Actual Status of Perioperative Treatment for Patients with Early-Stage Breast Cancer in Asia
Momoko Tokura1,2,3*, Yuki Kojima1,2, Mark Malalay Ando4, Shu Yazaki1,2, Kazuki Sudo1,2,5, Tatsunori Shimoi1,2, Akihiko Suto6, Kenichi Nakamura2, Kan Yonemori1,2,5 and Sho Shiino6
1Department of Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
2Department of International Clinical Development, National Cancer Center Hospital, Tokyo, Japan
3Department of Breast Surgery, Showa University Koto Toyosu Hospital, Tokyo, Japan
4Department of Medical Oncology, Cebu South Medical Center, Philippine
5Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo, Japan
6Department of Breast Surgery, National Cancer Center Hospital, Tokyo, Japan
Submission: November 08, 2023; Published: November 17, 2023
*Corresponding Address: Momoko Tokura, Showa University Koto Toyosu Hospital, 5-1-38 Toyosu, Koto-ku, Tokyo, 135-8577, Japan, E-mail address: mtokura@med.showa-u.ac.jp
How to cite this article: Momoko Tokura*, Yuki Kojima, Mark Malalay Ando, Shu Yazaki, Kazuki Sudo, Tatsunori Shimoi, Akihiko Suto, Kenichi Nakamura, Kan Yonemori and Sho Shiino. Actual Status of Perioperative Treatment for Patients with Early-Stage Breast Cancer in Asia. Canc Therapy & Oncol Int J. 2023; 25(4): 556166. DOI:10.19080/CTOIJ.2023.25.556166
Abstract
Introduction: To develop an optimal therapeutic regimen for Asian breast cancer (BC) patients, it is important to determine how treatments for patients with BC are performed in Asian countries and regions.
Methods: We conducted a questionnaire-based survey of physicians performing perioperative treatment for BC at cancer centers or university hospitals in Asian countries and regions between October 2021 and April 2022. The survey included questions regarding neoadjuvant chemotherapy (NAC), adjuvant chemotherapy, adjuvant hormonal therapy, and adjuvant radiation therapy.
Results: A total of 37 physicians from 15 Asian countries and regions participated in the survey. Most respondents recommended NAC for stage III cases, with varying results for stage I and II cases. In NAC for HER2-positive BC (HER2+ BC), 91.9% of the respondents (34/37) used HER2-targeted therapy, whereas 70.3% (26/37) used pertuzumab. In NAC for triple-negative BC (TNBC), 62.2% of the respondents (23/37) selected dose-dense therapy. Dose-dense therapy use for luminal BC tended to be lower than that for TNBC (48.6% (18/37 respondents). Only 62.2% of the respondents (23/37) selected trastuzumab emtansine (T-DM1) as adjuvant chemotherapy for patients with HER2+ BC in non-pathological complete response (non-pCR). Meanwhile, 89.2% of the respondents (33/37) selected capecitabine as adjuvant therapy for patients with non-pCR TNBC. In addition, 91.9% of the respondents (34/37) used pathological diagnosis to determine adjuvant chemotherapy indications for luminal BC, whereas 62.2% of the respondents (23/37) used Oncotype DX.
Conclusion: The survey revealed that perioperative treatment for BC varies among Asian countries and regions, particularly pertuzumab, TDM-1, dose-dense therapy, and gene expression assays.
Keywords: Breast Cancer; Perioperative Treatment; Asia; Prognosis
Abbreviations: BC: Breast cancer, NAC: Neoadjuvant chemotherapy, HER2+ BC: HER2-positive breast cancer, TNBC: Triple-negative breast cancer, T-DM1: Trastuzumab emtansine, pCR: Pathological complete response, ASCO: American society of clinical oncology, ESMO: The european society for medical oncology, NCCN: The U.S. national comprehensive cancer network, AC: Doxorubicin hydrochloride and cyclophosphamide, CMF: Cyclophosphamide, methotrexate, and fluorouracil, OFS: Ovarian function suppression, LH-RH: Luteinizing hormone releasing hormone, AIs: Aromatase inhibitors, PMRT: Postmastectomy radiation therapy, IM: Internal mammary, IDFS: Invasive disease free survival, DFS: Disease free survival, OS: Overall survival, G-CSF: Granulocyte colony-stimulating factor, HER2- BC: HER2 negative BC.
Introduction
The morbidity and mortality of breast cancer (BC) is the highest of all cancer types among women worldwide. BC related deaths in Asia are estimated to be the highest worldwide, with over 300,000 deaths in a population of 4.7 million in 2020 [1]. Although the number of BC survivors is increasing owing to the development of treatments, survival rates vary between countries [2]. The 5 years survival rates of BC in Asia are as follows: > 80% in China, Korea, and Japan; 80% in Singapore; 69% in Thailand; 66% in India; and 65% in Malaysia [3]. Perioperative treatment is important for reducing BC mortality [2]. There are guidelines for BC treatment established by American Society of Clinical Oncology (ASCO), the European Society for Medical Oncology (ESMO), the U.S. National Comprehensive Cancer Network (NCCN), and the St. Gallen International Breast Cancer Consensus Conference [4-6]. Treatments with proven efficacy and acceptable side effects in clinical trials are recommended as standard BC treatments [5]. In addition, non-compliance with recommended treatments has been shown to be associated with poor survival [7]. However, actual data on cancer treatment in Asia is limited.
Factors that influence treatment decisions have been reported to include personal values [8], financial ability [9], fear of treatment-related side effects [10], and inadequate health education [9]. In particular, the Asian health insurance model (offering only public or private insurance, or a mix of the two) and reimbersment status of drugs are different from country to country. Therefore, some patients find it difficult to take expensive drugs. Previous reports suggest that basic cytotoxic agents are reimbursed, and their costs are decreasing owing to the release of generic drugs [11,12]. However, some approved cancer drugs, such as anti-HER2 drugs, are not reimbursed in some countries [13]. To reveal the actual treatment status and relationship between treatment and prognosis are important to build a local evidence base and develop cost-effective treatment strategies that are appropriate to the local culture [14,15]. This study aimed to reveal how perioperative treatment is performed in Asia, using a questionnaire survey.
Methods
Questionnaire
A questionnaire-based survey was conducted between October 2021 and April 2022. This questionnaire was designed to elucidate the actual situation of perioperative BC treatment in Asian countries and regions. The questionnaire included seven questions on neoadjuvant chemotherapy (NAC), seven questions on adjuvant therapy, two questions on hormonal therapy, and four questions on radiation therapy, for each BC subtype, that is, HER2- positive BC (HER2+ BC), triple-negative BC (TNBC), and luminal BC from stage I to III (Supplemental Table 1). Each question had a checklist on which the participants could choose their answers. This study followed the ethical guidelines for epidemiological research by the Ministry of Health, Labour and Welfare (MHLW), and the regulations of the National Cancer Center Hospital (NCCH) institutional review board (IRB). These guidelines and NCCH IRB do not require the ethical approval of institutes for the questionnaires to medical staff without individual chart reviews. This study was allowed to be done without informed consents of patients according to ethic guidelines for epidemiological research by the MHLW and the regulations of NCCH IRB.
![Click here to view Large Table 1](images/CTOIJ.MS.ID.556166.T001.png)
![Click here to view Large Table 2](images/CTOIJ.MS.ID.556166.T002.png)
Participants
An online questionnaire was distributed to 251 physicians in 22 countries in collaboration with the National Cancer Center, Japan. The selected participants were physicians performing perioperative chemotherapy for early-stage BC at cancer centers or university hospitals in Asian countries and regions. One physician was selected from each institution. However, in some large institutions that treat BC in multiple departments, physicians working in different hospitals or departments were also selected. To confirm the affiliations of respondents, we collected data on institutional addresses and respondents’ job titles and eliminated duplicate responses.
Results
Backgrounds of Respondents
Overall, 37 physicians from 15 countries completed a survey questionnaire. The number of respondents from each country is presented in Supplemental Table 2. Most of the respondents (22/37) were medical oncologists, 11 were surgeons, two were radiologists, and two were of unknown subspecialties. Most of the participants (29.7%) reported that < 50 cases of NAC therapy were performed in their respective institutions annually.
![Click here to view Large Table 3](images/CTOIJ.MS.ID.556166.T003.png)
NAC for each Subtype of Stage I-III BC
The rate of NAC recommendation varied according to stage and subtypes (Table 1). NAC is recommended less commonly for stage I and II luminal BC than for HER2+ BC and TNBC. In addition, all respondents answered that they administer NAC for stage III HER2+ BC and TNBC. However, not all respondents administered NAC for stage III luminal BC (91.9%). Most respondents (91.9%) used HER2-targeted NAC for HER2+ BC, of which 100% utilized trastuzumab and only 76.5% (26/34) used pertuzumab. Institutions that use and do not use pertuzumab coexist within the same country (Figure 1). For TNBC, 62.2% of respondents preferred dose-dense therapy as a NAC regimen, whereas 35.1% of respondents selected both dose-dense therapy and non-dosedense therapy (Table 1). In each country, the dose-dense therapy usage ratio of NAC for TNBC varies by institution. The use of dosedense therapy is particularly high in India; however, in Japan, there are variations among institutions (Figure 2). For patients with luminal BC, only 48.6% of the respondents preferred dose-dense NAC therapy but 29.3% selected both (Table 1). Respondents equally chose dose-dense doxorubicin hydrochloride and cyclophosphamide (AC) followed by weekly paclitaxel and dosedense AC followed by paclitaxel every two weeks as a dosedense NAC regimen. For non-dose-dense therapy, anthracyclinebased followed by taxane regimens are predominantly used. A few respondents use cyclophosphamide, methotrexate, and fluorouracil (CMF) in both TNBC and luminal BC. However, only anthracycline-based regimen or only taxan-based regimen were more selected for luminal BC than TNBC.
![Click here to view Large Figure 1](images/CTOIJ.MS.ID.556166.G001.png)
Adjuvant Chemotherapy for each Subtype of Stage I-III BC
For adjuvant chemotherapy for non-pathological complete response (non-PCR) in patients with HER2+ BC, 62.2% of the respondents used trastuzumab emtansine (T-DM1) (Table 2). Focusing on each country, T-DM1-using and non-using institutions coexisted within the same country (Figure 3). In TNBC, 89.2% of the respondents used capecitabine as adjuvant therapy for non-PCR patients (Table 2). Adjuvant capecitabine was more commonly used than adjuvant T-DM1. In addition, all respondents answered that they used HER2-targeted therapy as an HER2+ BC adjuvant chemotherapy. In T1N0 HER2+ BC, 83.8% of the respondents used trastuzumab-including regimens, and 62.2% selected a lowerintensity regimen, such as trastuzumab plus taxane (Supplemental Table 3). Moreover, 16.2% of the respondents answered that they did not administer adjuvant chemotherapy. In contrast, 13.5% of the respondents selected pertuzumab-including regimens, even at the early stage. For T2N1 HER2+ BC, 100% of respondents used trastuzumab-including regimens, and 67.6% used pertuzumabincluding regimens. Adjuvant chemotherapy for T1N0 and T2N1 TNBC was administered by 89.2% and 97.3% of respondents, respectively. Anthracycline-based regimens followed by taxane were used by most respondents (T1N0, 51.4%; T2N1, 75.7%). A few respondents selected only anthracycline-based regimens (T1N0; 29.7%, T2N1; 5.4%), only taxane-based regimens (T1N0, 35.1%; T2N1, 13.5%), and CMF (T1N0; 10.8%, T2N1; 5.4%). Dosedense adjuvant chemotherapy tended to be used more frequently utilized in T2N1 TNBC than in T1N0 TNBC (64.9% vs. 37.8%).
![Click here to view Large Figure 2](images/CTOIJ.MS.ID.556166.G002.png)
![Click here to view Large Table 4](images/CTOIJ.MS.ID.556166.T004.png)
![Click here to view Large Figure 3](images/CTOIJ.MS.ID.556166.G003.png)
![Click here to view Large Table 5](images/CTOIJ.MS.ID.556166.T005.png)
![Click here to view Large Table 6](images/CTOIJ.MS.ID.556166.T006.png)
To decide whether to administer adjuvant chemotherapy to patients with luminal BC, a pathological diagnosis was commonly considered (91.9% of respondents). This was followed by Oncotype DX (62.2%), PAM50 (18.9%), and MammaPrint (5.4%). Others considered age, EndoPredict score, Ki67 score, and OncoFREE. As adjuvant chemotherapy for luminal BC, 81.1% of the respondents selected anthracycline-based regimes followed by taxanes. Subsequently, dose-dense therapy (54.1%), only anthracycline-based regimens (43.2%), only taxane-based regimens (37.8%), and CMF (13.5%) were selected. Among the respondents, 13.5% did not administer chemotherapy. Details of each regimen are presented in Supplemental Table 3.
Hormonal Therapy
All respondents selected tamoxifen as adjuvant hormonal therapy for premenopausal patients (Table 3). For ovarian function suppression (OFS), 75.7% and 40.5% of the respondents selected luteinizing hormone releasing hormone (LH-RH) agonist and oophorectomy, respectively. Among the respondents, 45.9% selected aromatase inhibitors (AIs). This question was multiplechoice, and almost all respondents who selected AIs selected OFS (16/17 respondents). However, 21.6% of the respondents did not use OFS. Only 5.4% selected toremifene. Factors considering 10-year hormonal therapy included, 89.2% selected lymph node metastasis, 78.4% selected tumor size, 73% selected age, 59.5% selected histological grade, and 45.9% selected lymphovascular invasion. Of the respondents, one answered that all hormone receptor-positive patients had received hormonal therapy for 10-years, and the other answered that they administered hormonal therapy according to the status of thrombosis or osteoporosis.
Radiation therapy
94.6% respondents answered that they conducted postmastectomy radiation therapy (PMRT), defined as radiation therapy including the chest wall and regional lymph nodes, administered to patients after mastectomy (Table 4). Wholebreast irradiation after lumpectomy was also performed in 94.6% of respondents. The radiation therapy protocol varied by institution: 48.6% selected 50 Gy/25 Fr, 29.7% selected 42.5 Gy/ 16 Fr, and 21.6% selected others. Among others, 62.5% (13.5% of all respondents) answered that they had administered RT at 40 Gy/15 Fr. In patients with suspected internal mammary (IM) lymph node metastasis, 75.7% of the respondents indicated that radiation therapy would be administered in this area.
Discussion
This study conducted an online questionnaire survey to determine the actual status of perioperative therapy in patients with early-stage BC in Asia. There is heterogeneity in BC treatment strategies in Asia, especially the use of HER2-targeted therapy, dose-dense therapy, and gene expression assays, which vary by institution. This heterogeneity may be caused by differences in approval and reimbursement status, insurance systems, patient characteristics, and problems with adverse effect management. The difference in the usage of pertuzumab and TDM-1 may be due to cost [16-19]. HER2 targeted therapy for NAC and adjuvant chemotherapy dramatically reduced recurrence risk [20-24]. In fact, four-years invasive disease-free survival (IDFS) rates are reported to be 90% in patients with HER2+ BC who achieved pCR after neoadjuvant pertuzumab plus trastuzumab followed by adjuvant trastuzumab [25]. In addition, the use of TDM-1 in patients with residual disease improved disease-free survival (3-years IDFS 88.3% with T-DM1 vs 77.0% with trastuzumab) [24]. However, our study suggested that not all institutions recommended pertuzumab and T-DM1 for preoperative treatment of HER2+ BC in Asia. Although the use of pertuzumab in NAC and TDM-1 in adjuvant therapy has been approved in India, Japan, South Korea, Malaysia, China, Singapore, and Taiwan [5]. Some respondents commented that these drugs were not covered by insurance and are too expensive to use. In contrast, the usage ratio of trastuzumab and capecitabine was higher than that of pertuzumab and T-DM1. Currently, trastuzumab and capecitabine are included in the WHO model list of essential medicines [26]. Trastuzumab biosimilars and generic forms of capecitabine, which are available on the market, are considered cost-effective and offer significant cost savings for BC patients. However, some institutions that use anti-HER2 drugs commented that they would not prescribe trastuzumab to patients who could not afford it. Unfortunately, cancer patients who are unable to afford these prescription drugs, especially when they lack insurance coverage, are more likely to report non-compliance with medication and forgo further treatment, leading to poorer clinical outcomes and increased cancer burden [27]. The low usage of gene expression assays for predicting prognosis might also be caused by their approval status and high cost.
![Click here to view Large Table 7](images/CTOIJ.MS.ID.556166.T007.png)
The heterogeneity of the dose-dense therapy usage rate might have been caused by the balance between positive and adverse effects. Meta-analyses have indicated that dose-dense therapy improves disease-free survival (DFS), especially in patients with hormone receptor-negative, lymph node involvement, and highly proliferative BC however, the results of overall survival (OS) are controversial [28-31]. In addition, the ratio of adverse effects was higher than that of standard therapy. Granulocyte colonystimulating factor (G-CSF) is required for preventing neutropenia. The incidence of anemia and transaminase elevation were higher than those in non-dose-dense therapy [31]. Thus, evaluation of the risk of recurrence and basic health conditions is important for dose-dense therapy. Although NCCN guideline recommends dosedense therapy for HER2 negative (HER2-) BC patients [6], some institutions use only non-dose-dense therapy.
Similarly, indications of OFS and 10-year hormonal therapy for premenopausal patients and the protocol of adjuvant radiation therapy also varied by institution In high-risk premenopausal patients e.g., young age, high-grade tumor, lymph node involvement who need chemotherapy should be considered OFS [32], but its effects are not clear in low-risk cases not requiring chemotherapy. The 10-years hormonal therapy has been reported to reduce recurrence and mortality rates. However, the risk of pulmonary embolism, ischemic heart disease, and endometrial cancer tend to increase with longer exposure to tamoxifen [33,34]. The decision to use OFS may depend on the overall risk assessment based on patient and tumor characteristics and may follow consideration of all the adverse effects that may develop with the addition of OFS in combination with hormonal therapy. In radiation therapy, clinical studies have shown that the effectiveness and safety of moderate hypofractionation schedules (15-16 fractions of ≦3 Gy/fraction) are like those of conventional treatments [35-38]. The difference in hypofractionated irradiation therapy usage may depend on the approval status, reimbursement status, and availability of equipment [5]. In addition, clinical trials of hypofractionated irradiation therapy are being conducted. This study had some limitations. First, the number of respondents was insufficient. Therefore, when interpreting these results, it should be noted that this study represents the actual situation in some Asian facilities. The small number of responses from each country suggests that the results do not fully reflect their actual status. Second, this study was conducted between October 2021 and April 2022, and the timing of insurance approval of T-DM1 for non-PCR patients may differ between countries. Third, the answers were self-reported, making it difficult to assess the accuracy of the estimated data. Fourth, there was heterogeneity in the respondents’ specializations, which could also explain the variation in their practices in terms of experience and level of expertise. In conclusion, the current study revealed that perioperative treatment for early-stage BC varies among Asia- Pacific countries and regions, particularly pertuzumab, TDM-1, dose-dense therapy, and gene expression assays. For improvement of treatment outcomes in BC patients throughout Asia, we should focus on promoting the use of therapeutic drugs and tests, setting guidelines, and conducting multicenter clinical trials in Asia [39].
Conclusion
The results of this online questionnaire survey revealed that perioperative BC treatment in Asia is heterogeneous in real-world practice. Particularly the use of pertuzumab, TDM-1, dose-dense therapy, and gene expression assays varies by institution.
Acknowledgement
We thank all the participants for their participation in this study. We thank Aya Watanabe for secretarial assistance. Editage- Cactus Communications provided editorial support in the form of medical writing, assembling tables, creating high-resolution images based on the authors’ detailed directions, collating author comments, copying, editing, fact-checking, and referencing. This study was funded by the Japan Agency for Medical Research and Development as part of the “Project Promoting Clinical Trials for Development of New Drugs” (20lk0201002j0001, 21lk0201005j0001, 22lk0201007j0001). The funder had no role in the design, data collection, data analysis, and reporting of this study.
Conflict of Interest
The authors have no conflicts of interest to declare.
Author Contributions
MT, YK, and SS designed the study and interpreted the data. MT, YK, SY, and SS analyzed the data. KS, TS, KY, AS, and KN supervised the project. MT, MA, YK, and SS wrote the manuscript and MT prepared all figures and tables. All authors have approved the final edition of the manuscript.
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