Abstract
Purpose
This study examines the factors distinguishing breast cancer (BC) subtypes.
Methods
We examined subtypes in 629 women with invasive BC, diagnosed from 2006–2012 and enrolled in an epidemiological study in New Jersey. Using molecular characteristics from pathology reports, BCs were categorized as luminal A, luminal B, non-luminal HER2-expressing, or triple-negative breast cancer [TNBC] subtypes. Multinomial logistic models (luminal A as referent) were used to describe BC subtype associations.
Results
Women with luminal B tumors were more likely to be younger at diagnosis (Odds ratio [OR] 1.8, 95% confidence interval [CI] 1.0–3.4) and to have higher grade (OR 2.6, 95% CI 1.5–4.7), larger (OR 1.9, 95% CI 1.0–3.6), and Ki67 positive tumors (OR 2.1, 95% CI 1.1–4.0). Women with non-luminal HER2-expressing BCs were more likely to have higher grade tumors (OR 14.5, 95% CI 5.3–39.7). Women with TNBCs were more likely to be African American (OR 1.9, 95% CI 1.0–3.4) and to have higher grade (Or 9.7, 95% CI 5.1–18.4), larger (OR 2.2, 95% CI 1.0–4.8), and Ki67 positive (OR 2.9, 95% CI 1.6–5.2) tumors. Notably, compared to the luminal A subtype, luminal B, non-luminal HER2-expressing and triple-negative subtypes were more frequently self-detected; however, these associations were attenuated in multivariable models.
Conclusions
These findings suggest that some BC subtypes were associated with features denoting more aggressive phenotypes, namely higher grade, larger size, and Ki67 positivity, and possibly patient self-detection among some women. These findings highlight a need for enhanced screening, particularly among younger women, racial/ethnic minorities and lower socioeconomic subgroups.
Keywords: breast cancer, clinicopathological factors, aggressive features, subtypes, African American women
Introduction
Breast cancer (BC) exists as several heterogeneous subtypes, based on global gene expression patterns [1–5] and/or clinical approximation using molecular expression patterns (immunohistochemistry [IHC]) [6–8], with differing distributions, risk factors, tumor behaviors and clinical outcomes [9,5,10–14]. Based on gene expression profiles, at least four intrinsic subtypes of BC have been identified, including luminal A, luminal B, HER2-enriched and basal-like, as well as a normal breast-like type [1,2]. Although gene expression profiling is the gold standard for BC subtyping, data have indicated that IHC expression patterns of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) are fairly concordant with gene expression profiles and have substantial clinical utility [9,3]. BCs that are clinically defined as ER+/PR+/HER2− approximate the luminal A subtype. The luminal B subtype include BCs that are categorized as having lower expression of ER and/or PR compared to the luminal A, increased growth factor receptor expression, increased Ki67 expression, and tend to be HER2 positive (with positive HER2 amplification and IHC expression levels in approximately 20% of tumors) [15–18]. HER2-positive cancers are similarly complex in that they may be of the luminal (i.e., ER+/PR+) or non-luminal (ER−/PR−) type; there is evidence to suggest these are clinically and biologically distinct [19]. While some studies have used the terms basal-like subtype (characterized as ER−/PR−/HER2−, cytokeratin [CK] 5/6 positivity, and/or epidermal growth factor receptor [EGFR] positivity) and “triple-negative breast cancer” (TNBC) interchangeably, evidence has shown that although most TNBCs are basal-like, up to 20–30% of them are not; additionally, not all basal-like BCs are TNBCs [20–22]. For simplicity, herein, we define TNBCs as ER−/PR−/HER2−, based only on IHC expression of these receptors.
Recent Surveillance, Epidemiology, and End Results (SEER) data has shown that, among incident BC cases in the U.S., the luminal A subtype is predominant (72%), followed by TNBC (12.2%), ER+/PR+/HER2+ (10.3%), and ER−/PR−/HER2+ (4.6%) [11]. The aforementioned study [11] and others [9,12,10,5] support marked differences in BC subtype distributions by age, race, socioeconomic status (SES), and BC stage and grade. These studies have demonstrated that BC subtypes exhibiting more aggressive phenotypes are more frequently diagnosed among African American than white women, and that this is particularly true among women diagnosed at younger ages (<50 years). For example, African American women have twice the odds of being diagnosed with TNBCs than whites and TNBCs have about 20 times the odds of being high grade (compared to luminal A BCs) [9,5,11,12,10]. The HER2-expressing subtypes are also associated with presenting more aggressive phenotypes. Compared to the luminal A subtype, the HER2-expressing subtypes are associated with substantially increased odds of advanced stage and higher grade [11,9,23]. Relatedly, it is clear that compared to whites, African Americans and other racial/ethnic minorities have increased risk of BC mortality, which may be related to differences in subtype incidence as well as differences in tumor biology by subtype in these groups [2,24].
The purpose of this study was to examine the associations between sociodemographic characteristics, clinical and reproductive factors, and clinicopathological tumor features, and BC subtypes approximated using molecular patterns defined by ER, PR, and HER2. We focused on factors associated with the HER2-expressing subtypes, luminal B (ER+/PR+/HER2+) and non-luminal HER2-expressing (ER−/PR−/HER2+), and TNBC (ER−/PR−/HER2−) in comparison to the luminal A subtype. These data would provide insight into etiological pathways as well as help explain some of the prognostic differences observed between BC subtypes, likely contributing to our understanding of the causes of disparities in BC outcomes.
Materials and Methods
Study sample
We conducted case-case analysis of 629 incident, early stage, invasive BC cases diagnosed in New Jersey, utilizing data collected through interview-administered questionnaires and abstraction of detailed medical and pathology records. BC cases were participants in the Breast Cancer Treatment Disparity Study (BCTDS) [25], which was an extension of the New Jersey site of the Women’s Circle of Health Study (WCHS) [26]. BC cases enrolled in WCHS included incident BC cases diagnosed in NJ, and: 1) self-identified as African American or white; 2) 20–75 years of age; 3) able to read and understand English; 4) were newly diagnosed (within 9 months of study enrollment) with histologically confirmed stage, I, II, or T3N1M0 BC between 2006–2012; and 3) had no history of cancer except non-melanoma skin cancer. BC cases were identified through rapid case ascertainment, by New Jersey State Cancer Registry (NJSCR) staff, from all major hospitals in nine counties: Bergen, Burlington, Essex, Hudson, Mercer, Middlesex, Monmouth, Passaic, and Union. All eligible African American cases were identified by the NJSCR and frequency-matched with white cases by age (±5 years) and county of residence. BC cases who agreed to the release of their medical records were included in BCTDS (approximately 84% of WCHS cases); all clinicopathological data required for the analysis described herein were available for these cases.
Verbal consent was obtained by NJSCR staff from identified cases prior to research staff contact. Written informed consent was obtained from all participants before data collection and this study was approved by the Institutional Review Board of all participating institutions.
Data collection
The data collection methods utilized in this study have been detailed elsewhere [26,27,25]. Briefly, in-depth, in-person interviews were conducted at participants’ homes or a mutually agreed upon location. The survey instrument queried on known and suspected BC risk factors, including: family history, medical and reproductive history, occupational history, and other lifestyle factors. Anthropometric measurements were also taken, using standardized protocols and instruments [27].
For collection of detailed BC diagnosis information, medical records and pathology reports were obtained for each participant upon consenting to having their medical records released [25]. Records were obtained from all providers (e.g., primary care physician, and surgical, medical, and radiation oncologists) and relevant institutions (e.g., hospitals where surgical procedures were performed) identified by the patient. Diagnostic information and pathology reports were obtained from one year prior to one year following the initial BC diagnosis. Trained abstractors reviewed each record, recorded data on a standardized medical records abstraction form, and entered data into an electronic database. For quality assurance, values were checked for errors during data entry, and if errors were detected the original abstractor was contacted with instructions to re-check the medical records/pathology report, allowing for confirmation of the recorded data.
Classification of breast cancer subtypes
Surrogate classifications, based on IHC expression of estrogen receptor (ER), progesterone receptor (PR), and overexpression of human epidermal growth factor receptor 2 (HER2; by IHC and/or FISH), recorded in pathology reports, were used to approximate BCs into four mutually exclusive subtypes. These subtypes were the following: luminal A (ER+ and/or PR+/HER2−), luminal B (ER+ and/or PR+/HER2+), non-luminal HER2-expressing (ER−/PR−/HER2+), and TNBC (ER−/PR−/HER2−).
Statistical analysis
Baseline participant characteristics overall and by BC subtype were described using frequencies and proportions. Chi-square tests were used to compare sociodemographic, clinical, reproductive, and tumor characteristics by BC subtype. Multinomial logistic regression models (with the luminal A subtype as the referent group) were used to estimate unadjusted and adjusted odds ratios (OR) and 95% confidence intervals (CI) of the associations between characteristics of interest and BC subtype. Variables that were statistically significant in univariate models were included in the multivariable models, to keep a parsimonious approach for adjustment. All reported P-values are two-sided and P <0.05 was considered statistically significant. Analyses were performed using SAS (v9.3 SAS Institute, Cary, NC).
Results
In this study of 629 women with early stage, invasive BC (49% African American), luminal A cancers were the most frequently diagnosed (68.4%), followed by the TNBC (14.5%), luminal B (11.1%), and non-luminal HER2-expressing (6.0%) subtypes. Sociodemographic characteristics of the study sample, overall and by BC subtype, are shown in Table 1. Higher proportions of luminal A BCs were diagnosed among women age ≥45 years (84.2%), while higher proportions of TNBCs were diagnosed among African American women (67.0%) and among women whose educational attainment was below a college degree (57.1%). Several striking differences in breast tumor clinicopathological features by subtype were observed (Table 2). A higher proportion of TNBCs were initially identified through patient self-detection (60.4%), whereas a higher proportion of luminal A tumors were not patient self-detected (63.5%; P <0.0001). Luminal A cancers more frequently exhibited clinicopathological features consistent with a less aggressive phenotype (namely, lower grade [74.9%], earlier stage [59.8%], smaller size [40.5%], and both p53 [96.5%] and Ki67 [82.3%] negativity) than non-luminal HER2-expressing and TNBC subtypes.
Table 1.
Sociodemographic characteristics of breast cancer patients, overall and by breast cancer subtype, N=629
| Characteristic | Overall (N = 629) | Luminal A (n = 430) | Luminal B (n = 70) | Non-luminal HER2-expressing (n = 38) | Triple-negative breast cancer (n = 91) | P-valuea |
|---|---|---|---|---|---|---|
|
| ||||||
| n (%) | n (%) | n (%) | n (%) | n (%) | ||
| Age at diagnosis (years) | 0.0197 | |||||
| <45 | 120 (19.1) | 68 (15.8) | 20 (28.6) | 10 (26.3) | 22 (24.2) | |
| ≥45 | 509 (80.9) | 362 (84.2) | 50 (71.4) | 28 (73.7) | 69 (75.8) | |
| Race | 0.0002 | |||||
| White | 322 (51.2) | 244 (56.7) | 29 (41.4) | 19 (50.0) | 30 (33.0) | |
| African American | 307 (48.8) | 186 (43.3) | 41 (58.6) | 19 (50.0) | 61 (67.0) | |
| Marital statusb | 0.5370 | |||||
| Married or living as married | 273 (43.4) | 188 (43.7) | 32 (45.7) | 14 (36.8) | 39 (42.9) | |
| Unmarried | 220 (35.0) | 144 (33.5) | 25 (35.7) | 19 (50.0) | 32 (35.2) | |
| Unknown | 136 (21.6) | 98 (22.8) | 13 (18.6) | 5 (13.2) | 20 (22.0) | |
| Education | 0.0425 | |||||
| Below college | 312 (49.6) | 209 (48.6) | 30 (42.9) | 21 (55.3) | 52 (57.1) | |
| College graduate and above | 240 (38.2) | 164 (38.1) | 36 (51.4) | 15 (39.5) | 25 (27.5) | |
| Unknown | 77 (12.2) | 57 (13.3) | 4 (5.7) | 2 (5.3) | 14 (15.4) | |
| Annual household incomec | 0.3840 | |||||
| <$70,000 | 220 (35.0) | 138 (32.1) | 26 (37.1) | 16 (42.1) | 40 (44.0) | |
| ≥$70,000 | 229 (36.4) | 165 (38.4) | 25 (35.7) | 13 (34.2) | 26 (28.6) | |
| Unknown | 180 (28.6) | 127 (29.5) | 19 (27.1) | 9 (23.7) | 25 (27.5) | |
| Primary health insurance | 0.2236 | |||||
| Non-private | 158 (25.1) | 118 (27.4) | 9 (12.9) | 8 (21.1) | 23 (25.3) | |
| Private | 433 (68.8) | 286 (66.5) | 56 (80.0) | 29 (76.3) | 62 (68.1) | |
| Unknown | 38 (6.0) | 26 (6.0) | 5 (7.1) | 1 (2.6) | 6 (6.6) | |
Abbreviations: ER, estrogen receptor; PR, progesterone receptor; HER2, human epidermal growth factor receptor 2.
P-values generated from chi-square or Fisher’s exact tests.
The unmarried group was composed of those who are single/never been married, separated, divorced, or widowed.
$70,000 is the median income among households in New Jersey and thus was used as the cut-point to dichotomize the income variable.
Table 2.
Reproductive, clinical, and tumor characteristics of breast cancer patients, overall and by breast cancer subtype
| Characteristic | Overall (N = 629) | Luminal A (n = 430) | Luminal B (n = 70) | Non-luminal HER2-expressing (n = 38) | Triple-negative breast cancer (n = 91) | P-valuea |
|---|---|---|---|---|---|---|
|
| ||||||
| n (%) | n (%) | n (%) | n (%) | n (%) | ||
| Reproductive and clinical characteristics | ||||||
| Menopausal status | 0.0831 | |||||
| Premenopausal | 220 (35.0) | 138 (32.1) | 33 (47.1) | 14 (36.8) | 35 (38.5) | |
| Postmenopausal | 409 (65.0) | 292 (67.9) | 37 (52.9) | 24 (63.2) | 56 (61.5) | |
| Age at menarche (years) | 0.7042 | |||||
| <12 | 144 (22.9) | 99 (23.0) | 12 (17.1) | 10 (26.3) | 23 (25.3) | |
| 12 – 13 | 246 (39.1) | 160 (37.2) | 32 (45.7) | 17 (44.7) | 37 (40.7) | |
| >13 | 97 (15.4) | 69 (16.0) | 13 (18.6) | 5 (13.2) | 10 (11.0) | |
| Unknown | 142 (22.6) | 102 (23.7) | 13 (18.6) | 6 (15.8) | 21 (23.1) | |
| Parity | 0.8557 | |||||
| Nulliparous | 104 (16.5) | 71 (16.5) | 11 (15.7) | 7 (18.4) | 15 (16.5) | |
| Parous | 385 (61.2) | 258 (60.0) | 47 (67.1) | 25 (65.8) | 55 (60.4) | |
| Unknown | 140 (22.3) | 101 (23.5) | 12 (17.1) | 6 (15.8) | 21 (23.1) | |
| Number of childrenb | 0.9681 | |||||
| 1 – 2 children | 242 (62.9) | 161 (62.4) | 31 (66.0) | 16 (64.0) | 34 (61.8) | |
| ≥3 children | 143 (37.1) | 97 (37.6) | 16 (34.0) | 9 (36.0) | 21 (38.2) | |
| History of breastfeedingb | 0.6232 | |||||
| No | 201 (52.2) | 133 (51.6) | 23 (48.9) | 12 (48.0) | 33 (60.0) | |
| Yes | 184 (47.8) | 125 (48.5) | 24 (51.1) | 13 (52.0) | 22 (40.0) | |
| History of oral contraceptive use | 0.7489 | |||||
| Never | 165 (26.2) | 115 (26.7) | 19 (27.1) | 11 (28.9) | 20 (22.0) | |
| Ever | 324 (51.5) | 214 (49.8) | 39 (55.7) | 21 (55.3) | 50 (54.9) | |
| Unknown | 140 (22.3) | 101 (23.5) | 12 (17.1) | 6 (15.8) | 21 (23.1) | |
| History of HRT use | 0.6899 | |||||
| Never | 387 (61.5) | 259 (60.2) | 49 (70.0) | 25 (65.8) | 54 (59.3) | |
| Ever | 100 (15.9) | 68 (15.8) | 9 (12.9) | 7 (18.4) | 16 (17.6) | |
| Unknown | 142 (22.6) | 103 (24.0) | 12 (17.1) | 6 (15.8) | 21 (23.1) | |
| Family history of breast cancer | 0.4919 | |||||
| Yes | 255 (40.5) | 181 (42.1) | 29 (41.4) | 12 (31.6) | 33 (36.3) | |
| No | 374 (59.5) | 249 (57.9) | 41 (58.6) | 26 (68.4) | 58 (63.7) | |
| BMI (kg/m2) | 0.1746 | |||||
| <25.0 | 205 (32.6) | 143 (33.3) | 25 (35.7) | 15 (39.5) | 22 (24.2) | |
| 25.0 – 29.99 | 181 (28.8) | 119 (27.7) | 18 (25.7) | 13 (34.2) | 31 (34.1) | |
| ≥30.0 | 237 (37.7) | 166 (38.6) | 26 (37.1) | 10 (26.3) | 35 (38.5) | |
| Unknown | 6 (1.0) | 2 (0.5) | 1 (1.4) | 0 (0.0) | 3 (3.3) | |
| Comorbid conditions | 0.1661 | |||||
| 0 | 144 (22.9) | 93 (21.6) | 23 (32.9) | 10 (26.3) | 18 (19.8) | |
| ≥1 | 485 (77.1) | 337 (78.4) | 47 (67.1) | 28 (73.7) | 73 (80.2) | |
| Diabetes | 0.4086 | |||||
| Yes | 83 (13.2) | 52 (12.1) | 11 (15.7) | 8 (21.1) | 12 (13.2) | |
| No | 546 (86.8) | 378 (87.9) | 59 (84.3) | 30 (78.9) | 79 (86.8) | |
| Hypertension | 0.4599 | |||||
| Yes | 287 (45.6) | 193 (44.9) | 31 (44.3) | 15 (39.5) | 48 (52.7) | |
| No | 342 (54.4) | 237 (55.1) | 39 (55.7) | 23 (60.5) | 43 (47.3) | |
| Osteoporosis/osteopenia | 0.0925 | |||||
| Yes | 174 (27.7) | 132 (30.7) | 15 (21.4) | 7 (18.4) | 20 (22.0) | |
| No | 455 (72.3) | 298 (69.3) | 55 (78.6) | 31 (81.6) | 71 (78.0) | |
| Arthritis | 0.3919 | |||||
| Yes | 145 (23.1) | 105 (24.4) | 15 (21.4) | 10 (26.3) | 15 (16.5) | |
| No | 484 (76.9) | 325 (75.6) | 55 (78.6) | 28 (73.7) | 76 (83.5) | |
| Tumor characteristics | ||||||
| Mode of detection | <.0001 | |||||
| Patient self-detecting | 270 (42.9) | 157 (36.5) | 36 (51.4) | 22 (57.9) | 55 (60.4) | |
| Patient not self-detecting | 359 (57.1) | 273 (63.5) | 34 (48.6) | 16 (42.1) | 36 (39.6) | |
| History of benign breast disease | 0.2025 | |||||
| No | 408 (64.9) | 270 (62.8) | 48 (68.6) | 23 (60.5) | 67 (73.6) | |
| Yes | 221 (35.1) | 160 (37.2) | 22 (31.4) | 15 (39.5) | 24 (26.4) | |
| Tumor grade | <.0001 | |||||
| Well/moderately differentiated | 380 (60.4) | 322 (74.9) | 34 (48.6) | 6 (15.8) | 18 (19.8) | |
| Poorly differentiated | 226 (35.9) | 93 (21.6) | 32 (45.7) | 29 (76.3) | 72 (79.1) | |
| Unknown | 23 (3.7) | 15 (3.5) | 4 (5.7) | 3 (7.9) | 1 (1.1) | |
| AJCC stage | 0.0087 | |||||
| Stage I | 343 (54.5) | 257 (59.8) | 31 (44.3) | 14 (36.8) | 41 (45.1) | |
| Stage II and above | 278 (44.2) | 167 (38.8) | 38 (54.3) | 24 (63.2) | 49 (53.8) | |
| Unknown | 8 (1.3) | 6 (1.4) | 1 (1.4) | 0 (0.0) | 1 (1.1) | |
| Tumor size (cm) | <0.0001 | |||||
| ≤1.0 | 215 (34.2) | 174 (40.5) | 18 (25.7) | 8 (21.1) | 15 (16.5) | |
| >1.0 | 414 (65.8) | 256 (59.5) | 52 (74.3) | 30 (78.9) | 76 (83.5) | |
| Lymph node status | 0.9316 | |||||
| Negative | 458 (72.8) | 318 (74.0) | 48 (68.6) | 28 (73.7) | 64 (70.3) | |
| Positive | 163 (25.9) | 106 (24.7) | 21 (30.0) | 10 (26.3) | 26 (28.6) | |
| Unknown | 8 (1.3) | 6 (1.4) | 1 (1.4) | 0 (0.0) | 1 (1.1) | |
| Histology | 0.0006 | |||||
| Invasive ductal | 519 (82.5) | 345 (80.2) | 60 (85.7) | 31 (81.6) | 83 (91.2) | |
| Invasive lobular | 66 (10.5) | 59 (13.7) | 5 (7.1) | 0 (0.0) | 2 (2.2) | |
| Other invasive | 44 (7.0) | 26 (6.0) | 5 (7.1) | 7 (18.4) | 6 (6.6) | |
| Lymphovascular invasion present | 0.0741 | |||||
| No | 408 (64.9) | 291 (67.7) | 41 (58.6) | 21 (55.3) | 55 (60.4) | |
| Yes | 123 (19.6) | 78 (18.1) | 21 (30.0) | 6 (15.8) | 18 (19.8) | |
| Indeterminate | 23 (3.7) | 12 (2.8) | 2 (2.9) | 4 (10.5) | 5 (5.5) | |
| Unknown | 75 (11.9) | 49 (11.4) | 6 (8.6) | 7 (18.4) | 13 (14.3) | |
| p53 status positive | 0.0001 | |||||
| No | 591 (94.0) | 415 (96.5) | 65 (92.9) | 34 (89.5) | 77 (84.6) | |
| Yes | 38 (6.0) | 15 (3.5) | 5 (7.1) | 4 (10.5) | 14 (15.4) | |
| Ki67 status positive | <.0001 | |||||
| No | 471 (74.9) | 354 (82.3) | 45 (64.3) | 24 (63.2) | 48 (52.7) | |
| Yes | 158 (25.1) | 76 (17.7) | 25 (35.7) | 14 (36.8) | 43 (47.3) | |
Abbreviations: ER, estrogen receptor; PR, progesterone receptor; HER2, human epidermal growth factor receptor 2; BMI, body mass index; HRT, hormone replacement therapy; AJCC, American Joint Committee on Cancer.
P-values generated from chi-square or Fisher’s exact tests.
Number of children and history of breastfeeding were among parous women only (N = 385).
In univariate multinomial logistic regression models where the luminal A subtype was the referent group (Table 3), women with the luminal B subtype were more likely to be younger at diagnosis (<45 years; OR 2.1, 95% CI 1.2–3.8), African American (OR 1.9, 95% CI 1.1–3.1), and premenopausal (OR 1.9, 95% CI 1.1–3.1) and less likely to have non-private health insurance (OR 0.4, 95% CI 0.2–0.08) and ≥1 comorbid condition (OR 0.6, 95% CI 0.3–1.0) relative to women with luminal A tumors. Women with luminal B BC were also more likely to have tumors that were self-detected (OR 1.8, 95% CI 1.1–3.1), poorly differentiated (OR 3.3, 95% CI 1.9–5.6), higher stage (OR 1.9, 95% CI 1.1–3.2), larger (OR 2.0, 95% CI 1.1–3.5), Ki67 positive (OR 2.6, 95% CI 1.5–4.5), and had lymphovascular invasion (OR 1.9, 1.1–3.4) compared to luminal A tumors. No sociodemographic, clinical or reproductive factors were associated with the non-luminal HER2-expressing BC subtype. Women with the non-luminal HER2-expressing subtype were also more likely to have tumors that were self-detected (OR 2.4, 95% CI 1.2–4.7), poorly differentiated (OR 16.7, 95% CI 6.7–41.5), higher stage (OR 2.6, 95% CI 1.3–5.2), larger (OR 2.5, 95% CI 1.1–5.7), p53 positive (OR 3.3, 95% CI 1.0–10.4), and Ki67 positive (OR 2.7, 95% CI 1.33–5.5) compared to the luminal A subtype. Compared to the luminal A subtype, women with TNBCs were more likely to be younger at diagnosis (OR 1.7, 95% CI 1.0–2.9), African American (OR 2.7, 95% CI 1.7–4.3), and of lower SES (less than college educated: OR 1.6, 95% CI 1.0–2.7 and income below the state median of $70,000: OR 1.8, 95% CI 1.1–3.2). Additionally, women with TNBCs were more likely to have tumors that were self-detected (OR 2.7, 95% CI 1.7–4.2), poorly differentiated (OR 13.8, 95% CI 7.9–24.4), higher stage (OR 1.8, 95% CI 1.2–2.9), larger (OR 3.4, 95% CI 1.9–6.2), p53 positive (OR 5.0, 95% CI 2.3–10.8), and Ki67 positive (OR 2.7, 95% CI 1.3–5.5); and were less likely to have a history of benign breast disease (OR 0.6, 95% CI 0.4–1.0).
Table 3.
Univariate multinomial logistic regression analyses of the associations between sociodemographic, reproductive, clinical, and tumor characteristics, and breast cancer subtype
| Characteristic | Luminal B (n = 70) | Non-luminal HER2-expressing (n = 38) | Triple-negative breast cancer (n = 91) |
|---|---|---|---|
|
| |||
| OR (95% CI)a | OR (95% CI)a | OR (95% CI)a | |
| Sociodemographic characteristics | |||
| Age at diagnosis (years) | |||
| <45 | 2.1 (1.2, 3.8) | 1.9 (0.9, 4.1) | 1.7 (1.0, 2.9) |
| ≥45 | 1.0 (Referent) | 1.0 (Referent) | 1.0 (Referent) |
| Race | |||
| White | 1.0 (Referent) | 1.0 (Referent) | 1.0 (Referent) |
| African American | 1.9 (1.1, 3.1) | 1.3 (0.7, 2.5) | 2.7 (1.7, 4.3) |
| Marital statusb | |||
| Married or living as married | 1.0 (Referent) | 1.0 (Referent) | 1.0 (Referent) |
| Unmarried | 1.0 (0.6, 1.8) | 1.8 (0.9, 3.7) | 1.1 (0.6, 1.8) |
| Unknown | 0.8 (0.4, 1.6) | 0.7 (0.2, 2.0) | 1.0 (0.5, 1.8) |
| Education | |||
| Below college | 0.7 (0.4, 1.1) | 1.1 (0.5, 2.2) | 1.6 (1.0, 2.7) |
| College graduate and above | 1.0 (Referent) | 1.0 (Referent) | 1.0 (Referent) |
| Unknown | 0.3 (0.1, 0.9) | 0.4 (0.1, 1.7) | 1.6 (0.8, 3.3) |
| Annual household incomec | |||
| <$70,000 | 1.2 (0.7, 2.3) | 1.5 (0.7, 3.2) | 1.8 (1.1, 3.2) |
| ≥$70,000 | 1.0 (Referent) | 1.0 (Referent) | 1.0 (Referent) |
| Unknown | 1.0 (0.5, 1.9) | 0.9 (0.4, 2.2) | 1.2 (0.7, 2.3) |
| Primary health insurance | |||
| Non-private | 0.4 (0.2, 0.8) | 0.7 (0.3, 1.5) | 0.9 (0.5, 1.5) |
| Private | 1.0 (Referent) | 1.0 (Referent) | 1.0 (Referent) |
| Unknown | 1.0 (0.4, 2.7) | 0.4 (0.1, 2.9) | 1.1 (0.4, 2.7) |
| Reproductive and clinical characteristics | |||
| Menopausal status | |||
| Pre | 1.9 (1.1, 3.1) | 1.2 (0.6, 2.5) | 1.3 (0.8, 2.1) |
| Post | 1.0 (Referent) | 1.0 (Referent) | 1.0 (Referent) |
| Age at menarche (years) | |||
| <12 | 0.6 (0.3, 1.5) | 1.4 (0.5, 4.3) | 1.6 (0.7, 3.6) |
| 12 – 13 | 1.1 (0.5, 2.1) | 1.5 (0.5, 4.1) | 1.6 (0.8, 3.4) |
| >13 | 1.0 (Referent) | 1.0 (Referent) | 1.0 (Referent) |
| Unknown | 0.7 (0.3, 1.5) | 0.8 (0.2, 2.8) | 1.4 (0.6, 3.2) |
| Parity | |||
| Nulliparous | 1.0 (Referent) | 1.0 (Referent) | 1.0 (Referent) |
| Parous | 1.2 (0.6, 2.4) | 1.0 (0.4, 2.4) | 1.0 (0.5, 1.9) |
| Unknown | 0.8 (0.3, 1.8) | 0.6 (0.2, 1.9) | 1.0 (0.5, 2.0) |
| Parityd | |||
| 1 – 2 children | 1.0 (Referent) | 1.0 (Referent) | 1.0 (Referent) |
| ≥3 children | 0.9 (0.4, 1.6) | 0.9 (0.4, 2.2) | 1.0 (0.6, 1.9) |
| History of breastfeedingd | |||
| No | 1.0 (Referent) | 1.0 (Referent) | 1.0 (Referent) |
| Yes | 1.1 (0.6, 2.1) | 1.2 (0.5, 2.6) | 0.7 (0.4, 1.3) |
| History of oral contraceptive use | |||
| Never | 1.0 (Referent) | 1.0 (Referent) | 1.0 (Referent) |
| Ever | 1.1 (0.6, 2.0) | 1.0 (0.5, 2.2) | 1.3 (0.8, 2.4) |
| Unknown | 0.7 (0.3, 1.6) | 0.6 (0.2, 1.7) | 1.2 (0.6, 2.3) |
| History of HRT use | |||
| Never | 1.0 (Referent) | 1.0 (Referent) | 1.0 (Referent) |
| Ever | 0.7 (0.3, 1.5) | 1.1 (0.4, 2.6) | 1.1 (0.6, 2.1) |
| Unknown | 0.6 (0.3, 1.2) | 0.6 (0.2, 1.5) | 1.0 (0.6, 1.7) |
| Family history of breast cancer | |||
| No | 1.0 (Referent) | 1.0 (Referent) | 1.0 (Referent) |
| Yes | 1.0 (0.6, 1.6) | 0.6 (0.3, 1.3) | 0.8 (0.5, 1.3) |
| BMI (kg/m2) | |||
| <25.0 | 1.0 (Referent) | 1.0 (Referent) | 1.0 (Referent) |
| 25.0 – 29.99 | 0.9 (0.5, 1.7) | 1.0 (0.5, 2.3) | 1.7 (0.9, 3.1) |
| ≥30.0 | 0.9 (0.5, 1.6) | 0.6 (0.3, 1.3) | 1.4 (0.8, 2.4) |
| Unknown | |||
| Comorbid conditions | |||
| 0 | 1.0 (Referent) | 1.0 (Referent) | 1.0 (Referent) |
| ≥1 | 0.6 (0.3, 1.0) | 0.8 (0.4, 1.6) | 1.1 (0.6, 2.0) |
| Diabetes | |||
| Yes | 1.4 (0.7, 2.7) | 1.9 (0.8, 4.5) | 1.1 (0.6, 2.2) |
| No | 1.0 (Referent) | 1.0 (Referent) | 1.0 (Referent) |
| Hypertension | |||
| Yes | 1.0 (0.6, 1.6) | 0.8 (0.4, 1.6) | 1.4 (0.9, 2.2) |
| No | 1.0 (Referent) | 1.0 (Referent) | 1.0 (Referent) |
| Osteoporosis/osteopenia | |||
| Yes | 0.6 (0.3, 1.1) | 0.5 (0.2, 1.2) | 0.6 (0.4, 1.1) |
| No | 1.0 (Referent) | 1.0 (Referent) | 1.0 (Referent) |
| Arthritis | |||
| Yes | 0.8 (0.5, 1.6) | 1.1 (0.5, 2.4) | 0.6 (0.3, 1.1) |
| No | 1.0 (Referent) | 1.0 (Referent) | 1.0 (Referent) |
| Tumor characteristics | |||
| Mode of detection | |||
| Patient self-detecting | 1.8 (1.1, 3.1) | 2.4 (1.2, 4.7) | 2.7 (1.7, 4.2) |
| Patient not self-detecting | 1.0 (Referent) | 1.0 (Referent) | 1.0 (Referent) |
| History of benign breast disease | |||
| No | 1.0 (Referent) | 1.0 (Referent) | 1.0 (Referent) |
| Yes | 0.8 (0.5, 1.3) | 1.1 (0.6, 2.2) | 0.6 (0.4, 1.0) |
| Tumor grade | |||
| Well/moderately differentiated | 1.0 (Referent) | 1.0 (Referent) | 1.0 (Referent) |
| Poorly differentiated | 3.3 (1.9, 5.6) | 16.7 (6.7, 41.5) | 13.8 (7.9, 24.4) |
| Unknown | -- | -- | -- |
| AJCC stage | |||
| Stage I | 1.0 (Referent) | 1.0 (Referent) | 1.0 (Referent) |
| Stage II and above | 1.9 (1.1, 3.2) | 2.6 (1.3, 5.2) | 1.8 (1.2, 2.9) |
| Unknown | -- | -- | -- |
| Tumor size (cm) | |||
| ≤1.0 | 1.0 (Referent) | 1.0 (Referent) | 1.0 (Referent) |
| >1.0 | 2.0 (1.1, 3.5) | 2.5 (1.1, 5.7) | 3.4 (1.9, 6.2) |
| Lymph node status | |||
| Negative | 1.0 (Referent) | 1.0 (Referent) | 1.0 (Referent) |
| Positive | 1.3 (0.8, 2.3) | 1.1 (0.5, 2.3) | 1.2 (0.7, 2.0) |
| Unknown | -- | -- | -- |
| Lymphovascular invasion present | |||
| No | 1.0 (Referent) | 1.0 (Referent) | 1.0 (Referent) |
| Yes | 1.9 (1.1, 3.4) | 0.9 (0.4, 2.4) | 1.2 (0.7, 2.1) |
| Unknown | 0.9 (0.3, 2.1) | 1.7 (0.7, 4.2) | 1.3 (0.7, 2.6) |
| p53 status positive | |||
| No | 1.0 (Referent) | 1.0 (Referent) | 1.0 (Referent) |
| Yes | 2.1 (0.7, 6.1) | 3.3 (1.0, 10.4) | 5.0 (2.3, 10.8) |
| Ki67 status positive | |||
| No | 1.0 (Referent) | 1.0 (Referent) | 1.0 (Referent) |
| Yes | 2.6 (1.5, 4.5) | 2.7 (1.3, 5.5) | 4.2 (2.6, 6.7) |
Abbreviations: HER2, human epidermal growth factor receptor 2; OR, odds ratio; CI, confidence interval; BMI, body mass index; HRT, Hormone Replacement Therapy; AJCC, American Joint Committee on Cancer.
ORs and 95% CIs were generated from univariate multinomial logistic regression models with the luminal A subtype as the referent group.
The unmarried group was composed of those who were single/never been married, separated, divorced, or widowed.
$70,000 is the median income among households in New Jersey and thus was used as the cut-point to dichotomize the income variable.
Number of children and history of breastfeeding were among parous women only (N = 385).
In multivariable multinomial logistic regression models (adjusted for all covariates in the model) where the luminal A subtype was the referent group (Table 4), women with luminal B cancers were less likely to have less than a college education (OR 0.5, 95% CI 0.3–1.0) and were more likely to be younger at diagnosis (OR 1.8, 95% CI 1.0–3.4), to have tumors that were poorly differentiated (OR 2.6, 95% CI 1.4–4.7), larger (OR 1.9, 95% CI 1.0–3.6), and Ki67 positive (OR 2.3, 95% CI 1.2–4.4). Compared to women with luminal A cancers, those with the non-luminal HER2-expressing subtype were more likely to have poorly differentiated tumors (OR 14.5, 95% CI 5.3–39.7), while those with TNBCs were more likely to be African American (OR 1.9, 95% CI 1.0–3.4), and to have tumors that were poorly differentiated (OR 9.7, 95% CI 5.1–18.4), larger (OR 2.2, 95% CI 1.0–4.8), and Ki67 positive (OR 2.9, 95% CI 1.6–5.2).
Table 4.
Multivariable multinomial logistic regression analyses of the associations between sociodemographic and clinicopathological characteristics, and breast cancer subtype
| Characteristic | Luminal B (n = 70) | Non-luminal HER2-expressing (n = 38) | Triple-negative breast cancer (n = 91) | P-value for heterogeneity of ORs |
|---|---|---|---|---|
|
| ||||
| OR (95% CI)a | OR (95% CI)a | OR (95% CI)a | ||
| Age at diagnosis (years) | 0.9351 | |||
| <45 | 1.8 (1.0, 3.4) | 1.6 (0.6, 3.7) | 1.7 (0.9, 3.2) | |
| ≥45 | 1.0 (Referent) | 1.0 (Referent) | 1.0 (Referent) | |
| Race | 0.6209 | |||
| White | 1.0 (Referent) | 1.0 (Referent) | 1.0 (Referent) | |
| African American | 1.6 (0.9, 2.8) | 1.2 (0.6, 2.7) | 1.9 (1.0, 3.4) | |
| Education | 0.0401 | |||
| Below college | 0.5 (0.3, 1.0) | 1.1 (0.5, 2.4) | 1.3 (0.7, 2.5) | |
| College graduate and above | 1.0 (Referent) | 1.0 (Referent) | 1.0 (Referent) | |
| Tumor grade | 0.0005 | |||
| Well/moderately differentiated | 1.0 (Referent) | 1.0 (Referent) | 1.0 (Referent) | |
| Poorly differentiated | 2.6 (1.5, 4.7) | 14.5 (5.3, 39.7) | 9.7 (5.1, 18.4) | |
| Tumor size (cm) | 0.8663 | |||
| ≤1.0 | 1.0 (Referent) | 1.0 (Referent) | 1.0 (Referent) | |
| >1.0 | 1.9 (1.0, 3.6) | 2.5 (0.8, 7.9) | 2.2 (1.0, 4.8) | |
| Ki67 status positive | 0.6065 | |||
| No | 1.0 (Referent) | 1.0 (Referent) | 1.0 (Referent) | |
| Yes | 2.1 (1.1, 4.0) | 2.0 (0.9, 4.5) | 2.9 (1.6, 5.2) | |
Abbreviations: HER2, Human Epidermal Growth Factor Receptor 2; OR, Odds Ratio; CI, Confidence Interval.
ORs and 95% CIs were generated from multivariable multinomial logistic regression models (mutually adjusting for all covariates in the model) with the luminal A subtype as the referent group.
Discussion
Findings from this study support associations between sociodemographic characteristics and clinicopathological breast tumor features indicative of more aggressive phenotypes among luminal B, non-luminal HER2-expressing, and TNBC subtypes as compared to luminal A tumors, which may increase the odds of patient self-detection. In particular, we observed that women with luminal B tumors were more likely to be younger age at diagnosis and to have tumors with higher grade, were larger, and Ki67 positive. Women with the non-luminal HER2-expressing subtype were more likely to have higher grade tumors. Women with TNBCs were more likely to be African American and to have tumors that were higher grade, larger, and Ki67 positive. This study highlights some similarities between non-luminal HER2-expressing tumors and TNBCs, in terms of prevalence of more aggressive clinicopathological features and the possibility that these tumors are more frequently self-detected (i.e., before screening). Furthermore, these data suggest that, as observed among TNBCs, younger age, African American race, and lower SES may also be predictors of the non-luminal HER2-expressing subtype.
These findings suggest differences in tumor biology by BC subtype and lend support to studies demonstrating that BC outcomes may vary markedly by clinicopathological features [2,24], warranting further exploration of etiological differences, risk factors and prognostic indicators among subtypes so as to address some of the observed disparities in BC outcomes. While many epidemiologic studies have focused primarily on the TNBC subtype as a result of its more (and maybe even most) aggressive nature and limited treatment options, our study demonstrates that HER2+ tumors overall (i.e., both luminal B and non-luminal HER2-expressing subtypes) may similarly be diagnosed more frequently among younger women belonging to racial/ethnic minority groups, and exhibit significantly more aggressive phenotypes than the luminal A subtype. Non-luminal HER2-expressing tumors particularly, while representing a very small proportion (approximately 6%) of breast tumors in this and other studies [12,11,9,14,10,5], were significantly associated with poor differentiation. This finding is consistent with previous studies [10,9,5,11]. The non-luminal HER2-expressing subtype was also associated with Ki67 positivity, a factor shown to be associated with higher grade [28]. Evidence also shows that Ki67 expression is highest among TNBCs, followed by non-luminal HER2-expressing and luminal B subtypes, as well as with poorer prognosis among early stage BC cases, specifically increased risk of relapse and mortality [29,30]. Although we observed no significant association between Ki67 positivity and the non-luminal HER2-expressing subtype in multivariable models, a statistically significant positive association was evident for the luminal B and TNBC subtypes in the present study. Studies [31–34] have suggested that Ki67 positivity may reliably predict prognosis in ER-positive tumors, whereas there are little data to support this association among HER2-positive and ER-negative tumors. Non-luminal HER2-expressing and TNBC subtypes were also associated with p53 positivity in this study. Although these associations were attenuated in the multivariable models, these data would be consistent with recent studies showing that p53 IHC expression was associated with more aggressive tumor characteristics, namely higher grade, ER- and PR-negativity, and poorer prognosis among African American women and those of lower SES [35,36]. It may be that Ki67 and p53 both contribute to the negative prognostic effect among HER2-expressing and TNBC subtypes; additional studies examining the clinical utility of these markers as well as the most clinically relevant cut-off values for these markers are needed to clarify these relationships.
Notably, findings from this study suggested that patient self-detection was highest among women with TNBCs, non-luminal HER2-expressing tumors, and luminal B tumors. We hypothesize that there are differences in tumor biology when comparing BC subtypes, which potentially translate into differences in the likelihood of patient self-detection. Specifically, larger tumor size and more noticeable symptoms associated with the more aggressive subtypes may inherently lead to more frequently self-detected interval tumors (i.e., those arising within the 12 months following a normal screening mammogram) [37,38] among TNBCs and HER2-expressing subtypes, which further exacerbate BC outcomes disparities. Patient self-detection was no longer significantly associated with BC subtype in multivariate analysis (which included adjustment for SES factors, race and education), suggesting that the associations with mode of breast tumor detection may have been confounded by SES [39]. Recent data has shown that a large proportion (approximately 60%) of BC cases in the U.S. is discovered through self-detection, particularly among low-SES women [40,39]. In our study, 42.9% of BC patients reported self-detection and HER2-expressing and TNBC subtypes were 2–3 times more likely to be self-detected than the luminal A subtype. Previous evidence supports the association between mode of detection and prognosis, indicating that BC self-detection is associated with significant disadvantage in survival outcomes [41–48]. It is plausible that tumors exhibiting aggressive features would be more symptomatic than those with less aggressive features, and therefore would have a tendency to be perceived by the patient before she seeks care from a medical professional. Additional research, particularly examining these associations among diverse samples of women in the U.S., is needed to confirm these associations.
There were some limitations of this study that should be considered in the interpretation of our findings. First, our use of hormone receptor expression by IHC rather than gene expression data for classification of BC subtypes was an obvious limitation, although one could argue that gene expression has its limitations as well. Several studies have demonstrated overall imperfect but fairly good concordance between IHC and gene expression classification schemes for the major intrinsic subtypes, supporting clinical utility of these biomarkers [3,9]. Furthermore, the distributions of the BC subtypes reported herein were similar as those observed in other studies [3,4,11,8,1,2,5]. An additional consideration was that given the sample size, there were relatively small samples of luminal B, non-luminal HER2-expressing, and TNBC subtypes (n = 70, 38, and 91, respectively), potentially resulting in limited statistical power to examine subtype-stratified associations. Nonetheless, we observed several statistically significant findings, which would likely prove stronger in larger studies. Despite these considerations, the population-based study design and our use of detailed data, collected through medical record and pathology report abstraction, from all major medical facilities in the target area, as well as data collected through interviewer-administered questionnaires, were important strengths. Additionally, our inclusion of SES, clinical, and clinicopathological tumor characteristics in the examination of predictors of BC subtypes also strengthened this study.
The findings of this study support associations between sociodemographic and clinicopathological features of tumors, and BC subtypes based on biomarker status, specifically showing that the more aggressive tumor phenotypes were more likely to occur among women who were younger at diagnosis, African American, and/or of lower SES. This study also suggests that these BC subtypes commonly exhibit Ki67 and p53 positivity, which may be important clinical markers for understanding differences in prognosis. Additionally, in light of the observation that larger tumors and those exhibiting more aggressive clinicopathological features are associated with BC self-detection, it may be necessary to enhance efforts to extend screening and minimize excess mortality, particularly among younger, racial/ethnic minority, and lower SES populations who would substantially benefit from earlier clinical diagnosis.
Acknowledgments
This work was supported by grants from the National Cancer Institute (R01CA133264, R01 CA100598, P01 CA151135, and Cancer Center Support Grants P30 CA072720 [Rutgers Cancer Institute of New Jersey] and P30 CA016056 [Roswell Park Cancer Institute]), the American Cancer Society (RSGT-07-291-01-CPHPS), the Susan G. Komen Breast Cancer Foundation (POP131006), the US Army Medical Research and Material Command (DAMD-17-01-1-0334), the Breast Cancer Research Foundation, a gift from the Philip L. Hubbell family, and a gift from the Buckingham Foundation. We sincerely thank our research personnel at the Rutgers Cancer Institute of New Jersey, Roswell Park Cancer Institute, Rutgers School of Public Health, and the New Jersey State Cancer Registry, as well as our African American breast cancer advocates and community partners, and all the women who generously donated their time and participation to the study.
List of abbreviations
- BC
breast cancer
- BCTDS
Breast Cancer Treatment Disparity Study
- EGFR
epidermal growth factor receptor
- ER
estrogen receptor
- HER2
human epidermal growth factor receptor 2
- IHC
immunohistochemistry
- NJ
New Jersey
- NJSCR
New Jersey State Cancer Registry
- PR
progesterone receptor
- SEER
Surveillance, Epidemiology, and End Results
- SES
socioeconomic status
- TNBC
triple-negative breast cancer
- WCHS
Women’s Circle of Health Study
Footnotes
Conflict of Interest: The authors declare that they have no conflict of interest.
Authors’ contributions: All authors made substantive intellectual contributions to this study. AL, SC, EB, KH, YL, CA, and KD 1) made substantial contributions to conception and design, or acquisition of data, and/or analysis and interpretation of data; 2) were involved in drafting the manuscript and revising it critically for intellectual content; 3) gave final approval of the final version; and 4) agree to be accountable for all aspects of the work.
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