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Breast cancer is a malignant tumor that seriously threatens the health of women all over the world, and HER2-positive breast cancer has the characteristics of poor prognosis and high recurrence rate, with a 5-year survival rate of only about 20%.
Recently, the 2024 National Breast Cancer Conference and the Annual Meeting of the Chinese Society of Clinical Oncology for Breast Cancer (CSCO BC) was held in Beijing. On the afternoon of April 12, Professor Yin Yongmei from the Department of Oncology of Jiangsu Provincial People's Hospital brought us a summary and introduction of the updated key points of the CSCO Guidelines for the Diagnosis and Treatment of Breast Cancer 2024 Edition (hereinafter referred to as the "Guidelines") on HER2-positive advanced breast cancer.
A list of update points
H, P: trastuzumab, pertuzumab and their subcutaneous preparations that have been approved in China
This guideline update divides patients into three different strata: trastuzumab (H) sensitivity (defined as no prior use of H; response to neoadjuvant therapy; recurrence 1 year after the end of adjuvant therapy; discontinuation after effective rescue therapy), H treatment failure, and TKI treatment failure. The updates are summarized below:
H treatment sensitivity: the level of evidence for TH+pyrotinib was adjusted from 2A to 1A, the level of evidence for THP regimen was adjusted from 1B to 1A, and HP recommended the addition of subcutaneous preparations
H treatment failure: T-DM1 regimen adjusted from grade I to grade II recommendation, T-DXd from grade II to grade I recommendation
TKI treatment failure: the evidence for T-DXd in the IL recommendation was revised from 2A to 1A
Trastuzumab is sensitive
Based on the PHILA study, the level of evidence for TH+flexinib was adjusted from 2A to 1A
The PHILA study is a randomized, double-blind, parallel-controlled, multicenter phase III clinical trial led by Academician Xu Binghe to evaluate the efficacy and safety of pyrotinib + trastuzumab + docetaxel versus placebo + trastuzumab + docetaxel in the first-line treatment of HER2+ recurrent/metastatic breast cancer, with the primary endpoint being progression-free survival (PFS) as assessed by investigators.
Efficacy analysis data showed that the median PFS assessed by investigators in the pyrotinib group was 24.3 months, which was significantly longer than that in the control group (10.4 months (HR=0.41; 95% CI 0.32~0.53; P<0.001), reducing the risk of disease progression and mortality by 59%, and the median PFS assessed by the independent review committee was 33.0 months in the pyrotinib group compared with 10.4 months in the control group (HR=0.35; 95% CI 0.27~0.46; P). <0.001）。 Subgroup analyses showed a significant PFS benefit in the pyrotinib group compared with the control group, regardless of whether the patient had received trastuzumab in the neoadjuvant/adjuvant therapy phase.
Overall, the results of the analysis of the phase III study PHILA showed that the regimen of pyrotinib + trastuzumab + docetaxel compared with placebo + trastuzumab + docetaxel significantly prolonged PFS in patients with HER2-positive recurrent/metastatic breast cancer in the first line with a manageable safety profile and manageable adverse events.
A new recommendation for HP subcutaneous agents has been added
The subcutaneous formulation was validated in the early treatment mode to be comparable to the intravenous formulation in terms of pharmacokinetics, efficacy, and safety, and was suitable for patients with advanced disease. In addition, compared with intravenous preparations, subcutaneous preparations have the advantages of saving treatment time and facilitating medication management.
In terms of patient preference, data from a phase II double-arm crossover PHranceSCa study showed that 85% of patients preferred subcutaneous PHESGO over intravenous preparations, and 93% expressed "very strong" or "fairly strong" intentions.
Trastuzumab treatment failure
T-DXd replaces T-DM1 as Level I recommendation, and T-DXd is adjusted from Level II to Level I
This adjustment is based on the open-label, randomized, multicenter phase III DESTINY-Breast03 study. The DESTINY-Breast03 study is designed to compare the efficacy and safety of the antibody-drug conjugate (ADC) trastuzumab (T-DXd) versus enmetuzumab (T-DM1) in the second-line treatment of HER2+ metastatic breast cancer (MBC).
In an interim analysis of PFS, the T-DXd group significantly outperformed the T-DM1 group in PFS (median PFS: 28.8 versus 6.8 months) while also reducing the risk of death by 36%, resulting in a statistically significant and clinically meaningful improvement. The second interim analysis updated the overall survival (OS), efficacy, and safety results: for patients with HER2+ MBC, T-DXd was associated with significantly better OS improvement than T-DM1, with the longest PFS to date, and was safe and controllable, with a longer duration of treatment.
Failure of TKI therapy
The evidence for T-DXd in the Level II recommendation was adjusted from 2A to 1A
Since there are no large-scale clinical studies specifically for this population, a Level II recommendation is made for the population with failed TKI treatment based on the enrollment population of existing studies, small exploratory studies, real-world data, and clinical experience.
T-DXd
Sixteen percent of patients in the T-DXd arm of the DESTINY-Breast03 study had received a prior TKI, while 50.5 percent of patients had received a prior TKI in the subsequent DESTINY-Breast01 study. The results of the study suggest that these patients can still benefit from progression-free survival with T-DXd.
HP + chemotherapy
The results of a small clinical study demonstrated that in patients who had failed previous trastuzumab and lapatinib therapy, a median PFS of 4.6 months to 4.9 months was obtained with a trastuzumab-based regimen re-administered.
T-DM1
The effect of using T-DM1 in patients who have failed TKI therapy has been demonstrated in TH3RESA studies. Patients in the T-DM1 group could prolong median PFS by nearly 3 months while prolonging median OS by nearly 7 months compared to the treatment regimen chosen by physicians.
HER2-positive breast cancer brain metastases
The incidence of brain metastases in advanced breast cancer is on the rise, mainly due to the improved effect of systemic treatment of breast cancer and the prolongation of patient survival. In addition, the use of brain magnetic resonance imaging can help to detect more patients with asymptomatic brain metastases. Patients with HER2+ breast cancer have a relatively high risk of developing brain metastases, with nearly 50% of metastatic breast cancers having brain metastases.
For the treatment of patients with HER2+ breast cancer brain metastases, breast cancer brain metastases are mainly treated locally, supplemented by systemic treatment. The recommended regimen for level I is local therapy, including surgical resection, stereotactic radiotherapy, and whole-brain radiotherapy. For a limited number of brain metastases, treatment with a centrally active anti-HER-2 agent (2A) may be considered for deferred radiotherapy with close follow-up if local symptoms are controllable.
Expert Profile
Professor Yin Yongmei
- Chief physician, doctoral supervisor
- Vice President of Jiangsu Provincial People's Hospital
- Vice President of the Chinese Society of Clinical Oncology (CSCO).
- Vice Chairman of Beijing Heath Clinical Oncology Foundation
- Secretary General of the CSCO Breast Cancer Expert Committee
- Member of the Standing Committee of the Breast Cancer Professional Committee of the Chinese Anti-Cancer Association
- Chairman of the CSCO Patient Education Expert Committee
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