Download Predictors of lymph node metastasis in patients with breast cancer

Oncothesis
Predictors of lymph node
metastasis in patients with
breast cancer
A. Smeets, MD, PhD1,2
The aim of this PhD-project was to identify predictors of lymph node metastasis in patients with breast
cancer and to integrate these findings in the surgical management of the axilla.
In first phase, we aimed to provide more insight in the biology of lymph node metastasis. We performed
gene and miRNA expression profiles of primary tumour tissue and showed that lymph node involvement
is not a genetically random process. In a next step, we built a model to predict lymph node involvement
based on clinicopathological variables. Tumour size, presence of lymphovascular invasion, multifocality
and the location of the tumour in the breast emerged as independent predictors of the lymph node status.
Additionally, our data provided evidence that the axillary lymph node status is not only a reflection of the
chronological age of a tumour, but also of tumour biology. We then demonstrated that the macrophage
density in primary tumour tissue is related to mitotic grade, but not to lymph node status.
In second phase, we aimed to optimise axillary surgery policy in patients with breast cancer. We showed
that sentinel lymph node biopsy is at least as accurate as axillary lymph node dissection to detect positive
lymph nodes. Additionally, we developed an algorithm for a tailored surgical approach of the axilla. We
suggested omitting completion axillary lymph node dissection in a subgroup of patients with a positive
lymph node and a low risk of positive non-sentinel lymph nodes. Finally, our findings indicated that implementation of a tailored surgical approach to the axilla results in significant inter-institutional differences.
(Belg J Med Oncol 2014;8(4):129-31)
Introduction
The axillary lymph node status is the most important
prognostic factor in patients with breast cancer. It remains controversial as to whether or not the relatively
poor prognosis of patients with lymph node positive
breast cancer is due to an increased biological aggressiveness of the tumour, to a higher chronological age at
diagnosis, or a combination of these factors. In addition,
it is unclear whether or not the lymph node status serves
as a marker of the host’s immune response.
None of the classic clinicopathological features has attained enough strength to be adopted as criteria to decide
1
in which patients axillary surgery may be avoided.
Emerging and promising factors that correlate with tumour progression are genetic- and microenvironmentrelated factors. The gene expression profile of a primary
tumour and the pattern of micro interference RNA
(miRNA) expression can be used to predict the metastatic potential of a tumour but it is unclear whether it
can also predict nodal metastasis. The microenvironment
seems to have a key role in cancer development and
spread. More specifically, it has recently been shown
that tumour-associated macrophages play a crucial role
in lymphatic metastasis.
Multidisciplinary Breast Centre, KULeuven, University Hospitals Leuven, Leuven, Belgium, 2Department of Oncology, KULeuven, Surgical Onco-
logy, University Hospitals Leuven, Leuven, Belgium.
Please send all correspondence to: A. Smeets, MD, PhD, University Hospitals Leuven, Surgical Oncology, Campus Gasthuisberg, Herestraat 49,
3000 Leuven, Belgium, tel: +32 1 634 68 32, fax +32 1 634 68 34, email: [email protected].
Conflict of interest: The author has nothing to disclose and indicates no potential conflict of interest.
Keywords: ALND, breast cancer, lymph node metastasis, sentinel.
Belgian Journal of Medical Oncology
Volume 8, Issue 4, September 2014
129
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Oncothesis
In recent years, management of the axilla in the treatment of breast cancer has become an evolving issue.
Since the routine clinical use of the sentinel lymph
node (SLN) biopsy, questions have been raised concerning the upstaging of a subset of patients with negative lymph node status on the one hand and an increase
in the overall percentage of patients with positive lymph
node status on the other hand. Moreover, recent trials
have shown that not all patients with positive SLN need
a completion axillary lymph node dissection (ALND). A
tailored surgical approach with careful risk-benefit assessment and aiming at high accuracy and low morbidity is
becoming the guiding principle in modern management
of the axilla for women with early breast cancer.
Biology of lymph node metastasis
We first performed gene and miRNA expression profiles of primary tumour tissue and evaluated whether it
is possible to predict the lymph node status based on
these expression profiles.1 We have shown that there
are measurable differences in gene expression profiles
between patients with node-negative and node-positive
breast cancer. As a result, lymph node involvement is
not a genetically random process. The performance of
our model was rather poor (area under the ROC curve
(AUC) of 0.66). This indicates that, besides tumour genetics, other factors influence lymph node involvement.
An integrated analysis of microarray and miRNA expression profiles pointed to general deregulation of the
miRNA expression machinery in the process of lymph
node metastasis.
Next, we aimed to determine clinical and pathological
features predictive of axillary lymph node involvement.2
Four variables emerged as independent predictors of the
lymph node status: tumour size, presence of lymphovascular invasion, presence of multiple foci and location
of the tumour in the breast. Based on these results, we
built a model to predict lymph node involvement based
on clinicopathological variables (AUC 0.78).
We then evaluated the impact of variables of tumour
chronology (tumour size) and biology (tumour grade,
lymphovascular invasion and the hormone receptor
status) on the lymph node status.3 We built a model to
predict lymph node involvement based on pathological
tumour size (AUC 0.67). Based on variables of tumour
biology, axillary lymph node status could be predicted
with an AUC of 0.68. Combining these variables, an
AUC of 0.74 was calculated.
In the preoperative setting, the lymph node status could
only be predicted with an AUC of 0.64. Consequently,
clinicians should omit using tumour size as criterion to
select patients for SLN biopsy.
To analyse whether the immune response of the host
on the tumour influences the process of lymph node
metastasis, we measured the expression of a panel of
cytokines in plasma. We observed a non-significant association between CCL5 levels and lymph node involvement (p0.077). Therefore, we further investigated
the correlation between CCL5 expression in plasma and
clinicopathological characteristics. Our results suggest
that CCL5 is a biomarker for tumour load rather than
for lymph node involvement.
To study the microenvironment, we evaluated the macrophage density in primary tumour tissue from patients
with bilateral synchronous tumours and calculated the
correlation with clinicopathological variables. The number of CD68 and CD163 positive macrophages strongly
correlated with tumour grade. Additionally, we showed
that the tumour associated macrophage density is dominated by the tumour and not by the immune response
of the host.
Surgical management of the axilla
We aimed to optimise axillary surgery policy in patients
with breast cancer. We showed that axillary staging
with SLN biopsy is at least as accurate as with ALND.5
The results of this study even suggested a higher probability of finding positive lymph nodes with the SLN
biopsy procedure.
The principle area of controversy in surgical management
of the axilla is the management strategy for patients
with positive SLN. We recommended an algorithm for
a tailored surgical approach of the axilla.6 We subsequently suggested omitting completion ALND in a subgroup of patients with a positive SLN and a low risk of
positive non-SLNs. To evaluate whether it was safe to
implement our algorithm, we performed a retrospective
simulation of this policy on two cohorts of patients.
This resulted in significant inter-institutional differences.
In one breast cancer centre, the proposed algorithm
seemed safe. On the contrary, in the other breast cancer
centre, the proposed strategy did not seem safe at all.
Therefore, we would suggest that each centre tests and
verifies guidelines before implementing them in clinical
practice.
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Volume 8, Issue 4, September 2014
Key messages for clinical practice
1.
Clinicians should omit using tumour size as criterion to select patients for sentinel lymph node
biopsy.
2.
Surgeons should be encouraged to implement the sentinel lymph node biopsy procedure for
axillary staging in most patients with a clinically node-negative tumour.
3.
It is safe to omit completion axillary lymph node dissection in a subgroup of patients with a
positive sentinel lymph node and a low risk of positive non-sentinel lymph nodes. However,
each centre should test and verify guidelines before implementing them in clinical practice.
Conclusion
We showed that lymph node involvement is not a genetically random process. Additionally, our data provided
sufficient evidence that the axillary lymph node status is
not only a reflection of the chronological age of a tumour,
but also of tumour biology.
Next, our data clearly indicates that tumour-associated
macrophages density is related to mitotic grade, and not
to lymph node status.
Our data demonstrated that SLN biopsy is at least as
accurate as ALND to detect positive lymph nodes. Additionally, we have shown that primary tumour size is
only a fair predictor of lymph node status. Finally, our
findings indicate that implementation of a tailored surgical approach to the axilla results in significant interinstitutional differences.
References
1. Smeets A, Daemen A, Vanden Bempt I, et al. Prediction of lymph node involvement in breast cancer from primary tumour tissue using gene expression
profiling and miRNAs. Breast Cancer Res Treat. 2011;129(3):767-76.
2. Yoshihara E, Smeets A, Laenen A, et al. Predictors of axillary lymph node
metastases in early breast cancer and their applicability in clinical practice. The
Breast. 2013;22(3):357-61.
3. Smeets A, Ryckx A, Belmans A, et al. Impact of tumour chronology and tumour
biology on lymph node metastasis in breast cancer. Springerplus. 2013;2:480.
4. Smeets A, Brouwers B, Hatse S, et al. Circulating CCL5 levels in patients with
breast cancer: is there a correlation with lymph node metastasis? ISRN Immunology. 2013;Article IK 453561.
5. Smeets A, Yoshihara E, Laenen A, et al. Is the SLN biopsy more sensitive for
the identification of positive lymph nodes in breast cancer than the ALND?
Springerplus. 2013;2: 275.
6. Smeets A, Carly B, Cocquyt V, et al. The changing role of the ALND in the
treatment of breast cancer. Belg J Med Oncol. 2012;6:87-95.
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Volume 8, Issue 4, September 2014
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