Factors Influencing Lymph Node Positivity in HER2/neu+ Breast Cancer Patients.

Article Factors Influencing Lymph Node Positivity in HER2/neu+ Breast Cancer Patients Katherine Englander 1 , Neha Chintapally 1 , Julia Gallagher 1 , Kelly Elleson 2 , Weihong Sun 2 , Junmin Whiting 3 , Christine Laronga 2 and Marie Catherine Lee 2, * 1 2 3 * University of South Florida Morsani College of Medicine, Tampa, FL 33602, USA Department of Breast Oncology, Moffitt Cancer Center, Tampa, FL 33612, USA Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, FL 33612, USA Correspondence: Abstract: Axillary lymph node metastases are a key prognostic factor in breast cancer treatment. Our aim was to evaluate how tumor size, tumor location, and imaging results correlate to axillary lymph node diseases for patients with stage I-III HER2/neu+ breast cancer. This is a single-institution retrospective chart review of female breast cancer patients diagnosed with primary invasive Her2/neu+ breast cancer who were treated with upfront surgical resection from 2000–2021. Of 75 cases, 44/75 (58.7%) had nodal metastasis, and there was a significant association of larger tumor size to nodal metastases (p ≤ 0.001). Patients with negative nodes had a smaller mean tumor size (n = 30; 15.10 mm) than patients with positive nodes (n = 45; 23.9 mm) (p = 0.002). Preoperative imaging detected suspicious nodes in 36 patients, and ultrasound detected the most positive nodes (14/18; p = 0.027). Our data confirms that tumor size at diagnosis is correlated with a higher likelihood of axillary involvement in patients with Her2/neu+ breast cancer; notably, a large proportion of Her2/neu+ breast cancers have metastatic involvement of axillary lymph nodes even with small primary lesions. Keywords: breast cancer; axillary lymph node metastasis; HER2/neu+ 1. Introduction Citation: Englander, K.; Chintapally, N.; Gallagher, J.; Elleson, K.; Sun, W.; Whiting, J.; Laronga, C.; Lee, M.C. Factors Influencing Lymph Node Positivity in HER2/neu+ Breast Cancer Patients. Curr. Oncol. 2023, 30, 2825–2833. https://doi.org/10.3390/ curroncol30030215 Received: 13 January 2023 Revised: 14 February 2023 Accepted: 24 February 2023 Published: 27 February 2023 Copyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). Breast cancer is the most common cancer affecting women worldwide, with an incidence in North America in 97 out of 100,000 women [1]. Mortality has decreased due to improved screening, prevention, and treatments [1]. Nodal involvement is one of the best prognostic factors in breast cancer because the lymph nodes in the axilla are often the first place that cancer cells may spread to from the breast. Many factors that influence nodal involvement have been evaluated, including tumor size, distance from the nipple, location, and receptor subtype. Tumor size has been shown to be a predictor of nodal involvement in several studies [2–5]. Smaller tumor distance to the nipple has also been reported as an independent predictor of axillary nodal involvement [5]. Studies have conflicting results on the tumor location associated with the highest likelihood of nodal disease. Both the retro-areolar and upper-outer quadrant or axillary tail have been reported to correlate with higher nodal involvement [2,4]. Breast cancer is divided into categories based on receptor subtype, which were initially used to guide only systematic treatment, but are increasingly being considered in surgical management as well. The receptors frequently targeted by treatment are the estrogen receptor (ER), progesterone receptor (PR), and the cell surface protein ERRB2, commonly known as HER2/neu. Breast cancers are classified into four groups by gene expression analysis, however, surrogate classification based on immunohistochemistry is an accepted clinical practice. Luminal A and Luminal B tumors are typically ER positive and PR positive (and HER2/neu negative), triple negative (ER/PR/HER2neu negative), and HER2/neu positive. HER2/neu is overexpressed in 20% of breast cancers [6]. HER2/neu is a tyrosine kinase receptor that activates genes involved in growth and differentiation of cells [6]. The Curr. Oncol. 2023, 30, 2825–2833. https://doi.org/10.3390/curroncol30030215 https://www.mdpi.com/journal/curroncol Curr. Oncol. 2023, 30 2826 overactivation of this receptor leads to increased angiogenesis, invasion, and proliferation of tumor cells [6]. Consequently, the HER2/neu+ subtype is associated with higher rates of early recurrence and metastasis [6]. Several studies have shown that HER2/neu positivity correlates with higher lymph node positivity [3,4,7]. The treatment and evaluation of patients with negative nodal involvement or 1–2 positive lymph nodes has evolved over recent years. Sentinel lymph node biopsy (SLNB) is often used to stage breast cancer. The prevalence of additional axillary metastasis in patients with positive sentinel lymph nodes has been reported to be 14.7–50.3% depending on the size of the metastasis in the SLN and the number of sentinel nodes with metastasis [8]. SLNB done without axillary lymph node dissection is now the standard for patients with clinically negative axillary lymph nodes (ALN), particularly those undergoing breast conserving surgery [9]. The necessity of SLNB in the radiologically negative axilla has been further investigated by many studies [10,11] Pooled data from four trials including 5139 patients suggests that pre-operative axillary ultrasound (AUS) has a negative predictive rate of 0.951 (95% confidence interval 0.941–0.960) [10]. It has also been suggested that patients with a radiologically positive axilla may progress straight to ALND without SLNB, but the false positive rates of imaging currently lead to 43.2% of patients undergoing unnecessary nodal clearance [12]. Because nodal burden is correlated with more advanced disease and a higher likelihood of recurrence, the accuracy of preoperative imaging must be further examined before using it to guide treatment [13]. A relationship between tumor size, location, distance to the nipple, and receptor status to nodal disease have all been established in the literature. However, these relationships have all been reported independent of hormone receptor subtype. Breast cancer is a complex and heterogenous disease, with different subtypes and molecular mechanisms. It is of interest to identify potential biological markers that can predict lymph node metastases [14]. Further evaluation of the behavior of specific subtypes of breast cancer is necessary to individualize treatment of patients. This is particularly important in the HER2/neu positive subtype, as these patients often experience earlier recurrence and higher rates of metastasis [3]. The primary aim of our study was to evaluate the relationship between tumor siz (...truncated)