Clinical Effects of Neoadjuvant Chemotherapy in Treating Breast Cancer

Abstract

Objective:

To explore clinical effects of neoadjuvant chemotherapy (NAC) in treating breast cancer.

Materials and Methods:

Retrospective analysis was performed among 26 breast cancer patients receiving NAC. Chemotherapeutic effects were evaluated using Response Evaluation Criteria In Solid Tumors (RECIST), Japanese Breast Cancer Society (JBCS) grading, and Miller and Payne (MP) grading.

Results:

After chemotherapy, the percentage of tumor cells was significantly reduced, but chemotherapeutic period possessed no dramatic influence on curative effects. Among 20 patients with complete data, 2 achieved clinically complete response (CR), 10 showed partial response (PR), 4 had stable disease (SD), and 4 exhibited progress disease (PD). The total effective rate (CR + PR) of NAC was 60% (12/20). Besides, evaluation results from RECIST were generally in line with those from JBCS grading and MP grading.

Conclusion:

NAC is effective among the majority of patients with breast cancer. In addition, tumor size determined through clinical palpation is generally in accordance with responses to chemotherapy, and consistent performance is observed for three systems in grading responses to chemotherapy.

Introduction

Neoadjuvant chemotherapy (NAC) is also termed as preoperative or induction chemotherapy, and refers to systemic adjuvant cytotoxic chemotherapy before the application of local treatments (including excision and radiotherapy), a critical component of systemic comprehensive treatment.^1,2 With a history of nearly 40 years, NAC was initially used only for treating inoperable local advanced breast cancer and inflammatory breast cancer. With the popularization of breast-conserving surgery, NAC currently could also be applied for treating early operable breast cancer.^3,4 This technique can reduce tumor size, and increase the opportunity of successful breast-conserving surgery and the rate of tumor excision, thus greatly elevating the patients' life quality.⁵ Moreover, the prognosis of breast cancer patients could be significantly improved after NAC treatment through enhancing the rate of pathological complete response (PCR) and the negative rate of lymph node metastasis.^6
–8

In this study, we retrospectively summarized the clinical data of 26 female patients with breast cancer who had undergone NAC treatment in our hospital, and analyzed clinical factors affecting chemotherapeutic effects, thus discussing the significance of NAC in treating breast cancer.

Materials and Methods

Clinical data

In this study, 26 eligible breast cancer patients were included. The inclusion criteria were as follows: (1) ≥18 years; (2) women; (3) pathologically diagnosed with breast cancer; (4) did not meet the criteria for breast-conserving surgery; and (5) had not evidences for previous anti-tumor treatments, such as chemotherapy, radiotherapy, or endocrine therapy. In addition, with the presence of the following conditions, the patients were excluded: (1) abnormalities in liver function, renal function, or cardiac function; (2) complication with other malignancies beside breast cancer; and (3) with the evidences for inflammation diseases. The age of the included patients ranged between 31 and 62 years, with a median age of 48.5 years. Of these patients, 8 had left lesions, 15 had right lesions, and 3 had bilateral lesions. All the patients received 14G puncture needle biopsy, and were diagnosed through pathological examination. The amount of puncture branches was between 3 and 8, with an average value of 4.86. The maximum tumor size was between 2 and 8 cm before chemotherapy, with an average value of 3.86 cm, whereas such figure was between 0 and 8 cm after chemotherapy, with an average value of 3.08 cm, including 3 neoplasms not touched after chemotherapy.

This study was approved by the Ethics Committee of Tongzhou Maternal and Child Health Hospital of Beijing. Patients signed written informed consent before recruitment. Study process was in accordance with the Declaration of Helsinki.

Core needle biopsy

In this study, core needle biopsy was performed using BARD needles (BARD, America), with a puncture depth of 15 or 20 mm. We selected the specification of 14G (outer diameter = 2 mm) for our study. This needle was adopted to perform breast neoplasm puncture using ultrasound and to extract tissue branches for pathological examination.

Hematoxylin–eosin staining

Tumor tissues were examined by hematoxylin–eosin (HE) staining according to the routine practice. In brief, the paraffin-embedded tissues were first dewaxed and rehydrated. Then the tissue section was stained by hematoxylin solution for 5 min, and washed with five times with 1% acid ethanol and three times with distilled water. Subsequently, the tissue section were stained with eosin solution for 3 min and followed by dehydration with graded alcohol and clearing in xylene. The staining results were analyzed under an Olympus BX53 fluorescence microscope (Tokyo, Japan).

NAC regimen

After being evaluated for their general condition and disease stages, the patients received the following docetaxel and epirubicin (TE) therapeutic regimen: on the first day, epirubicin (EPI) was given through intravenous injection at a dose of 60 mg/m²; on the second day, paclitaxel (PIX) was administered through intravenous drip for 3 h at a dose of 135–175 mg/m². In this study, one cycle lasted for 21 d, and all the patients received a complete NAC of 1–3 cycles.

Criteria for grading evaluation on therapeutic effect of NAC in breast cancer

Chemotherapeutic effect was evaluated according to Response Evaluation Criteria In Solid Tumors (RECIST)⁹: complete response (CR) refers to the disappearing of all lesions for >4 weeks; partial response (PR) means that the reduction of the longest diameter of lesions was no <30%, or the reduction of total diameters of all lesions was no <30%; progress disease (PD) represents a situation in which increase in the longest diameter of lesions was no <20%, or at the end of treatment, the sum of lesion diameters shows an upward tendency, or one or more new lesions appear; and stable disease (SD) represents a phenomenon in which lesions do not reduce to the level of PR nor progress into PD level after chemotherapy. Grading criteria released by Japanese Breast Cancer Society (JBCS) contain the following aspects¹⁰: grade 0 (G0) refers to nullity; G1 means mild response; G2 stands for significant response; and G3 represents CR. Miller and Payne (MP) grading contains the following contents¹¹: grade 1 refers to no alteration in the amount of invasive cancer tissues; grade 2 means that reduced percentage of the amount of invasive cancer tissues is not >30%; grade 3 refers to the percentage of reduced invasive cancer tissues to be between 30% and 90%; grade 4 represents that the percentage of reduced invasive cancer tissues is >90%, with few cancer cells showing diffused distribution; grade 5 symbolizes that all slices demonstrate no remnant invasive cancer cells, with visible remnant components of intraductal carcinoma.

Handling statistical data

In this experiment, continuous variables were expressed as mean ± standard deviation. T-test was adopted to perform comparisons between two groups, whereas analysis of variance (ANOVA) analysis was used for those between three groups. Besides, comparisons on categorical variables were implemented using χ ² test. All calculations were two-way, and p < 0.05 indicated that results were statistically significant. All statistical analyses were accomplished with SPSS 18.0 software (SPSS, Inc., Chicago, IL).

Results

Effectiveness of NAC

Twenty-six breast cancer patients received chemotherapy for 1–3 cycles. After NAC, the patients showed significant decreases in their average tumor size (3.43 ± 2.10 vs. 4.83 ± 1.82 cm, p = 0.017). Among the patients, the average percentage of tumor cells was 38.85% ± 12.19% and 34.62% ± 17.37% before and after chemotherapy, respectively, showing a downward trend without significant difference (p = 0.314). Besides, there was no significant alterations in the percentage of intercellular substance for the patients before and after chemotherapy (61.15% ± 12.19% vs. 65.38% ± 17.37%, p = 0.314) (Table 1).

Table 1.

Clinical Effects of Neoadjuvant Chemotherapy Among Patients with Breast Cancer

Item for evaluation	Before NAC	After NAC	p
Tumor size (cm)	4.83 ± 1.82	3.43 ± 2.10	0.017
Percentage of tumor cells (%)	38.85 ± 12.19	34.62 ± 17.37	0.314
Percentage of intracellular substance (%)	61.15 ± 12.19	65.38 ± 17.37	0.314

NAC, neoadjuvant chemotherapy.

Evaluation on the effects of NAC between different cycles

We analyzed the influences of chemotherapeutic cycles on curative effects, and the changes of metastatic lymph node (LN) numbers and tumor–node–metastasis (TNM) stage were used as evaluation indexes. The results demonstrated that chemotherapeutic cycle had no significant impact on LN and TNM stage (p > 0.05) (Table 2).

Table 2.

Influence of Chemotherapeutic Cycle Count on Clinical Effects

Item for evaluation	Chemotherapeutic cycle count			p
Item for evaluation	1	2	3	p
LN metastatic amount	2.00 ± 3.46	5.00 ± 6.87	2.83 ± 1.47	>0.05
TNM stage alteration
Downward	1	12	5	0.590
Leveling off	1	3	1

LN, lymph node; TNM, tumor–node–metastasis.

Comparisons between three criteria evaluating the effect of NAC

Among 26 cases receiving NAC, complete RECIST evaluation results were achieved only for 20 patients. Clinical CR was reached in 2 of these patients (Fig. 1A), accounting for 10%; PR was reached in 10 cases (Fig. 1B), accounting for 50%; SD was detected in 4 patients, accounting for 20%; and PD was observed in 4 cases (Fig. 1C), accounting for 20%. The total effective rate (CR + PR) of NAC was 60% (12/20) (Table 3).

FIG. 1.

HE staining for core needle biopsy tissue samples ( × 100). Arrows represent malignant cells. (A) CR to NAC with absent of malignant cells; (B) PR to NAC with residual clusters of cancer cells in primary cancer area; (C) PD to NAC with increased malignant cells. CR, complete response; HE, hematoxylin–eosin; NAC, neoadjuvant chemotherapy; PD, progress disease; PR, partial response.

Table 3.

Comparisons Between Three Systems for Grading

No.	RECIST evaluation	Pathological response	JBCS grading	MP grading
1	PR	Severe pathological response	2	4
2	SD	Mild pathological response	1	2
3	SD	Mild pathological response	1	2
4	PR	Severe pathological response	1	3
5	PR	Severe pathological response	2	4
6	SD	Moderate pathological response	1	2
7	SD	Moderate pathological response	1	2
8	PR	Severe pathological response	2	4
9	PD	Mild pathological response	1,0	2,1
10	PR	Severe pathological response	2	4
11	PR	Severe pathological response	2	4
12	PR	Moderate pathological response	1	3
13	PR	Severe pathological response	1	3
14	PD	Without pathological response	0	1
15	Not detected	Mild pathological response	1	2
16	PR	Severe pathological response	2	4
17	CR	Severe pathological response	2B nearly PCR	4, nearly PCR
18	Not detected	Moderate pathological response	1	2
19	Not detected	Mild pathological response	1	2
20	PD	Mild pathological response	1,0	2,1
21	CR	Severe pathological response	3, PCR, visible carcinoma in situ	5, PCR
22	Not detected	Severe pathological response	2	4
23	PD	Without pathological response	0	1
24	Not detected	Mild pathological response	1	2
25	Not detected	Mild pathological response	1	2
26	PR	Moderate pathological response	1	3

CR, compete response; JBCS, Japanese Breast Cancer Society; MP, Miller and Payne; PCR, pathological complete response; PD, progress disease; PR, partial response; RECIST, Response Evaluation Criteria In Solid Tumors; SD, stable disease.

Based on patients' pathological responses, we adopted JBCS and MP grading to evaluate therapeutic effects among them (Table 3). According to JBCS pathological response evaluation system, few remnant of carcinoma in situ was observed in sample 21, a case of grade 3 belonging to PCR; sample 17, nearly PCR, was classified into grade 2B; 7 cases of grade 2 accounted for 26.9%; 15 cases of grade 1 accounted for 57.7%; and 2 cases of grade 0 accounted for 7.7%.

In MP evaluation, sample 21 was considered as grade 5, or PCR; 8 cases of grade 4 (including 1 case, sample 17, of nearly PCR) accounted for 30.8%; 4 cases of grade 3 accounted for 15.4%; 11 cases of grade 2 accounted for 42.3%; and 2 cases of grade 1 accounted for 7.7%.

Discussion

Breast cancer is a solid tumor with high morbidity and mortality among women, and severely threatens women's health and lives.^12
–14 NAC can reduce tumor, and increase the opportunity of implementing breast-conserving surgery and the rate of surgical excision, so this technique has already been widely applied in clinical treatment for breast cancer.^15,16 Chemotherapeutic effect is closely related to patients' prognosis, and achieving PCR after NAC among primary breast cancer patients could significantly elevate their disease-free survival rate.^17
–19

In this study, we retrospectively analyzed the clinical data of 26 female patients with breast cancer who received NAC in our hospital. Among these patients, information on chemotherapy regimens was obtained for 24 cases (not available for samples 7 and 9). Sample 6 accepted the regimen of EPI and DOC, sample 8 received THP and PTX, sample 18 adopted CTX, EPI, and PTX, whereas sample 22 first took THP and PTX, and then changed to EPI and PTX after 1 week of bone marrow suppression; and other 20 cases all underwent the treatment of EPI and PTX.

Pathological response evaluation is currently regarded as the “gold standard” for measuring histological response and residual carcinoma when operating NAC.²⁰ In this study, the chemotherapeutic effects were estimated using three types of criteria, RECIST, JBCS, and MP. According to RECIST criteria, the total effective rate (CR + PR) was 60% (12/20), generally consistent with that in relevant report (54.71%). Evaluation results based on the three criteria were similar. Specifically, 2 cases showed clinical progression without pathological response, who were classified into grade 0 according to JBCS and into grade 1 according to MP criteria, whereas grade 0 in JBCS and grade 1 in MP were practically at the same level; 2 cases with clinical CR achieved severe pathological response, and were categorized into grade 2B according to JBCS and into grade 4 based on MP, whereas grade 2B in JBCS is equivalent to grade 4 in MP, nearly PCR; 1 case reaching PCR was classified into grade 3 in JBCS and grade 5 in MP; the rest of severe pathological responses were mainly equal to JBCS grade 2 and MP grade 4; meanwhile, mild and moderate pathological responses were equivalent to JBCS grade 1 and MP grade 2.

In our study, clinical palpation detected no lumps for 2 cases without clinically palpable lump (samples 17 and 21, accounting for 7.7%) after chemotherapy, who were regarded as CR based on RECIST criteria. As for the 17th patient, the percentage of tumor cells was reduced from 40% to 20%, showing minimal tumor cells, the percentage of interstitial tissues was increased from 60% to 80%, and pathological responses showed dispersion, diffusion, focal lymphocytes, monocytes, and plasma cell infiltration. When it came to the 21st patient, the percentage of tumor cells was decreased from 40% to 5% (only little carcinoma in situ left), the percentage of interstitial tissues elevated from 60% before chemotherapy to 95% after chemotherapy, inflammatory cell invasion rarely existed, preceding inflammatory cells were replaced by collagen, and pathological response was generally considered to be severe. Based on these findings, we concluded that severe pathological response might show the following two microscopic manifestations: (1) existing massive inflammatory cell invasions with minimal or no tumor cells; and (2) inflammatory cells were rarely observed, but a mass of collagen existed (collagen might substitute for inflammatory cells), with minimal or no tumor cells. In view of limited cases, such conclusion should be further verified by researches with larger sample size.

Lump enlargement was observed in 4 patients (samples 9, 14, 20, and 23) with swelling lumps after chemotherapy according to clinical palpation, who were classified into PD based on RECIST criteria. Pathological response for the 9th patient exhibited diffusion, local lymphocytes, monocytes, and plasma cells. No pathological response was detected for sample 14. Pathological response for the 20th case showed diffusion, little lymphocytes, plasma cells, monocytes, and foam cells. No pathological response was found for the 23th patient either. These cases generally belonged to mild or without pathological response.

Ten patients (samples 1, 4, 5, 8, 10, 11, 12, 13, 16, and 26) with reduced lumps through clinical palpation were regarded as PR according to RECIST criteria. For them, the percentages of tumor cells generally reduced or leveled off after chemotherapy compared with those before treatment, 8:10 = 80%, and the percentage of the cases with increased tumor cells was 2:10 = 20%. Similar result was obtained for interstitial cells. Responses mainly showed permeation, diffusion, local lymphocytes, monocytes, and plasma cell invasion, generally classified into moderate or severe pathological responses.

Clinical palpation found no change in 4 patients (samples 2, 3, 6, and 7), who were considered as nonresponse according to RECIST criteria. As for change in tumor cells before and after chemotherapy, it showed an upward tendency in two cases, leveled off in one case, and exhibited a downward trend in one case. Inflammatory cell responses mainly referred to diffusion in little lymphocytes, monocytes, and plasma cells, belonging to mild and moderate pathological responses.

Results from clinical palpation before and after chemotherapy were basically the same as those from RECIST evaluation and as patients' responses to chemotherapy, showing positive correlation. Therefore, NAC was effective in the majority of the cases, only showing differences in degrees.

Disputes still exist over the relationship between NAC effects and adopted cycle count in breast cancer treatment. The findings from this study demonstrated that NAC cycle might not influence the efficacy of chemotherapy. We therefore recommended that 2–4 courses of NAC could be performed for 2–4 courses to reduce tumor size to a degree at which performing surgery or breast-conserving operation was plausible, then the postoperative adjuvant chemotherapy could be applied to improve the clinical outcomes of the patients. Han et al. held that NAC effects were associated with the count of chemotherapy cycles, and NAC needed to be performed for 6–8 courses, or more.^21
–23 Similar conclusion were also achieved in ABCSG-14 experiment.²⁴ However, according to the results from GeparTrio experiment, the increased NAC cycles could not improve breast-conserving rate or PCR rate, but might facilitate NAC-related adverse reactions, affecting surgical performance and patients' postoperative recovery.²⁵ Therefore, many factors should be taken into considerations to determine the treatment cycle.

Conclusion

In summary, NAC is effective among the majority of breast cancer patients, and the rate of achieving PCR could not be elevated with NAC courses. In addition, tumor size determined through clinical palpation is generally in accordance with responses to chemotherapy, and consistent performance is observed in ECIST, JBCS, and MP grading systems.

Footnotes

Authors' Contributions

Conceived and designed the experiments: C.S., L.S.; Performed the experiments: Y.G., Y.H.; Analyzed the data: J.W., Y.L.; Contributed reagents/materials/analysis tools: W.M., W.Z.; Wrote the article: X.Z. All coauthors have reviewed and approved the article before submission.

Disclosure Statement

No competing financial interests exist.

Funding Information

No funding was received for this article.

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