Correlation of paracancerous area ultrasound characteristics and the 21-gene recurrence score: the clinical value for early-stage luminal A invasive breast cancer

Introduction

Breast cancer, the most prevalent cancer among women globally, has an annual incidence exceeding 20,000 cases (1), accounting for about 25% of all female cancers (2). In recent years, due to continuous advancements in diagnostic and therapeutic technologies, breast cancer management has entered the era of molecular subtyping. Estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative luminal A breast cancer accounts for approximately 70% of breast cancer cases and represents the most common molecular subtype (3,4). When managed effectively, patients with this subtype exhibit the highest survival rates among all subtypes.

Over the past decade, there have been significant shifts in the diagnostic and treatment approaches for breast cancer. The conventional anatomical staging and histological classification used for breast cancer can no longer meet the demands for precise prognostic assessment and individualized treatment decisions due to the highly heterogeneous molecular nature of the disease. With the rapid development of high-throughput gene analysis technologies, various multigene expression profiles for breast cancer have been gradually introduced into clinical practice. The Oncotype DX Breast recurrence risk score (RS) based on the 21-gene assay has been validated for assessing long-term recurrence risk in patients with luminal A breast cancer and guiding chemotherapy decisions (5-8), showing significant correlation with local recurrence risk (9). However, conducting the 21-gene test for all patients with early-stage luminal A invasive breast cancer involves substantial costs (10), and there is a scarcity of research exploring cost-saving strategies (11).

The development of a noninvasive, convenient, and cost-effective preoperative assessment has garnered increased attention. Ultrasound (US) is a simple, radiation-free, noninvasive method. Real-time imaging technique is the preferred method for breast cancer screening and diagnosis in women. Conventional US, elastography (UE), and contrast-enhanced US (CEUS) are widely accepted and recognized by patients and clinicians as common methods for detecting breast lesions and evaluating the efficacy of chemotherapy. Preliminary studies have indicated that both US imaging features and molecular expression in the paracancerous area (PA) of breast cancer differ from those in the tumor area (12-15). However, research on the US imaging features of the PA and their association with tumor prognosis is limited (16).

Therefore, with this context, we investigated the clinical significance of US imaging features in the PA and the RS in breast tumors. The aim of this study was to clarify the correlation between RS and information extracted from paracancerous US, UE, and CEUS imaging characteristics. The aim was to predict the recurrence risk of early-stage luminal A invasive breast cancer through US features. We present this article in accordance with the STARD reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-870/rc).

Methods

Patients

Patients diagnosed with early-stage invasive breast cancer by surgical pathology from October 2020 to September 2022 at Ruijin Hospital, Lu Wan Branch, and who underwent diagnostic breast US and subsequent 21-gene testing were consecutively included.

The other inclusion criteria were as follows: (I) invasive breast cancer; (II) administration of either breast-conserving surgery or radical surgical treatment; (III) ER-positive and HER2-negative status; (IV) preoperative US, UE, and CEUS; and (V) postoperative 21-gene RS testing.

Meanwhile, the exclusion criteria were as follows: (I) pT staging of Tis, T1a, or T4; (II) pN staging of N2 or N3; (III) metastatic breast cancer; and (IV) administration of any form of neoadjuvant therapy before surgery.

US examination

Instruments, contrast agents, and imaging methods

The US examination was conducted with the Aplio500 US diagnostic system (Canon Medical Systems Corp., Otawara, Japan) equipped with a linear array transducer operating within a frequency range of 10.0–18.0 MHz. This apparatus features strain UE technology, real-time contrast imaging capabilities, and incorporates time-intensity curve (TIC) analysis software for postcontrast TIC analysis. The contrast mode employs a mechanical index spanning from 0.06 to 0.08. The contrast agent employed was a second-generation US contrast agent, SonoVue (Bracco, Italy), administered as a bolus injection of 4.8 mL through the antecubital vein, which was followed by a 10 mL saline flush.

Image analysis

All examinations were conducted by two radiologists, each possessing over 10 years of experience in breast US and CEUS. In case of any discrepancies, a third radiologist, specializing in breast CEUS for 15 years, reviewed the imaging data independently. Consensus was reached through joint review and discussion to resolve any disparities. All radiologists were blinded to patient information and other imaging results.

Conventional US assessment was conducted following the guidelines of the American College of Radiology’s Breast Imaging Reporting and Data System (BI-RADS). Since this study focused on the PA, the evaluation of suspected lesions mainly included tumor size (maximum diameter), margin definition (circumscribed or not circumscribed), presence of echogenic halo (present or absent) (Figure 1A), and peritumoral vascularity (present or absent) (Figure 1B).

Figure 1 Images from a 44-year-old woman with early-stage luminal A invasive breast cancer. (A) US characteristics in PA. The red arrows indicate an echogenic halo in the PA, a characteristic reflective area surrounding the tumor. (B) US characteristics in PA. The green arrow points to peritumoral vascularity, highlighting the blood vessels adjacent to the tumor. (C) UE characteristics in PA. The black arrows denote an enlarged stiff area, suggesting a region of increased tissue rigidity. (D) CEUS characteristics in PA. The blue arrows illustrate the scope of enhancement, likely indicating areas of increased blood flow or cellular activity as seen on the imaging enhancement scope. CEUS, contrast-enhanced ultrasound; PA, paracancerous area; UE, elastography; UA, ultrasound.

For UE assessments, we used the Breast Strain UE Evaluation Methods and Optimal Thresholds outlined in the 2018 European Federation of Societies for US in Medicine and Biology (EFSUMB) Guidelines and Recommendations on the Clinical Use of US UE (17). The process entailed computing the ratio derived from the lesion size observed in UE divided by the lesion size as identified in B-mode US (E/B ratio). The evaluation was aimed at identifying suspected lesion areas with an enlarged, stiff area (Figure 1C). A ratio greater than 1 was considered to indicate the presence of an enlarged stiff area, while a ratio of 1 or less indicated an absence. Additionally, the assessment extended to measuring the elastic strain ratio between the 1 cm periphery around the tumor’s edge and the distant normal tissue (comprising glandular tissue and surrounding fat tissue), with 3 serving as the critical threshold. Measurements were obtained three times to derive an average value for accuracy.

CEUS evaluation included an analysis of both qualitative and quantitative parameters. Qualitative parameters included the peritumoral zone boundary (clear or blurred), penetrating vessels (present or absent), enhancement intensity (hypoenhancement or not), enhancement scope [enlarged or not; enlargement scope was defined as an increase of ≥3 mm in length or width as compared to conventional US measurements (18-20)], and radial peripheral perfusion (present or absent; radial peripheral perfusion was defined as a spoke-wheel pattern extending outward from the lesion (21,22) (Figure 1D).

Quantitative parameters were derived from the analysis of the TIC in the PA, with a specific focus on the area under the curve (AUC). These parameters included the following: (I) peak intensity (PI), maximum intensity of the TIC; (II) TTP, the time needed to reach PI from the time the first microbubble reached the lesion; (III) sharpness, the maximum wash-in velocity; (IV) MTT, the time for which intensity is higher than the mean value; and (V) AUC, the area formed between the TIC and the horizontal axis. The curve to the left of the PI’s projection on the horizontal axis, showing an ascending trend, is the wash-in curve, with its area referred to as the area under the wash-in curve (AWI); the curve to the right, showing a descending trend, was the washout curve, with its area referred to as the area under the washout curve (AWO).

For pathological diagnosis, 21-gene assay, and RS, all pathological results were diagnosed according to the eighth edition of the American Joint Committee on Cancer (AJCC) standards for histological grading and clinical staging of tumors (23). The 21-gene testing involved the assessment of the expression levels of 21 genes associated with breast conditions from breast tissue specimens obtained from the Pathology Department via real-time quantitative polymerase chain reaction (RT-qPCR) technology. Subsequently, the RS was calculated. The 21-gene RS assessment was conducted according to the National Comprehensive Cancer Network (NCCN) guidelines, St. Gallen consensus, American Society of Clinical Oncology (ASCO) guidelines, and the TAILORx and RxPONDER studies (24,25). Patients were stratified based on the RS scoring results (low-recurrence risk group with RS ≤25 and high-recurrence risk group with RS >25).

This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments, and was approved by the Institutional Review Board (IRB) of Ruijin Hospital Lu Wan Branch, Shanghai Jiao Tong University School of Medicine (No. LWEC2020026). Patients provided written informed consent to participate in the study before US examinations.

Statistical analysis

Data analysis was conducted with SPSS 25.0 (IBM Corp., Armonk, NY, USA) and Excel 2016 (Microsoft Corp., Redmond, WA, USA). Quantitative data (such as PI and MTT) are expressed as the mean ± standard deviation and were statistically analyzed via the independent samples t-test. Categorical data (such as margins and high-echo halos) are expressed as numbers with percentages and analyzed with the chi-squared (χ²) test. Receiver operating curve (ROC) curve analysis was performed on variables that differed in the multivariate logistic regression, with GraphPad Prism 8 (Dotmatics, Boston, MA, USA) used for ROC curve plotting. In this study, a P value of less than 0.05 was considered statistically significant.

Results

Patients’ clinical data

A total of 194 patients with early-stage luminal A invasive breast cancer were recruited in this study (Table 1), including 182 cases of invasive ductal carcinoma, 5 cases of invasive lobular carcinoma, and 7 cases of papillary carcinoma. All patients were female, ranging in age from 22 to 77 years, with an average age of 47±13.20 years. The maximum tumor diameters ranged from 6.7 to 55.6 mm, with an average of 20.45±13.65 mm.

Breast cancer PA US characteristics of the RS groups

In the conventional US presentation of the PA in breast cancer, a significant difference was observed in the incidence of echogenic halos (Figure 1A), with 78.8% (41/52) in the RS >25 group and 55.6% (79/142) in the RS ≤25 group (P=0.003). No significant differences were found between the groups in terms of margin (P=0.326) or peritumoral vascularity (P=0.531) in the PA (Table 2).

In UE, the proportion of an enlarged stiff area in the PA was 76.9% (40/52) in the RS >25 group, which was significantly higher than the 56.3% (80/142) in the RS ≤25 group (P=0.009) (Figure 1C). However, the elastic strain ratio in the PA showed no significant difference between the groups (P=0.588).

In CEUS, the incidence of patients showing enlarged enhancement scope was significantly higher in the RS >25 group (43/52, 82.7%) than in the RS ≤25 group (P=0.010) (Figure 1D), as was radial peripheral perfusion (65.4%, 34/52) (P=0.047). No significant differences between the two groups were noted in terms of boundary (P=0.139), penetrating vessels (P=0.562), or enhancement intensity (P=0.276). In terms of quantitative parameters, the RS >25 group exhibited higher PI values (P=0.038) and lower TTP values (P=0.030) compared to the RS ≤25 group, while other characteristics including MTT (P=0.244), sharpness (P=0.111), AUC (P=0.719), AWI (P=0.365), and AWO (P=0.883) showed no significant differences between the two groups.

The correlation between breast cancer PA US features and RS

As indicated in Table 3, a multivariate logistic regression analysis was conducted to identify the independent risk factors for RS >25. The final results indicated that compared to patients with circumscribed margins, those with noncircumscribed margins had a significantly increased likelihood of presenting with an RS >25 [95% confidence interval (CI): 0.108–0.726]. Patients exhibiting an echogenic halo in US had a 4.700-fold (95% CI: 2.331–13.937) increased risk of having RS >25 as compared to those without an echogenic halo. Patients with an enlarged stiff area in UE exhibited a 4.444-fold increased risk (95% CI: 2.204–13.446) of having an RS >25 as compared to those without such findings. Among CEUS features, the absence of hypoenhancement intensity was linked to a 1.899-fold increased risk (95% CI: 1.069–7.862) of an RS >25 as compared to the presence of hypoenhancement intensity. Additionally, the presence of enhancement scope, as compared to its absence, was associated with a 3.694-fold increased risk (95% CI: 1.831–12.030) of an RS >25. The quantitative parameter, PI, was identified as an independent diagnostic factor for an RS >25.

The six indicators correlated with RS in the multivariate regression analysis were included in the ROC curve analysis. In a logistic regression combined analysis, the AUC for RS >25 was predicted to be 0.815, with a 95% CI ranging from 0.746 to 0.883 (P<0.001). The model demonstrated a sensitivity of 75.0% and a specificity of 80.3% (Figure 2).

Figure 2 The area under the ROC curve of the logistic regression equation was 0.815, with a specificity of 0.803 and a sensitivity of 0.750. ROC, receiver operating characteristic.

Discussion

In recent years, advances in imaging technology have allowed for a greater number of early-stage breast cancers to be detected, making preoperative treatment choices and prognosis prediction particularly important. However, research on the US characteristics related to the prognosis of patients with luminal A breast cancer remains scarce. Our study sought to determine the association of US features of the PA in breast cancer with the 21-gene RS to predict the prognosis of breast cancer. The findings demonstrated that the US features of the PA differ significantly between the RS ≤25 and RS >25 groups among patients with early-stage luminal A invasive breast cancer. Logistic regression analysis identified echogenic halo, margin, enlarged stiff area, enhancement intensity, enhancement scope, and PI values as independent diagnostic factors for the RS >25. In the combined logistic regression analysis, the predicted AUC for RS >25 was 0.815, with a sensitivity of 0.750 and a specificity of 0.803.

Our study found that the incidence of echogenic halo was 78.8% in the RS >25 group as compared to 55.6% in the RS ≤25 group (P<0.05). In the multivariate analysis, patients with noncircumscribed margins were 3.57 times more likely to have an RS >25 than were those with circumscribed margins. Li et al. (26) reported that the presence of a high-echo halo surrounding breast cancer is a significant predictor of malignancy. The visibility of this halo is inversely correlated with the level of differentiation of the cancer cells (27). Based on the level of cellular differentiation, tumors are categorized into well-differentiated, moderately differentiated, and poorly differentiated types, with prognosis worsening progressively. Malignant tumors are often characterized by the absence of the basement membrane and rapid cellular proliferation. The rapidly proliferating cells release endothelial growth factors and induce the release of vascular permeability factors, which may explain the occurrence and development of focal edema around malignant tumors. This manifests in US images as an echogenic halo and noncircumscribed margins. Pathologically, tumors with poorer differentiation exhibit a greater severity of pathological changes in their surroundings, thereby correlating with an increased risk of RS recurrence.

Multiple studies have confirmed that in the assessment of UE, the paracancerous tissue may exhibit areas of increased stiffness (28,29) or present with a “stiff rim” sign (30,31). In our study, the occurrence of enlarged stiff areas was 76.9% (40/52) in the RS >25 group, significantly higher than the 56.3% in the RS ≤25 group (P<0.05). Pathologically, the biological basis at the edges of the tumor mass is associated with the proliferative response, proportion, and arrangement of the fibrous connective tissue surrounding the tumor (32). Cancer-associated fibroblasts at the tumor margin play a critical role in tumor progression. They interact with cancer cells through paracrine signaling by secreting various growth factors and cytokines. This interaction promotes continuous tumor growth and invasion, facilitates distant metastasis, and induces immune suppression. In addition, these fibroblasts participate in the induction of epithelial-mesenchymal transition, which further enhances the migratory and invasive capabilities of tumor cells. It has been found that the deposition of collagen fibers and the infiltration of myofibroblasts in the peritumoral tissue are closely related to the occurrence and progression of breast cancer (33). The tumor microenvironment is predominantly characterized by the malignant stromalization and heterogeneous angiogenesis, with the margin zone exhibiting features of invasive growth (34,35), all of which play a significant role in the invasion and metastasis of tumor cells. The interstitial infiltration of cancer cells contributes to increased stiffness in the PA. Consequently, the US reveals an expanded area of stiffness surrounding the tumor mass. This may explain the association between a higher risk of recurrence and the presentation of increased stiffness in the PA.

Our study indicates that for CEUS images, the RS >25 group exhibited enlarged enhancement scope and radial peripheral perfusion at rates of 82.7% (43/52) and 65.4% (34/52), respectively, significantly higher than those in the RS ≤25 group. Additionally, the PI values were higher in the RS >25 group, while the TTP values were lower (P<0.05). The peritumoral infiltration zone figures prominently in the tumor immune microenvironment framework of breast cancer development and progression. In this zone, a significant production of vascular endothelial growth factor stimulates the proliferation of new blood vessels. This vascular proliferation manifests as radiating or intertwining vessels around the tumor’s periphery, with some vessels branching through the tumor area itself. Certain rapidly growing segments of the tumor require an increased blood supply, which leads to the development of prominent feeding vessels in the PA (36). These vessels contribute to enhanced proliferative activity, resulting in an elevated microvessel density (MVD) in the vicinity of the tumor (37). Since CEUS is based on microvascular perfusion, the PA on CEUS typically shows an expanded area of enhancement. These processes are not only the physical basis for tumor growth and dissemination but also a significant part of the regulation and interaction within the tumor immune microenvironment. Cases with radial peripheral perfusion in the PA are more frequent, and those with higher proliferative activity have an increased risk of recurrence, with a higher proportion exhibiting peripheral perfusion characteristics. Consequently, cases with a higher risk of recurrence tend to exhibit shorter peak times and higher PI in contrast perfusion, aligning with the findings of Jia et al. (38).

This study involved certain limitations due to its single-center design. In the future, if possible, we will increase the sample size and obtain samples from multiple centers to reduce research bias. Additionally, our analysis focused on imaging features and did not incorporate clinical parameters such as tumor grade, lymph node status, or Ki-67 index. As the dataset grows, we plan to include a wider range of clinical factors to develop a more comprehensive and reliable predictive model.

Conclusions

The US evaluation of the PA can be valuable for preoperative assessment and prognostic prediction. Consequently, for patients exhibiting these US features, clinicians should be particularly wary and potentially adopt more aggressive therapeutic strategies, along with enhanced postoperative surveillance and regular follow-up.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STARD reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-2025-870/rc

Data Sharing Statement: Available at https://qims.amegroups.com/article/view/10.21037/qims-2025-870/dss

Funding: This work was supported by the program of Shanghai Municipal Health Commission (No. 202340290), Shanghai Huangpu District Top-notch Medical Talent Program (No. 2023BJ03), Key Specialty Construction in Shanghai Huangpu District (No. 2023ZDZK02), and the National Natural Science Foundation of China (No. 82071928).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-870/coif). All authors report that this work was supported by the program of Shanghai Municipal Health Commission (No. 202340290), Shanghai Huangpu District Top-notch Medical Talent Program (No. 2023BJ03), Key Specialty Construction in Shanghai Huangpu District (No. 2023ZDZK02), and the National Natural Science Foundation of China (No. 82071928). The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This retrospective study was approved by the Institutional Review Board (IRB) of Ruijin Hospital Lu Wan Branch, Shanghai Jiao Tong University School of Medicine (No. LWEC2020026). Patients provided written informed consent to participate in the study before US examinations.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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