Model based on ultrasound and clinicopathological characteristics for early prediction of pathological complete response to neoadjuvant chemotherapy in breast cancer

Introduction

The rate of incidence of breast cancer (BC) ranks first among incidence rates for female malignant tumors globally, and is one of the leading causes of death from female cancers (1). Neoadjuvant chemotherapy (NAC) is a routine treatment for BC. Pathological complete response (pCR) after NAC can downstage the tumor, increase surgical opportunities, and improve the breast preservation rate. Therefore, predicting pCR following NAC can be valuable for identifying patients who achieve pCR and may potentially be eligible for less invasive surgical options or personalized post-treatment plans. Additionally, it is crucial to balance the need to minimize chemotherapy-related toxicity with the risk of under-treating patients who are effectively responding to the treatment (2). Accurate evaluation of pCR enables timely adjustment of treatment strategies and is of great value in reducing chemotherapy-related toxicity in insensitive patients. At present, assessment of the efficacy of NAC is mainly based on the response evaluation criterion in solid tumors (RECIST) (3), which evaluates the tumor’s response to NAC by measuring the maximum change in diameter of the lesion. Among the commonly used methods in clinical practice to assess the changes in size of breast lesions [palpation, mammography, ultrasound (US), and magnetic resonance imaging (4)], conventional US has emerged as an essential evaluation method owing to its advantages of cost-effectiveness, convenience, and being non radiation-based (5). In addition, it can provide information on various characteristic changes that occur during NAC in breast lesion morphology, internal structure, and blood supply (6,7). This study aims to construct an early prediction model of pCR of NAC in BC based on US and clinicopathological characteristics at baseline and US features after one cycle of NAC, to provide a reference for timely clinical decision-making. We present this article in accordance with the TRIPOD reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-24-1268/rc).

Methods

The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study design and protocol were approved by the Fifth Hospital Affiliated Ethics Committee of Sun Yat-sen University Review Board (2023-K79-1), and the requirement for written informed consent was waived due to the retrospective nature of the study.

Patients and clinical data

Patients with BC confirmed by pathology who received NAC at the Fifth Affiliated Hospital of Sun Yat-Sen University from January 2022 to December 2023 were retrospectively collected. All patients who underwent US examination before and during NAC were divided into pCR and non-pCR groups according to the postoperative pathological remission status after NAC. The inclusion criteria were as follows: primary BC confirmed by pathological biopsy before NAC; availability of complete clinicopathological data and conventional US images (pre-NAC and after one cycle of NAC). The exclusion criteria were as follows: other treatments such as radiotherapy and endocrine therapy before NAC; incomplete NAC; no final surgical treatment; or inability to determine pCR status. All patients received either 6 or 8 cycles of NAC, following the regimen recommended by the Chinese Society of Clinical Oncology (CSCO) Breast Cancer guidelines 2022 (8). Preoperative neoadjuvant therapy was an option for patients who met any of the following criteria: large tumor size, axillary lymph node metastasis, human epidermal growth factor receptor 2 (HER2)-positive BC, triple-negative BC, or a desire to preserve breast function despite a large tumor size relative to breast volume. It’s important to note that NAC could be considered for primary breast tumors larger than 5 cm, while tumors measuring 2–5 cm required consideration of additional biological indicators to determine if preoperative drug treatment was appropriate. Patients with HER2-positive BC also received dual-targeted therapy with trastuzumab and pertuzumab. However, in some cases where dual-targeted therapy was not feasible due to specific patient factors, trastuzumab alone was administered. Age, tumor location, and clinical stage were recorded.

Histopathologic features and tissue specimens

For all patients, an US-guided biopsy of the target breast tumor was performed prior to NAC. Immunohistochemical (IHC) indices, including estrogen receptor (ER), progesterone receptor (PR), HER2, Ki67, and histological type and grade were collected from the pathology reports. After NAC and surgery, all BC lesions and regional lymph nodes were systematically sampled and prepared according to standardized protocols.

The Miller-Payne Grading System (9) was employed to assess tumor regression, with pCR defined as Miller-Payne Grade 5. This grade indicated a complete absence of invasive cancer in both the breast and regional lymph nodes. Specifically, pCR mean that after treatment, no residual invasive cancer cells were detected in the breast tissue or regional lymph nodes during pathological examination. It is important to note that the presence of in situ carcinoma, such as ductal carcinoma in situ, was not permitted in the definition of pCR. The diagnosis of pCR or non-pCR was based on a thorough pathological examination of the surgical specimens, including the breast and axillary lymph nodes, after NAC. The amount of embedded specimens was related to the surgical procedure, including all cancer lesions removed during breast-conserving surgery, all cancer lesions in specimens from modified radical mastectomy or extended mastectomy, and the dissected regional lymph nodes. The specific assessment protocol used by the pathologist involved systematic sampling and tissue embedding of all specimens, followed by serial sectioning and hematoxylin and eosin (H&E) staining. The tumor bed and regional lymph nodes were carefully evaluated under a microscope to determine the presence and proportion of invasive cancer components. When necessary, IHC was also used to confirm findings. Additionally, the pathologist assessed the degree of stromal fibrosis and inflammatory cell infiltration in the tumor, providing a comprehensive evaluation of the response to neoadjuvant therapy.

ER and PR status was assessed using IHC staining of tumor tissue samples, with a 1% positivity threshold for defining ER and PR positivity, according to the American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) guidline update 2020 (10). HER2 positive was defined as IHC 3+ or IHC 2+ with amplification by fluorescence in situ hybridization (FISH), and HER2 negative was defined as IHC 0, IHC 1+, or IHC 2+ with FISH negativity, according to the ASCO/CAP guidelines for HER2 testing in BC (11). The percentage of Ki67-stained cells out of the total counted tumor cells was considered to indicate the Ki67 status. According to the recommendations from the International Ki67 in Breast Cancer Working Group (12), Ki67 levels of ≤5% or ≥30% can be used to indicate prognosis, guide subsequent chemotherapy recommendations, and inform chemotherapy decisions after endocrine therapy, particularly in early-stage (stage I and II) BC. Additionally, the variability in IHC Ki67 assessments across different samples and laboratories was minimal at these thresholds, leading to the identification of these values as critical levels in the study.

US features and data

All patients had US examinations before and during NAC using high-frequency transducers (7–18 MHz) with several units (GE Healthcare, Philips Healthcare, Siemens, SuperSonic imaging, Esaote, and SonoScape). Two experienced doctors (who had over ten years of clinical experience in US-based diagnosis of BC at the time of this study) independently rescreened all the US images without access to the pathological results. The grayscale US features were recorded according to the 5^th BI-RADS lexicon (13). The color Doppler flow image (CDFI) was graded into four types (grade 0, 1, 2, 3) according to Adler’s classification (14). Discrepancies were resolved by joint consensus with one additional experienced ultrasonic doctor. The US features were recorded as follows: (I) pre-NAC: the maximum diameter measured with the US (mm), the anteroposterior diameter measured with the US (mm), echogenicity (hypoechoic or non-hypoechoic), shape (regular or irregular), orientation (parallel or non-parallel), margin (microlobulated/indistinct or angular/spiculated), posterior features (attenuation/combined feature or no feature/enhancement), microcalcification (present or absent), hyperechoic halo (presence or absence), and CDFI (Adler 0–1 or Adler 2–3); (II) after one cycle of NAC: the maximum diameter reduction (mm), the anteroposterior diameter reduction (mm), echogenicity change (yes or no), shape change (yes or no), orientation change (yes or no), margin (microlobulated/indistinct or angular/spiculated), posterior features (attenuation/combined feature or no feature/enhancement), microcalcification change (yes or no), hyperechoic halo change (yes or no), and CDFI change (downgraded from Adler 2–3 to Adler 0–1 or not).

Statistical analysis

SPSS 25.0 software was used for analysis. Continuous variables were expressed as mean ± standard deviation (SD) or median M (interquartile range, IQR) and the hypothesis tests were calculated using t-test or Mann-Whitney U-test. The categorical variables were expressed as percentages (%), and intergroup comparisons were conducted using the Chi-squared or Fisher’s exact test. P<0.05 was considered to indicate statistical significance. Using univariate analysis to identify US and clinicopathological characteristics associated with pCR, variables with P<0.05 were included in multivariate logistic regression analysis to identify independent factors associated with pCR and establish the predictive model. An receiver operating characteristic (ROC) curve was drawn to evaluate the prediction model’s performance, and the area under the curve (AUC) value greater than 0.8 was acceptable.

Results

Patient clinicopathological characteristics

A total of 74 patients (mean age ± SD, 52.07±9.80 years) ranging in age from 29 to 71 years old who received the complete NAC regimen were included in this study. All patients had pathologically confirmed invasive ductal carcinoma. Fifty-six of the included patients (75.68%) were treated by mastectomy with sentinel lymph node dissection and 18 (24.32%) underwent breast-conserving surgery. Postoperative pathology showed a breast pCR rate of 27.03% (20/74). In regard to the clinicopathological characteristics of the 74 patients with BC in Table 1, there was no statistical difference between the pCR and non-pCR groups in age, tumor location, clinical T stage, clinical N stage, histological type and grade, ER, PR, and Ki67 index (P>0.05). The proportion of HER2-positive patients in the pCR group was higher than in the non-pCR group (P=0.003).

US features

All 74 masses were included in the evaluation of conventional US features at baseline and after one cycle of NAC. (I) At baseline (pre-NAC), the tumor’s maximum and anteroposterior diameters were 7.30–90.40 mm (mean diameter: 31.17±14.26 mm) and 3.90–40.30 mm (mean diameter: 18.23±6.50 mm) measured by US. There was no significant difference between the pCR and non-pCR groups in terms of tumor size, echogenicity, shape, orientation, margin, microcalcification, hyperechoic halo, and CDFI; tumors with posterior acoustic enhancement and tumors with no posterior feature were more frequently observed in the pCR group, while in the non-pCR group, the posterior features of the tumor mainly were attenuated or combined (P=0.032) (Table 2). (II) After one cycle of NAC, the reductions in the tumor’s maximum diameter and anteroposterior diameter were −16.20 to 47.10 mm (mean reduction: 5.60±11.72 mm) and −15.30 to 25.30 mm (mean reduction: 4.30±5.96 mm), respectively, as measured with US. In the pCR group, the margin of the tumor was mainly angular or spiculated, while in the non-pCR group, the margin of the tumor mainly was microlobulated or indistinct (P=0.001). The proportion of microcalcification changes in the pCR group was lower than in the non-pCR group (P=0.045) (Table 3).

Univariate and multivariate analyses

For the univariate analysis, several variables were choosen for the multivariate model, such as tumor HER2 positivity, the presence of posterior acoustic enhancement or no feature at baseline, the maximum diameter reduction measured by US, the anteroposterior diameter reduction measured by US, microcalcification change, and angular or spiculated margin of the mass after one cycle of NAC (all P<0.05). Variables with P<0.05 in the univariate analysis were included in the binary logistic regression for multivariate analysis. In the multivariate analysis, tumor HER2 positivity, presence of posterior acoustic enhancement or no feature at baseline, the maximum diameter reduction measured by US, and the angular or spiculated margin of the lesion after one cycle of NAC were independent predictors of pCR (all P<0.05). As shown in the forest plot (Figure 1), tumor HER2 positivity, presence of posterior acoustic enhancement or no feature at baseline, the maximum diameter reduction measured by US, and the angular or spiculated margin of the lesion after one cycle of NAC were protective factors for pCR. Figure 2 displays representative US images of BC patients pre-NAC and after one cycle of NAC, illustrating the differences between patients in the pCR group and the non-pCR group.

Figure 1 Forest plot for multivariate logistic regression analysis. OR, odds ratio; CI, confidence interval; HER2, human epidermal growth factor receptor 2; NAC, neoadjuvant chemotherapy.

Figure 2 Changes in ultrasound characteristics of breast cancer before and after one cycle of NAC in pCR versus non-pCR cases. (A1,A2) The ultrasound feature changes of a breast cancer tumor that achieved pCR before and after one cycle of NAC: the tumor margin changed from microlobulated to angular, and the posterior echo characteristic changed from enhancement to no change. (B1,B2) Another pCR breast cancer tumor whose margin changed from indistinct before NAC to angular after one cycle of NAC. (C1,C2) A breast cancer tumor in pCR group with a microlobulated margin both before and after NAC. (D1,D2) A breast cancer tumor in non-pCR group with a microlobulated margin before NAC, which changed to spiculated after one cycle of NAC. (E1,E2) Another tumor in non-pCR group whose margin changed from angular before NAC to spiculated after one cycle of NAC. (F1,F2) A non-pCR tumor with a spiculated margin before NAC, which became indistinct after one cycle of NAC, with the posterior echo characteristic changing from attenuation to no change. pCR, pathological complete response; NAC, neoadjuvant chemotherapy.

Diagnostic performance

A prediction model was constructed using US and clinicopathological characteristics of tumors independently associated with pCR. Logit (p)=−1.442 + 2.226 × HER2 positive + 2.244 × presence of posterior acoustic enhancement or no feature of the mass + 0.078 × the maximum diameter reduction measured by US after one cycle of NAC + 2.249 × the angular or spiculated margin of the mass after one cycle of NAC. A ROC curve (Figure 3) drawn to assess the predictive efficacy indicated diagnostic performance with an AUC of 0.912 (0.842–0.982), sensitivity of 90.0%, and specificity of 79.6%, respectively.

Figure 3 The ROC curve of the predictive model. AUC, area under the curve; CI, confidence interval; ROC, receiver operating characteristic.

Discussion

The capacity of noninvasive methods to predict pCR after NAC in BC holds significant clinical implications. It can help identify patients who achieve pCR and may, in the future, be considered for less invasive surgical options or personalized post-treatment strategies. Additionally, it is crucial to balance the goal of reducing chemotherapy-related toxicity with the risk of insufficiently treating patients who are responding well to therapy. Conventional US is the most commonly used noninvasive imaging method for BC prior to administration of NAC, during NAC, and before surgery. Therefore, in this study, we sought to build a prediction model based on US features and clinicopathological characteristics for the pCR of NAC with the aim of early prediction of efficacy of chemotherapy, enabling chemotherapy-related toxicity to be minimized or avoided in chemotherapy resistant patients with BC. Independent predictors obtained by univariate and multivariate analyses were used as variables for the model. Our results showed that the model based on HER2 expression, posterior features of the mass pre-NAC, the reduction in diameter measured by US after one cycle of NAC, and the margin of the lesion after one cycle of NAC showed good predictive performance for pCR status of BC, with an AUC of 0.912.

Previous studies have reported US features of BC in multiple modes, including size in grayscale mode (15,16), echo in grayscale mode (17), elastic performance (18,19), contrast-enhanced ultrasonic findings (20), and automated breast ultrasonic characteristics (21), after two cycles of NAC (22), suggesting that certain variables have predictive value for NAC efficacy. This study aimed to evaluate the effectiveness of NAC at an earlier stage by exploring clinicopathological characteristics and the most commonly applicable US modality features. Accordingly, we included routine US findings after one cycle of NAC for analysis.

In our study, HER2-positive status was found to be an independent predictive factor for achieving pCR remission after NAC in BC. As well known, the inclusion of HER2-targeted drugs in NAC can significantly improve the pCR rate of early HER2-positive BC (23). All HER2-positive patients in this study received targeted medications during treatment. Extant studies have shown that clinical T stage and clinical N stage are related to the pCR of NAC in BC (24,25). However, our results were not consistent with these previous findings. The discrepancy may be due to the different research objects: in previous studies, the research population comprised HER2-positive and triple-negative breast cancer (TNBC) patients, while the cases in this study included luminal A, luminal B, HER2-positive, and TNBC patients. In addition, we compared the difference in molecular subtypes of BC between the pCR and non-pCR groups. The results showed that in the pCR group, HER2 and TNBC subtypes were more numerous than in the non-pCR group (P=0.020), consistent with those reported views (23-25). However, molecular subtypes and HER2 status are interrelated variables that influence each other. Additionally, there was only one case each of Luminal A and Luminal B in the pCR group, which led us to exclude molecular subtypes from the multivariate analysis.

Regarding US characteristics, this study showed that the maximum diameter reduction of the mass after one cycle of NAC was an independent predictor of the pCR in BC, similar to previous studies (22,26). Ochi et al. (15) found that the change in the anteroposterior diameter after NAC in TNBC, which frequently involves homogenous cell-rich tumors with expansive growth, was a predictive factor for pCR. Owing to the inclusion of four molecular subtypes of breast masses in this study, their anteroposterior diameter changes were only correlated with pCR in univariate analysis (P=0.018). In addition, the change in tumor anteroposterior diameter before and after the NAC was determined in Ochi’s study, whereas in this study, the corresponding change was measured between the tumor anteroposterior diameter before and the first cycle of NAC.

Studies have shown that accurate estimation of tumor size may not be possible due to the difficulty in distinguishing residual disease from chemotherapy-induced fibrosis, fragmentation, and necrosis (27). Therefore, despite the absence of a marked decrease in size in some cases, tumors typically become less cellular after NAC (28). The varying degrees of tissue and cell changes in tumors caused by NAC lead to morphological differences in BC, which are detectable by US imaging through examination of features such as echogenicity, margin, and posterior acoustic features. In this study, the angular or spiculated margin performance after one cycle of NAC was an independent predictor of pCR in BC. As well known, mass margins are partly related to the infiltrating pattern of the tumors, and it is generally recognized that angular, especially spiculated margins, are considered good prognostic factors for invasive BC (29). In the current study, HER2 and TNBC molecular subtypes of BC formed the majority of subtypes in the pCR group. TNBC often presents with smooth margins, and, as a result, is easy to be confused with benign tumors. Accordingly, there was no significant difference in the baseline tumor margin between the pCR and non-pCR groups. However, after NAC treatment, the pCR group showed more rapid shrinkage of breast masses in various directions asynchronously. Under the traction of collagen fibers and other factors, the angularity and spicules at the edge of the mass are more prominent on the US.

In addition, the presence or absence of posterior acoustic enhancement or posterior features of the mass at baseline was an independent predictor of pCR in BC. Posterior features are associated with internal tumor components. It has been reported that high-grade tumors with many tumor cell components exhibit acoustic enhancement on US (30). Meanwhile, previous studies have shown that necrosis in tumors is a feature of TNBC, which may reduce the acoustic impedance of tumors on the US image, resulting in the absence of posterior features or even posterior enhancement (31). Furthermore, previous studies revealed that BC s with more tumor cell components are more sensitive to NAC (32).

There are some limitations in our study. First, this is a single-center study with a small sample size. Second, the static US images stored in the workstation could not fully display all the US features of the lesion for the purposes of this retrospective investigation. Third, this study excluded breast lesions of which the size could not be accurately measured by US, which may lead to selective bias. Therefore, multicenter prospective studies with a large sample size are necessary to validate and improve the existing predictive model.

Conclusions

In conclusion, conventional US and clinicopathological characteristics at baseline and US features after one cycle of NAC are helpful in predicting pCR for BC. The prediction model in this study may prove useful for the early evaluation of efficacy and adjustment of treatment strategies.

Acknowledgments

Funding: This work was supported by the National Natural Science Foundation of China (82202168) and the Science and Technology Plan Medical and Health Project of Zhuhai (ZH22036201210064PWC).

Footnote

Reporting Checklist: The authors have completed the TRIPOD reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-24-1268/rc

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-24-1268/coif). The authors have no 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. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Fifth Hospital Affiliated Ethics Committee of Sun Yat-sen University Review Board (2023-K79-1), and the requirement for written informed consent was waived due to the retrospective nature of the study.

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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