Abstract
Background
Small‐sized primary tumor does not always indicate a better prognosis. We hypothesized that very small primary breast tumors with extensive lymph node (LN) metastases represented an aggressive biologic behavior in stage IV disease.
Materials and Methods
Data between 2010 and 2015 were retrieved retrospectively from the Surveillance, Epidemiology, and End Results database with inclusion criteria of female sex, unilateral, metastatic, and T1/2 invasive ductal carcinoma. Primary study variables included T stage, N stage, grade, metastatic sites, number of involved sites, estrogen receptor status, progesterone receptor status, and human epidermal growth factor receptor 2 status. Kaplan‐Meier and adjusted Cox proportional hazards models with interaction terms were used. One‐, 2‐ and 3‐year breast cancer‐specific mortality (BCSM) was examined according to tumor size.
Results
We identified 5,340 eligible patients with breast cancer. In multivariate analysis, race, age, grade, molecular subtype, surgery, brain metastases, and liver metastases were found to be independently associated with BCSM. For T1 tumors, the N0, N1, and N2+ groups had the same BCSM. In tumors smaller than 50 mm, the 1‐, 2‐, and 3‐year BCSM did not decline with the decrease of tumor size. For triple‐negative breast cancers (TNBCs), the T1a/T1bN2+ group had significantly worse BCSM than any other group did.
Conclusion
Patients with stage IV cancer with small‐sized tumors may have BCSM as high as those with larger tumors. In TNBCs, very small tumors with severe LN involvement are associated with the worst BCSM. Continued efforts are needed to further investigate Ta1/T1bN2 + M1 TNBCs and individualize the treatment for affected patients.
Implications for Practice
This study revealed that for stage IV breast cancer, smaller primary tumors were not always associated with better breast cancer‐specific mortality. This study illustrated that very small triple‐negative breast cancers (TNBCs) with extensive regional lymph node involvement may be a surrogate for biologically aggressive disease. Because of poor prognosis of T1a/T1bN2+ TNBCs, there might be an urgent need of more individualized treatment for affected patients. Future correlative studies ought to focus on the genetic and molecular differences in Ta1/T1bN2+ TNBCs that contribute to the biological behavior. Clarification of the regulation mechanism of very small‐sized primary TNBCs with metastatic outgrowth in nodes and distant sites will play an integral role in developing targeted therapies.
Keywords: Breast cancer, Stage IV, Tumor size, Breast cancer‐specific mortality
Short abstract
Clinical outcomes are highly variable in patients with metastatic breast cancer. This article analyzes breast cancer‐specific mortality according to tumor size, stratified by lymph node metastasis in stage IV breast cancer, using the SEER cancer database.
Introduction
Stage IV breast cancer can be recognized in approximately 6% of all breast cancers at initial diagnosis [1]. These breast cancers represent, unfortunately, a heterogeneous disease. Despite advances in the biomedical research of cancer treatment, up to 70%–80% of patients with stage IV breast cancer die of cancer‐specific causes in 5 years, demonstrating a disproportionally higher mortality compared with nonmetastatic breast cancer [2]. Contrary to popular belief, approximately 10% of women with de novo metastatic (stage IV) breast cancer can survive for 10 years or longer [3]. In patients with metastatic breast cancer, the clinical outcomes are therefore highly variable and depend on the patients’ individual characteristics, metastatic pattern, tumor burden, and the underlying tumor biology [4, 5, 6]. Local tumor size, regional lymph node (LN) status, and distant metastasis are the top three prognostic determinants that constitute the staging system suggested by American Joint Committee on Cancer [7]. Although little attention has been paid to the prognostic impact of local tumor size on stage IV disease, a commonly accepted theory states that as a tumor grows, the cells within the tumor acquire the capability to spread to, survive in, and proliferate within the regional LNs and other distant sites [8, 9]. Meanwhile, within any LN grouping, the growth of tumor size worsens the prognosis [10]. Consequently, many clinicians may underestimate the risk when patients have a smaller tumor with LN. Biologic characteristics might actually be more aggressive in cases of small tumors with LN metastases.
The process termed “self‐seeding” suggests that metastatic cells are able to return to and repopulate the primary tumor [11]. The growth and metastases of the primary tumor are essentially the same process; as a matter of fact, tumors may metastasize long before they can be detected clinically [12]. Moreover, there is evidence that a very small tumor size is a surrogate for a biologically aggressive disease in cases with extensive LN involvement [13]. On the contrary, tumors that fail to metastasize to the regional LNs, even at a late stage (e.g., a T3N0 tumor), may reflect a more biologically indolent phenotype [14]. Therefore, the effect of tumor size on the clinical outcome is variable, and stage IV breast cancers with small‐sized primary tumors may possess distinct biological behaviors. To date, some pieces of impressive evidence [13, 14] have illustrated the indication of tumor size–nodal interaction in nonmetastatic breast cancer, but the impact of size–nodal interaction in the context of stage IV breast cancer is still unclear. A better understanding of the mechanism of tumor size in stage IV disease would provide a significant reference for assessing prognosis, selecting appropriate treatments, determining disease monitoring measures, and leading the direction of research.
In view of the current research status, we hypothesized that very small primary breast tumors with extensive LN metastases may represent a more aggressive biologic behavior in stage IV disease than what we thought originally. We analyzed the breast cancer‐specific mortality (BCSM) according to the tumor size stratified by LN metastasis and further explored the tumor size–nodal interaction in four molecular subgroups. To collect sufficient stage IV cases with small tumors, the Surveillance, Epidemiology, and End Results (SEER) cancer database of the National Cancer Institute was used in this study.
Materials and Methods
Patients
Data were obtained from the SEER database of the National Cancer Institute, which is an open access resource for cancer‐based epidemiologic and survival analyses, consisting of a collection of 18 high‐quality population‐based cancer registries with very high estimated completeness of reporting. All data were publicly available, deidentified, and exempted from Institutional Review Board review.
The SEER*Stat software from the National Cancer Institute (Surveillance Research Program, National Cancer Institute SEER*Stat software, version 8.15, www.seer.cancer.gov/seerstat) was used to identify eligible patients based on the following inclusion criteria: female sex, pathological diagnosis of invasive ductal carcinoma, unilateral breast cancer, stage T1–T2, one primary site only, stage IV breast cancer, and known age at diagnosis. The information regarding the human epidermal growth factor receptor 2 (HER2/neu) status is only available in the SEER database from 2010, and patients diagnosed with breast cancer after 2015 were excluded to ensure an adequate follow‐up time. As a result, our study only included the cases diagnosed between 2010 and 2015. The pathologic diagnosis was based on the primary site according to the International Classification of Disease for Oncology, Third Edition. The morphology code for infiltrating duct carcinoma was 8500. SEER does not contain any information of chemotherapy and endocrine therapy; hence, such data were not evaluated. In the SEER database, hormone receptor positive/HER2−, hormone receptor positive/HER2+, hormone receptor negative/HER2+, and hormone receptor negative/HER2− were defined as luminal A, luminal B, HER2 amplified, and triple‐negative breast cancer (TNBC) subtype, respectively. The tumor size and lymph node status were analyzed by joint T and N stages (T1a/T1bN0, T1c/N0, T2N0, T1a/1bN1, T1cN1, T2N1, T1a/T1bN2+, T1cN2+, and T2N2+). Patients with stage T1a and T1b cancer were combined in order to formulate a sufficiently big sample. BCSM was targeted as the primary study outcome of the SEER data, which was calculated from the date of diagnosis to the date of breast cancer‐specific death. The causes of death were categorized as either breast cancer related or non–breast cancer related. Patients who died of non–breast cancer related causes were censored regarding the date of death. This study was carried out based on the public data released by the SEER database, and permission to access the research data files was acquired with the reference number 17297‐Nov2018. Before implementing any research work, approval from the Ethical Committee Review Board of Fudan University Shanghai Cancer Center was obtained.
Statistical Analysis
Patient characteristics were compared by means of independent t tests for continuous variables and the chi‐square or Fisher's exact test for categorical variables. Univariate and multivariate Cox regression models were established to analyze the risk factors for BCSM, and the adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated. Kaplan‐Meier curves, with the corresponding results of log‐rank tests, were constructed for breast cancer‐specific survival. The 1‐, 2‐, and 3‐year BCSMs were obtained and followed by smoothing based on the CI using the Lowess method. All statistical analyses were performed in SPSS (version 19.0; SPSS Company), SAS version 9.4 (SAS Institute, Cary, NC), and R version 3.1.0 (Vienna, Austria; http://www.R-project.org). All tests were two‐sided, and p < .05 was deemed statistically significant.
Results
Clinicopathologic Patient Parameters
A total of 5,340 eligible female patients were enrolled. The median follow‐up duration was 24.0 (0–83) months. By the end of the follow‐up period, 1,933 patients (37.3%) died of breast cancer and 1,148 (21.5%) died of another causes. Table 1 summarizes the sample demographics according to T stage. All patients with breast cancer in the cohort had a primary tumor with a recorded size of between 1 and 20 mm. As shown in Table 1, 7.6% (n = 408) of the patients were T1a/T1b, 21.5% (n = 1,150) were T1c, and 70.8% (n = 3,782) were T2. N stage, grade, HER2 status, subtype, brain metastases, lung metastases, cause of death, and surgery treatment were significantly different in terms of tumor size. Compared with the patients with T1c and T2 cancer, the patients with T1a/T1b cancer presented with fewer LN metastases (more N0 stage: 54.7% vs. 44.3% vs. 28.8%; p < .0001), less advanced disease (less grade III and undifferentiated: 32.4% vs. 38.7% vs. 47.7%; p < .0001), less HER2 amplification status (HER2 amplification: 23.5% vs. 27.1% vs. 28.7%; p = .0287), fewer brain metastases (88.2% vs. 90.7% vs. 92.5%; p = .0052), and fewer lung metastases (67.4% vs. 75.2% vs. 70%; p = .0048). Furthermore, patients with T1a/T1b cancer were more frequently treated with local regional surgery (65.4% vs. 60.3% vs. 58%; p = .0288), and the death of patients with T1a/T1b cancer was less likely to be caused by breast cancer (27.2% vs. 30.9% vs. 40.4%; p < .0001).
Table 1.
Baseline characteristics according to T stage
| Characteristic | Total (n = 5,340), n (%) | T1a/T1b (n = 408), n (%) | T1c (n = 1,150), n (%) | T2 (n = 3,782), n (%) | p value a |
|---|---|---|---|---|---|
| Year of diagnosis | .8161 | ||||
| 2010–2012 | 2,556 (47.9) | 194 (47.5) | 560 (48.7) | 1,802 (47.6) | |
| 2013–2015 | 2,784 (52.1) | 214 (52.5) | 590 (51.3) | 1,980 (52.4) | |
| Race | .2354 | ||||
| White | 4,166 (78.0) | 312 (76.5) | 920 (80.0) | 2,934 (77.6) | |
| Black | 774 (14.5) | 68 (16.7) | 161 (14.0) | 545 (14.4) | |
| Other b | 391 (7.3) | 28 (6.9) | 67 (5.8) | 296 (7.8) | |
| Unknown | 9 (0.2) | 0 (0.0) | 2 (0.2) | 7 (0.2) | |
| Age, years | .0934 | ||||
| ≤35 | 434 (8.1) | 33 (8.1) | 79 (6.9) | 322 (8.5) | |
| 36–65 | 2,848 (53.3) | 205 (50.2) | 601 (52.3) | 2,042 (54.0) | |
| >65 | 2,058 (38.5) | 170 (41.7) | 470 (40.9) | 1,418 (37.5) | |
| N stage | <.0001 | ||||
| N0 | 1,822 (34.1) | 223 (54.7) | 510 (44.3) | 1,089 (28.8) | |
| N1 | 2,426 (45.4) | 141 (34.6) | 463 (40.3) | 1,822 (48.2) | |
| N2+ | 1,092 (20.4) | 44 (10.8) | 177 (15.4) | 871 (23.0) | |
| Grade | <.0001 | ||||
| I | 382 (7.2) | 67 (16.4) | 99 (8.6) | 216 (5.7) | |
| II | 2,111 (39.5) | 159 (39.0) | 494 (43.0) | 1,458 (38.6) | |
| III and UD | 2,381 (44.6) | 132 (32.4) | 445 (38.7) | 1,804 (47.7) | |
| Unknown | 466 (8.7) | 50 (12.3) | 112 (9.7) | 304 (8.0) | |
| ER status | .1325 | ||||
| Positive | 4,022 (75.3) | 295 (72.3) | 884 (76.9) | 2,843 (75.3) | |
| Negative | 1,210 (22.7) | 99 (24.3) | 243 (21.1) | 868 (22.7) | |
| Unknown | 108 (2.0) | 14 (3.4) | 23 (2.0) | 71 (2.0) | |
| PR | .3278 | ||||
| Positive | 3,295 (61.7) | 248 (60.8) | 713 (62.0) | 2,334 (61.7) | |
| Negative | 1,924 (36.0) | 145 (35.5) | 409 (35.6) | 1,370 (36.2) | |
| Unknown | 121 (100.0) | 15 (3.7) | 28 (2.4) | 78 (64.5) | |
| HER2 status c | .0287 | ||||
| Amplification | 1,494 (28.0) | 96 (23.5) | 312 (27.1) | 1,086 (28.7) | |
| Not amplification | 3,662 (68.6) | 289 (70.8) | 798 (69.4) | 2,575 (68.1) | |
| Unknown | 184 (3.4) | 23 (5.6) | 40 (3.5) | 121 (3.2) | |
| Subtype | .2354 | ||||
| Luminal A | 2,960 (55.4) | 231 (56.6) | 650 (56.5) | 2,079 (55.0) | |
| Luminal B | 939 (17.6) | 58 (14.2) | 194 (16.9) | 687 (18.2) | |
| HER2 | 407 (7.6) | 27 (6.6) | 81 (7.0) | 299 (7.9) | |
| TNBC | 691 (12.9) | 57 (14.0) | 145 (12.6) | 489 (12.9) | |
| Unknown | 343 (6.4) | 35 (8.6) | 80 (7.0) | 228 (6.0) | |
| Surgery | .0288 | ||||
| Yes | 3,154 (59.1) | 267 (65.4) | 693 (60.3) | 2,194 (58.0) | |
| No | 2,162 (40.5) | 141 (34.6) | 451 (39.2) | 1,570 (41.5) | |
| Unknown | 24 (0.4) | 0 (0.0) | 6 (0.5) | 18 (0.5) | |
| Bone metastases | .9580 | ||||
| No | 1,955 (36.6) | 155 (38.0) | 423 (36.8) | 1,377 (36.4) | |
| Yes | 3,322 (62.2) | 248 (60.8) | 715 (62.2) | 2,359 (62.4) | |
| Unknown | 63 (1.2) | 5 (1.2) | 12 (1.0) | 46 (1.2) | |
| Brain metastases | .0052 | ||||
| No | 4,903 (91.8) | 360 (88.2) | 1,043 (90.7) | 3,500 (92.5) | |
| Yes | 328 (6.1) | 40 (9.8) | 82 (7.1) | 206 (5.4) | |
| Unknown | 109 (2.0) | 8 (2.0) | 25 (2.2) | 76 (2.0) | |
| Liver metastases | .4879 | ||||
| No | 3,882 (72.7) | 304 (74.5) | 839 (73.0) | 2,739 (72.4) | |
| Yes | 1,369 (25.6) | 96 (23.5) | 287 (25.0) | 986 (26.1) | |
| Unknown | 89 (1.7) | 8 (2.0) | 24 (2.1) | 57 (1.5) | |
| Lung metastases | .0048 | ||||
| No | 3,789 (71.0) | 275 (67.4) | 865 (75.2) | 2,649 (70.0) | |
| Yes | 1,435 (26.9) | 124 (30.4) | 260 (22.6) | 1,051 (27.8) | |
| Unknown | 116 (2.2) | 9 (2.2) | 25 (2.2) | 82 (2.2) | |
| Number of involved sites | .1655 | ||||
| 0 d | 664 (12.4) | 49 (12.0) | 165 (14.3) | 450 (11.9) | |
| 1 | 3,229 (60.5) | 245 (60.0) | 696 (60.5) | 2,288 (60.5) | |
| 2 | 1,063 (19.9) | 80 (19.6) | 204 (17.7) | 779 (20.6) | |
| 3 | 313 (5.9) | 25 (6.1) | 68 (5.9) | 220 (5.8) | |
| 4 | 40 (0.7) | 7 (1.7) | 9 (0.8) | 24 (0.6) | |
| Unknown | 31 (0.6) | 2 (0.5) | 8 (0.7) | 21 (0.6) | |
| Cause of death | <.0001 | ||||
| Alive | 2,199 (41.2) | 122 (29.9) | 455 (39.6) | 1,622 (42.9) | |
| Breast cancer | 1,993 (37.3) | 111 (27.2) | 355 (30.9) | 1,527 (40.4) | |
| Other | 1,148 (21.5) | 175 (42.9) | 340 (29.6) | 633 (16.7) |
p value of the χ2 test comparing the T1a/T1b, T1c, and T2 groups.
Including American Indian/Alaskan native, and Asian/Pacific Islanders.
HER2 amplification was defined as 3+ immunohistochemistry or gene amplification in fluorescence in situ hybridization.
The involved sites only take into account organ metastases; distant lymph node involvement counts as zero.
Abbreviations: ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; PR, progesterone receptor; TNBC, triple‐negative breast cancer; UD, undifferentiated.
Interaction Between Tumor Size and LN Status Regarding BCSM
In univariate analysis, each of the following variables significantly increased the BCSM: diagnosed in 2020–2012, Black, age over 65, grade III and undifferentiated, estrogen receptor (ER) negative, progesterone receptor (PR) negative, HER2 negative, TNBC, no surgery, brain metastases, liver metastases, lung metastases, and two or more metastatic sites (Table 2). In T1 stage groups, T1a/T1bN0 (reference group), T1cN0 (HR, 1.204; 95% CI, 0.886–1.636; p = .235), T1a/T1bN1 (HR, 1.119; 95% CI, 0.739–1.695; p = .595), T1cN1 (HR, 1.175; 95% CI, 0.865–1.596; p = .301), T1a/T1bN2 (HR, 1.178; 95% CI, 0.666–2.083; p = .573), and T1cN2+ (HR, 0.907; 95% CI, 0.619–1.328; p = .615) had similar BCSM. In the N0, N1, and N2+ group, the BCSM of T2 tumors was higher than that of T1a/T1b tumors (HR, 1.547 vs. 1; 1.590 vs. 1.119; 1.423 vs. 1.178; p < .05), whereas the BCSM of T1c tumors was no higher than that of T1a/T1b tumors (p > .1). ER/PR− patients had significantly higher BCSM than ER+/PR+ patients, and HER2− patients had significantly higher BCSM than HER2+ patients. In general, the TNBC subtype was associated with significantly higher BCSM than the luminal A subtype (HR, 2.828; 95% CI, 2.518–3.177; p < .001). In multivariate analysis, the variables race, age at diagnosis, grade, subtype, brain metastases, liver metastases, and receipt of surgery were independently associated with the BCSM (Table 3). Luminal A and HER2 amplified subtypes had similar BCSM, whereas the TNBC subtype had significantly higher BCSM than the luminal A subtype (HR, 2.65; 95% CI, 2.33–3.014; p < .0001). Age over 65 was associated with significantly higher BCSM than younger groups (HR, 1.671; 95% CI, 1.4–1.993; p < .0001). For T2 stage tumors, the BCSM of N2+ was higher than that of N1 or N0 (HR, 1.738 vs. 1.538 vs. 1.482; p < .05). For T1 stage tumors, however, the BCSM remained the same regardless of specific tumor size or number of lymph nodes involved (HR, 1.176 vs. 0.989 vs. 1.107 vs. 1.599 vs. 1.122; p > .05). Kaplan‐Meier analysis was performed to determine BCSM based on tumor size and LN status. Meanwhile, individual survival curves were plotted for each of the various T stage and N stage combinations (Fig. 1). The T1 stage groups had similar BCSM for T1a/T1bN0, T1cN0, T1a/T1bN1, T1cN1, T1a/T1bN2, and T1cN2 (Fig. 1A; p > .05). The T2 stage groups had similar BCSM for T2N0, T2N1, and T2N2+ (Fig. 1B; p > .05). In patients with a tumor size less than 50 mm, the 1‐ or 2‐year BCSM was similar regardless of tumor size (Fig. 2A and B); however, the 3‐year BCSM seemed to be slightly increased in smaller tumors compared with 20 mm tumors (Fig. 2C).
Table 2.
Univariate analysis on breast cancer‐specific mortality
| Variable | Hazard ratio (95% CI) | p value | SE |
|---|---|---|---|
| Year of diagnosis | |||
| 2010–2012 (ref.) | |||
| 2013–2015 | 0.958 (0.871–1.053) | .3750 | 0.049 |
| Race | |||
| White (ref.) | |||
| Black | 1.406 (1.250–1.582) | <.0001 | 0.060 |
| Other | 0.833 (0.695–0.998) | .0480 | 0.092 |
| Unknown | 0.000 (0.000–53.736) | .8480 | 46.683 |
| Age, years | |||
| ≤35 (ref.) | |||
| 36–65 | 1.116 (0.944–1.319) | .1990 | 0.085 |
| >65 | 1.503 (1.267–1.783) | <.0001 | 0.087 |
| Grade | |||
| I (ref.) | |||
| II | 1.663 (1.326–2.086) | <.0001 | 0.116 |
| III and UD | 2.359 (1.888–2.947) | <.0001 | 0.114 |
| Unknown | 2.405 (1.784–2.979) | <.0001 | 0.131 |
| ER status | |||
| Positive (ref.) | |||
| Negative | 2.054 (1.865–2.261) | <.0001 | 0.049 |
| Unknown | 1.802 (1.335–2.434) | <.0001 | 0.153 |
| PR | |||
| Positive (ref.) | |||
| Negative | 1.998 (1.827–2.184) | <.0001 | 0.046 |
| Unknown | 1.651 (1.233–2.212) | .0010 | 0.149 |
| HER2 status a | |||
| Amplification (ref.) | |||
| Not amplification | 1.263 (1.140–1.399) | <.0001 | 0.052 |
| Unknown | 1.348 (1.044–1.740) | .0220 | 0.130 |
| Subtype | |||
| Luminal A (ref.) | |||
| Luminal B | 0.903 (0.793–1.028) | .1240 | 0.066 |
| HER2 | 1.049 (0.881–1.250) | .5890 | 0.089 |
| TNBC | 2.828 (2.518–3.177) | <.0001 | 0.059 |
| Unknown | 1.316 (1.095–1.581) | .0030 | 0.094 |
| Surgery | |||
| No (ref.) | |||
| Yes | 0.511 (0.466–0.562) | <.0001 | 0.048 |
| Unknown | 1.089 (0.602–1.972) | .7770 | 0.303 |
| Bone metastases | |||
| No (ref.) | |||
| Yes | 1.021 (0.931–1.120) | .6530 | 0.047 |
| Unknown | 1.599 (1.154–2.216) | .0050 | 0.167 |
| Brain metastases | |||
| No (ref.) | |||
| Yes | 2.783 (2.399–3.230) | <.0001 | 0.076 |
| Unknown | 1.409 (1.075–1.848) | .0130 | 0.138 |
| Liver metastases | |||
| No (ref.) | |||
| Yes | 1.844 (1.678–2.026) | <.0001 | 0.048 |
| Unknown | 1.806 (1.361–2.395) | <.0001 | 0.144 |
| Lung metastases | |||
| No (ref.) | |||
| Yes | 1.516 (1.378–1.669) | <.0001 | 0.049 |
| Unknown | 1.653 (1.276–2.141) | <.0001 | 0.132 |
| Number of involved sites | |||
| 0 b (ref.) | |||
| 1 | 1.138 (0.975–1.329) | .1010 | 0.079 |
| 2 | 2.218 (1.877–2.621) | <.0001 | 0.085 |
| 3 | 3.240 (2.629–3.992) | <.0001 | 0.107 |
| 4 | 4.396 (2.897–6.673) | <.0001 | 0.213 |
| Unknown | 2.019 (1.593–2.558) | <.0001 | 0.121 |
| Tumor nodal interaction | |||
| T1a/T1bN0 (ref.) | |||
| T1cN0 | 1.204 (0.886–1.636) | .2350 | 0.156 |
| T2N0 | 1.547 (1.170–2.045) | .0020 | 0.142 |
| T1a/T1bN1 | 1.119 (0.739–1.695) | .5950 | 0.212 |
| T1cN1 | 1.175 (0.865–1.596) | .3010 | 0.156 |
| T2N1 | 1.590 (1.212–2.086) | .0010 | 0.138 |
| T1a/T1bN2+ | 1.178 (0.666–2.083) | .5730 | 0.291 |
| T1cN2+ | 0.907 (0.619–1.328) | .6150 | 0.195 |
| T2N2+ | 1.423 (1.074–1.887) | .0140 | 0.144 |
HER2 amplification was defined as 3+ immunohistochemistry or gene amplification in fluorescence in situ hybridization.
The involved sites only take into account organ metastases; distant lymph node involvement counts as zero.
Abbreviations: CI, confidence interval; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; PR, progesterone receptor; TNBC, triple‐negative breast cancer; UD, undifferentiated.
Table 3.
Multivariate analysis on breast cancer‐specific mortality
| Variable | Hazard ratio (95% CI) | p value |
|---|---|---|
| Race | ||
| White (ref.) | ||
| Black | 1.308 (1.160–1.475) | <.0001 |
| Other | 0.892 (0.743–1.071) | .2200 |
| Unknown | 0.000 (0.000–38.445) | .8420 |
| Age, years | ||
| ≤35 (ref.) | ||
| 36–65 | 1.152 (0.972–1.365) | .1020 |
| >65 | 1.671 (1.400–1.993) | <.0001 |
| Grade | ||
| I (ref.) | ||
| II | 1.511 (1.203–1.899) | .0004 |
| III and UD | 2.066 (1.640–2.604) | <.0001 |
| Unknown | 1.757 (1.354–2.280) | <.0001 |
| Subtype | ||
| Luminal A (ref.) | ||
| Luminal B | 0.758 (0.662–0.868) | <.0001 |
| HER2 | 0.874 (0.728–1.050) | .1510 |
| TNBC | 2.650 (2.330–3.014) | <.0001 |
| Unknown | 1.137 (0.944–1.370) | .1760 |
| Surgery | ||
| No (ref.) | ||
| Yes | 0.511 (0.461–0.566) | <.0001 |
| Unknown | 1.048 (0.577–1.905) | .8780 |
| Bone metastases | ||
| No (ref.) | ||
| Yes | 1.112 (0.830–1.489) | .4760 |
| Unknown | 1.255 (0.764–2.060) | .3700 |
| Brain metastases | ||
| No (ref.) | ||
| Yes | 2.115 (1.562–2.863) | <.0001 |
| Unknown | 0.936 (0.621–1.412) | .7530 |
| Liver metastases | ||
| No (ref.) | ||
| Yes | 1.574 (1.178–2.103) | .0020 |
| Unknown | 1.309 (0.858–1.997) | .2110 |
| Lung metastases | ||
| No (ref.) | ||
| Yes | 1.085 (0.810–1.454) | .5840 |
| Unknown | 0.971 (0.642–1.469) | .8880 |
| Number of involved sites | ||
| 0 b (ref.) | ||
| 1 | 1.042 (0.755–1.438) | .8030 |
| 2 | 1.404 (0.785–2.512) | .2530 |
| 3 | 1.442 (0.611–3.401) | .4040 |
| 4 | 0.971 (0.298–3.161) | .9610 |
| Unknown | 1.428 (0.749–2.722) | .2790 |
| Tumor nodal interaction | ||
| T1a/T1bN0 (ref.) | ||
| T1cN0 | 1.176 (0.864–1.599) | .3020 |
| T2N0 | 1.482 (1.120–1.961) | .0060 |
| T1a/T1bN1 | 0.989 (0.652–1.499) | .9570 |
| T1cN1 | 1.107 (0.814–1.505) | .5180 |
| T2N1 | 1.538 (1.170–2.021) | .0020 |
| T1a/T1bN2+ | 1.599 (0.901–2.840) | .1090 |
| T1cN2+ | 1.122 (0.764–1.649) | .5570 |
| T2N2+ | 1.738 (1.305–2.314) | .0002 |
The involved sites only take into account organ metastases; distant lymph node involvement counts as zero.
HER2 amplification was defined as 3+ immunohistochemistry or gene amplification in fluorescence in situ hybridization.
Abbreviations: CI, confidence interval; HER2, human epidermal growth factor receptor 2; TNBC, triple‐negative breast cancer; UD, undifferentiated.
Figure 1.
Breast cancer‐specific survival according to tumor size, stratified by lymph node metastasis. (A): T1 stage cohort, p = .552. (B): T2 stage cohort, p = .207.
Figure 2.
One‐, 2‐, and 3‐year breast cancer‐specific mortality (BCSM) according to tumor size. (A): One‐year BCSM for all enrolled patients. (B): Two‐year BCSM for all enrolled patients. (C): Three‐year BCSM for all enrolled patients. (D): One‐year BCSM for the group of patients with N0 TNBC. (E): One‐year BCSM for the group of patients with N1 TNBC. (F): One‐year BCSM for the group of patients with N2+ TNBC.Abbreviation: TNBC, triple‐negative breast cancer.
Determination of Interactions After Stratification According to Breast Cancer Subtype
The impact of tumor size and LN metastasis on BCSM was further analyzed in every breast cancer subtype (Table 4). The Kaplan‐Meier analyses showed that metastatic TNBCs presented worse BCSM compared with metastatic breast cancer of other molecular subtypes in T1a/T1bN0, T1c/N0, T2N0, T1cN1, T2N1, T1a/T1bN2+, T1cN2+, and T2N2+ subgroups (supplemental online Fig. 1). However, the small TNBCs with minimal node involvement (T1a/1bN1) had the same BCSM as the luminal A, luminal B, and HER2 amplified subtypes (log‐rank p = .663). Patients with luminal A subtype breast cancer with T1 tumors had similar BCSM regardless of nodal status, whereas patients with luminal A breast cancer with T2 tumors had worse BCSM than those with T1 tumors. For the luminal B subtype patients, various interaction groups showed no difference in BCSM. A similar trend was seen in HER2 amplified subtype patients. The TNBC subtype, node‐negative group showed no difference in BCSM based on tumor size as well (Table 4) and presented no obvious sign of BCSM decline with tumor size increase (Fig. 2D). For N1 TNBC, patients with T2 had higher BCSM than patients with T1c and T1a/T1b (HR, 2.271 vs. 1.619 vs. 0.860; p < .05). In the N1 group with tumor size less than 25 mm, 1‐year BCSM seemed to decrease in larger tumors (Fig. 2E). However, for N2+ TNBC, patients with T1a/T1b had significantly higher BCSM than patients with T1c and T2 (HR, 5.847 vs. 1.778 vs. 2.254; p = .004, p = .204, and p = .027, respectively). In the N2+ group with tumor size less than 30 mm, 1‐year BCSM significantly decreased in larger tumors (Fig. 2F).
Table 4.
Breast cancer‐specific mortality according to tumor size and lymph node metastasis stratified by subtype
| Stage | Luminal A | Luminal B | HER2 | TNBC | ||||
|---|---|---|---|---|---|---|---|---|
| HR (95% CI) | p value | HR (95% CI) | p value | HR (95% CI) | p value | HR (95% CI) | p value | |
| T1a/T1bN0 (ref.) | 1.000 | 1.000 | 1.000 | 1.000 | ||||
| T1cN0 | 1.367 (0.858–2.179) | .188 | 0.821 (0.383–1.763) | .614 | 0.776 (0.239–2.515) | .672 | 1.686 (0.788–3.611) | .178 |
| T2N0 | 1.782 (1.158–2.744) | .009 | 1.196 (0.605–2.363) | .607 | 0.588 (0.214–1.617) | .303 | 1.742 (0.850–3.571) | .130 |
| T1a/T1bN1 | 1.335 (0.725–2.459) | .354 | 0.638 (0.207–1.967) | .435 | 0.627 (0.162–2.433) | .500 | 0.860 (0.314–2.356) | .769 |
| T1cN1 | 1.465 (0.918–2.338) | .110 | 0.504 (0.234–1.088) | .081 | 0.439 (0.146–1.322) | .143 | 1.619 (0.753–3.482) | .218 |
| T2N1 | 1.862 (1.22–2.841) | .004 | 0.869 (0.450–1.681) | .677 | 0.532 (0.204–1.386) | .196 | 2.271 (1.127–4.575) | .022 |
| T1a/T1bN2+ | 1.857 (0.794–4.341) | .153 | 0.600 (0.127–2.825) | .518 | 0.312 (0.037–2.636) | .285 | 5.847 (1.738–19.672) | .004 |
| T1cN2+ | 1.221 (0.677–2.203) | .508 | 0.726 (0.271–1.951) | .526 | 0.425 (0.123–1.471) | .176 | 1.778 (0.732–4.320) | .204 |
| T2N2+ | 1.957 (1.258–3.047) | .003 | 1.180 (0.594–2.345) | .636 | 0.619 (0.227–1.689) | .349 | 2.254 (1.094–4.643) | .027 |
HER2 amplification was defined as 3+ immunohistochemistry or gene amplification in fluorescence in situ hybridization.
The involved sites only take into account organ metastases; distant lymph node involvement counts as zero.
Abbreviations: CI, confidence interval; HER2, human epidermal growth factor receptor 2; HR, hazard ratio; TNBC, triple‐negative breast cancer.
Discussion
This study intended to find out whether there was a significant interaction between tumor size and LN involvement in predicting the BCSM of stage IV breast cancer. We hypothesized that stage IV breast cancers with very small primary lesions (defined as T1a/T1b tumors) and LN metastases were associated with aggressive prognosis. After adjusting for known prognostic factors of breast cancer, we observed that patients with T1a/T1bN2+ had similar BCSM as those with T1cN2+ cancers (HR, 1.599 vs. 1.122; p > .05). This regularity in smaller‐sized tumors was also seen in patients with less extensive nodal involvement. However, for TNBC, patients with T1a/T1bN2+ breast cancer had significantly higher BCSM than those with T1cN2+ and T2N2+. When tumor size was less than 50 mm, the 1‐ and 2‐year BCSM of patients with smaller tumors were similar to those with larger tumors, but the 3‐year BCSM seemed to be slightly increased in smaller tumors compared with 20 mm tumors (Fig. 2), which might be attributed to the prominently high BCSM in the T1a/T1bN2+ TNBC subgroup. This phenomenon suggested that for stage IV breast cancers, smaller tumor size was not associated with better prognosis. Although the conventional view of cancer spread holds that cancer gains the metastatic ability through accumulation of mutations in the growing process [11], our findings implied that very small primary TNBCs with extensive LN and distant metastases represented a subset of cancers with more prominent invasion/metastases pathways. The consistency between our results and previous studies [13, 14] further reinforces the idea that in certain subsets of cancers, the potential of distant dissemination is more likely to be determined by initial biological features than by accumulated metastatic ability during tumor evolution.
Our study provides further support to a growing body of literature suggesting that certain subtypes of breast cancer (e.g., TNBC) have an enhanced propensity to metastasis and exhibit worse prognosis even when the primary lesion is very small [10, 12]. Previous studies have revealed that tumors expressing basal‐like markers present as interval cancers (tumors that develop between two screening interventions) more often than other types of breast cancer [15]. Basal‐like breast cancers have the highest expression of proliferation‐related genes by microarray profiling of any subtype and show the highest Ki67 labeling indices (an indirect immunohistochemical assessment of the proliferation fraction of a tumor) [16, 17]. Interestingly, basal‐like and BRCA1‐related tumors are frequently composed of solid sheets of densely packed tumor cells, with little or no tubule formation and minimal intervening stroma, and such tumors have an enhanced proclivity to arouse distant metastases and rapid progression [18]. These findings are consistent with our observation that TNBCs presented worse BCSM compared with metastatic breast cancer of other molecular subtypes (supplemental online Fig. 1). Small‐sized TNBCs with severe LN involvement exhibited even more aggressive clinical behaviors. It was plausible that T1a/T1b N2+ TNBCs might have acquired stronger capability to invade the tissue surrounding the primary tumor, to enter either the lymphatics or the bloodstream, to survive and eventually arrest in the circulation, to extravasate into a tissue and grow at the new site. Compared with T2N2+ TNBCs, T1a/T1bN2+ TNBCs showed that the acquisition of metastatic potential may occur early in cancer development [19] instead of gaining metastatic ability through an accumulation of mutations as they grow to a large size [11]. In contrast to T1a/T1bN0 TNBCs, T1a/T1bN2+ TNBCs appeared to be capable of metastasizing in multiple ways, including both lymphatics and bloodstream. And T1a/T1bN2+ TNBCs seemed to be aggressive enough to colonize and proliferate massively in lymph nodes.
Our findings also support another population‐based study suggesting that women diagnosed with stage IV breast cancer at a younger age, even after adjusting for other known prognostic factors, have better survival compared with older women [20]. In our study, age over 65 was found to be an independent predictor of worse BCSM (HR, 1.671; p < .0001). Moreover, our study consolidates the notion [21, 22] that involvement of brain or liver is an independent prognostic factor for stage IV breast cancer. In multivariate analysis, brain or liver metastasis indicated worse BCSM (HR, 2.115, 1.574; p < .0001, p = .002, respectively). In addition, our study showed that Black race was an independent predictor of increased BCSM (HR, 1.308; p < .0001), which supports some earlier studies that suggest worse BCSM in Black patients [23, 24].
Based on our analysis results, very small tumor size with severe nodal disease may be an implication for intrinsic biologic aggressiveness in stage IV TNBCs. Following the discovery and validation of prognostic categorization of breast cancers into distinct biologic subtypes by gene expression profiling studies, there is increasing awareness of tumor biology in predicting the clinical outcome [25, 26, 27]. Although some of the significance of our findings may be attributed to inability to adjust for systematic treatment, this is unlikely to explain all of the increased mortality found in T1a/T1b TNBCs with extensive nodal disease seen in our study. It suggests that additional biomarkers, which may be related to the progression potential of breast cancers but not yet identified, may aid in prognostic determination. Extensive LN involvement with a very small tumor suggests that T1a/T1bN2+ TNBC cells may have earlier acquisition of metastatic potential and tend to progress rapidly. Further studies evaluating patients with T1a/T1bN2+ TNBCs may help elucidate the genetic or molecular differences that contribute to the development of the progression potential. For these tumor cells with rapid progression potential, clarification of the regulation mechanism of very small primary TNBCs with metastatic outgrowth in nodes and distant sites will play an integral role in developing targeted therapies. Additionally, our study reinforces that patients with very small TNBCs alongside significant LN involvement have a substantial risk of increased BCSM and should be treated aggressively. Although we expect that most patients with metastatic disease would receive aggressive systemic therapy whether their tumors are small‐sized or not, our study reasserts that this patient population with small‐sized tumor remains at substantial risk for breast cancer–related death and should not be undertreated.
Our study has several limitations. First, the information regarding HER2/neu status is only available in the SEER database from 2010. Therefore, we only included cases diagnosed after 2010, which led to a notable reduction of the sample size. Despite a large initial study population, substratification by variables made the size of each individual subgroup relatively small, yielding a limited statistical power. Consequently, it resulted in wide overlapping CIs in certain subgroups and limited our ability to detect meaningful differences. Meanwhile, T1a and T1b tumors were pooled into the same group because of inadequate cases. Second, the SEER database lacks information about systemic cancer therapy. Thus, this potential confounding factor could not be analyzed. Third, the retrospective nature of our study may have introduced a certain level of bias to our analysis results.
Conclusion
Our study revealed that stage IV breast cancer with small primary breast tumors did not have significantly different BCSM compared with those with larger size. We further illustrated that very small TNBCs with extensive regional LN involvement represented a prominent increase in BCSM compared with larger tumors, suggesting that very small tumor size in the context of severe LN disease may be a surrogate for biologically aggressive disease. Because of the poor prognosis of T1a/T1bN2+ TNBCs, there might be an urgent need of more individualized treatment for the affected patients. If our findings are validated by other databases, future correlative studies ought to focus on the genetic and molecular differences in Ta1/T1bN2+ TNBCs that contribute to the biological behavior.
Author Contributions
Conception/design: Yi‐Zi Zheng, Xian‐Ming Wang, Lei Fan, Zhi‐Ming Shao
Provision of study material or patients: Yi‐Zi Zheng, Lei Fan
Collection and/or assembly of data: Yi‐Zi Zheng, Lei Fan
Data analysis and interpretation: Yi‐Zi Zheng, Lei Fan
Manuscript writing: Yi‐Zi Zheng, Lei Fan
Final approval of manuscript: Yi‐Zi Zheng, Xian‐Ming Wang, Lei Fan, Zhi‐Ming Shao
Disclosures
The authors indicated no financial relationships.
Supporting information
See http://www.TheOncologist.com for supplemental material available online.
Supplemental Figure 1 Breast Cancer‐Specific Mortality in Small‐Sized Tumor with Stage IV Breast Cancer: a Population‐Based Study Yi‐Zi Zheng et al.
Acknowledgments
This study was sponsored by Shanghai Committee of Science and Technology Funds (Shanghai Sailing Program 19YF1408900 to Y.Z.Z.) and by grants from the National Natural Science Foundation of China (81902682 to Y.Z.Z.).
Disclosures of potential conflicts of interest may be found at the end of this article.
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Contributor Information
Lei Fan, Email: drfanlei@gmail.com.
Zhi‐Ming Shao, Email: zhimingshao@yahoo.com.
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Supplementary Materials
See http://www.TheOncologist.com for supplemental material available online.
Supplemental Figure 1 Breast Cancer‐Specific Mortality in Small‐Sized Tumor with Stage IV Breast Cancer: a Population‐Based Study Yi‐Zi Zheng et al.