Journal of J Breast Cancer 2018 September; 21(3): 315-320https://doi.org/10.4048/jbc.2018.21.

e35

Breast
Cancer
O R I GINAL ARTICLE

Evaluating the Prediction of Breast Cancer Survival Using Lymph Node Ratio
Man Hung1,2,3, Julie Xu1, Dominique Nielson1, Jerry Bounsanga1, Yushan Gu1, Alec Roger Hansen1, Maren Wright Voss1
1
Department of Orthopaedics and 2Study Design and Biostatistics Center, University of Utah School of Medicine, Salt Lake City; 3Huntsman Cancer
Institute, University of Utah, Salt Lake City, USA

Purpose: Previous oncological studies showed that lymph node variable was conducted to determine whether LNR could predict
ratio (LNR) (ratio of number of lymph nodes that tested positive cancer progression, coded as regional or distant. Analysis was
for metastasis to the total number of lymph nodes examined) is a conducted using SPSS version 24. Results: Patient’s mean age
negative indicator of cancer survival. The American Joint Committee was 59.43± 18.62. Logistic regression analysis revealed that for
on Cancer (AJCC) staging system incorporates tumor size, every 1.3% increase in LNR, the odds of falling into the distant
lymph node involvement, and metastasis in a comprehensive stage of the TNM staging system increased by 13.7% (odds ratio,
model of cancer progression, but LNR alone has been shown to 14.73; 95% confidence interval, 12.00–18.08). Conclusion: LNR,
outperform the AJCC system in prognostic and survival predic- while correlated with breast cancer staging, serves as a better
tions for various types of cancer. The effectiveness of LNR has predictor of survival. Precision staging can influence treatment
not been evaluated in breast cancer staging. Evaluating LNR for modality, and improved treatments can significantly improve
predicting cancer staging in breast cancer has the potential to quality of life. Additional research and diagnostic examinations
improve treatment recommendations. Methods: The Surveillance, using LNR as a potential tool for accurate staging in breast can-
Epidemiology, and End Results dataset was used to identify cer patients are warranted.
10,655 breast cancer patients who underwent nodal evaluation
from 2010 to 2013, and their LNRs were calculated. Descriptive
statistics of lymph node evaluation in the patients are provided. Key Words: American Joint Committee on Cancer, Breast neoplasms, Lymph
Logistic regression with LNR as the continuous independent node, Neoplasm staging, Survival

INTRODUCTION the total expected cancer related deaths for both sexes in the
United States. In women, breast cancer is expected to account
Cancer is the second leading cause of death in the United for 29% of new cancer diagnoses. While breast cancer patients
States. A total of 1,685,210 new cancer cases were expected to have increased survival rates in comparison with other cancer
be diagnosed in 2016, with 595,650 expected deaths [1]. Of types, the high incidence places breast cancer as one of the
these, 249,260 newly diagnosed breast cancer cases were esti- most common causes of cancer-related deaths [1]. Since 1990,
mated, with 40,890 expected deaths. Breast cancer makes up the rate of mortality from breast cancer has been declining
14.79% of the total expected cancer diagnoses and 6.86% of due to improved treatments and early detection methods [2].
These have been shown to be important predictors of survival,
Correspondence to:  Man Hung as early detection has been associated with reduced breast
Department of Orthopaedics, University of Utah School of Medicine, 590 cancer morbidity and mortality rates [3].
Wakara Way, Salt Lake City, UT 84108, USA A key component in identifying the appropriate treatment
Tel: +1-801-587-5372, Fax: +1-801-587-5411
E-mail: [email protected] course is an evaluation of the cancer at the time of diagnosis
This study was supported by the Quality Outcomes Research and Assessment,
[4]. Breast cancer staging is a method of determining severity
Department of Orthopaedics, University of Utah School of Medicine (http:// of the disease and may include a physical examination of the
QualityOutcomesResearch.com), the Huntsman Cancer Institute, and the skin, mammary glands, and lymph nodes, with the axillary,
Center for Clinical & Translational Science, with funding in part from the
National Center for Research Resources and the National Center for
supraclavicular, and cervical nodes as the primary nodes of
Advancing Translational Sciences, National Institutes of Health, through evaluation [5]. Different methods exist for classifying clinical
Grant 5UL1TR001067-02. and pathological findings into stages, though the most com-
Received: March 28, 2018  Accepted: July 4, 2018 monly used guidelines in the world are from the American

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This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ eISSN 2092-9900
licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
316  Man Hung, et al.

Joint Committee on Cancer (AJCC) [6]. The AJCC staging dicting survival for breast cancer than either staging system
system is standardized, with specifically defined criteria for alone [13], indicating that even the most updated version of
each known stage of breast cancer. The system has traditional- the AJCC manual needed the extra nuances of a supplemen-
ly included the size of the tumor (T), the extent of spreading tary staging system.
to the regional lymph nodes (N), along with the presence of The addition of new staging criteria reflects an awareness of
metastasis to relatively distal areas (M) with numbers and concerns with the TNM approach, not just in breast cancer
lowercase letters for subtyping as needed (e.g., T1a, T1N2M0). but in multiple areas of oncology. Recently, the evaluation of
The tumor can be measured based on its clinical features, ap- lymph node ratio (LNR) in gastric cancer staging was shown
pearance on imagery, size, and growth. Extent of spreading to to outperform the 7th edition guidelines of the AJCC’s TNM
regional lymph nodes is typically staged by pathology of tissue staging system in sensitivity measures and overall survival
samples obtained by biopsy, which is known as pathologic [14]. LNR also proved useful in the prognosis of postsurgical
staging (pN). pN staging is the most accurate way to assess pancreatic cancer patients as one of the most powerful predic-
nodal involvement because of the distinctive histological pro- tors of survival time [15]. The 7th edition of the AJCC’s stag-
files of tumor cells. Collectively, these categories coupled with ing system requires the examination of 15 lymph nodes for
the metastasis staging are known as the TNM staging system. accurate staging and classifies stage by location of the involved
Even though the extent of metastasis is critical to assess a nodes. Yet, the examination of 15 lymph nodes is often not
patient’s prognosis, the classifications have proven to be diffi- performed as some nodes are unavailable for resection, result-
cult to define further than “evidence of tumor cells in areas ing in under-staging. Increased identification of involved
beyond the tumor site and regional lymph nodes.” This may nodes and surgical resections of these nodes resulted in in-
be due to the lack of clinical presentation of the pathological creased staging accuracy and colon cancer survival prediction
M0 stage which can only be proven at autopsy. The 7th edi- [16]. Inadequate analysis of lymph node involvement is a re-
tion of the AJCC’s staging system raised this issue, yet the sult of certain types of operations or a tumor with few local
staging for this category remained the same in the AJCC’s 8th lymph nodes for assessment. LNR has been used to augment
edition. Also mentioned were isolated tumor cells which are staging determination and successfully predict prognosis [17].
single or small clusters of submillimeter tumor cells which Even in cases where sufficient nodal resection was performed,
could be indicative of distant metastasis. These have not been LNR has been shown to be superior to the AJCC’s staging sys-
assessed for their role in cancer prognosis. With these contin- tem via the assessment of the number of positive lymph nodes
ually unaddressed gaps in classification and additions to treat- for predicting prognosis in colon cancer [18]. Survival rates
ment protocols such as neoadjuvant therapy and multigene predicted with LNR, metastatic lymph nodes, and log odds of
panel screening, it is important to consider the use of comple- positive lymph nodes as the staging method were superior to
mentary staging systems. The AJCC released the 8th edition the AJCC’s 7th edition TNM staging system in rare perihilar
of its cancer staging manual in 2017 with major changes rec- cholangiocarcinoma as well [19].
ommended for breast cancer staging [7,8]. The new consensus There is evidence of the prognostic value in using LNR to
staging system maintained the TNM staging but added in- predict breast cancer survival from multiple small studies
creased details of tumor dimension parameters, consideration (sample sizes of less than 1,800) [20] and limited studies of
of neoadjuvant therapy, and adjustments for multigene panels larger size [21,22]. There are a number of factors that can in-
for cancers with known genetic etiologies that allow more terfere with the value of LNR as a useful tool for prognosis in
flexibility and precision for breast cancer staging. Breast can- breast cancer, including very large tumor sizes or advanced
cer subtypes were categorized by involvement of several hor- disease, very-early stage disease, residual disease, or the use of
mone receptors which are commonly implicated in breast neoadjuvant therapy which can interfere with nodal evalua-
cancer: human epidermal growth factor receptor 2 (HER2), tion [23], though other research shows LNR is effective for
estrogen receptor (ER), and progesterone receptor (PR) [9]. prognostic prediction of high-risk breast cancers, even when
Gándara-Cortes et al. [10] elucidated targeted and sensitive neoadjuvant therapy is used [24]. In one study combining
treatments for cancers characterized by the involvement of multiple cancer trials for an overall analysis of over 7,000
these receptors. Prognosis generally tended to be worse for breast cancer patients, LNR was useful for prognosis in a sub-
those diagnosed with triple-negative (HER2–/ER–/PR–) and set of patients with 1–3 affected lymph nodes [25]. The effec-
HER2-positive breast cancers, though cases within a specific tiveness of LNR as a prognostic indicator has resulted in sug-
subtype will vary somewhat in presentation [11,12]. This gestions for inclusion of LNR in breast cancer staging [21].
combined TNM and subtype staging system is better at pre- Newer research as well as AJCC’s 8th edition staging system

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Breast Cancer Survival Using Lymph Node Ratio 317

has focused on breast can­cer subtypes as an adjunct to surviv- scriptive statistics (Table 1).
al prediction and will be an important part of prospective The definitions in the SEER summary staging manual were
studies. However, the recent development of assays and imag- used to distinguish each summary stage of breast cancer. The
ing approaches to identify the genetic subtypes are still under localized stage cases were excluded from analysis because the
development and range in both cost and availability [10,26, localized stage is the only stage aside from the in situ stage that
27], making large scale analysis inaccessible at present. The does not include any measurable or significant degree of
purpose of this study was to access the large number of sam- lymph node involvement. The intrinsic nature of these stages
ples available in a national cancer data registry to evaluate the precludes their ability to participate in the evaluation of a
effectiveness of LNR in predicting breast cancer survival com- lymph node-based staging system. SEER defines regional
pared to TNM staging. lymph nodes as the most proximal lymph nodes which serve
as immediate drainage sites for the site of the tumor and are
METHODS therefore good indicators for the metastatic behavior of the
cancer. For tumors of the breast, these include the axillary
The study employed a retrospective analysis of The Surveil- lymphatic plexus, paramammary lymph nodes, and interpec-
lance, Epidemiology, and End Results (SEER) dataset. The toral axillary lymph nodes.
SEER dataset collects information from 12 population-based Metastasis classifications are binary: M0 (no distant metas-
cancer registries which comprise 14% of the United States tasis) or M1 (distant metastasis). LNR was calculated as the
population. Patient demographic information, cancer diagno- number of lymph nodes tested positive for metastasis after re-
sis, and clinical indicators such as primary tumor size, grade, section divided by the total number of lymph nodes that were
and extension were obtained on 10,651 breast cancer patients examined. Local, regional, and distant SEER categorizations
who underwent nodal evaluation between 2010 and 2013. are determined by the TNM staging system and incorporate
These characteristics were examined and reported with de- factors of tumor size, multiplicity, depth of invasion, extension
to regional or remote areas, and histologic grade, in addition
Table 1. Demographics of patients in the SEER population (n= 10,655) to lymph node involvement. Independent sample t-tests were
run to test the hypothesis that staging and LNR are each asso-
Variable No. (%)
ciated with survival months. Correlational analysis was con-
Age (yr)* 59.43± 18.62
ducted to examine the relationship between LNR and TNM
Sex
staging. Logistic regression was performed using SPSS version
Female 10,523 (98.8)
Male 132 (1.2) 24 (IBM Corp., Armonk, USA) to identify whether LNR and
Race TNM staging could predict survival months, and whether
White 8,426 (79.1) LNR could predict cancer staging as either local, regional, or
Black 1,201 (11.3) distant.
Asian or Pacific Islander 883 (8.3)
Other 60 (0.6)
Unknown 85 (0.8) RESULTS
Location
San Francisco 9 (0.1) There were 10,523 women (98.8%) and 132 men (1.2%) in-
Connecticut 2,728 (25.6) cluded in the study. Patient’s mean age was 59.43 ± 18.62
Detroit 3,252 (30.5) (Table 1). There were 267 individuals under age 35 years; aged
Hawaii 1,047 (9.8)
35–54 years, 3,848; aged 55–75 years, 5,117; and over age 75
Iowa 2,233 (21.0)
New Mexico 1,382 (13.0)
years, 1,423. Only two patients were in the localized group,
Missing 4 (0.1) thus these cases were excluded due to the small sample size. A
Breast subtype total of 9,736 individuals (91.4%) were identified to be in the
HER2+/HR+ 1,172 (11.0) regional cancer stage group, and 913 (8.6%) in the distant
HER2+/HR– 519 (4.9) cancer stage group (Figure 1). There were 7,423 cases (59.7%)
HER2–/HR+ 7,285 (68.4)
that had 15 or fewer nodes examined (Table 2). A chi-square
Triple-negative 1,189 (11.1)
Missing 490 (4.6)
test was performed but no relationship was found between
age and LNR (χ2(3, N= 10,647)= 5.03; p= 0.170).
SEER = Surveillance, Epidemiology, and End Results; HER2 = human epider-
mal growth factor receptor 2; HR= hormone receptor. LNR and TNM staging for the classification of cases into ei-
*Mean± SD. ther regional or distant cancer stages had a Spearman’s rho of

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 318  Man Hung, et al.

10,000 9,736 Table 2. Number of nodes examined and frequency of positive nodes
9,000 for patients in the SEER

8,000 No. of nodes No. of positive

No. (%) No. (%)
examined nodes
7,000
1–5 3,014 (28.3) 1–5 8,755 (82.2)
No. of cases

6,000
6–10 1,970 (18.5) 6–10 1,086 (10.2)
5,000 11–15 2,439 (22.9) 11–15 457 (4.3)
4,000 16–20 1,747 (16.4) 16–20 202 (1.9)
21–25 873 (8.2) 21–25 85 (0.8)
3,000
> 25 607 (5.7) > 25 63 (0.6)
2,000 Missing 1 (0.0) Missing 3 (0.0)
913
1,000
2 SEER= Surveillance, Epidemiology, and End Results.
0
Local Regional Distant
Breast cancer stage Table 3. Regression analyses: LNR and staging on survival months
Standard
Figure 1. Distribution of the Surveillance, Epidemiology, and End Re- β t p-value r2
error
sults population for three progressions of breast cancer stage.
Intercept of LNR 24.133 0.209
LNR –4.986 0.424 –11.751 < 0.001 0.013
0.237, which was a small but significant correlation (p < Intercept of regional/ 22.451 0.140
0.001). LNR was negatively correlated with survival months distant stage
Regional/distant stage –2.456 0.477 –5.154 < 0.001 0.002
(r= –0.113, p< 0.001) such that a lower ratio of positive nodes
resulted in longer survival months. Linear regression analysis LNR= lymph node ratio.
found that LNR was a stronger predictor of survival months
(β = –0.113, p < 0.001, r2 = 0.013) than TNM staging (β = is necessary for the findings to reflect the impact on the popu-
–0.050, p< 0.001, r2 = 0.002) for both regional and distant can- lation at large.
cer stages (Table 3). Other multivariate models were tested, We found that while LNR and TNM cancer staging have a
including the addition of age at diagnosis and breast can­cer small but significant correlation, LNR was a better predictor
subtypes, but these variables did not alter the significance of of survival than TNM. Our results, while consistent with pre-
LNR in predicting survival months (results available upon re- vious studies that showed LNR may be warranted as a superi-
quest). LNR, while more predictive of survival months, was or method of breast cancer prognosis, also found that LNR
related to TNM staging as logistic regression analysis revealed exponentially increases the odds of falling into the distant
that for every 1% increase in LNR, the odds of falling into the stage of the TNM cancer staging system. This association be-
distant cancer stage of the TNM staging system increased by tween LNR and distant stage TNM potentially explains the
13.7% (odds ratio, 14.73; 95% confidence interval, 12.00– higher prediction value of LNR over TNM staging.
18.08). The present study on a broad population of over 10,000
breast cancer patients evaluated whether LNR would be a use-
DISCUSSION ful prognostic indicator for today’s oncology providers. LNR
was able to provide a greater prediction of overall survival
In this study, we sought to evaluate the prognostic value of than TNM staging, though the r2 value suggested that just
LNR within the breast cancer node positive cohort of the over 1% of the variation in survival months could be ex-
SEER dataset in comparison to the survival prediction value plained by LNR. While statistically significant, this level of
of the TNM staging system in SEER. It is well-established that prediction may not be clinically meaningful or relevant for
LNR can be a strong prognosis factor for several cancer types treatment considerations for cases without node involvement,
[18]. More specifically, the prognostic use of LNR in breast or node-negative cases. This finding was consistent with other
cancer has been shown to be a significant predictor of patient LNR analyses that suggested only a small, defined subpopula-
overall survival, spanning all stages of breast cancer and vari- tion of breast cancer patients would benefit from the use of
ous treatment types [20,22,28]. The present analysis used a LNR [25]. The analysis could have benefited from the consis-
larger cohort of the SEER cancer registry than previous stud- tent implementation of active post-study follow-up. Several
ies to compare the predictive value of LNR to TNM staging in SEER regions input survival as a “presumed alive” date (no
breast cancer survival for a diverse patient population, which death certificate or autopsy of patient during the study period)

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Breast Cancer Survival Using Lymph Node Ratio 319

as the study end date, which was December 31, 2013. Other axillary lymph nodes. Of note, the use of neoadjuvant thera-
regions proceeded with active follow-up and gave “date of last pies will likely decrease the number of cases staged as distant
contact” (with the research staff) as date of survival. metastasis, a consideration for the refinement of future LNR
To incorporate LNR meaningfully into clinical practice, the research to be specific and attentive to regional node metasta-
relationship between ratios and changes in ability to predict sis. The success of LNR for the prediction of survival in the
overall survival must be defined. The AJCC reviews their nebulous and possibly less predictable intermediate stages
guidelines among multitudes of researchers and physicians to warrants research into a supplementary role as the impact of
update the system’s parameters on a regular basis. Reviews biologically-based intervention on prognosis changes the
have found the range of LNR between 0.20 and 0.65 to be the landscape of breast oncology. Further investigation should
most common cutoff points for increases and decreases in evaluate known breast can­cer subtypes that exhibit aggressive
overall survival [29]. Future studies should investigate and metastasis as well as survival rates for the concurrent usage of
suggest guidelines for evaluating these ratios. the AJCC and LNR staging systems.
Broad level analysis is limited by the inclusion of almost all
breast cancer types and levels of disease progression, which CONFLICT OF INTEREST
are factors that can inhibit the usefulness of LNR in survival
prediction [23]. It should be understood that the patient pop- The authors declare that they have no competing interests.
ulation chosen for analysis excluded those with in situ and lo-
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