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Abstract

Background:

Hormone receptor (HR)-low human epidermal growth factor receptor 2 (HER2)-negative breast cancers (BC) have similar outcomes to triple-negative BC; however, there is a lack of consensus on treatment recommendations for this subset. We present results from a US National Cancer Database (NCDB) analysis of patients with stage I–III HER2-negative BC categorized into groups by estrogen and progesterone receptor (PR) expression: HR-Neg, HR-Low, HR-Intermediate (HR-Int), and HR-High.

Objectives:

The primary objective was to assess the effect of HR expression on neoadjuvant chemotherapy (NAC) pathologic complete response (pCR) rates. Secondary objectives included assessment of clinico-pathologic characteristics and practice patterns.

Design and methods:

Patients with stage I–III HER2-negative BC diagnosed in 2018 were identified in the NCDB, a nationwide oncology outcomes database in the United States. Quantitative HR expression was unavailable prior to 2018. Data were categorized into four groups by estrogen receptor (ER) and PR expression: ER <1% and PR <1% (HR-Neg); ER 1%–10% and/or PR 1%–10% (HR-Low); ER >11%–30% and/or PR >11%–30% (HR-Int); and ER >30% and/or PR >30% (HR-High). Those with undocumented HR status (3%) or without curative intent surgery (5%) were excluded.

Results:

Significant differences were found between HR groups with higher grade, clinical stage, and Ki-67 in HR-Low versus HR-Int or HR-High groups. pCR rates in those receiving NAC were significantly different by HR status, with higher pCR rates in HR-Low versus HR-High groups (p < 0.001). NAC utilization significantly differed between groups, with a higher proportion of patients with HR-Low BC receiving NAC than other HR-positive groups (p < 0.001). Less than half of patients with HR-Low BC received endocrine therapy compared to higher rates in the HR-Int and HR-High groups (p < 0.001).

Conclusion:

This large real-world analysis shows variability in NAC utilization and endocrine therapy for HR-Low and HR-Int BC, with further work needed to enhance representation of these in trials.

Plain language summary

Impact of low hormone receptor expression on treatment of early-stage breast cancer

Measurement of hormone receptors commonly found on breast cancer tumors are used to make treatment decisions for people diagnosed with breast cancer. However, there is a lack of consensus on how to treat tumors that express low or intermediate levels of hormone receptors. We present results from a national database analysis of patient data in which we separated patients with breast cancer into groups depending on their tumor’s hormone receptor level. We found that those with low or intermediate receptor expression were more likely to have a strong response to chemotherapy, which is similar to hormone receptor negative breast tumors. We additionally obtained other demographic data on these patients and described treatment differences seen between the groups. Ultimately, there is much variability in treatment of hormone receptor low and intermediate breast cancers compared to highly positive ones and this requires further study to determine how best to treat these cancers.

Keywords

breast cancer chemotherapy estrogen-directed therapy endocrine therapy hormone receptor-positive breast cancer hormone therapy

Background and objectives

Determination of hormone receptor (HR; measured by estrogen receptor (ER) and progesterone receptor (PR) expression) and human epidermal growth factor receptor 2 (HER2) status is critical for the appropriate management of invasive breast cancer (BC). These markers are most often used to sort BC into three major clinical subtypes: HR+/HER2-negative, HR−/HER2-negative (triple negative breast cancer or TNBC), and HER2-positive, each of which has unique treatment approaches.¹

The 2010 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines recommend that BCs with ER or PR quantitative expression of ⩾1% tumor nuclei staining are HR positive. By contrast, tumors with ER and PR expression of <1% are considered HR negative.² The ASCO/CAP 2020 guideline update on this topic acknowledged that there are limited data on the benefit of endocrine therapy for cancers with ER expression of 1%–10% (which they defined as ER Positive Low).³ Similarly, the European Society for Medical Oncology BC practice guidelines define ER and PR positivity to be IHC staining ⩾1%,⁴ though with a similar cautionary note that ER-Low (ER positivity in 1%–9% tumor cells) cancers may be less sensitive to endocrine therapy.⁵

BCs with lower levels of HR expression behave differently from those with higher levels of HR. Several small retrospective studies suggest worse prognoses for patients with HR-Low tumors than those with HR-high disease.^6–10 In addition, gene expression analyses demonstrate HR-Low tumors to be more similar to TNBCs, though small sample sizes and lack of generalizability limit these studies.^11–14 Importantly, prognostic and molecular differences between HR-Low and HR-High tumors are most relevant for tumors which are also HER2-negative.^10,15

This distinction between HR-Low and other HR positive cancers is important given its impact on the therapeutic approach and disparities in clinical trial enrollment. HR+/HER2-negative BCs and TNBC are treated very differently. While NCCN clinical practice guidelines indicate the heterogeneous biology of the ER-low positive (1%–10%) group, its treatment recommendations for these patients leave much room for interpretation. The guidelines state that “individualized consideration of risks versus benefits of endocrine therapy and additional adjuvant therapies should be incorporated into decision-making.” Despite the prognostic and molecular similarities between HR-Low and TNBC, HR-Low patients have historically been excluded from landmark TNBC clinical studies (e.g., KEYNOTE-522, KEYNOTE-355, ASCENT).^16–18 These issues ultimately impact access to care, presenting challenges in the optimal management of patients with HR low disease. There is even more limited data in patients with intermediate levels of HR expressing BC (11%–30%), and what impact this may have on outcomes and treatment response.

Current questions surrounding HR-Low and HR-Intermediate (HR-Int) BCs represent a clear opportunity for better disease characterization and reducing disparities in care. We looked to the US National Cancer Database (NCDB) to investigate response to neoadjuvant chemotherapy (NAC), learn more about tumor biology, and describe practice patterns for HER2-negative BCs based on HR expression. The primary objective was to assess the effect of HR expression on NAC pathologic complete response (pCR) rates. Secondary objectives included assessment of clinico-pathologic characteristics and practice patterns.

Methodology

Study population

The US NCDB is a nationwide oncology outcomes database representing a combined effort of the Commission on Cancer of the American College of Surgeons and the American Cancer Society. It contains de-identified hospital registry data from over 1500 accredited facilities and represents more than 70% of newly diagnosed cancer cases in the United States. The NCDB gathers information on patient demographics and comorbidities, tumor characteristics and staging details, primary therapies administered, and overall survival. Since all data are de-identified, this study was deemed exempt by the Ohio State University Medical Center’s Cancer Institutional Review Board. The reporting of this study conforms to the STROBE guideline (Supplemental File 1).¹⁹

Patients with stage I–III HER2-negative invasive BC diagnosed between January 1 and December 31, 2018, were identified in the NCDB for this study. HER2-negative status was defined as HER2 IHC negative (0 or 1+) or HER2 IHC equivocal (2+) with negative fluorescence in situ hybridization (FISH) testing. Cases diagnosed prior to these dates were not included in the analysis due to the lack of reporting quantitative HR expression.

Study variables

Data were categorized into four groups by ER and PR expression: ER <1% and PR <1% (HR-Neg), ER 1%–10% and/or PR 1%–10% with neither exceeding 10% (HR-Low), ER 11%–30%, and/or PR 11%–30% with neither exceeding 30% (HR-Int), ER >30%, and/or PR >30% (HR-High). A cutoff of 30% was used to define HR-Int cases to keep in line with Allred scoring.²⁰

The primary objective was to assess the effect of HR expression on NAC pCR rates. Key secondary objectives included assessment of clinicopathologic characteristics and describing practice patterns. For each group, age was measured as a continuous variable. Categorical variables included the following: sex; race; facility type (academic/research program, community cancer program, comprehensive community cancer program, integrated network cancer program, or unknown); primary payor (private insurance, Medicare, Medicaid, other government insurance, not insured, unknown); clinical stage (stage 1 or stage 2/3); tumor grade (grade 1, grade 2, grade 3, or unknown); Ki-67% (<10%, 10%–50%, >50%, or missing/unknown); lymphovascular invasion (present, not present, not applicable, unknown); Oncotype DX result obtained (result obtained, no ordered/missing/no result available); Oncotype DX score (low risk, intermediate risk, high risk); breast surgery (partial mastectomy, mastectomy, or other/unknown); chemotherapy use (yes, no, or unknown); NAC use (yes, no, or unknown); immunotherapy use (yes, no, unknown); hormone therapy (yes, no, or unknown); and NAC response (pCR, partial response, no response, or unknown).

Statistical analysis

Patient demographics, disease characteristics, and NAC response are presented as frequency (%) for categorical variables, and age is presented as median and interquartile range overall and by HR expression group. Categorical variables, including NAC response, were compared between the four groups using Chi-square tests. Age was compared using a Kruskal–Wallis test. Analyses were conducted using SAS 9.4 (SAS Institute Inc., Cary, NC, USA) with two-sided tests and a significance level of 0.05.

Results

Patient demographics of HR-Low and HR-Int tumors

The US NCDB reported on a total of 140,243 incident stage I–III HER2-negative BC cases between January 1 and December 31, 2018 (Figure 1). Cases with undocumented HR status (4%) and/or those that did not undergo curative intent surgery (5%) were excluded from the study analysis. The remaining 128,325 eligible cases were categorized based on HR expression as follows: 15,935 (12.4%) as HR-Neg; 3072 (2.4%) as HR-Low; 1509 (1.2%) as HR-Int; and 107,809 (84%) as HR-High (Table 1). The median age at diagnosis was slightly younger in HR-Neg, HR-Low, and HR-Int subgroups compared to HR-High tumors (HR-Neg (60 years), HR-Low (60 years), HR-Int (59 years), and HR-High (64 years); p < 0.001). In contrast to the HR-High subgroup, HR-Neg, HR-Low, and HR-Int cohorts reported a higher proportion of Black patients (HR-Neg (22%), HR-Low (20%), HR-Int (19%), HR-High (9%); p < 0.001). The racial distribution of HR-Low and HR-Int cases was more comparable to the HR Neg cohort, where the black population represented 22% of all incident cases. There were 1134 (1%) cases of male BC with a vast majority reporting high HR expression (<1% in HR-Neg (44), <1% HR-Low (11), 1% HR-Int (3), and 1% in HR-High (1076); p < 0.001). Table 1 provides additional details on facility types and primary payor, also found to be significantly different between HR groups (p < 0.001).

Figure 1.

CONSORT diagram.

Table 1.

Patient demographics.

Variable	HR-Neg (n = 15,935)	HR-Low (n = 3072)	HR-Int (n = 1509)	HR-High (n = 107,809)	Total (n = 128,325)	p-Value
Age at diagnosis
Median (IQR) (min, max)	60 (50, 70) (19, 90)	60 (49, 70) (18, 90)	59 (49, 69) (19, 90)	64 (54, 72) (19, 90)	63 (53, 71) (18, 90)	<0.001
Sex
Female	15,891 (100%)	3061 (100%)	1506 (100%)	106,733 (99%)	127,191 (99%)	<0.001
Male	44 (0%)	11 (0%)	3 (0%)	1076 (1%)	1134 (1%)
Race
White	11,510 (72%)	2215 (72%)	1090 (72%)	90,897 (84%)	105,712 (82%)	<0.001
Black	3483 (22%)	627 (20%)	286 (19%)	9689 (9%)	14,085 (11%)
Other	820 (5%)	205 (7%)	118 (8%)	6402 (6%)	7545 (6%)
Unknown	122 (1%)	25 (1%)	15 (1%)	821 (1%)	983 (1%)
Facility type
Academic/research program	4704 (30%)	790 (26%)	422 (28%)	31,188 (29%)	37,104 (29%)	<0.001
Community cancer program	1036 (7%)	223 (7%)	90 (6%)	7512 (7%)	8861 (7%)
Comprehensive community cancer program	4985 (36%)	1012 (40%)	487 (39%)	35,293 (41%)	41,777 (40%)
Integrated network cancer program	3031 (19%)	535 (17%)	264 (17%)	21,709 (20%)	25,539 (20%)
Unknown	1375 (9%)	304 (10%)	146 (10%)	3388 (3%)	5213 (4%)
Primary payor
Private insurance	8004 (50%)	1544 (50%)	794 (53%)	50,546 (47%)	60,888 (47%)	<0.001
Medicare	586 (37%)	1133 (37%)	533 (35%)	47,965 (44%)	55,499 (43%)
Medicaid	1387 (9%)	281 (9%)	126 (8%)	5796 (5%)	7590 (6%)
Other government insurance	210 (1%)	34 (1%)	18 (1%)	1145 (1%)	1407 (1%)
Not insured	269 (2%)	49 (2%)	23 (2%)	1026 (1%)	1367 (1%)
Unknown	171 (1%)	24 (1%)	10 (1%)	1042 (1%)	1247 (1%)

HR, hormone receptor; IQR, interquartile range.

HR-Low and HR-Int tumor clinico-pathologic features

Comparisons of clinical and pathologic features of breast tumors between HR expression levels are presented in Table 2. Over half of HR-Neg, HR-Low, and HR-Int cases were diagnosed at clinical stage 2 or 3, whereas only a small proportion of the HR-High cases were diagnosed at an advanced stage (HR-Neg (58%), HR-Low (55%), HR-Int (54%), and HR-High (16%); p < 0.001). Most tumors had ductal histology; however, increasing HR expression level was associated with a greater likelihood of lobular histology (HR-Neg (1%), HR-Low (4%), HR-Int (5%), HR-High (14%); p < 0.001). Grade 3 tumors made up the majority of HR-Neg (70%), HR-Low (68%), and HR-Int (63%) cases, whereas this was the minority (11%) for HR-High cases (p < 0.001). HR-Neg, HR-Low, and HR-Int tumors were also more likely to report a high tumor proliferation score (Ki-67 >50%) than HR-High tumors (HR-Neg (28%), HR-Low (28%), HR-Int (28%), HR-High (4%); p < 0.001). The ordering of Oncotype DX recurrence scores (RS) was also measured and found to be less frequent for HR-Low (11%) and HR-Int (28%) than HR-High (41%) tumors (p < 0.001). For the tumors that had Oncotype DX results, HR-Low (13%) and HR-Int (12%) were much less likely to have low-risk scores (defined as RS between 0 and 17) than HR-High (62%) tumors. As a low Oncotype DX score suggests a favorable prognosis and lack of benefit from adjuvant chemotherapy,²¹ higher 21-gene RS was found along with higher grade and Ki-67 in HR-Low and HR-Int compared to HR high tumors, suggesting a distinct biology.

Table 2.

Breast cancer characteristics.

Variable	HR-Neg (n = 15,935)	HR-Low (n = 3072)	HR-Int (n = 1509)	HR-High (n = 107,809)	Total (n = 128,325)	p-Value
Clinical stage
Stage 1	6646 (42%)	1396 (45%)	689 (46%)	90,924 (84%)	99,655 (78%)	<0.001
Stage 2/3	9289 (58%)	1676 (55%)	820 (54%)	16,885 (16%)	28,670 (22%)
Histology
Ductal carcinoma	14,607 (92%)	2737 (89%)	1328 (88%)	83,162 (77%)	101,834 (79%)	<0.001
Lobular carcinoma	191 (1%)	110 (4%)	81 (5%)	14,714 (14%)	15,096 (12%)
Mixed ductal and lobular carcinoma	11,156 (70%)	2079 (68%)	944 (63%)	11,489 (11%)	25,668 (20%)
Other subtype	1178 (7%)	217 (7%)	103 (7%)	8913 (8%)	10,409 (8%)
Tumor grade
1	338 (2%)	155 (5%)	92 (6%)	35,739 (33%)	36,324 (28%)	<0.001
2	3263 (20%)	621 (20%)	370 (25%)	51,668 (48%)	55,922 (44%)
3	11,156 (70%)	2079 (68%)	944 (63%)	11,489 (11%)	25,668 (20%)
Unknown	1178 (7%)	217 (7%)	103 (7%)	8913 (8%)	10,409 (8%)
Ki-67 (%)
<10	607 (4%)	167 (5%)	94 (6%)	18,320 (17%)	19,188 (15%)	<0.001
10–50	2148 (13%)	446 (15%)	249 (17%)	30,276 (28%)	33,119 (26%)
>50	4502 (28%)	847 (28%)	420 (28%)	4029 (4%)	9798 (8%)
Missing/unknown	8678 (54%)	1612 (52%)	746 (49%)	55,184 (51%)	66,220 (52%)
Lymphovascular invasion
Present	2429 (15%)	471 (15%)	269 (18%)	15,215 (14%)	18,384 (14%)	<0.001
Not present	10,355 (65%)	2030 (66%)	1010 (67%)	80,149 (74%)	93,544 (73%)
Not applicable	15 (0%)	3 (0%)	1 (0%)	56 (0%)	75 (0%)
Unknown	3136 (20%)	568 (18%)	229 (15%)	12,389 (11%)	16,322 (13%)
Oncotype DX result obtained
Result obtained	145 (1%)	331 (11%)	347 (23%)	44,319 (41%)	45,319 (35%)	<0.001
Not ordered, missing, or no result available	15,790 (99%)	2741 (89%)	1162 (77%)	63,490 (59%)	83,183 (65%)
Oncotype DX score (% of those with an available Oncotype DX score)
Low risk (0–17)	44 (30%)	44 (13%)	42 (12%)	27,532 (62%)	27,662 (22%)	<0.001
Intermediate risk (18–30)	24 (17%)	49 (15%)	55 (16%)	13,368 (30%)	13,496 (11%)
High risk (31–100)	77 (53%)	238 (72%)	250 (72%)	3419 (8%)	3984 (3%)

HR, hormone receptor.

Practice patterns based on HR expression levels

Additional information was abstracted to determine the potential differences in the treatment of HER2-negative early BC with varying levels of HR expression (Table 3). Surgically, most patients underwent breast conservation, particularly in the HR-High cohort (HR-Neg (54%), HR-Low (54%), HR-Int (56%), and HR-High (66%); p < 0.001). Chemotherapy use was significantly greater with HR-Low and HR-Int tumors in contrast to HR-High tumors (HR-Low (74%), HR-Int (70%), HR-High (21%); p < 0.001), and more comparable to those with HR-Neg disease (80%). Specifically, NAC use was much more common in HR-Low and HR-Int tumors over HR-High tumors (HR-Low (41%), HR-Int (33%), HR-High (11%); p < 0.001), similar to use in HR-Neg tumors (44%). The utilization of endocrine therapy positively correlated with increasing HR expression, with less than half in the HR-Low group reporting use of any adjuvant endocrine therapy (HR-Neg (3%), HR-Low (44%), HR-Int (67%), and HR-High (85%); p < 0.001). In patients younger than 50 years old compared to those 50 years or older, the use of endocrine therapy was somewhat higher in younger patients when looking specifically at the HR-Neg (5% vs 3%; p < 0.001) and HR-High (87% vs 84%, p < 0.001) groups (Supplemental File 2). There were no differences in endocrine therapy use in HR-Low or HR-Int groups, dependent on age.

Table 3.

Treatment patterns.

Variable	HR-Neg(n = 15,935)	HR-Low(n = 3072)	HR-Int(n = 1509)	HR-High(n = 107,809)	Total(n = 12,8325)	p-Value
Breast surgery
Partial mastectomy (lumpectomy)	8667 (54%)	1654 (54%)	838 (56%)	70,946 (66%)	82,105 (64%)	<0.001
Mastectomy	7222 (45%)	1409 (46%)	668 (44%)	36,612 (34%)	45,911 (36%)
Other/unknown	46 (0%)	9 (0%)	3 (0%)	251 (0%)	309 (0%)
Chemotherapy use
Yes	12,812 (80%)	2284 (74%)	1058 (70%)	22,643 (21%)	38,797 (30%)	<0.001
No	2979 (19%)	755 (25%)	440 (29%)	84,295 (78%)	88,469 (69%)
Unknown	144 (1%)	33 (1%)	11 (1%)	871 (1%)	1059 (1%)
Neoadjuvant chemotherapy use
Yes	7039 (44%)	1257 (41%)	500 (33%)	12,036 (11%)	20,832 (16%)	<0.001
No	8894 (56%)	1815 (59%)	1008 (67%)	95,763 (89%)	107,480 (84%)
Unknown	2 (0%)	0 (0%)	1 (0%)	10 (0%)	13 (0%)
Immunotherapy use
Yes	486 (3%)	87 (3%)	36 (2%)	1019 (1%)	1628 (1%)	<0.001
No	15,388 (97%)	2972 (97%)	1470 (97%)	106,573 (99%)	126,403 (99%)
Unknown	61 (0%)	13 (0%)	3 (0%)	217 (0%)	294 (0%)
Hormone therapy use
Yes	489 (3%)	1348 (44%)	1010 (67%)	91,435 (85%)	94,282 (73%)	<0.001
No	15,319 (96%)	1629 (53%)	443 (29%)	13,494 (13%)	30,885 (24%)
Unknown	127 (1%)	95 (3%)	56 (4%)	2880 (3%)	3158 (2%)

HR, hormone receptor.

Neoadjuvant treatment response

pCR is known to be a strong positive predictor of event-free survival in HR-negative BC.²² HR-Neg tumors traditionally have higher rates of pCR, as was shown in this study (32%; 53% of those with reported neoadjuvant treatment outcome information; Table 4). HR-Low (31%; 54% of those with outcome information) and HR-Int (26%; 53% of those with outcome information) tumors were found to have very similar pCR rates to HR-Neg tumors. By contrast, HR-High tumors had the lowest rates of pCR (5%; 15% of those with reported outcome information) in our analysis.

Table 4.

Neoadjuvant chemotherapy response.

Neoadjuvant chemotherapy response	HR-Neg (n = 7039)	HR-Low (n = 1257)	HR-Int (n = 500)	HR-High (n = 12,036)	Total (n = 20,832)	p-Value
Pathologic complete response	2231 (32%)	395 (31%)	128 (26%)	590 (5%)	3344 (16%)	<0.001
Partial response	1521 (22%)	259 (21%)	76 (15%)	2469 (21%)	4325 (21%)
No response	421 (6%)	77 (6%)	37 (7%)	995 (8%)	1530 (7%)
Unknown/not documented	2866 (41%)	526 (42%)	259 (52%)	7982 (66%)	11,633 (56%)

HR, hormone receptor.

Discussion

ER and PR are integral prognostic and predictive biomarkers driving therapeutic recommendations and determining benefit from endocrine therapy in BC. However, current guidelines do not differentiate treatment recommendations between tumors with low or high HR levels. Similar to previous studies,²³ this large US contemporary NCDB-based analysis confirms that HER2-negative tumors with HR expression <30% are less common (HR-Low 2.4%; HR-Int 1.2%). In addition, we show that HR low and HR-Int tumors tend to be treated differently than HR-high tumors and have distinct biology and clinical outcomes, as shown by significant differences in clinico-pathologic features and pCR rates. To our knowledge, this study serves as the largest analysis to date to focus on HR-Int disease in addition to HR low tumors.

Clinical and patient differences

In terms of patient demographics, those with HR-Low or HR-Int tumors tended to be younger and more likely to identify racially as Black than those with HR-High tumors. Black women tend to have worse BC outcomes and survival rates than White women due to disparities in healthcare access, socioeconomic barriers, systemic racism, being diagnosed at later stages, and an increased likelihood of being diagnosed with TNBC.^24–26 Interestingly, a prior study on HR-Low tumors suggested that while White women with HR-Low tumors had longer disease-free intervals (DFI) when treated with adjuvant endocrine therapy, Black women had no endocrine therapy benefit and tended to have overall worse DFI.²⁷ Understanding how to optimally manage HR-Low and HR-Int tumors may contribute to lessening at least one component of racial disparities in BC treatment.

Breast tumors that were HR-Low or HR-Int were also more likely to be clinical stage II–III, have higher Ki-67 percentages, and have higher-grade disease than HR-High cases. The fact that these numbers were more in line with HR-Neg proportions also supports the idea that HR-Low and HR-Int tumors are biologically more like TNBCs. Oncotype DX testing (a prognostic and predictive 21-gene expression assay²¹) additionally suggested a greater number of intermediate or high scores in HR-Low and HR-Int, suggesting these tumors to be associated with aggressive biology and more likely to benefit from (neo)adjuvant chemotherapy. The data are consistent with prior smaller studies showing similarities between HR-Low and HR-Neg biology. For example, intrinsic subtyping of HR-low tumors demonstrated that a vast majority are basal-like or HER2 enriched, with less than 10% being classified as luminal A/B.^12,28 HR-Low tumors have also been reported to have a similar incidence of germline BRCA mutations compared to TNBCs, especially germline BRCA1 mutations.¹⁵ HR-Low and HR-Int tumors are additionally more likely to have high tumor-infiltrating lymphocyte numbers, CD8+ T cells, and PD-L1 levels similar to TNBC, suggesting the tumor microenvironment may contain immunostimulatory potential that is not typically seen in HR-High tumors.²⁹

Patterns of multimodal treatment received

In terms of treatment patterns, HR-Low and HR-Int (74%, 70%, respectively) tumors were more likely to be treated with chemotherapy than HR-High (21%). However, this proportion is still lower than the percentage of patients treated with chemotherapy in the HR-Neg (80%) group, suggesting that there is some discrepancy in how these are managed among oncologists. As NCDB data mature, it will be of interest to assess how many patients with HR-Low and HR-Int tumors are offered immunotherapy (e.g., pembrolizumab), as this has only in the last few years been part of an FDA-approved neoadjuvant BC regimen.¹⁶ It is possible that the small percentage of patients in this 2018 cohort who were recommended immunotherapy were offered this in the context of a clinical trial. Of note, more recent combination chemotherapy/immunotherapy neoadjuvant trials (e.g., KEYNOTE-756, CheckMate 7FL) of HR-positive HER2-negative BCs have been able to show that small ER <10%, HER2-negative tumors benefit more from the addition of checkpoint inhibitors than their higher ER expression counterparts.^30,31

Another point of interest from our study is that there was a clear positive association between the amount of HR expression and the number of patients who received endocrine therapy: HR-Neg (3%), HR-Low (44%), HR-Int (67%), and HR-High (85%). Reports on whether adjuvant endocrine therapy is as beneficial for patients with HR-Low and HR-Int tumors as it is for HR-High tumors have been very conflicting, with some studies showing significant improvements in disease-free and overall survival and others showing no survival benefits.^7,32–34 There does seem to be more of a consensus that the amount of ER expression positively correlates with increased endocrine therapy benefit.^34,35 While typically thought to be less toxic than chemotherapy, there are many barriers to endocrine therapy adherence due to the substantial side effect burden these treatments can cause.^36,37 Therefore, there is a critical need to learn more about whether the potential benefit outweighs any untoward risks associated with endocrine therapy for the HR-Low and HR-Int subset of patients. Identifying novel predictive biomarkers of endocrine therapy response besides HR expression can help appropriately select candidates in this subset to optimize the therapeutic risk/benefit ratio. In addition, further studies in physician prescribing patterns may help determine if the difference in hormone therapy use is coming from the healthcare provider level or is a patient-related factor.

It is established that pCR is a strong indicator of TNBC disease-free survival rates as well as overall survival rates, but the data are less compelling in HR-positive, HER2-negative tumors.^22,38 To our knowledge, this study represents the largest analysis of pCR rates for HR-Low and HR-Int, HER2-negative BCs. Previously, smaller studies have reported between 37% and 44% pCR rates in patients with ER and PR levels at 33% or less in HER-2 negative BC.^1,9,39 NAC use was much more frequent for HR-Low and HR-Int compared to HR-High tumors, which was comparable to the HR-Neg cohort. pCR rates after NAC were significantly greater for HR-Low or HR-Int tumors, which were numerically similar to the HR-Neg cohort. Unfortunately, these findings are limited by the high number of missing data points in the NAC treatment response in this dataset.

While not reported in this study, radiation therapy practices may also differ in terms of HR-Low and HR-Int tumors. As clinical trial data and expert panels have suggested that many older patients with low-risk HR-positive, HER2-negative BCs may be able to omit radiation therapy after breast-conserving surgery,⁴⁰ they have not specified if HR-Low and HR-Int tumors should still be considered for omission. As the field continues to refine the appropriate targets, dose, and fractionation of radiation therapy delivered based on a patient’s risk factors, further study may be needed into these distinct biologic subgroups. Recently, a study looking at omission of radiotherapy in women who undergo lumpectomy and are 65 years or older updated a subgroup analysis of ER-Low compared to ER-High tumors, which revealed that ER-Low tumors have a greater local recurrence risk than ER-High tumors.⁴¹ A follow-up study to assess the patterns of locoregional therapy in these pre-specified subgroups utilizing this NCDB data is currently ongoing.

Interestingly, analysis from the PALOMA-3 trial suggests that the benefits of palbociclib (CDK4/6 inhibitor) plus endocrine therapy for previously treated advanced/metastatic BC treatment for HR-positive, HER2-negative BC were independent of ER expression.⁴² Moreover, their results revealed that the presence of PIK3CA mutations (an important treatment target) was also independent of ER expression level. CDK 4/6 inhibitors and PIK3CA-directed oral therapies provide non-chemotherapeutic and potentially better-tolerated options for patients with BC than standard options for metastatic TNBC treatment (e.g., chemotherapy ± immunotherapy).⁴³ While our current study was limited to stage I–III BC patient data and treatment patterns, there is clearly a strong need to understand the implication of different HR levels of expression in the advanced/metastatic setting as well, and this analysis is ongoing.

Limitations

There are several limitations to this current study. One important piece is that prior to 2018, NCDB did not report quantitative ER and PR expression. In addition, no survival outcomes were available for the 2018 cohort. As this is a retrospective study, it is limited by reporting bias, selection bias, and missing data. Further years of accumulating data, which include quantification of HR expression levels, will be beneficial in adding to the limited number of HR-Low and HR-Int tumors that were diagnosed during this 1-year time point. In addition, NCDB does not record information on important attributes such as patient genetics, the specific type of chemotherapies used, and the compliance or duration of adjuvant endocrine therapy. Future studies where this information could be obtained would be particularly important as the pool of systemic therapy options for early-stage BC expands (e.g., CDK4/6 inhibitors). We also did not differentiate distinctly between different combinations of ER and PR expression (e.g., ER-negative, but PR higher). Certain prior studies have suggested that higher amounts of PR-positivity in ER-low tumors tend to have more favorable prognosis; therefore, additional analyses are needed to address these discrepancies as well.⁴⁴

Conclusion

In summation, these findings suggest that HER2-negative BCs with lower levels of HR expression (⩽30%), while uncommon, are distinct based on disease characteristics, treatment patterns, and response to NAC than HR-High tumors. The large majority of TNBC clinical trials have historically excluded tumors with ER and PR levels at 1% or higher and while some clinical trials and guidelines have begun to include tumors with ER and PR expression <10% into the TNBC category, there are virtually no TNBC trials that allow for ER/PR expression up to 30%. With our current information, there is much to suggest that HR-Low and HR-Int tumors may benefit from being treated similarly to HR-Neg tumors. This strongly highlights the need to be more inclusive of HR-Low and HR-Int tumors in prospective randomized trials that include traditionally TNBC-directed treatments. Additional investigation is needed to assess the efficacy of immunotherapy in HR-Low and HR-Int tumor treatment and overall survival trends. Further consideration should be given to address the shortcomings of using the binary “negative/positive” categorization of HR expression and identify other predictive biomarkers that will help reduce outcome disparities for this relatively rare subgroup of patients.

Supplemental Material

sj-docx-1-tam-10.1177_17588359251342874 – Supplemental material for Impact of low hormone receptor expression on neoadjuvant chemotherapy response and patterns of care in non-metastatic HER2-negative breast cancer: a US National Cancer Database analysis

Supplemental material, sj-docx-1-tam-10.1177_17588359251342874 for Impact of low hormone receptor expression on neoadjuvant chemotherapy response and patterns of care in non-metastatic HER2-negative breast cancer: a US National Cancer Database analysis by Dionisia Quiroga, Charles Pei, Julie A. Stephens, Kai C. C. Johnson, Nicole Williams, Preeti Sudheendra, Mathew Cherian, Daniel Stover, Ashley Davenport, Margaret Gatti-Mays, Robert Wesolowski, Jose G. Bazan, Sasha Beyer, Ko Un Park, Bridget A. Oppong, Julia White, Sachin R. Jhawar and Sagar Sardesai in Therapeutic Advances in Medical Oncology

Supplemental Material

sj-docx-2-tam-10.1177_17588359251342874 – Supplemental material for Impact of low hormone receptor expression on neoadjuvant chemotherapy response and patterns of care in non-metastatic HER2-negative breast cancer: a US National Cancer Database analysis

Supplemental material, sj-docx-2-tam-10.1177_17588359251342874 for Impact of low hormone receptor expression on neoadjuvant chemotherapy response and patterns of care in non-metastatic HER2-negative breast cancer: a US National Cancer Database analysis by Dionisia Quiroga, Charles Pei, Julie A. Stephens, Kai C. C. Johnson, Nicole Williams, Preeti Sudheendra, Mathew Cherian, Daniel Stover, Ashley Davenport, Margaret Gatti-Mays, Robert Wesolowski, Jose G. Bazan, Sasha Beyer, Ko Un Park, Bridget A. Oppong, Julia White, Sachin R. Jhawar and Sagar Sardesai in Therapeutic Advances in Medical Oncology

Footnotes

Acknowledgements

The authors would like to thank the patients and their families, the investigators, research nurses, study coordinators, and operations staff who contributed to data obtained from the US NCDB.

Declarations

ORCID iDs

Dionisia Quiroga

Robert Wesolowski

Supplemental material

Supplemental material for this article is available online.

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