Comments to the Chinese Society of Clinical Oncology (CSCO) Breast Cancer Guidelines 2022

This is a superb clinical guideline (CG) for breast cancer that is practical with cutting-edge content. It also clearly describes the background, therapeutic concepts, approaches, regimens, and limitations. The current issues and future perspectives are also carefully and thoughtfully stated. There are a few additional comments, but we will touch upon the differences between the Japanese breast cancer CG and the questions that physicians often encounter in routine clinical practice.

The current recommendations for neoadjuvant and adjuvant therapies for HER2-positive disease, especially the indications for various anti-HER2 therapies with cytotoxic chemotherapy, are clearly summarized. It also includes the indications and options for anti-HER2 tyrosine kinase inhibitors (TKIs). So far, TKIs have not been approved for adjuvant or neoadjuvant treatment and are not included in the Japanese CG.

According to recent advances in preoperative neoadjuvant systemic therapy, the pathological complete response (pCR) rate for HER2-positive and estrogen receptor (ER)-negative breast cancer exceeds 70%. Historically, the pCR rate for ER-positive and HER2-positive breast cancer was not considerably high; however, the currently reported pCR rate has risen to 50% or higher, with the introduction of recent new approaches such as the antibody-drug conjugate, etc. ypT0 and ypT0/is in the definition of pCR are considered to be similar from the perspective of the indications of postoperative adjuvant therapy, but have important implications for local therapy, such as surgery and radiation therapy. For example, in cases of ypT0ypN0, various new local de-escalating therapies are currently under investigation. Therefore, the prediction of ypT0 and ypN0 and ypT0/is and ypN0 is an important aspect of treatment planning.

For patients with residual disease after neoadjuvant therapy with anti-HER2 antibodies, the Japanese CG widely recommends trastuzumab emtansine (T-DM1) in the postoperative setting (1). There is no comparison with trastuzumab plus pertuzumab (HP), so it may be reasonable to place T-DM1 and HP. It seems clinically possible to use these agents flexibly, depending on the amount or characteristics of the residual cancer burden.

The Chinese Society of Clinical Oncology (CSCO) breast cancer CG recommends pyrotinib and neratinib based on the results of prospective controlled trials. Pyrotinib can be used in combination with anti-HER2 antibody and taxane as neoadjuvant therapy, and neratinib is considered as an adjuvant treatment for patients at high-risk of recurrence. Recent advances in tumor genomics have enabled the discovery of more information about genomic abnormalities in each patient prior to the initiation of drug therapy or after treatment. Advances in liquid biopsy techniques have also bolstered this trend. Therefore, depending on the context of the genomic abnormality, therapeutic regimens involving TKIs may be a rational option. Moreover, the selection of this class of drugs can be also influenced by ER expression.

One of the most frequently asked questions in the treatment of HER2-positive breast cancer is the choice of therapeutic de-escalation and escalation. For instance, the following two strategies should be considered when the tumor is small but the possibility of lymph node metastases cannot be eliminated, or when lymph node metastases appear negative but the tumor size is 2 cm or slightly larger: a simple combination of trastuzumab and weekly paclitaxel is an option for de-escalation, whereas neoadjuvant full-spec anti-HER2 therapy and chemotherapy, followed by postoperative adjuvant therapy with anti-HER2 agents, or T-DM1 is an escalation option in case of invasive residual disease (2-4). Single adjuvant T-DM1 therapy may also be considered for de-escalation (5). Patients need to choose one option and provide consent in real-world clinical situations. The toxicity profiles of de-escalation therapy and escalation therapy are so different that it is worth developing new decision support tools.

The Japanese CG recommends treatment regimens consisting of anthracyclines and taxanes for preoperative chemotherapy in triple negative breast cancer (TNBC), and strongly recommends dose-dense/dose-intensified chemotherapy when the risk of recurrence is high. Moreover, we recommend pembrolizumab in the neoadjuvant setting (6). Platinum is also recommended. There does not appear to be a significant difference between the Chinese and Japanese CGs regarding other TNBC treatment recommendations. In the future, immunotherapy with anti-PD-1 antibody will be administered before surgery for most cases of stage 2 and stage 3 disease. In this case, the postoperative adjuvant therapeutic regimen will also have to be changed. Treatment may vary depending on the presence or absence of invasive residual lesions, and on the characteristics of the residual disease. The American and European CGs have already tackled this point. This is a commonly encountered clinical issue, necessitating the creation of a treatment strategy in the near future.

Apropos the use of oral fluoropyrimidines as adjuvant therapy, capecitabine is recommended for patients with TNBC with invasive residual disease after neoadjuvant chemotherapy in several global CGs, including the Japanese CG (7). The CSCO CG for breast cancer also includes capecitabine as an adjuvant for high-risk TNBC patients. This indication is compelling, since recent Chinese clinical trials have demonstrated the efficacy of capecitabine for this patient population.

In Japan, we also tested the significance of S-1, another major oral fluoropyrimidine, for patients with primary breast cancer at intermediate or high risk of recurrence in the adjuvant setting (the POTENT trial) (8). S-1 plus endocrine therapy reduced the recurrence of invasive disease significantly compared to standard endocrine therapy alone. Postoperative oral fluoropyrimidines can provide survival benefits and various possibilities for use in adjuvant therapy for non-HER2-positive disease.

Abemaciclib plus endocrine therapy has been approved for anatomical and histological high-risk ER-positive and HER2-negative tumors in Japan (9). Hence, it is necessary to personalize abemaciclib and oral fluoropyrimidines for ER-positive and HER2-negative patients with high-risk disease. These agents can be used separately according to the magnitude of the risk of recurrence.

Boost and accelerated partial breast irradiation are weakly recommended and fractionated irradiation is strongly recommended for both ductal carcinoma in situ and invasive ductal carcinoma disease. Irradiation to the N1-3 area is weakly recommended (depending on the risk). Generally, the recommendations are remarkably similar, but some differences exist with respect to postoperative radiation treatment.

We have several changes in the CG for advanced breast cancer (ABC) in Japan.

The order of treatment for HER2-positive ABC will be changed as follows: first-line therapy, trastuzumab plus pertuzumab plus taxane; second-line therapy, trastuzumab deruxtecan (T-DXd); and third-line therapy, others. This sequence for the line of therapy differs slightly between the two countries. T-DXd is preferably used for HER2-positive patients with brain metastases, because of recent results from a comparative study between T-DXd and T-DM1 (10). The magnitude and duration of the response elicited by T-DXd for patients with brain metastases was remarkably superior compared to T-DM1.

Drug delivery systems such as liposomal paclitaxel and liposomal doxorubicin have not been approved yet in Japan. In addition, alpelisib, neratinib, pyrotinib, sacituzumab govitecan, etc. have not been approved either in Japan.

Finally, the CSCO CG clearly elucidated the importance of the development and application of artificial intelligence for the treatment of breast cancer in clinical practice. This is one of most important aspects of breast cancer management in the near future. We are also intriguing to develop it with international collaboration in the future.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Breast Cancer Research. The article did not undergo external peer review.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tbcr.amegroups.com/article/view/10.21037/tbcr-22-31/coif). M Takada received research grants from Eisai, Yakult and Medbis, and honorarium from Chugai, AstraZeneca, Daiichi Sankyo, Lilly, Eisai, Nipponkayaku, Pfizer, and Mitaka Khoki. M Toi reports research grants from Chugai, Takeda, Pfizer, Taiho, JBCRG assoc., KBCRN assoc., Eisai, Eli Lilly, Daiichi-Sankyo, AstraZeneca, Astellas, Shimadzu, Yakult, Nippon Kayaku, AFI technology, Luxonus, Shionogi, GL Science, Sanwa Shurui, and honorarium from Chugai, Takeda, Pfizer, Kyowa-Kirin, Taiho, Eisai, Daiichi-Sankyo, AstraZeneca, Eli Lilly, MSD, Exact Science, Novartis, Shimadzu, Yakult, Nippon Kayaku, Devicore medical Japan. M Toi is a member of advisory board of Daiichi-Sankyo, Eli Lilly, BMS, Athenex Oncology, Bertis, Terumo, Kansai Medical Net, the board of directors (no salary) of JBCRG association, Organisation for Oncology and Translational Research, Kyoto Breast Cancer Research Network, the associate editor of British Journal of Cancer, Scientific Reports, Breast Cancer Research and Treatment, Cancer Science, Frontiers in Women’s Cancer, Asian Journal of Surgery, Asian Journal of Breast Surgery, and the deputy editor of International Journal of Oncology. M Toi serves as an unpaid editorial board member of Translational Breast Cancer Research from December 2021 to November 2023. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work, including ensuring that any questions related to the accuracy or integrity of any part of the work have been appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. von Minckwitz G, Huang CS, Mano MS, et al. Trastuzumab Emtansine for Residual Invasive HER2-Positive Breast Cancer. N Engl J Med 2019;380:617-28. [Crossref] [PubMed]
2. Gianni L, Pienkowski T, Im YH, et al. 5-year analysis of neoadjuvant pertuzumab and trastuzumab in patients with locally advanced, inflammatory, or early-stage HER2-positive breast cancer (NeoSphere): a multicentre, open-label, phase 2 randomised trial. Lancet Oncol 2016;17:791-800. [Crossref] [PubMed]
3. Tolaney SM, Barry WT, Dang CT, et al. Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer. N Engl J Med 2015;372:134-41. [Crossref] [PubMed]
4. von Minckwitz G, Procter M, de Azambuja E, et al. Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer. N Engl J Med 2017;377:122-31. [Crossref] [PubMed]
5. Tolaney SM, Tayob N, Dang C, et al. Adjuvant Trastuzumab Emtansine Versus Paclitaxel in Combination With Trastuzumab for Stage I HER2-Positive Breast Cancer (ATEMPT): A Randomized Clinical Trial. J Clin Oncol 2021;39:2375-85. [Crossref] [PubMed]
6. Schmid P, Cortes J, Dent R, et al. Event-free Survival with Pembrolizumab in Early Triple-Negative Breast Cancer. N Engl J Med 2022;386:556-67. [Crossref] [PubMed]
7. Masuda N, Lee SJ, Ohtani S, et al. Adjuvant Capecitabine for Breast Cancer after Preoperative Chemotherapy. N Engl J Med 2017;376:2147-59. [Crossref] [PubMed]
8. Toi M, Imoto S, Ishida T, et al. Adjuvant S-1 plus endocrine therapy for oestrogen receptor-positive, HER2-negative, primary breast cancer: a multicentre, open-label, randomised, controlled, phase 3 trial. Lancet Oncol 2021;22:74-84. [Crossref] [PubMed]
9. Johnston SRD, Harbeck N, Hegg R, et al. Abemaciclib Combined With Endocrine Therapy for the Adjuvant Treatment of HR+, HER2-, Node-Positive, High-Risk, Early Breast Cancer (monarchE). J Clin Oncol 2020;38:3987-98. [Crossref] [PubMed]
10. Cortés J, Kim SB, Chung WP, et al. Trastuzumab Deruxtecan versus Trastuzumab Emtansine for Breast Cancer. N Engl J Med 2022;386:1143-54. [Crossref] [PubMed]