Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
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 4 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. Belgian Journal of Medical Oncology 130 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. Belgian Journal of Medical Oncology Volume 8, Issue 4, September 2014 131 4