Focus on academic dynamics and interpret the updated points of the 2021 "OFS Consensus"

*For medical professionals only

The "OFS Consensus" update iteration, taking stock of the key points of the new version of the consensus in 2021.

On December 31, 2021, the Chinese Journal of Cancer published the "Expert Consensus on the Clinical Application of Ovarian Functional Suppression in Early Breast Cancer in China (2021 Edition)" [1], hereinafter referred to as the Ovarian Functional Suppression (OFS) Consensus. The 2021 version of the OFS consensus is based on the previous consensus (2018 version)[2], based on the latest clinical research results that everyone is concerned about, and based on the joint discussion of many well-known experts in this field across the country, the new version of the consensus has made some changes to related issues, mainly including new chapters and original chapter updates, this article will sort out some of the content as follows.

New consensus chapters

▌ Premenopausal patients are encouraged to participate in clinical trials with adequate estrogen suppression

Based on the guidelines issued by the US FDA, if all pharmaceutical companies declare breast cancer treatment drugs, mainly endocrine treatment drugs, breast cancer is no longer divided into postmenopausal and premenopausal, that is, it is hoped that premenopausal breast cancer patients can enter effective drug clinical trials as soon as possible, and early participation in treatment may benefit early. At present, about 60% of patients in mainland China are in a premenopausal state at the time of diagnosis [3], and it is necessary to focus on the needs of this part of the patient, most experts believe that premenopausal patients after the use of ovarian function inhibitors can be endocrine therapy according to the principle of postmenopausal treatment, or enter the relevant clinical trials of postmenopausal patients, but some experts believe that it is still necessary to carry out relevant clinical studies for premenopausal patients.

The new version of consensus mainly updates the interpretation of chapters

First, ofs beneficiaries

1. The scope of application of the medium and high risk judgment standards is expanded compared with the previous one

In terms of postoperative recurrence risk grouping, the new version of the consensus lists er/PR status as a separate interpretation point, and the classification of metastatic lymph nodes in medium-risk patients has changed greatly, from the original "negative or 1-3 positive" to "other conditions that do not meet the definition of low/high risk", and different risk groups have been adjusted accordingly in other situations, especially in high-risk patients, when the metastatic lymph nodes are 1-3 and ER/PR positive, the discrimination points of other conditions are more abundant, from simple HER2 positive to " Histology grade III.; pT>5 cm; HER2 positive; high-risk polygenic testing" any of the conditions can be met.

Table 1. Grouping of Breast Cancer Recurrence Risk after Surgery (2018 Edition)

Table 2. Grouping of Breast Cancer Recurrence Risk after Surgery (2021 Edition)

2. Added premenopausal patients who use AI instead of SERM therapy need to receive OFS treatment at the same time

Both versions of the consensus recommend endocrine therapy from OFS for medium- and high-risk premenopausal hormone receptor-positive breast cancer, but in terms of treatment recommendations for low-risk patients, the new consensus recommends estrogen receptor modulator (SERM) monotherapy instead of the original tamoxifen monotherapy. And the new consensus emphasizes that premenopausal patients who use aromatase inhibitors (AI) instead of SERM therapy need to receive OFS at the same time. This may be due to the fact that several retrospective studies in China and other Asian countries show that there are some patients with metabolic disorders in the Asian population (e.g., CYP2D6*10 TT type), even in clinically low-risk patients, who often show resistance to SERM and need to use AI instead of endocrine therapy strategies, and given that a series of results such as soft studies and TEXT studies [5] have confirmed the benefit of of offline combined AI treatment, Therefore, if AI is used for premenopausal patients, it is also necessary to combine OFS at the same time.

Figure 1. Clinical pathway of adjuvant endocrine therapy for premenopausal hormone receptor-positive early breast cancer (left: 2018 edition; right: 2021 edition)

3. New ASTRRA study evidence shows that OFS combined with tamoxifen has significant therapeutic benefits for patients with menstrual recovery after postoperative adjuvant chemotherapy

In the Phase III ASTRRA study [6] conducted by the Korean Breast Cancer Research Group, patients with early-stage breast cancer who were estrogen receptor positive, younger than 45 years of age, who had previously received (neo)adjuvant chemotherapy, and who had not been menopause or subsequently restored ovarian function were evaluated to evaluate the efficacy of tamoxifen (5 years) + OFS (2 years) versus tamoxifen (5 years). The study underwent a baseline assessment of ovarian function within 3 months after the last chemotherapy and an assessment of ovarian function every 6 months for 2 years, randomized when assessed as premenopausal patients. Patients with chemotherapy-induced amenorrhea are given oral tamoxifen first. The results showed that compared with 5 years of tamoxifen treatment combined with 2 years of OFS, compared with tamoxifen monotherapy, DFS (5 years DFS 91.1% vs 87.5%) and a 31% reduction in the risk of recurrence, OS (5 years OS 99.4% vs 97.8%) also significantly improved, the risk of death was reduced by 69%. And more than 90% of the patients in the study recovered from amenorrhea to a premenopausal state within 2 years of the end of chemotherapy. The study showed that OFS combined with tamoxifen had a significant therapeutic benefit for patients who recovered menstrual periods after postoperative adjuvant chemotherapy.

Second, the best course of GnRHa

▌ The new consensus states that the standard adjuvant course of GnRHa is 5 years

The new consensus states that the standard course of GnRHa-assisted endocrine therapy should be 5 years. After completion of 5-year endocrine therapy with OFS, if it is not menopausal and well tolerated, it is recommended to continue 5-year endocrine therapy with OFS or 5-year SERM therapy. In low-risk patients who choose OFS instead of chemotherapy, OFS plus endocrine therapy may be considered for a period of 2 years. The old consensus recommended that the duration of GnRHa-assisted endocrine therapy be 5 years, and that applications shorter than 5 years but more than 2 years would also benefit.

The above changes are mainly due to the fact that the new consensus refers to more new research evidence on a previous basis and domestic and foreign guidelines, such as the monarchE study [7], the PALLAS study [8] and the PENELOPE-B study [9] conducted by CDK4/6 inhibitors in patients with early hormone receptor-positive high-risk breast cancer (including premenopausal and postmenopausal) [7], and the treatment duration of the selected standard endocrine therapy control group is at least 5 years. And since there are no comparative studies of different courses of GnRHa, based on the concept of prolonged therapy for endocrine therapy and the results of long-term follow-up of the SOFT/TEXT trial [5], it is recommended that the standard course of adjuvant GnRHa be 5 years [1]. In addition, the 2015 ESMO Clinical Practice Guidelines for the Diagnosis, Treatment and Follow-up of Primary Breast Cancer and the Guidelines and Specifications for the Diagnosis and Treatment of Breast Cancer of the Chinese Anti-Cancer Association (2019 Edition) recommended gnRHa treatment courses of 2-5 years. The 2021 St. Gallen Expert Consensus, the 2016 ASCO Guideline Update on OFS, and the 2020 BCY4 Guidelines recommend a course of treatment for 5 years.

Patients who have completed 5 years of OFS standard treatment, lack of research evidence for follow-up extended treatment, the 2021 St. Gallen Conference voted on this topic, the results showed that patients who have completed 5 years of OFS + SERM treatment, if still in a premenopausal state, 41% of expert group members recommended continuing OFS + AI, and 45% of expert group members recommended continuing tamoxifen treatment for 5 years. The 2021 CSCO guidelines recommend SERM for 5 years or OFS+AI for those who have not been menopausal after completing the initial 5-year treatment of OFS+AI and are well tolerated.

The 5 "Unchanged" of the New Consensus

First, ofs methods and choices

GnRHa can rapidly reduce serum estrogen levels in women to reach a postmenopausal state, and this effect is reversible after discontinuation. Because ovarian function inhibitors are now covered by medicare, considering the invasive and irreversible nature of surgery and the limited effect of radiation therapy, drug castration (GnRHa) is recommended as the first choice for premenopausal hormone receptor-positive early breast cancer OFS.

Second, the choice of of OFS joint program

OFS plus AI therapy is also a reasonable option for medium- and high-risk patients with premenopausal hormone receptor-positive early-stage breast cancer, or higher-risk patients with STEPP analysis. For patients of any risk level with contraindications to SERM, OFS in combination with AI is recommended.

Third, the timing of GnRHa medication

Based on the functional state of the ovaries before chemotherapy for hormone receptor-positive breast cancer, adjuvant endocrine therapy regimens are determined. It is not recommended to use GnRHa after confirming the functional status of the ovaries in patients who have received chemotherapy.

4. Safety management of GnRHa adjuvant therapy

Communicate with patients about possible adverse events and select appropriate drug castration regimens. Reasonable safety management can effectively alleviate adverse event symptoms and increase patient compliance with treatment.

5. Estrogen level detection

For patients undergoing drug castration, it is not routinely recommended to monitor estrogen levels during drug castration therapy and decide whether to continue drug castration based on test reports. However, estrogen testing may be performed after drug castration, when incomplete suppression of ovarian function is suspected [including changes in usage such as the injecting person's lack of proficiency in injecting the drug, change of dosage form, or when there are certain physiological changes that may indicate ovarian function restoration, such as menstrual recovery and/or periodic fluctuations in menopausal symptoms].

summary:

The 2021 edition of the OFS Consensus summarizes and updates all the evidence-based medical evidence on OFS in recent years, hoping to provide better services for premenopausal breast cancer patients.

Expert Profiles

Yu Zhiyong

Title: Professor, Researcher, Chief Physician, Doctoral Supervisor

Department: Director of The Third Ward of Breast Surgery

Education: Ph.D

Specialties: Diagnosis and treatment of breast tumors and postoperative rehabilitation

Academic achievements: Discipline leader of Shandong Cancer Hospital, member of Academic Professional Committee of Shandong Cancer Hospital, chairman of Breast Expert Committee of Shandong Clinical Oncology Society, vice chairman of Tumor Plastic Surgery Committee of China Anti-Cancer Association, vice chairman of Breast Disease Branch of China Association for the Promotion of Traditional Chinese Medicine, vice chairman of Breast and Thyroid Committee of Shandong Medical Doctor Association, vice chairman of Breast Professional Committee of Shandong Medical Education Association, standing committee member of Breast Disease Committee of China Medical Education Association, outstanding graduate instructor of Shandong Academy of Medical Sciences The most beautiful physician of Shandong Provincial Cancer Hospital in 2020; and the well-known expert of Shandong Provincial Cancer Hospital in 2021.

bibliography:

[1] Expert Consensus on the Clinical Application of Ovarian Function Inhibition in Early Breast Cancer in China (2021 Edition)

[2] Expert Consensus on the Clinical Application of Ovarian Function Inhibition in Early Breast Cancer in China (2018 Edition)

[3] FAN L,STRASSER-WEIPPL K,LI J J,et al. Breast cancer in

China［J］.Lancet Oncol,2014,15(7):e279-e289.

[4] Lan B,Ma F et al. Int J Cancer 2018,143:184;J Clin Oncol.2007 Sep 1;25(25):3837-45;Ann Oncol.2008 Aug;19(8):1423-9.

[5] FRANCIS P A,PAGANI O,FLEMING G F,et al. Tailoring adjuvant endocrine therapy for premenopausal breast cancer［J］.N Engl J Med,2018,379(2):122-137.

[6] NOH W C,LEE J W,NAM S J,et al. Role of adding ovarian function suppression to tamoxifen in young women with hormone-sensitive breast cancer who remain premenopausal or resume menstruation after chemotherapy:The ASTRRA study［J］.J Clin Oncol,2018,36(15_suppl):502.

[7] Johnston SRD,Harbeck N,Hegg R,et al.monarchE Committee Members and Investigators.Abemaciclib Combined With Endocrine Therapy for the Adjuvant Treatment of HR+,HER2-,Node-Positive,High-Risk,Early Breast Cancer(monarchE). J Clin Oncol.2020 Dec 1;38(34):3987-3998.

[8] Mayer EL,Dueck AC,Martin M,et al. Palbociclib with adjuvant endocrine therapy in early breast cancer(PALLAS):interim analysis of a multicentre,open-label,randomised,phase 3 study. Lancet Oncol.2021 Feb;22(2):212-222.

[9] Loibl S,MarméF,Martin M,et al. Palbociclib for Residual High-Risk Invasive HR-Positive and HER2-Negative Early Breast Cancer-The Penelope-B Trial.J Clin Oncol.2021 May 10;39(14):1518-1530.

This article is supported by AstraZeneca and is intended for medical professionals only.

Approval number CN-95127 is valid until 2023-4-28

*The copyright of this article belongs to the original author, if you need to reprint, please contact the original author for authorization