9.2%)	7 (10.6%)	0 (0%)
Chemo + Endocrine + CDK 4/6i	1 (1.3%)	1 (1.5%)	0 (0%)
Chemo + Immunotherapy	3 (3.9%)	0 (0%)	3 (30.0%)
Endocrine alone	11 (14.5%)	11 (16.7%)	0 (0%)
Endocrine + CDK 4/6i	33 (43.4%)	33 (50.0%)	0 (0%)
Endocrine + Immunotherapy	1 (1.3%)	1 (1.5%)	0 (0%)
Immunotherapy	1 (1.3%)	0 (0%)	1 (10.0%)
Targeted + Immunotherapy	1 (1.3%)	1 (1.5%)	0 (0%)
Second lineb
Chemo alone	19 (25.0%)	14 (21.2%)	5 (50.0%)
Chemo + Endocrine + CDK 4/6i	1 (1.3%)	1 (1.5%)	0 (0%)
Endocrine alone	6 (7.9%)	6 (9.1%)	0 (0%)
Endocrine + Targeted	3 (3.9%)	3 (4.5%)	0 (0%)
Endocrine + CDK 4/6i	10 (13.2%)	10 (15.2%)	0 (0%)
Immunotherapy alone	1 (1.3%)	0 (0%)	1 (10.0%)
Targeted alone	2 (2.6%)	1 (1.5%)	1 (10.0%)
Targeted + Immunotherapy	2 (2.6%)	2 (3.0%)	0 (0%)
CDK 4/6i alone	2 (2.6%)	2 (3.0%)	0 (0%)
Clinical trials	2 (2.6%)	2 (3.0%)	0 (0%)
Progression but no treatment	2 (2.6%)	1 (1.5%)	1 (10.0%)
No progression	26 (34.2%)	24 (36.4%)	2 (20.0%)

^a2 patients with stage IIIB and IIIC disease had undocumented hormone receptor status

^bLine of therapy was relative to diagnosis of advanced disease. For stage IIIB/IIIC patients, this could potentially be in the adjuvant/neoadjuvant setting

CDK 4/6i CDK 4/6 inhibitors, Chemo chemotherapy, Endocrine endocrine therapy, HR Hormone receptor status, Targeted targeted therapy

Fig. 3.

Treatment pathways from 1st to 2nd line among HER2-low patients with treatment initiation from 2017 onwards, stratified by hormone receptor (HR) status and staging (A Stage IIIB/IIIC, HR+; B Stage IIIB/IIIC, HR-; C Stage IV, HR+; D Stage IV, HR−). The size of flows from first- to second line treatment is representative of the number of patients. Other regimens include endocrine + immune, endocrine + targeted, chemo + targeted, targeted therapy alone, immunotherapy alone and targeted + immune. CDK 4/6i CDK 4/6 inhibitors, Chemo chemotherapy, Endocrine endocrine therapy, Immuno immunotherapy, Targeted targeted therapy

A total of 76 HER2-low patients presented with distant metastasis (stage IV) when diagnosed with advanced disease and received treatment in 2017 or later. Similar to stage IIIB and IIIC patients, HR-negative HER2-low patients who presented at stage IV were most likely to receive chemotherapy alone in both first line (n = 6, 60.0%) and second line (n = 5, 50.0%) setting. For HR-positive patients, the most common first line treatment regimen was endocrine therapy plus CDK 4/6 inhibitors (n = 33, 50.0%) while chemotherapy alone was most common in the second line setting (n = 14, 21.2%), followed by endocrine therapy plus CDK 4/6 inhibitors (n = 10, 15.2%) and endocrine therapy alone (n = 6, 9.1%) (Table 2). A substantial proportion of HR+ patients who did not receive CDK4/6 inhibitors in the first line setting received them if second line therapy was needed (Fig. 3C) while most HR- patients who received chemotherapy alone at first line also received chemotherapy alone in the second line setting (Fig. 3D).

Survival outcomes among HER2-low patients with treatment in 2017 or later

Limiting to only patients who received treatment for advanced breast cancer in 2017 or later (median follow-up time = 20.9 months), the median OS, PFS from first line treatment and PFS from second line treatment was 37.7, 18.0 and 8.1 months, respectively. Stratified by disease staging, OS and PFS from first line treatment were superior for HR-positive patients than for HR-negative patients with the same disease staging. For patients with metastatic disease, the median OS and PFS was 36.7 and 15.3 months, respectively, for HR-positive patients compared to 16.9 and 9.0 months, respectively, for HR-negative patients. Median PFS from second line treatment was also shorter than median PFS from first line treatment in general and for most patient subgroups, except for among stage IV HR-negative patients (Table 3).

Table 3.

Clinical outcomes of HER2-low patients with treatment initiation from 2017 onwards stratified by hormone receptor status and staging at advanced diagnosis (n = 122)

	N	Median in months	95% CI	% alive/progression-free
				At 1 year	At 2 years	At 3 years
Follow-up time
Overall cohort	122	20.9	–
OS
Overall cohort	121a	37.7	LB: 33.1 (UB not reached)	89.7%	72.5%	55.9%
Stage IIIB/IIIC, HR+	32	38.1	LB: 31.4 (UB not reached)	100%	91.3%	73.8%
Stage IIIB/IIIC, HR−	12	NR	UB, LB not reached	66.7%	NR	NR
Stage IV, HR+	65	36.7	LB: 28.2 (UB not reached)	90.4%	70.2%	54.4%
Stage IV, HR−	10	16.9	LB: 1.2 (UB not reached)	65.6%	39.4%	NR
PFS from first line
Overall cohort	121a	18.0	14.7 to 26.1	68.9%	42.4%	29.8%
Stage IIIB/IIIC, HR+	32	37.7	LB: 24.6 (UB not reached)	87.1%	72.3%	51.2%
Stage IIIB/IIIC, HR−	12	17.2	LB: 3.7 (UB not reached)	70.0%	NR	NR
Stage IV, HR+	65	15.3	9.4 to 20.3	63.3%	31.2%	21.8%
Stage IV, HR−	10	9.0	LB: 1.2 (UB not reached)	30.0%	NR	NR
PFS from second line
Overall cohort	70	8.1	4.9 to 10.6	33.3%	24.1%	16.0%
Stage IIIB/IIIC, HR+	15	7.1	3.0 to 11.0	18.8%	NR	NR
Stage IIIB/IIIC, HR−	6	2.8	LB: 0.6 (UB not reached)	33.3%	NR	NR
Stage IV, HR+	41	8.1	3.7 to 12.4	35.9%	23.6%	NR
Stage IV, HR−	7	10.1	LB: 1.3 (UB not reached)	34.3%	34.3%	NR

^aThe exact treatment start date for one patient was not documented while 2 patients with stage IIIB and IIIC disease had undocumented hormone receptor status

CI Confidence interval, HR Hormone receptor status, LB lower bound, NR not reached, OS Overall survival, PFS Progression-free survival, UB upper bound

Discussion

In our cohort of patients with advanced breast cancer, 58% were determined to have HER2-low status, which is close to the upper limit of prevalence estimates that have been reported in the literature (between 31% and 66%) [10, 12, 15, 16]. Among patients with HER2-low disease, most HR-positive patients received endocrine-based therapy while chemotherapy alone remains the mainstay treatment for HR-negative patients. Trends of longer survival were demonstrated among HR-positive patients compared to HR-negative patients in the first line setting but were similar in the second line setting across patient subgroups stratified by HR status and staging at advanced diagnosis.

In accordance with treatment guidelines during the study period, the use of HER2-targeted agents was minimal in our cohort of HER2-low patients. Chemotherapy alone was the most frequent treatment of choice among HR-negative patients although immunotherapy was employed in some cases, particularly in the metastatic setting. This observation was in line with clinical recommendations that favor cytotoxic drugs such as anthracyclines and taxanes in the treatment of advanced HR-negative breast cancer [17]. In contrast, HR-positive patients typically received endocrine treatment sequenced after chemotherapy as first line treatment among stage IIIB and IIIC patients or combined with CDK 4/6 inhibitors among stage IV patients [17]. In patients with stage IIIB and IIIC, HR-positive disease, the high use of chemotherapy followed by endocrine therapy in the first-line setting is possibly due to treatment with curative intent where patients may have resectable or potentially resectable tumors with no distant metastasis as neoadjuvant or adjuvant therapy [14]. In our study, advanced breast cancer was determined solely based on staging as surgical data was not collected and thus it was not feasible to identify patients with unresectable tumors among those with stage IIIB and IIIC disease. Notably, the utilization rate of CDK 4/6 inhibitors in our patient cohort was lower than expected compared to findings of other real-world studies in the United States at approximately 60% in first line therapy for HR+ metastatic breast cancer patients [18, 19]. This is likely due to a delay in adopting new treatment paradigms and usage is expected to gradually increase over time. Some HR-positive patients received chemotherapy without endocrine therapy in both first- and second line settings, most likely to manage visceral crises or to achieve a rapid response in tumor size reduction. A small proportion of patients with stage IV HR-positive disease also had limited bone-only metastasis and were managed as having oligometastatic disease, receiving chemotherapy as neoadjuvant therapy, followed by surgery and maintenance endocrine therapy if resolution of lesions was observed [20, 21].

The median OS observed in our study among HER2-low patients who received treatment for advanced disease in 2017 or later was 37.7 months, among which HR-negative patients (1-year survival for stage IIIB/IIIC: 66.7%, stage IV: 65.4%) consistently demonstrated worse survival outcomes compared to HR-positive patients (1-year survival for stage IIIB/IIIC: 100%, stage IV: 90.4%) with the same disease staging. Among patients with metastatic disease, progression was observed in more than half of the patients within a year after initiation of first line treatment for HR-negative patients and within 1.5 years for HR-positive patients. In the second line setting, median PFS was less than a year for all patient subgroups, stratified by staging at advanced diagnosis and HR status. These observations indicate a need to expand the existing range of treatment options available for advanced breast cancer patients with HER2-low disease. Unlike HER2-positive breast cancer patients, HER2-low patients were not candidates for traditional HER2-directed agents, such as trastuzumab and trastuzumab emtansine, due to the lack of efficacy observed in the HER2-negative and HER2-low populations in clinical trials [22–24]. With the development of novel HER2-directed antibody-drug conjugates (ADCs), HER2-low patients may potentially benefit from HER2-targeted therapy [8, 25]. One such ADC, trastuzumab deruxtecan, was demonstrated to significantly prolong PFS and OS among HER2-low metastatic breast cancer patients in the DESTINY-Breast04 trial and was approved by the FDA in 2022 for the treatment of HER2-low breast cancer after a prior chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy [8].

These findings should be interpreted in the context of our study limitations. As participants in our study were diagnosed before the classification of patients with HER2-low disease would have clinical relevance and led to differences in treatment pathways, the discrimination between HER2 expression levels corresponding to IHC1+ and IHC0 disease may be less reliable, and some patients with low HER2 expression may have been categorized as IHC0. Given the retrospective nature of our study, retesting of all samples was not feasible. Additionally, data was collected from a single institution, hence our results may not be reflective of the wider population of breast cancer patients due to differences in demographics such as ethnicity composition. The number of eligible patients was further reduced by excluding patients with no documented IHC results, likely due to conclusive FISH results. Due to the small sample size, this study was also not powered to compare patient characteristics or clinical outcomes between HER2-low and IHC0 patients. Attrition of participants to focus on those who received treatment in 2017 onwards further reduced the number of patients analyzed for treatment patterns and outcomes. With more data collected from multiple sites, subgroup analyses based on diagnosis and treatment time can be conducted to examine the changes in treatment patterns over time. Future work extending to other clinical sites will therefore increase the generalizability of the findings and provide sufficient sample size for comparisons between HER2-low and IHC0 patients.

Our findings show that a substantial proportion of patients with advanced breast cancer who are classified as HER2-negative according to existing algorithms have low but detectable levels of HER2 expression. Though traditional HER2-targeted therapies demonstrated poor clinical outcomes in these patients, novel HER2-directed agents such as traztuzumab deruxtecan have shown clinical benefit in clinical trials, albeit in later lines compared to the study population. Real-world studies of novel HER2-directed agents among HER2-low patients are critical to evaluate if treatment outcomes of HER2-low patients can be improved with these new drugs.

Supplementary Information

Below is the link to the electronic supplementary material.

Author contributions

C.W., C.L., S.M., J.K., L.P., M.P.K. and D.S. contributed to the study conception and design. C.W., C.J.T., A.C. and A.W. contributed to data acquisition and analysis. C.W., C.J.T., C.L., S.M., L.P., X.X., K.K. and D.S. contributed to data interpretation. The first draft of the manuscript was written by C.W. and C.J.T. All authors reviewed and commented on iterations of the manuscript and approved the final version submitted to the journal.

Funding

This study is sponsored by AstraZeneca. In March 2019, AstraZeneca entered into a global development and commercialization collaboration agreement with Daiichi Sankyo for trastuzumab deruxtecan (T-DXd; DS-8201).

Data availability

The data that support the findings of this study are not openly available due to reasons of sensitivity and are available from the corresponding author upon reasonable request. Data is located in controlled access data storage at the University of Utah.

Declarations

Competing interests

C.W., C.J.T., A.C., A.W., and D.S. received research funding through the University of Utah from AstraZeneca to conduct this study. C.L, L.P., M.P.K. and X.X. were employees of AstraZeneca while S.M. and J.K. were employees of Daiichi Sankyo at the time of the study.

Ethical approval

This study was exempted from ethical review by the University of Utah Institutional Review Board on 20 August 2020 (IRB_00134235).