Correlation Analysis between Traditional Chinese Medicine Syndromes and Estrogen/Progesterone Receptors before and after Adjuvant Chemotherapy in Breast Cancer

Abstract

Objective

This study aims to explore the correlation between traditional Chinese medicine (TCM) syndromes and the expression status of estrogen receptor (ER) and progesterone receptor (PR) in breast cancer patients before and after adjuvant chemotherapy.

Methods

A total of 222 breast cancer patients with consistent ER and PR expression scheduled to undergo adjuvant chemotherapy were classified according to TCM syndrome differentiation before and after chemotherapy. The data were analyzed using chi-square tests and binary logistic regression with SPSS 26.0 software, and compared with ER/PR expression results.

Results

(i) In the ER-positive/PR-positive group, compared with prechemotherapy, syndromes of spleen qi deficiency, spleen deficiency with dampness-phlegm, and spleen–kidney deficiency significantly increased during mid-chemotherapy and after chemotherapy. Compared with mid-chemotherapy, spleen yang deficiency syndrome significantly increased after chemotherapy, with statistical significance (p < 0.05). (ii) In the ER-negative/PR-negative group, compared with prechemotherapy, syndromes of spleen qi deficiency and spleen deficiency with dampness-phlegm significantly increased during mid-chemotherapy, while spleen qi deficiency, spleen yang deficiency, and spleen–kidney deficiency significantly increased after chemotherapy. Compared with mid-chemotherapy, spleen–kidney deficiency and spleen yang deficiency syndromes significantly increased after chemotherapy, with statistical significance (p < 0.05). (iii) The distribution of spleen qi deficiency syndrome during mid-chemotherapy and after chemotherapy was significantly higher in the ER-positive/PR-positive group than in the ER-negative/PR-negative group, with statistical significance (p < 0.05). (iv) ER and PR were not independent influencing factors for the various syndrome types before and after adjuvant chemotherapy (p > 0.05).

Conclusion

After chemotherapy initiation, syndromes of spleen qi deficiency, spleen yang deficiency, and spleen–kidney deficiency significantly increased in both ER-positive/PR-positive and ER-negative/PR-negative groups. The distribution of spleen qi deficiency during mid-chemotherapy and after chemotherapy was significantly higher in the ER-positive/PR-positive group than in the ER-negative/PR-negative group. ER and PR were not independent influencing factors for the syndrome types before and after adjuvant chemotherapy.

Keywords

breast cancer - adjuvant chemotherapy - TCM syndromes - estrogen receptor - progesterone receptor

Introduction

Breast cancer is the most common cancer worldwide.[1] Chemotherapy, as a critical method in the clinical treatment of breast cancer, inhibits tumor cell growth but also affects normal cell functions. The adverse effects can severely impact patients' physiological and psychological health, causing significant suffering. Some patients may even interrupt or abandon chemotherapy due to intolerable side effects, seriously affecting prognosis and long-term survival. Estrogen receptor (ER) and progesterone receptor (PR) are also important factors influencing breast cancer prognosis. Patients who are ER-negative and PR-negative are prone to recurrence and metastasis, have a poor prognosis,[2] [3] and rely more heavily on chemotherapy. Different ER and PR expressions may lead to different chemotherapy regimens and potentially different patterns of syndrome evolution. Henan Province in China has a large population base, with more breast cancer patients than other regions, and there are currently no clinical reports on syndrome research in breast cancer patients specifically in Henan Province, China. Therefore, exploring the patterns of syndrome changes during chemotherapy under different ER/PR expression statuses in Henan Province, China, to accurately guide traditional Chinese medicine (TCM) treatment of complications during breast cancer chemotherapy, is a practical issue clinicians hope to resolve.

Under the guidance of Professor Xufeng Cheng, our research team observed and analyzed the correlation between TCM syndromes and ER/PR expression status in 222 breast cancer patients before and after adjuvant chemotherapy starting from January 2020, aiming to clarify the syndrome characteristics and evolutionary patterns at different stages of chemotherapy in breast cancer patients with different ER/PR statuses.

Methods

Traditional Chinese Medicine Syndrome Differentiation Criteria and Determination

With reference to the Expert Consensus on Internal Treatment of Early Breast Cancer Based on TCM Syndrome Differentiation,[4] Diagnostics of TCM (10th Edition, the 13th Five-Year Plan Textbook for Higher Education in TCM Nationwide, China Press of TCM), External Medicine of TCM (10th Edition, the 13th Five-Year Plan Textbook for Higher Education in TCM Nationwide, China Press of TCM), and the GB National Standard for TCM Clinical Diagnosis and Treatment Terminology (Syndrome Part), the perichemotherapy TCM syndromes of breast cancer were classified into liver depression syndrome, yin deficiency syndrome, spleen yang deficiency syndrome, spleen qi deficiency syndrome, stomach yin deficiency syndrome, kidney yin deficiency syndrome, qi–yin deficiency syndrome, qi–blood deficiency syndrome, spleen–stomach disharmony syndrome, liver–kidney deficiency syndrome, spleen deficiency with dampness-phlegm syndrome, spleen–kidney deficiency syndrome, heart–kidney imbalance syndrome, qi deficiency and blood stasis syndrome, and marrow sea deficiency syndrome. Determinations were made by two associate chief physicians or higher with a background in TCM oncology research.

Inclusion and Exclusion Criteria

Inclusion Criteria

(i) Pathologically confirmed diagnosis of breast cancer; (ii) indication for chemotherapy and scheduled to receive adjuvant chemotherapy; (iii) clear ER and PR values from pathological immunohistochemistry results, with consistent expression status between ER and PR; (iv) no prior radiotherapy, chemotherapy, TCM treatment, or other therapies for malignant tumors before treatment; (v) good general condition, Karnofsky score >60, and tolerance to chemotherapy; and (vi) agreement to participate in the clinical study and signed informed consent.

Exclusion Criteria

(i) Those who did not meet the inclusion criteria; (ii) poor compliance; (iii) use of Chinese patent medicines during chemotherapy that promote blood circulation, resolve stasis, soften hard masses, or disperse nodules, and where the drug instruction manual explicitly indicates antibreast cancer effects and is supported by high-level evidence-based medical evidence; (iv) pregnant or lactating women; (v) patients with organic diseases of other vital organs (e.g., heart, lung, kidney impairment) or psychiatric disorders; (vi) patients whose treatment regimen was changed due to disease progression during chemotherapy; (vii) patients with two or more primary malignant tumors; and (viii) other conditions deemed necessary for exclusion by the research team.

General Information

Study Subjects

All cases in this study were sourced from hospitals at various levels in Henan Province, China, with independent breast disease departments. Hospitals, including Henan Cancer Hospital, The First Affiliated Hospital of Zhengzhou University (Zhengdong Branch), The First Affiliated Hospital of Zhengzhou University (Heyi Branch), Zhengzhou Central Hospital, The First Affiliated Hospital of Henan University of Science and Technology, Linying County People's Hospital, and Xihua County People's Hospital, were selected using simple random sampling. A total of 222 breast cancer patients hospitalized between January 2020 and September 2021, who were pathologically diagnosed, scheduled for adjuvant chemotherapy, and met the inclusion criteria, were selected. Patient ages ranged from 27 to 80 years, with a mean age of (51.77 ± 10.071) years; 221 were female and 1 was male. This study was approved by the Ethics Committee of the First Affiliated Hospital of Henan University of Chinese Medicine (approval number: 2021HL-067).

Estrogen Receptor and Progesterone Receptor Data and Result Determination

Pathological data from breast cancer patients scheduled for adjuvant chemotherapy were collected. Basic information, such as patient name and age, along with ER and PR results, was recorded in an Excel spreadsheet. Nuclear staining in at least 1% of cells was interpreted as positive for ER and PR expression.

Statistical Methods

Statistical analysis was performed using SPSS 26.0 software. Measurement data were compared using t-tests. Correlations between continuous numerical variables and binary categorical variables were analyzed using binary logistic regression. A p < 0.05 was considered statistically significant.

Results

Distribution of Traditional Chinese Medicine Syndromes before and after Adjuvant Chemotherapy for Breast Cancer

Before Chemotherapy Initiation

The distribution of TCM syndromes was as follows: Liver depression syndrome (95 cases, 42.79%), qi deficiency syndrome (49 cases, 22.07%), qi–yin deficiency syndrome (25 cases, 11.26%), qi–blood deficiency syndrome (18 cases, 8.11%), yin deficiency syndrome (12 cases, 5.41%), liver depression syndrome + yin deficiency syndrome (7 cases, 3.15%), spleen–stomach disharmony syndrome (4 cases, 1.80%), qi–blood deficiency syndrome + liver depression syndrome (4 cases, 1.80%), qi–yin deficiency syndrome + liver depression syndrome (4 cases, 1.80%), liver depression syndrome + spleen–stomach disharmony syndrome (3 cases, 1.35%), liver depression syndrome + spleen yang deficiency syndrome (1 case, 0.45%).

Due to the complexity, diversity, and repetition of syndrome manifestations, overlapping syndromes were disaggregated and summarized as follows: Liver depression syndrome (114 cases, 51.35%), qi deficiency syndrome (49 cases, 22.07%), qi–yin deficiency syndrome (29 cases, 13.06%), qi–blood deficiency syndrome (22 cases, 9.91%), yin deficiency syndrome (19 cases, 8.56%), spleen–stomach disharmony syndrome (7 cases, 3.15%), and spleen yang deficiency syndrome (1 case, 0.45%).

Mid-chemotherapy

TCM syndromes mostly presented as compound syndromes such as spleen–stomach disharmony syndrome + kidney yin deficiency syndrome (32 cases, 14.41%), spleen–stomach disharmony syndrome + liver–kidney deficiency syndrome (29 cases, 13.06%), spleen qi deficiency syndrome + kidney yin deficiency syndrome (14 cases, 6.31%), spleen qi deficiency syndrome + liver–kidney deficiency syndrome (11 cases, 4.95%), spleen–stomach disharmony syndrome + yin deficiency syndrome (10 cases, 4.50%), spleen qi deficiency syndrome + qi deficiency and blood stasis syndrome (9 cases, 4.05%), liver depression syndrome + spleen–stomach disharmony syndrome (9 cases, 4.05%), liver depression syndrome + spleen qi deficiency syndrome (8 cases, 3.60%), etc.

Due to the complexity, diversity, and repetition of syndrome manifestations, overlapping syndromes were disaggregated and summarized as follows: Spleen–stomach disharmony syndrome (115 cases, 51.80%), kidney yin deficiency syndrome (70 cases, 31.53%), liver–kidney deficiency syndrome (69 cases, 31.08%), spleen qi deficiency syndrome (59 cases, 26.58%), liver depression syndrome (42 cases, 18.92%), yin deficiency syndrome (34 cases, 15.32%), qi deficiency and blood stasis syndrome (28 cases, 12.61%), spleen deficiency with dampness-phlegm syndrome (23 cases, 10.36%), spleen–kidney deficiency syndrome (11 cases, 4.95%), stomach yin deficiency syndrome (10 cases, 4.50%), heart–kidney imbalance syndrome (6 cases, 2.70%), spleen yang deficiency syndrome (2 cases, 0.90%), qi–yin deficiency syndrome (2 cases, 0.90%), qi–blood deficiency syndrome (1 case, 0.45%).

Late Chemotherapy

TCM syndromes mostly presented as compound syndromes such as spleen qi deficiency syndrome + liver–kidney deficiency syndrome + qi deficiency and blood stasis syndrome (32 cases, 14.41%), spleen–kidney deficiency syndrome + qi deficiency and blood stasis syndrome (23 cases, 10.36%), spleen qi deficiency syndrome + marrow sea deficiency syndrome + qi deficiency and blood stasis syndrome (20 cases, 9.01%), spleen yang deficiency syndrome + marrow sea deficiency syndrome + qi deficiency and blood stasis syndrome (17 cases, 7.66%), spleen–stomach disharmony syndrome + liver–kidney deficiency syndrome + qi deficiency and blood stasis syndrome (14 cases, 6.31%), spleen yang deficiency syndrome + liver–kidney deficiency syndrome + qi deficiency and blood stasis syndrome (11 cases, 4.95%), etc.

Due to the complexity, diversity, and repetition of syndrome manifestations, overlapping syndromes were disaggregated and summarized as follows: Qi deficiency and blood stasis syndrome (202 cases, 90.99%), liver–kidney deficiency syndrome (75 cases, 33.78%), spleen qi deficiency syndrome (67 cases, 30.18%), marrow sea deficiency syndrome (62 cases, 27.93%), spleen yang deficiency syndrome (39 cases, 17.57%), spleen–stomach disharmony syndrome (36 cases, 16.22%), spleen–kidney deficiency syndrome (31 cases, 13.96%), heart–kidney imbalance syndrome (30 cases, 13.51%), spleen deficiency with dampness-phlegm syndrome (13 cases, 5.86%), stomach yin deficiency syndrome (12 cases, 5.41%), liver depression syndrome (11 cases, 4.95%), kidney yin deficiency syndrome (9 cases, 4.05%), and yin deficiency syndrome (2 cases, 0.90%).

Correlation between TCM Syndromes and Estrogen/Progesterone Receptors before and after Adjuvant Chemotherapy

Correlation between TCM Syndromes and Estrogen/Progesterone Receptor Positivity before and after Adjuvant Chemotherapy

As shown in [Table 1], a comparative study was conducted on the distribution of TCM syndromes in 163 breast cancer patients with positive estrogen and progesterone receptors (ER/PR-positive) before and during adjuvant chemotherapy. Using the χ² test (when t [theoretical frequency] ≥ 5, the χ² test was applied; when 1 ≤ t < 5, the corrected χ² test result was used; when t < 1, Fisher's exact test was applied, the same below), the results showed that during mid-chemotherapy, syndromes of spleen–stomach disharmony, liver–kidney deficiency, spleen qi deficiency, kidney yin deficiency, qi deficiency and blood stasis, spleen deficiency with dampness-phlegm, heart–kidney imbalance, and spleen–kidney deficiency were significantly increased compared with before chemotherapy, while syndromes of liver depression, qi–yin deficiency, qi–blood deficiency, and qi deficiency were significantly decreased, with statistical significance (p < 0.05). Although syndromes of yin deficiency, spleen yang deficiency, and stomach yin deficiency increased during mid-chemotherapy compared with before chemotherapy, and thoroughfare–conception vessel disorder decreased, the differences were not statistically significant (p > 0.05).

Table 1 Comparison of TCM syndrome distribution in the estrogen receptor/progesterone receptor-positive group before and during chemotherapy

TCM syndromes	Before chemotherapy (cases)	Mid-chemotherapy (cases)	χ2	p-Value
Liver depression syndrome	80	28	33.085	0.000
Yin deficiency syndrome	19	28	1.927	0.217
Qi–yin deficiency syndrome	21	2	16.553	0.000
Qi–blood deficiency syndrome	14	0	14.456	0.000
Spleen–stomach disharmony syndrome	7	78	73.348	0.000
Spleen yang deficiency syndrome	1	2	0.000	1.000
Thoroughfare–conception vessel disorder syndrome	1	0	0.000	1.000
Qi deficiency syndrome	37	0	40.364	0.000
Liver–kidney deficiency syndrome	0	48	53.818	0.000
Spleen qi deficiency syndrome	0	49	55.078	0.000
Kidney yin deficiency syndrome	0	57	65.395	0.000
Qi deficiency and blood stasis syndrome	0	23	24.257	0.000
Spleen deficiency with dampness-phlegm syndrome	0	17	17.677	0.000
Stomach yin deficiency syndrome	0	2	0.502	0.499
Heart–kidney imbalance syndrome	0	8	6.237	0.007
Spleen–kidney deficiency syndrome	0	7	5.225	0.015

As shown in [Table 2], a comparative study was conducted on the distribution of TCM syndromes in 163 ER/PR-positive breast cancer patients during mid-chemotherapy and after chemotherapy. Using the χ² test, the results showed that after chemotherapy, syndromes of qi deficiency and blood stasis, stomach yin deficiency, heart–kidney imbalance, spleen yang deficiency, and marrow sea deficiency were significantly increased compared with mid-chemotherapy, while syndromes of spleen–stomach disharmony, kidney yin deficiency, liver depression, and yin deficiency were significantly decreased, with statistical significance (p < 0.05). Although syndromes of liver–kidney deficiency, spleen qi deficiency, and spleen–kidney deficiency increased after chemotherapy compared with mid-chemotherapy, and syndromes of spleen deficiency with dampness-phlegm and qi–yin deficiency decreased, the differences were not statistically significant (p > 0.05).

Table 2 Comparison of TCM syndrome distribution in the estrogen receptor/progesterone receptor-positive group during mid-chemotherapy and after chemotherapy

TCM syndromes	Mid-chemotherapy (cases)	Late chemotherapy (cases)	c2	p-Value
Spleen–stomach disharmony syndrome	78	27	32.444	0.000
Liver–kidney deficiency syndrome	48	59	1.490	0.267
Spleen qi deficiency syndrome	49	57	0.793	0.436
Kidney yin deficiency syndrome	57	9	41.004	0.000
Qi deficiency and blood stasis syndrome	23	149	150.670	0.000
Liver depression syndrome	28	5	17.317	0.000
Yin deficiency syndrome	28	2	24.166	0.000
Spleen deficiency with dampness-phlegm syndrome	17	9	2.615	0.156
Stomach yin deficiency syndrome	2	11	6.419	0.021
Heart–kidney imbalance syndrome	8	20	5.489	0.030
Spleen–kidney deficiency syndrome	7	17	4.405	0.057
Spleen yang deficiency syndrome	2	25	20.861	0.000
Qi–yin deficiency syndrome	2	0	0.502	0.499
Marrow sea deficiency syndrome	0	48	53.818	0.000

As shown in [Table 3], a comparative study was conducted on the distribution of TCM syndromes in 163 ER/PR-positive breast cancer patients before and after adjuvant chemotherapy. Using the χ² test, the results showed that after chemotherapy, syndromes of spleen yang deficiency, qi deficiency and blood stasis, liver–kidney deficiency, spleen qi deficiency, marrow sea deficiency, spleen–stomach disharmony, heart–kidney imbalance, spleen–kidney deficiency, spleen deficiency with dampness-phlegm, stomach yin deficiency, and kidney yin deficiency were significantly increased compared with before chemotherapy, while syndromes of liver depression, yin deficiency, qi–yin deficiency, qi–blood deficiency, and qi deficiency were significantly decreased, with statistical significance (p < 0.05). Although the syndrome of thoroughfare–conception vessel disorder decreased after chemotherapy compared with before chemotherapy, the difference was not statistically significant (p > 0.05).

Table 3 Comparison of TCM syndrome distribution in the estrogen receptor/progesterone receptor-positive group before and after chemotherapy

TCM syndromes	Before chemotherapy (cases)	Late chemotherapy (cases)	χ2	p-Value
Liver depression syndrome	80	5	81.845	0.000
Yin deficiency syndrome	19	2	14.445	0.000
Spleen yang deficiency syndrome	1	25	23.532	0.000
Qi–yin deficiency syndrome	21	0	22.043	0.000
Qi–blood deficiency syndrome	14	0	14.456	0.000
Thoroughfare–conception vessel disorder syndrome	1	0	0.000	1.000
Qi deficiency syndrome	37	0	40.364	0.000
Qi deficiency and blood stasis syndrome	0	149	224.258	0.000
Liver–kidney deficiency syndrome	0	59	68.042	0.000
Spleen qi deficiency syndrome	0	57	65.395	0.000
Marrow sea deficiency syndrome	0	48	53.818	0.000
Spleen–stomach disharmony syndrome	7	27	13.135	0.000
Heart–kidney imbalance syndrome	0	20	20.943	0.000
Spleen–kidney deficiency syndrome	0	17	17.677	0.000
Spleen deficiency with dampness-phlegm syndrome	0	9	7.258	0.004
Stomach yin deficiency syndrome	0	11	11.279	0.000
Kidney yin deficiency syndrome	0	9	7.258	0.004

Correlation between TCM Syndromes and Estrogen Receptor/Progesterone Receptor Negativity before and after Adjuvant Chemotherapy

As shown in [Table 4], a comparative study was conducted on the distribution of TCM syndromes in 59 breast cancer patients with negative ER and PR before and during adjuvant chemotherapy. Using the χ² test, the results showed that during mid-chemotherapy, syndromes of spleen–stomach disharmony, liver–kidney deficiency, spleen qi deficiency, kidney yin deficiency, qi deficiency and blood stasis, and spleen deficiency with dampness-phlegm were significantly increased compared with before chemotherapy, while syndromes of liver depression, qi–yin deficiency, qi–blood deficiency, and qi deficiency were significantly decreased, with statistical significance (p < 0.05). Although syndromes of yin deficiency, stomach yin deficiency, heart–kidney imbalance, and spleen–kidney deficiency increased during mid-chemotherapy compared with before chemotherapy, the differences were not statistically significant (p > 0.05).

Table 4 Comparison of TCM syndrome distribution in the estrogen receptor/progesterone receptor-negative group before and during chemotherapy

TCM syndromes	Before chemotherapy (cases)	Mid-chemotherapy (cases)	χ2	p-Value
Liver depression syndrome	34	14	9.343	0.003
Yin deficiency syndrome	0	5	3.236	0.061
Qi–yin deficiency syndrome	8	0	6.237	0.007
Qi–blood deficiency syndrome	8	1	4.083	0.037
Spleen–stomach disharmony syndrome	0	36	39.176	0.000
Qi deficiency syndrome	12	0	12.333	0.000
Liver–kidney deficiency syndrome	0	20	20.943	0.000
Spleen qi deficiency syndrome	0	11	11.279	0.000
Kidney yin deficiency syndrome	0	14	14.456	0.000
Qi deficiency and blood stasis syndrome	0	6	4.224	0.030
Spleen deficiency with dampness-phlegm syndrome	0	6	4.224	0.030
Stomach yin deficiency syndrome	0	2	0.502	0.499
Heart–kidney imbalance syndrome	0	3	1.342	0.248
Spleen–kidney deficiency syndrome	0	4	2.270	0.123

As shown in [Table 5], a comparative study was conducted on the distribution of TCM syndromes in 59 breast cancer patients with negative ER and PR during mid-chemotherapy and after chemotherapy. Using the χ² test, the results showed that after chemotherapy, syndromes of qi deficiency and blood stasis, spleen–kidney deficiency, spleen yang deficiency, and marrow sea deficiency were significantly increased compared with mid-chemotherapy, while syndromes of spleen–stomach disharmony and kidney yin deficiency were significantly decreased, with statistical significance (p < 0.05). Although the syndrome of heart–kidney imbalance increased after chemotherapy compared with mid-chemotherapy, and syndromes of liver–kidney deficiency, liver depression, yin deficiency, spleen deficiency with dampness-phlegm, stomach yin deficiency, and qi–blood deficiency decreased, the differences were not statistically significant (p > 0.05).

Table 5 Comparison of TCM syndrome distribution in the estrogen receptor/progesterone receptor-negative group during mid-chemotherapy and after chemotherapy

TCM syndromes	Mid-chemotherapy (cases)	Late chemotherapy (cases)	χ2	p-Value
Spleen–stomach disharmony syndrome	36	9	18.027	0.000
Liver–kidney deficiency syndrome	20	16	0.484	0.603
Spleen qi deficiency syndrome	11	11	0.000	1.000
Kidney yin deficiency syndrome	14	0	14.456	0.000
Qi deficiency and blood stasis syndrome	6	53	43.178	0.000
Liver depression syndrome	14	6	3.351	0.107
Yin deficiency syndrome	5	0	3.236	0.061
Spleen deficiency with dampness-phlegm syndrome	6	4	0.409	0.751
Stomach yin deficiency syndrome	2	1	0.000	1.000
Heart–kidney imbalance syndrome	3	10	3.883	0.088
Spleen–kidney deficiency syndrome	4	14	5.790	0.028
Spleen yang deficiency syndrome	0	14	14.456	0.000
Qi–blood deficiency syndrome	1	0	0.000	1.000
Marrow sea deficiency syndrome	0	15	15.524	0.000

As shown in [Table 6], a comparative study was conducted on the distribution of TCM syndromes in 59 breast cancer patients with negative ER and PR before and after adjuvant chemotherapy. Using the χ² test, the results showed that after chemotherapy, syndromes of spleen yang deficiency, qi deficiency and blood stasis, liver–kidney deficiency, spleen qi deficiency, marrow sea deficiency, spleen–stomach disharmony, heart–kidney imbalance, and spleen–kidney deficiency were significantly increased compared with before chemotherapy, while syndromes of liver depression, qi–yin deficiency, qi–blood deficiency, and qi deficiency were significantly decreased, with statistical significance (p < 0.05). Although syndromes of spleen deficiency with dampness-phlegm and stomach yin deficiency increased after chemotherapy compared with before chemotherapy, the differences were not statistically significant (p > 0.05).

Table 6 Comparison of TCM syndrome distribution in the estrogen receptor/progesterone receptor-negative group before and after chemotherapy

TCM syndromes	Before chemotherapy (cases)	Late chemotherapy (cases)	χ2	P-Value
Liver depression syndrome	34	6	21.541	0.000
Spleen yang deficiency syndrome	0	14	14.456	0.000
Qi–yin deficiency syndrome	8	0	6.237	0.007
Qi–blood deficiency syndrome	8	0	6.237	0.007
Qi deficiency syndrome	12	0	12.333	0.000
Qi deficiency and blood stasis syndrome	0	53	60.184	0.000
Liver–kidney deficiency syndrome	0	16	16.598	0.000
Spleen qi deficiency syndrome	0	11	11.279	0.000
Marrow sea deficiency syndrome	0	15	15.524	0.000
Spleen–stomach disharmony syndrome	0	9	7.258	0.004
Heart–kidney imbalance syndrome	0	10	10.230	0.002
Spleen–kidney deficiency syndrome	0	14	14.456	0.000
Spleen deficiency with dampness-phlegm syndrome	0	4	2.270	0.123
Stomach yin deficiency syndrome	0	1	0.000	1.000

Comparison of TCM Syndrome Distribution between Estrogen Receptor/Progesterone Receptor-Positive and Estrogen Receptor/Progesterone Receptor-Negative Groups before and after Chemotherapy

As shown in [Table 7], a comparative study was conducted on the distribution of TCM syndromes in 222 breast cancer patients between ER/PR-positive and ER/PR-negative groups before and after adjuvant chemotherapy. Using the χ² test, the results showed that before chemotherapy, the distributions of liver depression syndrome, yin deficiency syndrome, qi–yin deficiency syndrome, qi deficiency syndrome, and spleen–stomach disharmony syndrome were significantly higher in the ER/PR-positive group than in the ER/PR-negative group. During mid-chemotherapy, the distributions of spleen–stomach disharmony syndrome, liver–kidney deficiency syndrome, spleen qi deficiency syndrome, kidney yin deficiency syndrome, qi deficiency and blood stasis syndrome, liver depression syndrome, yin deficiency syndrome, and spleen deficiency with dampness-phlegm syndrome were significantly higher in the ER/PR-positive group than in the ER/PR-negative group. After chemotherapy, the distributions of qi deficiency and blood stasis syndrome, liver–kidney deficiency syndrome, spleen qi deficiency syndrome, marrow sea deficiency syndrome, spleen–stomach disharmony syndrome, stomach yin deficiency syndrome, and kidney yin deficiency syndrome were significantly higher in the ER/PR-positive group than in the ER/PR-negative group, with statistical significance (p < 0.05). Although the distributions of qi–blood deficiency syndrome, thoroughfare–conception vessel disorder syndrome, and spleen yang deficiency syndrome before chemotherapy; heart–kidney imbalance syndrome, spleen–kidney deficiency syndrome, spleen yang deficiency syndrome, and qi–yin deficiency syndrome during mid-chemotherapy; and spleen yang deficiency syndrome, heart–kidney imbalance syndrome, spleen–kidney deficiency syndrome, spleen deficiency with dampness-phlegm syndrome, and yin deficiency syndrome after chemotherapy were higher in the ER/PR-positive group than in the ER/PR-negative group, and although the distributions of qi–blood deficiency syndrome during mid-chemotherapy and liver depression syndrome after chemotherapy were lower in the ER/PR-positive group than in the ER/PR-negative group, the differences were not statistically significant (p > 0.05).

Table 7 Comparison of TCM syndrome distribution between estrogen receptor/progesterone receptor-positive and estrogen receptor/progesterone receptor-negative groups before and after chemotherapy

TCM syndromes	ER/PR-positive (cases)	ER/PR-negative (cases)	χ2	p-Value
Liver depression syndrome before chemotherapy	80	34	24.974	0.000
Yin deficiency syndrome before chemotherapy	19	0	19.849	0.000
Qi–yin deficiency syndrome before chemotherapy	21	8	6.235	0.020
Qi–blood deficiency syndrome before chemotherapy	14	8	1.722	0.274
Thoroughfare–conception vessel disorder syndrome before chemotherapy	1	0	0.000	1.000
Qi deficiency syndrome before chemotherapy	37	12	14.337	0.000
Spleen–stomach disharmony syndrome before chemotherapy	7	0	5.225	0.015
Spleen yang deficiency syndrome before chemotherapy	1	0	0.000	1.000
Mid-chemotherapy spleen–stomach disharmony syndrome	78	36	20.819	0.000
Mid-chemotherapy liver–kidney deficiency syndrome	48	20	13.615	0.000
Mid-chemotherapy spleen qi deficiency syndrome	49	11	27.827	0.000
Mid-chemotherapy kidney yin deficiency syndrome	57	14	30.999	0.000
Mid-chemotherapy qi deficiency and blood stasis syndrome	23	6	10.662	0.002
Mid-chemotherapy liver depression syndrome	28	14	5.154	0.034
Mid-chemotherapy yin deficiency syndrome	28	5	17.317	0.000
Mid-chemotherapy spleen deficiency with dampness-phlegm syndrome	17	6	5.548	0.030
Mid-chemotherapy stomach yin deficiency syndrome	2	2	0.000	1.000
Mid-chemotherapy heart–kidney imbalance syndrome	8	3	2.330	0.221
Mid-chemotherapy spleen–kidney deficiency syndrome	7	4	0.839	0.544
Mid-chemotherapy spleen yang deficiency syndrome	2	0	0.502	0.499
Mid-chemotherapy qi–yin deficiency syndrome	2	0	0.502	0.499
Mid-chemotherapy qi–blood deficiency syndrome	0	1	0.000	1.000
Qi deficiency and blood stasis syndrome after chemotherapy	149	53	83.706	0.000
Liver–kidney deficiency syndrome after chemotherapy	59	16	29.664	0.000
Spleen qi deficiency syndrome after chemotherapy	57	11	36.745	0.000
Marrow sea deficiency syndrome after chemotherapy	48	15	20.144	0.000
Spleen–stomach disharmony syndrome after chemotherapy	27	9	9.794	0.003
Spleen yang deficiency syndrome after chemotherapy	25	14	3.401	0.093
Heart–kidney imbalance syndrome after chemotherapy	20	10	3.575	0.087
Spleen–kidney deficiency syndrome after chemotherapy	17	14	0.312	0.710
Spleen deficiency with dampness-phlegm syndrome after chemotherapy	9	4	1.981	0.260
Stomach yin deficiency syndrome after chemotherapy	11	1	8.565	0.006
Liver depression syndrome after chemotherapy	5	6	0.093	1.000
Kidney yin deficiency syndrome after chemotherapy	9	0	7.258	0.004
Yin deficiency syndrome after chemotherapy	2	0	0.502	0.499

Abbreviations: ER, estrogen receptor; PR, progesterone receptor.

Correlation between TCM Syndromes and Continuous Estrogen Receptor/Progesterone Receptor Values before and after Adjuvant Chemotherapy

Binary logistic regression was used to analyze the correlation between TCM syndromes and continuous ER/PR values before and after adjuvant chemotherapy. Since logistic regression requires that the positive rate of the dependent variable should not be less than 15% of the total sample size, and the total sample size of this study was 222, the syndromes that met the application conditions for logistic regression analysis were liver depression syndrome and qi deficiency syndrome before chemotherapy; spleen–stomach disharmony syndrome, liver–kidney deficiency syndrome, spleen qi deficiency syndrome, kidney yin deficiency syndrome, and liver depression syndrome during mid-chemotherapy; and qi deficiency and blood stasis syndrome, liver–kidney deficiency syndrome, spleen qi deficiency syndrome, marrow sea deficiency syndrome, spleen–stomach disharmony syndrome, and spleen yang deficiency syndrome after chemotherapy.

As shown in [Table 8], neither ER nor PR was an independent influencing factor for any of the syndrome types before or after adjuvant chemotherapy (p > 0.05).

Table 8 TCM syndromes and continuous estrogen receptor/progesterone receptor values before and after chemotherapy

TCM syndromes	Variables	B	Standard error	Wald	p-Value	OR	95% CI
Liver depression syndrome before chemotherapy
	ER	0.000	0.005	0.002	0.967	1.000	0.991–1.009
	PR	−0.007	0.005	1.984	0.159	0.993	0.984–1.003
Qi deficiency syndrome before chemotherapy
	ER	0.002	0.006	0.099	0.753	1.002	0.991–1.013
	PR	−0.003	0.006	0.333	0.564	1.003	0.992–1.015
Spleen–stomach disharmony syndrome during chemotherapy
	ER	−0.005	0.005	1.219	0.270	0.995	0.986–1.004
	PR	−0.003	0.005	0.486	0.486	0.997	0.987–1.006
Liver–kidney deficiency syndrome during chemotherapy
	ER	0.003	0.005	0.408	0.523	1.003	0.994–1.013
	PR	−0.007	0.005	2.091	0.148	0.993	0.983–1.003
Spleen qi deficiency syndrome during chemotherapy
	ER	0.005	0.005	1.035	0.309	1.005	0.995–1.016
	PR	0.001	0.005	0.049	0.824	1.001	0.991–1.011
Kidney yin deficiency syndrome during chemotherapy
	ER	−0.003	0.005	0.314	0.575	0.997	0.987–1.007
	PR	0.007	0.005	2.000	0.157	1.007	0.997–1.018
Liver depression syndrome during chemotherapy
	ER	−0.005	0.006	0.742	0.389	0.995	0.983–1.007
	PR	0.000	0.006	0.005	0.945	1.000	0.988–1.013
Qi deficiency and blood stasis syndrome after chemotherapy
	ER	0.009	0.010	0.807	0.369	1.009	0.990–1.028
	PR	−0.013	0.010	1.718	0.190	0.987	0.969–1.006
Liver–kidney deficiency syndrome after chemotherapy
	ER	0.005	0.005	0.973	0.324	1.005	0.995–1.014
	PR	−0.003	0.005	0.427	0.513	0.997	0.987–1.006
Spleen qi deficiency syndrome after chemotherapy
	ER	0.001	0.005	0.025	0.875	1.001	0.991–1.011
	PR	0.009	0.005	2.903	0.088	1.009	0.999–1.019
Marrow sea deficiency syndrome after chemotherapy
	ER	0.003	0.005	0.415	0.520	1.003	0.993–1.013
	PR	−0.002	0.005	0.187	0.665	0.998	0.988–1.008
Spleen–stomach disharmony syndrome after chemotherapy
	ER	0.004	0.006	0.411	0.521	1.004	0.992–1.015
	PR	−0.008	0.006	1.667	0.197	0.992	0.980–1.004
Spleen yang deficiency syndrome after chemotherapy
	ER	0.005	0.006	0.761	0.383	1.005	0.994–1.016
	PR	−0.011	0.006	3.012	0.083	0.989	0.978–1.001

Abbreviations: ER, estrogen receptor; PR, progesterone receptor.

Discussion

The hormone receptors in breast cancer cells primarily include ER and PR. The main ligand of ER is 17-β-estradiol, which regulates downstream genes involved in breast cancer cell survival, proliferation, invasion, and tumor angiogenesis.[5] PR is a product induced by the binding of ER and PR, and its quantity maintains a balanced relationship with the amount of ER complexes in the nucleus, indicating a benign state of ER functional mechanisms.[6] Lower levels of ER and PR are associated with higher malignancy and poorer prognosis in breast cancer.[7]

The results of this study indicate that among the 163 breast cancer patients with positive ER and PR receiving adjuvant chemotherapy, compared with before chemotherapy initiation, both deficiency–excess complex syndromes (e.g., spleen–stomach disharmony syndrome, spleen deficiency with dampness-phlegm syndrome, qi deficiency and blood stasis syndrome) and deficiency syndromes (e.g., spleen qi deficiency syndrome, liver–kidney deficiency syndrome, spleen–kidney deficiency syndrome) significantly increased during mid-chemotherapy and after chemotherapy, while excess syndromes (e.g., liver depression syndrome) and deficiency syndromes (e.g., qi deficiency syndrome, qi–blood deficiency syndrome, qi–yin deficiency syndrome) significantly decreased, with statistical significance (p < 0.05). Compared with mid-chemotherapy, after chemotherapy, deficiency–excess complex syndromes (e.g., qi deficiency and blood stasis syndrome) and deficiency syndromes (e.g., spleen yang deficiency syndrome, heart–kidney imbalance syndrome, marrow sea deficiency syndrome) significantly increased, while excess syndromes (e.g., liver depression syndrome), deficiency–excess complex syndromes (e.g., spleen–stomach disharmony syndrome), and deficiency syndromes (e.g., kidney yin deficiency syndrome, yin deficiency syndrome) significantly decreased, with statistical significance (p < 0.05). Among the 59 breast cancer patients with negative ER and PR receiving adjuvant chemotherapy, compared with before chemotherapy initiation, both deficiency–excess complex syndromes (e.g., spleen–stomach disharmony syndrome, qi deficiency and blood stasis syndrome) and deficiency syndromes (e.g., spleen qi deficiency syndrome, liver–kidney deficiency syndrome) significantly increased during mid-chemotherapy and after chemotherapy, while excess syndromes (e.g., liver depression syndrome) and deficiency syndromes (e.g., qi deficiency syndrome, qi–blood deficiency syndrome, qi–yin deficiency syndrome) significantly decreased, with statistical significance (p < 0.05). Compared with mid-chemotherapy, after chemotherapy, deficiency–excess complex syndromes (e.g., qi deficiency and blood stasis syndrome) and deficiency syndromes (e.g., spleen yang deficiency syndrome, spleen–kidney deficiency syndrome, marrow sea deficiency syndrome) significantly increased, while deficiency–excess complex syndromes (e.g., spleen–stomach disharmony syndrome) and deficiency syndromes (e.g., kidney yin deficiency syndrome) significantly decreased, with statistical significance (p < 0.05).

Analysis of the results indicates that before and after adjuvant chemotherapy, patients exhibited varying degrees of liver depression and spleen qi deficiency symptoms. Before chemotherapy, patients often presented with deficiency syndromes due to prior surgical treatment. As chemotherapy progressed, the impact of surgery-induced deficiency gradually diminished, and the effects of chemotherapeutic drugs became dominant. Chemotherapy, as a method of combating toxins with toxins, tends to consume qi and damage yang.[8] After chemotherapy initiation, the spleen and stomach functions are primarily affected, leading to syndromes related to spleen and stomach dysfunction, such as spleen qi deficiency syndrome, spleen–stomach disharmony syndrome, and spleen deficiency with dampness-phlegm syndrome. As the cumulative dose of chemotherapeutic drugs increases in the body, the impact on spleen and stomach functions affects the generation and transportation of qi and blood, further evolving into syndromes related to qi and blood production and transportation, such as liver–kidney deficiency syndrome, qi deficiency and blood stasis syndrome,[9] and heart–kidney imbalance syndrome. Finally, prolonged spleen qi deficiency damages spleen yang, and prolonged spleen yang deficiency affects the kidney, resulting in spleen–kidney deficiency syndrome.[10]

International studies have shown that from ductal carcinoma in situ to invasive ductal carcinoma, the positive expression rate of ER exhibits a significant declining trend, indicating a shift toward a more aggressive phenotype resistant to endocrine therapy.[11] Research by Zhou and Zhong[12] demonstrated that the metastasis and recurrence rate of ER/PR-positive breast cancer are lower than that of the ER/PR-negative group, and the 5-year survival rate is higher than that of the ER/PR-negative group, both with statistical significance (p < 0.05). Studies by Shi et al[13] indicated that ER and PR status are related to patient prognosis, with ER(−) and PR(−) patients having a relatively poorer prognosis and shorter survival time. Research by Bi et al[14] showed that patients with the highest ER and PR positivity rates are more likely to present with thoroughfare–conception vessel disorder syndrome and qi–yin deficiency syndrome, respectively, while those with the lowest positivity rates are more likely to present with spleen deficiency with dampness-phlegm syndrome, with statistically significant differences (p < 0.05). Studies by Lan et al[2] and Gu et al[15] indicated that the proportion of liver depression and qi stagnation syndrome is higher in the ER/PR-positive group, with statistically significant differences (p < 0.05). Henan Province in China has a large population base and more breast cancer patients than other regions, but there are currently no clinical reports on syndrome research specifically for breast cancer patients in Henan Province, China. Relatively, clinicians lack evidence-based medical evidence for syndromes and a scientific theoretical basis for the application of TCM.

Our research group has focused on the study of syndromes in breast cancer patients in Henan Province, China, as the main research direction and core work over the past 3 years. Importantly, patients did not receive any TCM intervention during the study period, making the results more authentic and reliable. Through long-term clinical observation, the group has found that many breast cancer patients, due to damage from high-dose chemotherapy drugs, often experience low spirits and yang qi stagnation, failing to circulate. Over time, this leads to an inability to control yin, resulting in a pattern of cold evil congealing and stagnation due to relative exuberance of yin qi, mostly caused by a decline in the warming, promoting, defending, and exciting functions due to yang qi failing to reach the exterior.[16] In particular, patients with negative ER and PR expression are more prone to exhibit spleen–kidney deficiency syndrome compared with positive expression, and spleen–kidney deficiency is a key pathogenesis mechanism for breast cancer recurrence and metastasis. Prolonged spleen–kidney yang deficiency allows cold pathogens to enter and remain, leading over time to qi stagnation, phlegm congelation, blood stasis, and toxin binding. The accumulation and blockage of these pathological products promote breast cancer recurrence and metastasis. For example, spleen–kidney yang deficiency should be an important pathogenesis mechanism for bone metastasis cancer, and pleural or peritoneal effusions in patients with lung or liver metastases are also mostly caused by spleen–kidney deficiency, dysfunction of the triple energizer water passage, water retention, and accumulation in the pleural or peritoneal cavities. This study found that during mid-chemotherapy and after chemotherapy, the distribution of spleen qi deficiency syndrome was significantly higher in the ER/PR-positive group than in the ER/PR-negative group, with statistical significance (p < 0.05). Furthermore, after chemotherapy initiation, both the ER/PR-positive and ER/PR-negative groups showed a significant increase in spleen qi deficiency syndrome, spleen yang deficiency syndrome, and spleen–kidney deficiency syndrome (p < 0.05). Although the distributions of spleen yang deficiency syndrome and spleen–kidney deficiency syndrome during mid-chemotherapy and after chemotherapy were higher in the ER/PR-positive group than in the ER/PR-negative group, the differences were not statistically significant (p > 0.05). Due to the large difference in the number of patients between the ER/PR-positive and ER/PR-negative groups, future studies could expand the sample size to achieve similar cohort sizes for patients with negative and positive receptor expression. This would allow for more precise verification of the correlation between different ER/PR expression statuses and spleen–kidney deficiency syndrome, uncover clearer patterns of syndrome evolution, and ultimately provide a scientific evidence-based basis for reducing chemotherapy side effects and improving prognosis for breast cancer patients in Henan Province, China.

Conflict of Interest

The authors declare no conflict of interest.

CRediT Authorship Contribution Statement

Bingxin Meng: Conceptualization, data curation, formal analysis, investigation, visualization, writing -original draft, and writing-review and editing.

Xufeng Cheng: Conceptualization, funding acquisition, data curation, project administration, supervision, writing -original draft, and writing-review and editing.

Huiduo Zhao: Data curation, formal analysis, investigation, writing -original draft, and writing-review and editing.

Beibei Wang: Conceptualization, data curation, formal analysis, investigation, project administration, writing -original draft, and writing-review and editing.

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Publication History

Received: 02 June 2025

Accepted: 24 July 2025

Article published online:
30 December 2025