Correlation and predictive value of pathological complete response and ultrasound characteristic parameters in neoadjuvant chemotherapy for breast

Abstract

BACKGROUND

Breast cancer ranks as one of the most prevalent malignant tumors among women, significantly endangering their health and lives. While radical surgery has been a pivotal method for halting disease progression, it alone is insufficient for enhancing the quality of life for patients.

AIM

To investigate the correlation between ultrasound characteristic parameters of breast cancer lesions and clinical efficacy in patients undergoing neoadjuvant chemotherapy (NAC).

METHODS

Employing a case-control study design, this research involved 178 breast cancer patients treated with NAC at our hospital from July 2019 to June 2022. According to the Miller-Payne grading system, the pathological response, i.e. efficacy, of the NAC in the initial breast lesion after NAC was evaluated. Of these, 59 patients achieved a pathological complete response (PCR), while 119 did not (non-PCR group). Ultrasound characteristics prior to NAC were compared between these groups, and the association of various factors with NAC efficacy was analyzed using univariate and multivariate approaches.

RESULTS

In the PCR group, the incidence of posterior echo attenuation, lesion diameter ≥ 2.0 cm, and Alder blood flow grade ≥ II were significantly lower compared to the non-PCR group (P < 0.05). The area under the curve values for predicting NAC efficacy using posterior echo attenuation, lesion diameter, and Alder grade were 0.604, 0.603, and 0.583, respectively. Also, rates of pathological stage II, lymph node metastasis, vascular invasion, and positive Ki-67 expression were significantly lower in the PCR group (P < 0.05). Logistic regression analysis identified posterior echo attenuation, lesion diameter ≥ 2.0 cm, Alder blood flow grade ≥ II, pathological stage III, vascular invasion, and positive Ki-67 expression as independent predictors of poor response to NAC in breast cancer patients (P < 0.05).

CONCLUSION

While ultrasound characteristics such as posterior echo attenuation, lesion diameter ≥ 2.0 cm, and Alder blood flow grade ≥ II exhibit limited predictive value for NAC efficacy, they are significantly associated with poor response to NAC in breast cancer patients.

Key Words: Breast cancer; Ultrasound; Neoadjuvant chemotherapy; Efficacy; Pathological complete response

Core Tip: This study explored the relationship between ultrasound characteristic parameters of breast cancer lesions and clinical efficacy in patients undergoing neoadjuvant chemotherapy (NAC). In all, 59 cases achieved pathological complete response and 119 cases did not. The ultrasound characteristics of the lesions before NAC were compared between both groups of patients, and the relationship between various factors and the efficacy of NAC in breast cancer was explored using univariate and multivariate analyses. In conclusion, the ultrasound characteristics of breast cancer lesions have limited value in predicting NAC efficacy but are closely related to poor outcomes in breast cancer patients undergoing NAC.

INTRODUCTION

Breast cancer ranks as one of the most prevalent malignant tumors among women, significantly endangering their health and lives. While radical surgery has been a pivotal method for halting disease progression, it alone is insufficient for enhancing the quality of life for patients[1,2]. In current clinical settings, a multifaceted treatment approach is predominantly utilized for managing breast cancer. The efficacy of neoadjuvant chemotherapy (NAC) in reducing tumor stages and facilitating surgical interventions has been well documented[3-5]. The assessment of pathological responses post-NAC is a standard measure of treatment efficacy[6]. However, studies indicate that the rates of pathological complete response (PCR) post-NAC are suboptimal[7], underscoring the importance of predicting pathological responsiveness for tailoring clinical management strategies[8]. Biomarkers such as Ki-67 are widely recognized for guiding therapy and monitoring response[9]. Furthermore, imaging technologies have been shown to reflect prognostic factors in breast cancer, sparking considerable interest among researchers globally[10-12]. Despite this, limited reports exist on the use of ultrasound to evaluate PCR in breast cancer post-NAC, and there is a paucity of literature confirming its validity.

Thus, this study analyzed clinical and ultrasound parameters to investigate the correlation between ultrasound characteristic parameters of breast cancer lesions and clinical outcomes in patients undergoing NAC, thereby providing a theoretical foundation for clinical application.

MATERIALS AND METHODS

General data

This study received approval from the Ethics Committee of Xingtai People's Hospital (Xingtai, China). Utilizing a case-control design, we enrolled 178 breast cancer patients who underwent NAC. The pathological response to NAC was evaluated using the Miller-Payne method, determining the efficacy on initial breast lesions. Of these participants, 59 achieved a PCR, while 119 did not (non-PCR group).

Inclusion criteria were as follows: (1) Patients were diagnosed according to the criteria outlined in the 'Breast Cancer Volume', employing ultrasound with a molybdenum target, magnetic resonance imaging, and lesion biopsy[13]; (2) Patients were at clinical stages II to III; (3) All patients were diagnosed for the first time; (4) Age ranged from 35 years to 59 years; (5) Breast cancer lesions were measurable by imaging; and (6) The study protocol received approval from the Medical Ethics Committee.

Exclusion criteria were as follows: (1) Patients presenting with distant metastases; (2) Patients with primary malignant tumors in tissues or organs other than the breast; (3) Patients diagnosed with immune system disorders; (4) Patients who did not complete the required chemotherapy cycles; (5) Patients with severe hepatic or renal dysfunction; (6) Patients suffering from significant immune system diseases, such as systemic lupus erythematosus; and (7) Patients lacking preoperative ultrasound data.

Preoperative ultrasound examination method

Ultrasound examinations were conducted using the Sequoia 512 color Doppler ultrasound system (Siemens, Munich, Germany), which was equipped with a high-frequency probe operating between 8.0 MHz and 9.0 MHz. Patients were positioned supine with their arms elevated to ensure full exposure of both axillae and breasts. An acoustic coupling agent was applied to facilitate the scanning process. The ultrasound captured detailed images that included characteristic Breast Imaging Reporting and Data System descriptors such as the boundaries of breast cancer, microcalcification, mass morphology, peripheral high-echo halos, posterior echo attenuation, longest baseline diameter of the lesion, and blood flow classification. These images were subjected to a double-blind evaluation by two experienced breast pathologists.

NAC

The NAC regimen was as follows: docetaxel + epirubicin + cyclophosphamide, epirubicin: 60 mg/m², day 1; paclitaxel: 175 mg/m², 3 h on day 1; cyclophosphamide: 500 mg/m² on day 1, 21 d as one cycle, with a total of four cycles. Surgical treatment began 2 wk after the last chemotherapy. Two days after the completion of NAC, all patients underwent ultrasound examination.

Chemotherapy efficacy evaluation

The Miller-Payne method is employed to assess the efficacy of NAC in breast cancer patients[14]. The grading is as follows: Grade 1: no change observed in the lesions post-NAC; Grade 2: a reduction in tumor lesion density of less than 30% relative to pre-treatment, with no pathological changes; Grade 3: tumor lesion density decreases between 30% and 90% compared to before treatment; Grade 4: tumor lesion density reduces by more than 90% compared to pre-treatment levels; and Grade 5: complete disappearance of the tumor, indicative of complete remission on pathological examination.

Statistical analyses

Statistical analyses were conducted using SPSS version 21.0 (IBM, Armonk, NY, United States). The quantitative variables, including age and body mass index, followed a normal distribution. Descriptive statistics for these parameters are presented as the mean ± standard deviation. The independent samples t-test was utilized for hypothesis testing between the two groups for these quantitative data. Categorical variables, such as the distribution of the affected side, menopausal status, and Ki-67 expression, were summarized as counts and percentages. Differences between groups were assessed using the χ² test. The predictive value of ultrasonic features for the efficacy of NAC in breast cancer was evaluated using the receiver operating characteristic (ROC) curve analysis. A logistic regression model was applied to perform multivariate analysis exploring the relationship between the efficacy of NAC and patient outcomes in breast cancer.

RESULTS

Comparison of ultrasound characteristics between the PCR and non-PCR groups

The proportion of patients exhibiting posterior echo attenuation, a lesion diameter of ≥ 2.0 cm, and an Alder blood flow classification of grade II or higher was significantly lower in the PCR group compared to the non-PCR group (P < 0.05). Refer to Table 1 and Figure 1 for detailed data.

Figure 1 A 43-yr-old female patient had a left breast mass with a diameter of 2.2 cm. The mass was irregular in shape and low echo in the rear. The Alder blood flow grade was grade II, and the pathological complete response effect was achieved after chemotherapy. A: Pre-chemotherapy; B: Post-chemotherapy.

Table 1 Comparison of ultrasound characteristics between pathological complete response group and non-pathological complete response group.

Ultrasonic feature	PCR group, n = 59	Non PCR group, n = 59	χ2	P value
Edge of lesion			1.374	0.241
Burr	41 (69.49)	72 (60.50)
Smooth	18 (30.51)	47 (39.50)
Calcification lesion			1.532	0.216
Yes	27 (45.76)	43 (36.13)
No	32 (54.24)	76 (63.87)
Peripheral echo halo			2.053	0.152
High and low echo dizziness	32 (54.24)	51 (42.86)
No	27 (45.76)	68 (57.14)
Posterior echo			6.767	0.009
Attenuation	38 (64.41)	52 (43.7)
Unchanged	21 (35.59)	67 (56.3)
Tumor morphology			1.464	0.226
Quasi-circular object	11 (18.64)	32 (26.89)
Irregular	48 (81.36)	87 (73.11)
Lesion diameter			6.769	0.006
≥ 2.0 cm	36 (61.02)	48 (40.34)
< 2.0 cm	23 (38.98)	71 (59.66)
Alder blood flow grading			4.448	0.035
≥ II stage	41 (69.49)	63 (52.94)
< II stage	18 (30.51)	56 (47.06)

Data are n (%). PCR: Pathological complete response.

The value of ultrasound features before NAC in predicting the efficacy of NAC in breast cancer

ROC curves were constructed for variables that showed statistical significance in univariate analysis, including posterior echo attenuation, lesion diameter, and Alder blood flow grade. The results indicated that the area under the curve (AUC) values for predicting the efficacy of NAC in breast cancer were 0.604 for posterior echo attenuation, 0.603 for lesion diameter ≥ 2.0 cm, and 0.583 for Alder grade ≥ II. Refer to Figure 2 and Table 2 for detailed results.

Figure 2  Receiver operating characteristic curve of ultrasonographic features in predicting the efficacy of neoadjuvant chemotherapy in breast cancer.

Table 2 The value of ultrasound features in predicting the efficacy of neoadjuvant chemotherapy in breast cancer.

Ultrasonic feature	Sensitivity	Specificity	Missed diagnosis	Misdiagnosis rate	AUC value
Posterior echo	64.41	56.30	35.59	43.70	0.604
Lesion diameter	61.02	59.66	38.98	40.34	0.603
Alder blood flow grading	69.49	47.06	30.51	52.94	0.583

Data are %. AUC: Area under the curve.

Comparison of general data and pathological data between the PCR and non-PCR groups

The proportion of patients in the PCR group presenting with pathological stage II, lymph node metastasis, vascular infiltration, and positive Ki-67 expression was significantly lower compared to the non-PCR group (P < 0.05). Detailed data can be found in Table 3.

Table 3 Comparison of general data and pathological data between pathological complete response group and non-pathological complete response group.

Index	PCR group, n = 59	Non PCR group, n = 119	t/χ2	P value
Age in year	44.8 ± 5.2	46.1 ± 6.4	-1.354	0.178
BMI in kg/m2	22.62 ± 1.33	22.85 ± 1.41	-1.044	0.298
Menstrual status			1.447	0.229
Menopause	16 (27.12)	43 (36.13)
Premenopausal	43 (72.88)	76 (63.87)
Affected side distribution			0.634	0.426
Left	27 (45.76)	62 (52.1)
Right	32 (54.24)	57 (47.9)
Pathological type			0.565	0.452
Infiltrating ductal carcinoma	48 (81.36)	102 (85.71)
Other types	11 (18.64)	17 (14.29)
Pathological staging			4.893	0.027
II stage	18 (30.51)	57 (47.9)
III stage	41 (69.49)	62 (52.1)
Lymph node metastasis			3.898	0.048
Yes	11 (18.64)	39 (32.77)
No	48 (81.36)	80 (67.23)
Vascular invasion			8.128	0.004
Yes	34 (57.63)	93 (78.15)
No	25 (42.37)	26 (21.85)
Ki-67			5.704	0.017
Positive	22 (37.29)	67 (56.3)
Negative	37 (62.71)	52 (43.7)
HER-2			2.706	0.100
Positive	33 (55.93)	51 (42.86)
Negative	26 (44.07)	68 (57.14)
ER			3.497	0.061
Positive	21 (35.59)	60 (50.42)
Negative	38 (64.41)	59 (49.58)

Data are n (%). BMI: Body mass index; PCR: Pathological complete response.

Multivariate analysis of the relationship between NAC efficacy and breast cancer patients

In this study, logistic regression was utilized to assess the relationship between clinical outcomes post-NAC and various predictors, including posterior echo attenuation, lesion diameter, Alder blood flow classification, pathological staging, lymph node metastasis, vascular infiltration, and Ki-67 expression. These factors served as independent variables with the clinical efficacy of NAC as the dependent variable. The analysis identified posterior echo attenuation, lesion diameter ≥ 2.0 cm, Alder blood flow classification ≥ grade II, pathological stage III, vascular infiltration, and positive Ki-67 expression as independent risk factors for poor NAC response in breast cancer patients (P < 0.05). Results are detailed in Table 4.

Table 4 Multivariate analysis results.

Index	β	SE	Walds	P value	OR	95%CI
Posterior echo	0.511	0.221	5.346	0.025	1.667	1.081	2.571
Lesion diameter	0.481	0.24	4.017	0.048	1.618	1.011	2.589
Alder blood flow grading	0.602	0.251	5.752	0.003	1.826	1.116	2.986
Pathological staging	0.648	0.238	7.413	0.000	1.912	1.199	3.048
Lymph node metastasis	0.392	0.203	3.729	0.073	1.480	0.994	2.203
Vascular invasion	0.711	0.251	8.024	0.000	2.036	1.245	3.330
Ki-67	0.641	0.227	7.974	0.000	1.898	1.217	2.962
Constant term	1.403	0.784	3.202	0.096	4.067	0.875	18.909

DISCUSSION

The utilization of NAC for the treatment of breast cancer is increasingly prevalent. Early evaluation of NAC efficacy is crucial for optimizing treatment strategies and improving patient outcomes[15]. While pathological assessments, tumor markers, and genetic methods are traditionally employed to evaluate the effectiveness of NAC, these approaches are predominantly invasive[16-18]. In recent years, imaging techniques have gained traction in clinical practice as non-invasive alternatives for assessing NAC efficacy[19-21]. Despite this advancement, studies focusing on early evaluation using ultrasound are sparse. This study aimed to delineate the relationship between ultrasound characteristic parameters and PCR in NAC.

Ultrasound not only visualizes lesion characteristics but also detects changes in blood flow intensity at the lesion site[22]. The findings indicate that the rates of posterior echo attenuation, lesion diameter ≥ 2.0 cm, and Alder blood flow classification ≥ grade II are significantly lower in the PCR group compared to the non-PCR group (P < 0.05). Ultrasound effectively delineates the fine structure of tumors and precisely measures tumor diameters, while also depicting the boundary characteristics between lesions and surrounding tissues[23,24]. Prior studies utilizing ultrasound analysis to monitor lesion changes post-two cycles of NAC have demonstrated correlations with pathological assessments[25,26]. Moreover, ultrasound can evaluate changes in lesions before and after treatment by analyzing tumor blood flow classifications and hemodynamic parameters, offering the advantages of repeatability and ease of operation[27].

This study confirms that ultrasound can provide detailed internal images of lesions and inform prognostic evaluations of NAC outcomes. Notably, the AUC values for posterior echo attenuation, lesion diameter ≥ 2.0 cm, and Alder classification ≥ grade II were 0.604, 0.603, and 0.583, respectively, indicating moderate predictive power. Future enhancements may include the integration of quantitative indicators such as lesion hardness and density to further refine the assessment of treatment efficacy.

This study demonstrated that the rates of pathological stage II, lymph node metastasis, and vascular invasion were significantly lower in the PCR group compared to the non-PCR group (P < 0.05). Clinical data can often serve as a benchmark for determining whether patients have achieved PCR[28]. Numerous studies have analyzed clinical data from patients undergoing NAC, although results can vary due to differing inclusion criteria and patient heterogeneity. Previous research[29] has identified body weight and estrogen receptor levels as independent predictors of PCR post-NAC in breast cancer patients, with the number of chemotherapy cycles and lymph node metastasis also playing influential roles[30,31].

Pathological characteristics were found to be closely linked to the efficacy of NAC. Current clinical research in breast cancer increasingly emphasizes biological analysis, recognizing the significance of biological factor expression in evaluating and predicting NAC outcomes[32]. Ki-67, a protein related to cell proliferation, is noted for its utility in assessing tumor cell activity post-chemotherapy. High Ki-67 expression has been reported as a sensitive predictor of NAC response[33], corroborating findings from this study that high Ki-67 expression levels are significantly associated with NAC clinical efficacy.

Logistic regression analysis revealed that posterior echo attenuation, lesion diameter ≥ 2.0 cm, Alder blood flow classification ≥ grade II, pathological stage III, vascular invasion, and positive Ki-67 expression are independent risk factors for ineffective NAC in breast cancer patients (P < 0.05). Ultrasound imaging provides valuable insights into tumor size, shape, echo, and blood flow characteristics from various angles. Breast cancer lesions, which are typically vascular-rich with elastic-poor vessels, exhibit increased blood flow and reduced internal echo. Post-NAC, a significant reduction in cancer cells leads to diminished and narrowed blood vessels within the lesion, enhancing the internal echo. Furthermore, a decrease in lesion diameter and volume can reduce vascular pressure, improving internal echo characteristics. Higher Alder blood flow classifications, indicating elevated levels of blood perfusion, correlate with poorer clearance of lesions post-chemotherapy.

In conclusion, posterior echo attenuation, lesion diameter ≥ 2.0 cm, and Alder blood flow classification are useful metrics for evaluating the efficacy of NAC. Ki-67 serves as a robust biological marker to gauge tumor proliferation activity after chemotherapy, with higher expression levels indicating less favorable postoperative outcomes. The study confirms that larger tumor diameters, vascular invasion, and advanced staging are predictive of poor response to NAC in breast cancer patients.

This study further substantiates the significance of vascular infiltration and positive Ki-67 expression in evaluating and predicting the efficacy of NAC. Previous research[34] has demonstrated that ultrasound is highly sensitive in reflecting the histological characteristics of residual tumors post-NAC. The technique provides comprehensive visualization of the tumor’s size, shape, internal echo, and blood flow characteristics. Our analysis utilizes multiple parameters to evaluate PCR, with ROC analysis indicating that the integration of various ultrasound parameters with pathological data can enhance the prediction of NAC outcomes.

Advancements in ultrasound technology have notably improved resolution for detecting small lesions and facilitated more accurate quantitative tumor measurements. Analyzing ultrasound characteristics enables clinicians to tailor chemotherapy regimens effectively, potentially averting ineffective treatments and boosting PCR rates. Future research could benefit from incorporating additional advanced ultrasound technologies to refine the evaluation process further.

CONCLUSION

The ultrasound characteristics of breast cancer lesions, specifically posterior echo attenuation, lesion diameter ≥ 2.0 cm, and Alder blood flow classification ≥ II, demonstrate limited predictive value for the efficacy of NAC. Nonetheless, these parameters are closely associated with poorer outcomes in breast cancer patients undergoing NAC, underscoring their relevance in clinical assessment and treatment planning.