*For medical professionals only
Interpretation of the key points of the update of the Expert Consensus on the Clinical Application of Ovarian Function Inhibition in Early Breast Cancer in China (2024 Edition).
Breast cancer patients in China have a relatively young age of onset, and 60% of female patients are premenopausal at the time of diagnosis. Compared with postmenopausal, premenopausal women have vigorous ovarian function, which can continue to secrete estrogen and promote the proliferation of breast cancer cells. Ovarian function suppression (OFS) has been widely used in the clinical treatment of HR+ early breast cancer, and a large body of evidence-based evidence suggests that the addition of OFS can significantly reduce the risk of recurrence and improve survival of breast cancer in premenopausal women. Some long-term follow-up data (12 and 13 years of follow-up in the SOFT/TEXT study, 20 years of follow-up in the STO-5 study, and 8-year follow-up in the ASTRRA study in Asian populations) have been published recently, further confirming that the addition of OFS to patients with early-stage breast cancer can significantly reduce the risk of recurrence for more than 10 years and improve the probability of cure. In the monarchE and NATALEE studies, the combination of certain CDK4/6 inhibitors with adjuvant endocrine therapy regimens containing drug castration (gonadotropin-releasing hormone agonists (GnRHa)) in patients with early premenopausal breast cancer demonstrated a further increase in survival benefit [1]. Based on these new evidence, the Breast Cancer Committee of the Chinese Anti-Cancer Association convened clinical experts in the field of breast cancer treatment in China to discuss and compile the Expert Consensus on the Clinical Application of Ovarian Function Inhibition in Early Breast Cancer in China (2024 Edition) (hereinafter referred to as the OFS Consensus) on the basis of the 2021 edition. The Medical Oncology Channel invited Professor Wu Jiong from Fudan University Cancer Hospital to interpret the updated points in the 2024 version of the OFS consensus.
OFS benefits a wide range of people, bringing a chance of cure to more patients with HR+ early breast cancer
■ For patients with premenopausal intermediate- and high-risk breast cancer with hormone receptor positive, it is recommended to add specific CDK4/6 inhibitors to GnRHa in combination with endocrine therapy
On the basis of OFS combined with traditional endocrine therapy, CDK4/6 inhibitors combined with endocrine therapy can further reduce the risk of recurrence in patients with HR+ early-stage breast cancer. The OFS consensus incorporates new evidence-based evidence, such as the monarchE study and the NATALEE study, into the risk assessment and clinical pathway system of early-stage breast cancer, and further standardizes the treatment options for premenopausal patients at intermediate and high risk levels.
monarchE is a randomized, open-label, multicenter phase III clinical study to compare the efficacy and safety of abeciclib in combination with endocrine therapy and adjuvant endocrine therapy alone in patients with early stage breast cancer who are at high risk of HR+/HER2- recurrence (4 positive lymph ≥nodes; or 1~3 lymph nodes) and meet at least one of the following: tumor ≥5 cm, histologic grade 3, or Ki-67 ≥20%). Among them, 43.5% were premenopausal patients, and about 22% of the enrolled patients were treated with OFS. The 5-year results of the study, based on a pre-planned analysis, were presented at the 2023 ESMO Congress [2], showing that the benefit of abeciclib in adjuvant therapy was sustained, with an absolute benefit of 7.6% and 6.7% for 5-year invasive disease-free survival (iDFS) and distant recurrence-free survival (DRFS), respectively, compared with the 2-, 3-, and 4-year results. The monarchE study demonstrated for the first time the clinical benefit of CDK4/6 inhibitors + aromatase inhibitors (AI)/tamoxifen (TAM)± OFS in the adjuvant treatment of HR+/HER2- early breast cancer with a high risk of recurrence.
NATALEE is the second clinical trial in which a CDK4/6 inhibitor has received positive results in the field of adjuvant intensive endocrine therapy for early-stage breast cancer, following monarchE. This Phase III study is designed to investigate the efficacy and safety of rebociclib + nonsteroidal AI± goserelin in patients with HR+/HER2- early-stage breast cancer at risk of recurrence (in a population of stage II.A: N0 with G2 and at high risk [Ki-67 proliferative index ≥20%/21 gene score ≥26 or other high-risk genetic characteristics), N0 with G3, N1; stage II.B: N0 or N1; stage III]. Notably, all of the included premenopausal patients (43.9%) were treated with goserelin for castration. At the 2023 ASCO Congress, the results of the second analysis of iDFS, the pre-defined interim efficacy endpoint of the NATALEE study[3], were presented with a median follow-up of 27.7 months, with an absolute benefit of 3.3% and a 25.2% reduction in the risk of disease progression compared with the control group. The updated results from the 2023 ESMO Congress[4] showed that the analysis of the premenopausal subgroup was consistent with the primary results, with the rebociclib combination reducing the risk of disease progression by 27.8% compared with the control group. The latest findings [5] further support the use of reboxiclib + non-steroidal AI± goserelin as a new treatment option for patients at risk of recurrence of stage II or stage III HR+/HER2- early breast cancer, including node-negative patients.
In terms of the enrollment population, compared with monarchE, which only included node-positive patients, the NATALEE study included a broader population, including almost all patients with stage II.A to III.C, of which 28.1% of N0 patients were included. Therefore, the 2024 version of the consensus recommends that the beneficiaries of HR+ premenopausal breast cancer with specific CDK4/6 inhibitors added to GnRHa combined with endocrine therapy include: node-positive, node-negative and meet any of the conditions [G3, G2 with Ki-67 proliferative index ≥20%, G2 with multigenic testing (21-gene score, Prosigna PAM50, MammaPrint, EndoPredict high-risk)]. This update provides an important basis for better clinical guidance for the individualized treatment of high-risk and some intermediate-risk patients.
In addition, the expert opinion of the 2024 version of the OFS consensus believes that the STEPP score is helpful in identifying the high-benefit population with GnRHa addition. For patients with HR+ premenopausal intermediate- and high-risk breast cancer, it is recommended to add specific CDK4/6 inhibitors to GnRHa in combination with endocrine therapy, but it is necessary to meet the enrollment population of the corresponding clinical study as much as possible.
■ Immunomenopausal patients with intermediate- and high-risk hormone receptor-positive breast cancer with an indication for chemotherapy are recommended to receive GnRHa-containing endocrine therapy, and premenopausal patients who decide to use AI should receive GnRHa at the same time
The 2024 version of the OFS consensus refers to a number of international guidelines, which takes the risk factor of indications for chemotherapy as one of the applicable judgment criteria for OFS, so as to facilitate the identification of patients who benefit from OFS in clinical practice and provide a reference for further standardizing the clinical decision-making of HR+ early breast cancer.
- According to the 2023 5th edition of the NCCN Guidelines for Breast Cancer [6], patients with invasive cancer > 0.5 cm and pN0 who intend to receive chemotherapy are highly recommended for evaluation by 21 gene testing, and if the recurrence risk score is ≤ 15, adjuvant endocrine therapy ±OFS) is recommended if the recurrence risk score is < 16 <, and adjuvant endocrine therapy ±OFS or adjuvant chemotherapy sequential endocrine therapy is recommended for patients with pT1-3 and pN+, and whether to choose whether to combine or sequential OFS drugs after chemotherapy is evaluated for patients with pT1-3 and pN+.
- In the 2021 St. Gallen consensus [7], the factors that recommended OFS were considered as follows: stage I/II breast cancer has a high risk of recurrence (especially in patients with an indication for chemotherapy), age < 40 years, recurrence risk score of 16~25 points, and stage III breast cancer.
- The 2022 BCY5 guideline [8] recommends that patients at higher risk of recurrence should be treated with GnRHa in addition to SERM or AI, and that young women with breast cancer with stage I/II who cannot take SERM (due to contraindications or serious adverse events) may receive GnRHa alone, oophorectomy, or AI plus GnRHa. Women who are at high risk of recurrence and whose ovarian function has recovered with TAM within 2 years of the end of chemotherapy should be considered for GnRHa.
In addition, several previous studies have shown that patients with indications for chemotherapy benefit significantly from OFS treatment. In 2023, Francis et al. [9] reported data from the SOFT study with a median follow-up of 12 years, and the results showed that TAM combined with OFS significantly improved DFS rate (HR=0.82, 95% CI: 0.69~0.98) and OS rate (HR=0.78, 95% CI: 0.60~1.01) compared with TAM, and the distant recurrence rate was also lower. Among patients who had received prior chemotherapy, the OS rate was 78.8% in the TAM group, 81.1% in the TAM plus OFS group, and 84.4% in the AI plus OFS group. Overall, after 12 years of follow-up, the benefit of OFS in combination with adjuvant endocrine therapy was sustained, especially in patients who had received prior chemotherapy.
The ASTRRA study included patients with early-stage breast cancer who were positive for estrogen receptor (ER), younger than 45 years of age, who had received (neo)adjuvant chemotherapy and who had not been postmenopausal or who had subsequently recovered ovarian function. At the 2022 ASCO Congress, the 8-year follow-up results of the study were updated and showed that at a median follow-up of 106.4 months, the 8-year DFS rate in the TAM plus OFS group was still better than that in the TAM group (85.4% vs 80.2%, HR=0.67, 95% CI: 0.51~0.87) [10,11]. The results suggest that the survival benefit of TAM+OFS persists over time in patients who remain premenopausal or whose ovarian function has recovered after chemotherapy.
In fact, the current guidelines/consensus recommended indications for adjuvant chemotherapy (Table 1) [12] are consistent with the clinicopathologic features of patients considering OFS (Table 2). Expert opinion of the 2024 version of the OFS consensus: Immunomenopausal patients with intermediate- and high-risk HR+ breast cancer with an indication for chemotherapy are recommended to receive endocrine therapy containing GnRHa, and premenopausal patients who decide to use AI need to receive GnRHa at the same time. The following clinical pathways (Table 2) are recommended to assist in the selection of adjuvant endocrine therapy. Patients with early-stage breast cancer who have received single-agent adjuvant chemotherapy sequential SERM are recommended to be combined with GnRHa on the basis of SERM if they are judged to be "non-menopausal" within 2 years. Monotherapy with SERM is recommended for low-risk patients. For patients with contraindications to the use of SERMs, OFS monotherapy or OFS+AI therapy is recommended.
Table 1. Guidelines and Norms for the Diagnosis and Treatment of Breast Cancer of the Chinese Anti-Cancer Association (2024 Edition): Adjuvant chemotherapy is recommended for those who are postoperative
Table 2. The 2024 version of the OFS consensus: recommended clinical pathway for adjuvant endocrine therapy for premenopausal HR+/HER2- early breast cancer
■ Perimenopausal patients should be treated according to the hormone level before chemotherapy and premenopausal patients
This consensus adds a new definition of perimenopause, which is the transition state from normal menstruation to menopause. The beginning of perimenopause is characterized by irregular menstrual cycles (a difference of ≥ 7 days from previous cycles), alternating anovulatory cycles with ovulatory cycles, and elevated follicle-stimulating hormone (FSH) that persists until 12 months of amenorrhea.
With the continuous improvement of medical standards, the life expectancy of Chinese women has increased significantly. The average age at which women begin perimenopause is 46 years old, the average age of menopause is 48~52 years old, about 90% of women are menopausal between 45~55 years old, and perimenopausal symptoms can last up to 4.5 years. This patient population is of increasing clinical interest [13].
Currently HR+Perimenopausal patients are only partially included in breast cancer-related clinical trials, and treatment decisions are recommended in NCCN guidelines and St. Gallen consensus based on menopausal status, and hormone levels fluctuate in perimenopausal women, even if there is transient amenorrhea, ovarian function may not yet fail, which cannot be equated with postmenopausal status, and it should be noted that patients who are receiving GnRHa therapy cannot determine their menopausal status, and those who are not menopausal before chemotherapy cannot be judged to be postmenopausal even if they are amenorrhea after chemotherapy. The results of the ASTRRA study [9] also showed that 95.1% of patients regained ovarian function within two years of the end of chemotherapy. Together, these suggest that perimenopausal treatment regimens should refer to premenopausal adjuvant endocrine therapy, and that OFS is the key to the benefit of endocrine therapy in perimenopausal breast cancer patients.
Based on this, the 2024 version of the OFS consensus expert opinion: despite the existence of treatment-induced amenorrhea, patients who are premenopausal or perimenopausal before starting treatment should be treated as premenopausal patients. The decision to use OFS should be based on the menstrual status prior to chemotherapy, and it is not recommended to interfere with the choice of OFS based on the presence or absence of amenorrhea after chemotherapy. Perimenopausal patients should be treated according to the hormone level before chemotherapy and refer to the treatment of premenopausal patients, and patients who need to be combined with OFS will be converted into AI if it is clearly judged that they have reached the menopausal state between 2~5 years of OFS+ endocrine therapy.
Expand the timing of GnRHa concurrent chemotherapy and standardize the medication of patients
■ Timing of OFS administration: GnRHa concurrent chemotherapy is recommended regardless of whether ovarian protection is considered
Compared with the 2021 consensus, the highlight of this update is that GnRHa concurrent chemotherapy is recognized regardless of whether ovarian protection is considered or not. It may be updated on the following grounds:
Refer to the NCCN Breast Cancer Guidelines (2024.V2) for recommendations on the timing of OFS: start at the same time as chemotherapy (neoadjuvant or adjuvant), if no chemotherapy is planned, OFS should be started at least 1-2 cycles alone or at the same time as TAM until estradiol (E2) is in the postmenopausal range, at which point AI can be considered.
In addition, the GnRHa concurrent chemotherapy treatment model has accumulated rich clinical evidence. In the TEXT study [14], patients who were scheduled to receive chemotherapy and received concurrent chemotherapy with OFS showed that the 5-year DFS rates of OFS in combination with AI and OFS in combination with TAM were 89.8% and 84.6%, respectively, and the 8-year DFS rates were 86.8% and 82.8%, respectively, with an overall good benefit. In premenopausal patients enrolled in the PROMISE-GIM6 study [15] who received chemotherapy with GnRHa versus chemotherapy alone, 80 percent of whom had HR+, there was no significant difference in the 5-year DFS rates of 80.5 and 83.7 percent, respectively. In a meta-analysis of short-term ovarian suppression with GnRHa during chemotherapy in patients with premenopausal early-stage breast cancer [16], there was no statistically significant difference in the five-year DFS rate (85.1 versus 87.6 percent, P >0.05) and five-year OS rate between the GnRHa concurrent chemotherapy group and chemotherapy alone (96.6 versus 95.6 percent, P >0.05). Together, these pieces of evidence suggest that concurrent chemotherapy with OFS does not affect the survival benefit of patients.
It is also worth mentioning that patients enrolled in the SOFT study [17] who received chemotherapy and confirmed their premenopausal status within 8 months after the last chemotherapy were treated with OFS, and the results showed that the 5-year DFS rates of OFS plus AI and OFS plus TAM were 84.3% and 80.6%, respectively, and the 8-year DFS rates were 85.9% and 83.2%, respectively. In terms of study design, the SOFT study was a sequential OFS treatment mode after chemotherapy ended, while the TEXT study was OFS concurrent chemotherapy, and the study enrolled a more high-risk population. However, in terms of efficacy data, the TEXT study appears to have a better therapeutic benefit with the OFS concurrent chemotherapy modality. Similar results were reported in a meta-analysis reported at the 2019 ASCO Congress [18], which included 37,225 patients in 37 clinical trials comparing chemotherapy concurrently versus sequential OFS, and then using the Bayesian algorithm to rank the relative superiority of different treatment modalities with no statistically significant differences in efficacy. The results showed that in the subgroup of premenopausal women, the chemotherapy sequential/concurrent OFS+AI and chemotherapy sequential/concurrent OFS+TAM regimens ranked higher than the sequential regimens. These evidences suggest that concurrent chemotherapy with OFS may lead to better DFS and OS benefits in premenopausal women.
Based on this, the expert opinion of the 2024 version of the OFS consensus is that if ovarian protection is considered, GnRHa concurrent chemotherapy is recommended without affecting the survival benefit of patients, and if ovarian protection is not considered, GnRHa concurrent chemotherapy and GnRHa are both recognized for sequential use after chemotherapy, and the latter is more recommended.
A new whole-process management pathway for the use of OFS drugs in patients with early/locally advanced breast cancer,
Further support clinical decision-making
For premenopausal patients with HR+/HER2- early/locally advanced breast cancer, the application of OFS drugs is of great significance. In order to better guide clinical practice and improve treatment efficacy, the 2024 version of the OFS consensus refers to the Guidelines and Specifications for the Diagnosis and Treatment of Breast Cancer of the Chinese Anti-Cancer Association (2024 Edition), and adds a new management path for the whole process of OFS drug application in patients with early/locally advanced breast cancer.
The management pathway is presented in the form of a visual flow chart, which aims to help doctors clearly and intuitively understand the clinical decision-making and management pathway of premenopausal HR+/HER2- breast cancer patients throughout the disease course. The design of the flowchart fully considers the latest guidelines of the Guidelines and Specifications for the Diagnosis and Treatment of Breast Cancer of the Chinese Anti-Cancer Association (2024 Edition), and combines new evidence and clinical practice experience to ensure its scientific and practicality.
The flow chart starts from the diagnosis of the patient, and describes in detail the key links such as the beneficiary population, combination regimen, and timing of OFS drugs. At the same time, the flowchart also emphasizes the importance of patient wishes, and advocates that doctors and patients jointly decide on endocrine extension regimens to improve patients' treatment compliance and satisfaction.
In conclusion, the new whole-process management pathway for the use of OFS drugs in patients with early/locally advanced breast cancer will provide clinicians with a clearer and more practical decision-making tool, which is expected to promote the standardization, precision and individualization of breast cancer treatment.
Figure 1. A whole-process management pathway for OFS drug application in patients with early/locally advanced breast cancer
On the basis of the 2021 version, this consensus integrates the latest research results and diagnosis and treatment experience, and provides more guiding suggestions for the clinical practice of HR+ early breast cancer. The consensus further refines the beneficiary population of OFS and provides clear guidance for the use of OFS in patients with indications for chemotherapy and perimenopause, especially the applicable population of CDK4/6 inhibitors + endocrine therapy + OFS. At the same time, the consensus also emphasizes that the use of GnRHa concurrent chemotherapy is recommended regardless of ovarian protection. In addition, in order to better assist clinical decision-making, this consensus also adds a new management path for the whole process of OFS drug use, which provides a clear treatment direction for premenopausal HR+ breast cancer patients through an intuitive and easy-to-understand flow chart. These updates not only reflect the continuous progress of medical research, but also highlight the attention and importance of the medical community to individualized treatment for patients. It is believed that with the wide promotion and application of the new version of the consensus, the treatment effect of breast cancer will continue to improve, and the quality of life of patients will also be significantly improved.
Expert Profile
Professor Wu Jiong
- Fudan University Cancer Hospital, Executive Vice President, Chief Physician, Doctoral Supervisor
- Director of the Drug Clinical Trial Agency
- Chairman of the Breast Cancer Professional Committee of the Chinese Anti-Cancer Association
- Vice Chairman of the Breast Surgeon Committee of the Surgeon Branch of the Chinese Medical Doctor Association
- Vice Chairman of the Oncologist Branch of the Chinese Medical Doctor Association
- Member of the Standing Committee of the Oncology Branch of the Chinese Medical Association
- Chairman of the Board of Directors of Shanghai Anti-Cancer Foundation
- Executive Director of the 9th Council of Shanghai Anti-Cancer Association
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* This article is only for the purpose of providing scientific information to medical professionals and does not represent the views of this platform