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DOI: 10.1055/s-0043-1777332
Correlation between the Distribution of Traditional Chinese Medicine Syndromes and Molecular Types of Breast Cancer in Perichemotherapy Period
Funding This work was supported by 2022 Special Project of Henan Province Chinese Medicine Scientific Research (2022ZY1048), 2023 Special Project of Henan Province Chinese Medicine Scientific Research (2023YZ2043), and Natural Science Foundation of Henan Province (232300421183).
Abstract
Objectives The objective of this study was to explore the correlation between the distribution of traditional Chinese medicine (TCM) syndromes and molecular types of breast cancer in the perichemotherapy period.
Methods A total of 325 cases with perichemotherapy breast cancer was classified according to syndrome differentiation in TCM , and R × C table χ2 test was used to examine and analyze the relationship between TCM syndromes and molecular types of breast cancer in the perichemotherapy period.
Results (1) In the early stage of chemotherapy, there was no significant difference in the distribution of different TCM syndromes among molecular types, mainly liver depression syndrome and liver depression and phlegm coagulation syndrome (p > 0.05). (2) In the middle stage of chemotherapy, there were significant differences in the distribution of spleen deficiency and phlegm-dampness syndrome among HER-2 positive (HR positive), HER-2 positive (HR negative), and Luminal A type, Luminal B type (HER-2 negative), and triple-negative type (p < 0.01). (3) After chemotherapy, there were significant differences in the distribution of spleen and kidney yang deficiency syndrome and marrow sea insufficiency syndrome among HER-2 positive (HR negative), triple-negative type, and HER-2 positive (HR positive), Luminal A type, Luminal B type (HER-2 negative), and triple-negative type (p < 0.01).
Conclusion (1) In the middle stage of chemotherapy, HER-2 positive (HR positive) and HER-2 positive (HR negative) are more likely to show spleen deficiency and phlegm-dampness syndrome than other molecular types. (2) In the late stage of chemotherapy, the HER-2 positive (HR negative) and triple-negative type is more likely to show spleen-kidney yang deficiency syndrome than other molecular types, and the triple-negative type is more likely to show marrow sea insufficiency syndrome than other molecular types.
Introduction
According to the latest cancer research data released by the International Agency for Research on Cancer of the World Health Organization, breast cancer ranks first in the number of new medical cases and fifth in the death rate,[1] which seriously endangers health. As the cornerstone of breast cancer treatment, chemotherapy plays an irreplaceable role, but its adverse effects also affect the quality of life and mental health of patients, and even affect the prognosis and long-term survival. Molecular types of breast cancer are an important factor that affects the chemotherapy plans. The intervention of Chinese medicine for the treatment of breast cancer in the peri-chemotherapy period can reduce adverse reactions and improve patients' quality of life.[2] [3] [4] [5] There are reports in the literature that there is a certain correlation between traditional Chinese medicine (TCM) syndromes and molecular types in the consolidation phase of breast cancer,[6] but there is no report in the literature about whether TCM syndromes in the perichemotherapy period are related to molecular types. The study group observed 325 patients with breast cancer in the perichemotherapy period, analyzed the clinical data, and found that there was a correlation between TCM syndromes and molecular types in the perichemotherapy period of breast cancer. The results are reported below.
Data and Methods
Diagnostic Criteria
According to the China Standards for Diagnosis and Treatment of Common Malignant Tumors and the China Anti-Cancer Association Guidelines and Standards for the Diagnosis and Treatment of Breast Cancer (2021 Edition),[7] all has pathological diagnosis basis.
Inclusion Criteria
Inclusion criteria were confirmed case of breast cancer by pathological examination; with the indication of chemotherapy, willingness to undergo preoperative neo-adjuvant chemotherapy or postoperative adjuvant chemotherapy, both kinds of chemotherapy are standard regimens recommended by Guidelines of Chinese Society of Clinical Oncology (CSCO) (2019 edition); no radiotherapy, chemotherapy or TCM treatment performed for malignant tumors before treatment; patients in good general condition, with a Carlisle score of >60 and tolerating chemotherapy; and patients with willingness to participate in this clinical investigation and having signed the informed consent form.
Exclusion Criteria
Exclusion criteria were patients who do not meet the inclusion criteria; patients with poor compliance; during chemotherapy period patients with medication of herbs with effects of promoting blood circulation and removing blood stasis, softening hardness and dissipating nodules, and having clear inhibitory effect on breast cancer in the usage instructions, or patients with medication of high-level evidence-based Chinese patent medicine; pregnant or lactating women; patients with diseases related to important organs such as severe damage to the heart, lung, and kidney; patients with mental diseases; patients changing other chemotherapy regimens due to the progression of the disease during chemotherapy; and patients with two or more primary malignancies.
General Data
A total of 325 patients with breast cancer hospitalized from January 2020 to September 2021 and met the inclusion criteria were selected, among which 89 were from Henan Cancer Hospital, 119 from The First Hospital Affiliated to Henan University of Chinese Medicine, 22 from Zhengzhou Central Hospital, 36 from the First Affiliated Hospital of Henan University of Science and Technology, 24 from People's Hospital of Linying County, and 35 from People's Hospital of Xihua County. The mean age of patients was 50.84 ± 9.801 years, of these, 324 were female and 1 was male; 138 cases of Luminal B type (HER-2 negative), 59 cases of HER-2 positive (HR positive), 56 cases of HER-2 positive (HR negative), 40 cases of triple-negative type, and 32 cases of Luminal A type were observed. The protocol was reviewed and approved by the Ethics Committee of the First Affiliated Hospital of Henan University of Chinese Medicine (Ethical No.: 2021HL-067).
Methods
Design of Traditional Chinese Medicine Syndrome Questionnaire
The questionnaire was formulated based on the Expert Consensus on Traditional Chinese Medicine Syndrome Differentiation and Internal Treatment of Early Breast Cancer,[8] Consensus on Diagnosis and Treatment of Breast Cancer with Integrated Chinese and Western Medicine,[9] Guidelines for Chinese Medicine Diagnosis and Treatment of Malignant Tumors,[10] Guiding Principles for Clinical Research of New Chinese Medicinals,[11] and clinical practice. After the preliminary completion of the questionnaire, the clinical presurvey was conducted, and experts were consulted for further improvement, forming 15 TCM syndromes (as specified in [Table 1]). A formal Questionnaire on Syndromes of Patients with Breast Cancer in the Peri-chemotherapy Period (hereinafter referred to as the Questionnaire) was formulated.
Notes: For each of the above syndromes, at least 3 primary symptoms and 0 secondary symptom should be involved; or 2 primary symptoms and 2 secondary symptoms should be involved; or 1 primary symptom and 3 secondary symptoms should be involved; the necessary symptoms are required before diagnosis.
Filling and Judgement of Questionnaire
Patients' syndrome data were collected by on-site investigation combined with off-site investigation (telephone follow-up). Complete information was collected, and questionnaires were filled in the early period of chemotherapy, middle period of chemotherapy and late period of chemotherapy, respectively.
For the judgment of syndromes, it is required to be recognized by two deputy chief physicians or above with oncology research background and TCM specialty.
Criteria for Western Medicine Molecular Types
Molecular types of breast cancer are based on CSCO Breast Cancer (2019 Edition),[12] which is divided into the following 5 types: Luminal A type, Luminal B type (HER-2 negative), HER-2 positive (HR positive), HER-2 positive (HR negative), and triple-negative type.
Statistical Methods
SPSS 26.0 statistical software was used for statistical analysis. χ2 test was used for the comparison of counting data, and p < 0.05 was considered as statistically significant difference.
Results
Distribution of Traditional Chinese Medicine Syndromes of 325 Patients with Breast Cancer in the Perichemotherapy Period
In the early stage of chemotherapy, the frequency of TCM syndromes from high to low was 172 cases (52.92%) of liver depression syndrome, 61 cases (18.77%) of liver depression and phlegm coagulation syndrome, 26 cases (8.00%) of qi and yin deficiency syndrome, 24 cases (7.38%) of qi and blood deficiency syndrome, 21 cases (6.46%) of syndrome of thoroughfare vessel and conception vessel dysfunction, and 21 cases (6.46%) of intermingled phlegm and blood stasis syndrome.
In the middle stage of chemotherapy, TCM syndromes were mainly liver depression and spleen deficiency syndrome + qi deficiency and blood stasis syndrome, spleen deficiency and phlegm-dampness syndrome + qi deficiency and blood stasis syndrome. Accurate statistical analysis of each single syndrome was made, and the frequency after integration of the same syndrome from high to low was 227 cases (65.04%) of liver depression and spleen deficiency syndrome, 57 cases (16.33%) of spleen qi deficiency syndrome, 38 cases (10.89%) of qi deficiency and blood stasis syndrome, and 27 cases (7.74%) of spleen deficiency and phlegm-dampness syndrome.
In the late stage of chemotherapy, the main TCM syndromes were marrow sea insufficiency syndrome + qi deficiency and blood stasis syndrome, and spleen and stomach yang deficiency syndrome + qi deficiency and blood stasis syndrome. Accurate statistical analysis of each single syndrome was made and the frequency after integration of the same syndrome from high to low was 120 cases (28.78%) of liver and kidney yin deficiency syndrome, 111 cases (26.62%) of qi deficiency and blood stasis syndrome, 59 cases (14.15%) of spleen and kidney yang deficiency syndrome, 44 cases (10.55%) of marrow sea insufficiency syndrome, 35 cases (8.39%) of spleen qi deficiency syndrome, 23 cases (5.52%) of spleen and stomach yang deficiency syndrome, 13 cases (3.12%) of heart-kidney imbalance syndrome, and 12 cases (2.88%) of spleen deficiency and phlegm dampness syndrome.
Correlation between Traditional Chinese Medicine Syndromes and Molecular Types in Patients with Breast Cancer in the Early Stage of Chemotherapy
In the early stage of chemotherapy, there were mainly liver depression syndrome, liver depression and phlegm coagulation syndrome, qi and yin deficiency syndrome, qi and blood deficiency syndrome, syndrome of thoroughfare vessel and conception vessel dysfunction, and intermingled phlegm and blood stasis syndrome. There is no significant difference in the distribution of each syndrome among HER-2 positive (HR positive), HER-2 positive (HR negative), Luminal A type, Luminal B type (HER-2 negative), and triple-negative type (p > 0.05), as specified in [Table 2].
Abbreviation: TCM, traditional Chinese medicine.
Note: If the letters marked are the same, it indicates that there is no difference between the corresponding two sets of data, while if the letters marked are different, it indicates that the difference is statistically significant.
Correlation between Traditional Chinese Medicine Syndromes and Molecular Types in Breast Cancer Patients in the Middle Stage of Chemotherapy
In the middle stage of chemotherapy, there were mainly liver depression and spleen deficiency syndrome, spleen qi deficiency syndrome, qi deficiency and blood stasis syndrome, and spleen deficiency and phlegm-dampness syndrome. There were significant differences in the distribution of spleen deficiency and phlegm-dampness syndrome among HER-2 positive (HR positive), HER-2 positive (HR negative), Luminal A type, Luminal B type (HER-2 negative), and triple-negative type (p < 0.01). HER-2 positive (HR positive) and HER-2 positive (HR negative) were more likely to show spleen deficiency and phlegm-dampness syndrome than Luminal A type, Luminal B type (HER-2 negative), and triple-negative type, as specified in [Table 3].
Abbreviation: TCM, traditional Chinese medicine.
Note: If the letters marked are the same, it indicates that there is no difference between the corresponding two sets of data, while if the letters marked are different, it indicates that the difference is statistically significant.
Correlation between Traditional Chinese Medicine Syndromes and Molecular Types in Breast Cancer Patients in the Late Stage of Chemotherapy
In the late stage of chemotherapy, there were mainly liver and kidney yin deficiency syndrome, qi deficiency and blood stasis syndrome, spleen and kidney yang deficiency syndrome, marrow sea insufficiency syndrome, spleen qi deficiency syndrome, spleen-stomach yang deficiency syndrome, heart-kidney imbalance syndrome, and spleen deficiency and phlegm-dampness syndrome. There were significant differences in the distribution of spleen and kidney yang deficiency syndrome and marrow sea insufficiency syndrome among HER-2 positive (HR positive), HER-2 positive (HR negative), Luminal A type, Luminal B type (HER-2 negative), and triple-negative type (p < 0.01). HER-2 positive (HR negative) and triple-negative type was more likely to show spleen and kidney yang deficiency syndrome than HER-2 positive (HR positive), Luminal A type, and Luminal B type (HER-2 negative). Triple-negative type was more likely to show marrow sea insufficiency syndrome than other molecular types, as specified in [Table 4].
Abbreviation: TCM, traditional Chinese medicine.
Note: If the letters marked are the same, it indicates that there is no difference between the corresponding two sets of data, while if the letters marked are different, it indicates that the difference is statistically significant.
Discussion
The research group have been long engaged in the study of TCM syndromes of breast cancer in recent years. Through clinical practice, it is found that there is a certain correlation between syndromes and molecular types, especially in the perichemotherapy period. The research group believe that the pathogenetic process in the perichemotherapy period is from qi depression to qi deficiency, yang deficiency, and finally yin impairment. Chemotherapy first impairs the spleen and stomach. The spleen governs rise of the clear and the stomach governs descent of the turbid. If the spleen fails to raise the clear and the stomach fails to descend the turbid and the spleen becomes too weak to transport, phlegm and dampness will generate, and body fluid distribution becomes abnormal. The stomach fails to descend, and this causes upward flowing of qi. And thus, spleen deficiency and phlegm dampness syndrome will occur marked by primary symptoms of poor appetite, abdominal distension, and loose stools. Then, with the gradual progress of chemotherapy, the chemotherapeutic drugs accumulate in the body and cause low spirits, which further develops from the spleen qi deficiency syndrome to the impairment of the spleen and stomach yang. Internal stagnation of yang qi cannot be channeled, and yin cannot be controlled, which results in relatively excess yin qi and depleted yang qi.[13] Long-term spleen and stomach yang deficiency involves the kidney and consumes yang qi in the kidney, and thus the spleen and kidney yang deficiency syndrome occurs and it is marked by the primary symptoms of poor appetite, cold body and limbs, and alopecia. Yin and yang interact with each other, and long-term kidney yang deficiency involve kidney. The brain is the “marrow sea” and depends on the nourishment of kidney yin essence to give full play of its physiological function of “housing original spirit.” If kidney yin essence is insufficient and the marrow sea is malnourished, dizziness, memory loss and other symptoms related to marrow sea insufficiency are prone to occur.
In this study, 325 patients with breast cancer in the perichemotherapy period were observed. The results showed that there was no significant difference in the distribution of TCM syndromes in the early stage of chemotherapy among HER-2 positive (HR positive), HER-2 positive (HR negative), Luminal A type, Luminal B type (HER-2 negative), and triple-negative type. The molecular types were mainly liver depression syndrome (pertaining to qi stagnation). In the middle stage of chemotherapy, there were significant differences in the distribution of spleen deficiency and phlegm-dampness syndrome among HER-2 positive (HR positive), HER-2 positive (HR negative), Luminal A type, Luminal B type (HER-2 negative), and triple-negative type. HER-2 positive (HR positive) and HER-2 positive (HR negative) were more likely to show spleen deficiency and phlegm-dampness syndrome (pertaining to qi deficiency) than Luminal A type, Luminal B type (HER-2 negative), and triple-negative type. In the late stage of chemotherapy, there were significant differences in the distribution of spleen and kidney yang deficiency syndrome and marrow sea insufficiency syndrome among HER-2 positive (HR positive), HER-2 positive (HR negative), Luminal A type, Luminal B type (HER-2 negative), and triple-negative type. HER-2 positive (HR negative) and triple-negative type was more likely to show spleen and kidney yang deficiency syndrome (pertaining to yang deficiency) than HER-2 positive (HR positive), Luminal A type, and Luminal B type (HER-2 negative). Triple-negative type was more likely to show marrow sea insufficiency syndrome (pertaining to yin deficiency). The results were consistent with the long-term clinical observation of the research group.
According to the HER-2 status and the expression levels of ER, PR, and ki-67 in immunohistochemistry, the molecular types of breast cancer in current breast cancer CSCO guidelines[12] are divided into HER-2 positive (HR negative), HER-2 positive (HR positive), and triple-negative type, Luminal A type and Luminal B type (HER-2 negative), and these five types are clinically recognized. Zeng[14] explored the correlation between the molecular types of breast cancer and different TCM staging syndromes, and the results showed that after two rounds of chemotherapy, the triple-negative type mainly manifests as spleen and kidney deficiency syndrome, and the HER-2 amplified type mainly manifests as liver and kidney deficiency syndrome. Zhang[15] discussed the correlation between breast cancer-related gene expression and TCM syndromes after breast cancer surgery, and the results showed that HER-2 over-expression and triple-negative type accounted for a larger proportion in the spleen and kidney yang deficiency syndrome. These results are similar to the results of this study.
Conclusion
In the middle stage of chemotherapy, HER-2 positive (HR positive) and HER-2 positive (HR negative) are more likely to show spleen deficiency and phlegm-dampness syndrome than other molecular types. In the late stage of chemotherapy, the HER-2 positive (HR negative) and triple-negative type is more likely to show spleen-kidney yang deficiency syndrome than other molecular types, and the triple-negative type is more likely to show marrow sea insufficiency syndrome than other molecular types. However, this project needs further in-depth study due to limited study time and sample size.
Conflict of Interest
The authors declare no conflict of interest.
Authors' Contribution
B.M. was responsible for conceptualization, data curation, formal analysis, investigation, and writing—original draft. X.C. was responsible for writing—original draft, data curation, funding acquisition, project administration, supervision, and writing—review and editing. Q.L. was responsible for data curation, formal analysis, investigation, and writing—review and editing. H.Z. was responsible for data curation, formal analysis, and investigation. B.W. was responsible for data curation, formal analysis, investigation, data curation, investigation, and writing—original draft. L.X. was responsible for data curation, formal analysis, investigation, and writing—original draft.
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References
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- 10 Lin HS. Guidelines of TCM Diagnosis and Treatment of Malignant Tumor. 2014 ed. Beijing: People's Medical Publishing House;; 2014
- 11 Zheng XY. Guidelines for the Clinical Research of Chinese Medicine New Herbs. Beijing:: China Medical Science Press;; 2002
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- 13 Meng BX, Cheng XF, Jiang MQ. et al. Wang wanlin's experience in treating breast cancer with “tongfa”. Zhonghua Zhongyiyao Zazhi 2021; 36 (07) 4032-4036
- 14 Zeng YZ. Correlation between molecular classification of breast cancer and TCM staging syndrome differentiation. Nanjing:: Nanjing University of Chinese Medicine;; 2017
- 15 Zhang LX. Correlation between breast cancer-related gene expression and TCM syndrome and prognosis after breast cancer surgery. Guangzhou: Ji'nan University;; 2017
Address for correspondence
Publikationsverlauf
Eingereicht: 10. Juli 2023
Angenommen: 25. August 2023
Artikel online veröffentlicht:
28. Dezember 2023
© 2023. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)
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References
- 1 Oncology Medicine Forum. Interpretation of the latest global cancer data in 2020. Chin J Clin Oncol Rehabil 2021; 28 (03) 301
- 2 Lyu F, Zhu GG, Liu T. et al. Clinical study on Xinmailong injection in the treatment of chronic congestive heart failure. Chin J Integr Med Cardio/Cerebrovascular Dis 2015; 13 (01) 83-84
- 3 Yang ZH, Que YM, Zhou XF. et al. Discussion on the efficacy and side effects of Shenqi Fuzheng injection combined with chemotherapy in the treatment of advanced gastric cancer. Zhonghua Zhongyiyao Xuekan 2015; 33 (03) 732-734
- 4 Huang XP, Li F, Chen LB. et al. Effects of Astragalus-Angelica compatilibity on bone marrow hematopoiesis suppression induced by Cyclophosphamide in mice. Chin Tradit Herbal Drugs 2017; 48 (01) 121-128
- 5 Liu Y, Li XM. Progress of the prevention and treatment of hand-foot syndrome induced by chemotherapeutic drugs with integrated Chinese and Western medicine. Electron J Clin Med Lit 2020; 7 (52) 189-190
- 6 Gong LY, Chen HF. Correlation study between syndrome types of Chinese medicine and molecular types of breast cancer in consolidate period. Chung Kuo Chung Hsi I Chieh Ho Tsa Chih 2017; 37 (02) 174-178
- 7 Specialty Committee of China Anti-Cancer Association. Guidelines and norms for diagnosis and treatment of breast cancer of China anti-cancer association (2021 Edition). China Oncol 2021; 31 (10) 954-1040
- 8 Chen QJ, Pei XH. Consensus on TCM syndrome differentiation and internal therapy for early-stage breast cancer. J Beijing Univ Tradit Chin Med Clin Med 2020; 27 (03) 5-8
- 9 Specialty Committee of Oncology of Chinese Association of the Integrative Medicine, Beijing Breast Disease Prevention and Treatment Society of Integrative Medicine Specialty Committee, National Expert Committee for the Integrative Prevention and Treatment of Breast Cancer of Beijing Integrative Chinese and Western Medicine Promotion Association for Prevention and Treatment of Chronic Diseases. Consensus on diagnosis and treatment of breast cancer with Integrative medicine. Chin J Front Med Sci 2021; 13 (07) 44-64
- 10 Lin HS. Guidelines of TCM Diagnosis and Treatment of Malignant Tumor. 2014 ed. Beijing: People's Medical Publishing House;; 2014
- 11 Zheng XY. Guidelines for the Clinical Research of Chinese Medicine New Herbs. Beijing:: China Medical Science Press;; 2002
- 12 Working Committee of Guidelines of the Chinese Clinical Oncology Association. Diagnosis and Treatment Guidelines of Breast Cancer of Chinese Society of Clinical Oncology-2019. Beijing:: People's Medical Publishing House;; 2019
- 13 Meng BX, Cheng XF, Jiang MQ. et al. Wang wanlin's experience in treating breast cancer with “tongfa”. Zhonghua Zhongyiyao Zazhi 2021; 36 (07) 4032-4036
- 14 Zeng YZ. Correlation between molecular classification of breast cancer and TCM staging syndrome differentiation. Nanjing:: Nanjing University of Chinese Medicine;; 2017
- 15 Zhang LX. Correlation between breast cancer-related gene expression and TCM syndrome and prognosis after breast cancer surgery. Guangzhou: Ji'nan University;; 2017