WU Yun,WEI Yuhan,MA Fei (Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Oncology/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021)
Funds: Major Collaborative Innovation Project of Medical and Health Science and Technology Innovation Project of Chinese Academy of Medical Sciences(2021-I2M-1-014)
通信作者：马飞 E-mail：[email protected]
Wu Yun and Wei Yuhan are the joint first authors
Professor Ma Fei
Chief Physician, Professor, Doctoral Supervisor, Changjiang Scholar Distinguished Professor of the Ministry of Education.
He is currently the Director of the Internal Medicine Treatment Center of the National Cancer Center/Cancer Hospital of the Chinese Academy of Medical Sciences.
He is also the vice chairman of the Breast Cancer Expert Committee of the National Cancer Quality Control Center, the secretary-general of the National Expert Committee for Monitoring the Clinical Application of Anti-tumor Drugs, the secretary-general of the Breast Cancer Screening, Early Diagnosis and Early Treatment Standard Committee of the National Cancer Center, the health science popularization expert of the Healthy China Action Promotion Committee, the vice chairman of the Oncology Pharmacist Branch of the Chinese Pharmacists Association, the vice chairman of the Integrated Oncology Cardiology Branch of the Chinese Anti-Cancer Association, the vice chairman of the Multi-primary and Unknown Primary Tumor Professional Committee of the Chinese Anti-Cancer Association, the secretary-general of the Tumor Drug Clinical Research Professional Committee of the Chinese Anti-Cancer Association, and the vice chairman of the National Female Ovarian Protection and Anti-aging Promotion Engineering Professional CommitteeHe is the director general of the Geriatric Oncology Branch of the Chinese Society of Gerontology and Geriatrics, the president of the Chinese Institute of Cancer Health Management, the vice president of the Health Communication Branch of the Chinese Health Management Association, the chairman of the Boao Cancer Innovation Institute, the vice chairman of the Beijing Society for the Prevention and Treatment of Breast Disease, and the chairman of the Tumor Chemotherapy Quality Control Professional Committee of the Beijing Cancer Treatment Quality Control and Improvement Center.
He won the second prize of the National Science and Technology Progress Award, and won the honorary titles of "Top Ten Outstanding Young Doctors in the Capital" and "China Young Cancer Scientist Award".
【Abstract】This article summarizes the latest progress of chemotherapy, targeted therapy, endocrine therapy and immunotherapy for breast cancer in 2023, and looks forward to the research direction of future treatment of breast cancer, aiming to better guide the individualized precision treatment of breast cancer, improve the prognosis of patients, and improve the quality of life of patients.
【Keywords】breast cancer, chemotherapy, targeted therapy, endocrine therapy, immunotherapy
According to the latest cancer statistics, there are about 416,000 new cases of breast cancer and 117,000 deaths in mainland China every year, ranking first among new cases of female malignant tumors, which seriously endangers women's lives and health [1]. With the update of breast cancer treatment drugs and the establishment of precision diagnosis and treatment models based on molecular typing, the level of comprehensive diagnosis and treatment of breast cancer has been improved year by year, and the 5-year survival rate has reached 90% [2]. In recent years, with the vigorous development of multi-omics sequencing technology, breast cancer treatment has also entered a new development model guided by the concept of precision medicine, taking into account both efficacy and safety, and improving the quality of life of patients. This article summarizes the major advances in the field of breast cancer in 2023 from the aspects of chemotherapy, targeted therapy, endocrine therapy, and immunotherapy, and looks forward to the future research directions of breast cancer treatment, in order to better guide the individualized treatment of breast cancer.
1. Chemotherapy
At present, although the treatment of breast cancer has developed from chemotherapy to individualized precision treatment based on molecular typing, chemotherapy still occupies an important position in the comprehensive treatment of breast cancer because it can significantly prolong the survival time of patients and improve the prognosis of patients. However, the problems of chemotherapy resistance, drug-related toxicity and poor tolerability still need to be addressed urgently. At present, clinical studies are still exploring the optimal treatment mode of capecitabine resistance, including dose, dosage form and drug combination. The X-7/7 trial, reported at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting, compared fixed-dose capecitabine (FD-7/7 group: 1500 mg twice daily for 7 days and 7 days off) with the US Food and Drug Administration-approved standard regimen (SD-14/7 group: 1250 mg/m2 twice daily for 14 days and 7 days off). d), the FD-7/7 group had similar progress free survival (PFS), overall survival (OS) time, and objective response rate (ORR) compared with the SD-14/7 group, and 27.4% of patients in the SD-14/7 group had 3, Grade 4 treatment-related adverse events (TRAEs) were only 11.3 percent in the FD-7/7 group (P=0.02) [3]. The study demonstrated that capecitabine still guarantees efficacy and low toxicity despite down-regulation of overall dose intensity, which also adds new evidence-based evidence to fixed-dose capecitabine.
Eribulin is a novel microtubule inhibitor that continues to show promising efficacy in patients with metastatic breast cancer (MBC) who are resistant to chemotherapeutic agents such as taxanes due to its unique binding site [4-5]. A multicenter, single-arm Phase II clinical study evaluating the efficacy and safety of adequate levels of eribulin (1.4 mg/m2) in combination with gemcitabine (1.0 g/m2) ≥ second-line human epidermal growth factor receptor 2 (HER-2)-negative MBC was reported at the 2023 ASCO Annual Meeting [6]. In the study, which included 54 patients who had received prior anthracycline and taxane chemotherapy with a median of three lines of chemotherapy, the results showed that the median PFS of eribulin combined with gemcitabine in MBC was 7.7 months, the ORR was 40.7%, and the disease control rate (DCR) was 66.7%, while the most common grade 3 and 4 TRAEs included leukopenia (35.2%), anemia (18.6%), and thrombocytopenia (9.4%) ), no treatment-related deaths were observed. The above results suggest that the efficacy of adequate elibulin combined with gemcitabine is definite and reliable.
2. Targeted therapy
2.1 Anti-HER-2 targeted therapy
HER-2 positive breast cancer accounts for about 15%~20% of all breast cancers, and has the characteristics of strong aggressiveness and poor prognosis. In recent decades, HER-2-targeted therapies such as trastuzumab, pertuzumab, antibody-drug conjugates (e.g., trastuzumab deruxtecan (T-DXd)), and tyrosine kinase inhibitors (e.g., lapatinib, neratinib, pyrotinib, tucatinib) have significantly improved the prognosis of HER-2-positive breast cancer. However, the efficacy of existing anti-HER-2 therapies is still limited, and better treatment strategies need to be explored. According to statistics, 45%~55% of breast cancers have low HER-2 expression and cannot benefit from traditional anti-HER-2 targeted therapy. The emergence of T-DXd has changed the treatment prospect of HER-2 low expression breast cancer.
2.1.1 Neoadjuvant therapy KN026 is a novel bispecific antibody that can target HER-2 extracellular domains II (pertuzumab binding site) and IV (trastuzumab binding site) with antitumor activity similar to or better than trastuzumab in combination with pertuzumab [7]. At the 2023 European Society for Medical Oncology (ESMO) Annual Meeting, the results of the phase II single-arm clinical study of KN026 in combination with docetaxel neoadjuvant therapy in patients with HER-2-positive early or locally advanced breast cancer were presented, in which the overall pathological complete response (pCR) rate in HER-2-positive patients was 56.7% (17/30), ORR 90 percent (27/30), and the most common grade 3 TRAEs ≥ neutropenia (15/30, 50 percent) and decreased lymphocyte count (3/30, 10 percent) [8]. This study confirmed that KN026 combined with docetaxel neoadjuvant treatment of HER-2-positive patients with early or locally advanced breast cancer has good clinical efficacy, and the safety is acceptable and controllable, but it still needs to be further verified by large-scale randomized controlled trials.
2.1.2 HER-2-positive advanced breast cancer The 2-year follow-up data on the efficacy and safety of KN026 in combination with docetaxel in the first-line treatment of patients with HER-2-positive recurrent or metastatic breast cancer were presented at the 2023 ESMO Annual Meeting, with an ORR of 76.4%, a median duration of response of 26.8 months, a median PFS of 26.9 months, and a 24-month OS rate of 84.2% and a ≥3-grade TRAE of 40.4% (23/57) [ 9]。 The study confirmed that KN026 in combination with docetaxel has a good clinical benefit and is well tolerated as a first-line treatment option for HER-2-positive advanced breast cancer, but a large-scale phase III study is still needed to verify the efficacy and safety. A Phase III NCT05838066 study with trastuzumab, pertuzumab and docetaxel as a comparator is currently underway to further explore the efficacy and safety of KN026.
Anti-HER-2 therapy, represented by trastuzumab, significantly improves the prognosis of patients with HER-2-positive breast cancer, but about 10% of HER-2-positive breast cancer patients exhibit trastuzumab resistance, and these patients often have a poor prognosis. Pyrotinib is an irreversible pan-HER receptor tyrosine kinase inhibitor that has shown excellent efficacy in both first- and second-line treatment of HER-2-positive MBC [10-11]. In the phase II PICTURE study, pyrotinib plus capecitabine was reported in 100 patients with trastuzumab-resistant, HER-2-positive advanced breast cancer, with a median PFS of 11.8 months and a median OS of 41.7 months, with no new safety signals identified [12-13]. The study supports the potential of pyrotinib in combination with capecitabine as a new treatment option for trastuzumab-resistant, HER-2-positive breast cancer patients.
2.1.3 Advanced breast cancer with low HER-2 expression T-DXd is a novel antibody-drug conjugate targeting HER-2, consisting of an anti-HER-2 antibody, a cleavable linker, and a topoisomerase I inhibitor [14]. The higher drug-antibody ratio (8:1) and bystander effect make it effective in HER-2-low breast cancer. DESTINY-Breast 04 is the first Phase III clinical trial to demonstrate positive results for T-DXd in the treatment of HER-2-low expression metastatic breast cancer, and updated survival results with a median follow-up of up to 32 months were reported at the 2023 ESMO Annual Meeting [15]. In the study, the median PFS time in the T-DXd group and the physician-selected chemotherapy group (referred to as the chemotherapy group) was 9.6 months and 4.2 months (HR=0.37), and the median OS time was 23.9 months and 17.6 months (HR=0.69), respectively, and the risk of death in the T-DXd group was significantly reduced by 31%. Overall, the median duration of PFS was 4.6 months (8.8 months versus 4.2 months, HR = 0.36) and the median duration of OS was 6.1 months (22.9 months versus 16.8 months, HR = 0.69) in the T-DXd group compared with the chemotherapy group [16]. The results of this update showed that the overall survival benefit of the T-DXd treatment group compared with the chemotherapy group was consistent with the results of the first analysis, regardless of HR status, and that there were no newly diagnosed safety events in T-DXd, suggesting that the long-term safety profile was controllable, regardless of intrinsic subtype, ESR1 mutation, PIK3CA mutation, or known cyclin-dependent kinase 4 and 6 (CDK4/ 6) The status of inhibitor resistance markers, T-DXd has a significant consistent clinical benefit [16]. This update of follow-up data reaffirms the sustained survival benefit and long-term safety of T-DXd, and establishes the status of T-DXd as the standard of care in HER-2 low expression breast cancer.
2.1.4 Breast cancer brain metastases 30%~50% of advanced breast cancer patients have brain metastases, among which HER-2-positive breast cancer is more prone to brain metastases than other molecular subtypes, and up to 50% of HER-2-positive advanced breast cancer patients have brain metastases in disease progression. The overall prognosis of patients with brain metastases from breast cancer is poor, and it seriously affects the quality of life, which is one of the biggest challenges in the treatment of advanced breast cancer. At the 2023 ESMO Annual Meeting, the efficacy and safety of T-DXd in the treatment of HER-2-positive breast cancer with brain metastases in the DESTINY-Breast 01, DESTINY-Breast 02 and DESTINY-Breast 03 studies were summarized and analyzed, and the results showed that among patients with previously treated or stable brain metastases, the intracranial ORR of the T-DXd group and the control group was 45.2% and 27.6%, respectively , median CNS PFS duration was 12.3 months versus 8.7 months, and in patients with untreated or active brain metastases, the intracranial ORR in the T-DXd group was superior to that in the control group (45.5 versus 12.0 percent) and significantly prolonged the median CNS PFS time (18.5 months versus 4.0 months, HR = 0.19), and the incidence of TRAE in patients treated with brain metastases treated with T-DXd was similar to that in the control group, at 94.5 and 94.0 percent, respectively [17]. These data confirm the significant efficacy and controllable safety profile of T-DXd in brain metastases. At the ESMO Annual Meeting, the intracranial efficacy of T-DXd in the DESTINY-Breast 04 study in patients with HER-2-low breast cancer with baseline asymptomatic brain metastases was reported, and the intracranial efficacy of the T-DXd group was significantly improved compared with the chemotherapy group (intracranial ORR was 25% to 0%), and the median CNS PFS time reached 9.7 months [18]. This study provides a new treatment option for the treatment of brain metastases in HER-2-low breast cancer.
2.2 抗人滋养层细胞表面抗原2（human trophoblast cell-surface antigen 2，Trop-2）靶向治疗
Trop-2 is a transmembrane calcium signal transducer that has been implicated in tumor progression and poor prognosis. Trop-2 is highly expressed in a variety of solid tumors, with approximately 78 percent of breast cancers and 95 percent of triple negative breast cancers (TNBCs) [19]. At present, Trop-2 has become an important target for drug development of antibody-drug conjugates in the field of breast cancer. Sacituzumab govitecan (SG) is a novel antibody-drug conjugate from an anti-Trop2 human monoclonal antibody conjugated to the cytotoxic metabolite SN-38 [20], which has been approved for patients with metastatic TNBC who have received ≥ first-line therapy. The phase III TROPiCS-02 study was designed to explore the efficacy and safety of SG in patients with HR-positive and HER-2-negative metastatic breast cancer who had received endocrine therapy, CDK4/6 inhibitors, and second, third, and fourth lines of chemotherapy, and the final analysis results showed that compared with the chemotherapy group, the median OS time was significantly longer in the SG group (14.4 months versus 11.2 months, HR=0.79, P=0.020), and the overall mortality risk was significantly reduced by 21%; Consistent with previous studies, no new safety signals were observed in the SG group. In a post-hoc analysis, the SG group improved the prognosis of patients with HR-positive, HER-2-negative metastatic breast cancer, regardless of the level of Trop-2 expression and the number of prior lines of therapy compared with chemotherapy [21-22]. These data support SG as a new treatment option for these patients.
Datopotamab deruxtecan (Dato-DXd) is a novel antibody-drug conjugate targeting Trop2, consisting of an anti-Trop2 monoclonal antibody conjugated to a payload DXd [23]. Data from the randomized controlled phase III TROPION-Breast 01 study, with endpoints of PFS and OS, were presented for the first time at the 2023 ESMO Annual Meeting to investigate the efficacy and safety of Dato-DXd in patients with HR-positive, HER-2-negative MBC [24]. The results of this study showed that compared with the chemotherapy group, the median PFS time was significantly longer in the Dato-DXd group (6.9 months versus 4.9 months, HR=0.63, P<0.000 1), and the risk of progression or death was significantly reduced by 37%. 6 Inhibitor-treated patients showed consistent PFS benefits with the overall population, OS data were not mature, but the Dato-DXd group had shown a trend of benefit (HR=0.84), ;D incidence of grade 3 TRAEs ≥in the ato-DXd group and chemotherapy group was 21% and 45%, respectively, and there were no new safety signals in the Dato-DXd group. The TROPION-Breast 01 study is the first phase III clinical study of Dato-DXd in the field of breast cancer, and the results confirm the good anti-tumor activity and controllable safety profile of Dato-DXd, suggesting that Dato-DXd can provide a new treatment option for patients with HR-positive and HER-2-negative advanced breast cancer.
SKB264 is a Trop-2-targeting antibody-drug conjugate, which consists of a humanized anti-Trop-2 monoclonal antibody conjugated to cytotoxic T030 (topoisomerase I inhibitor) through a CL2A linker with optimized stability, with an average drug-antibody ratio of 7.4:1. In a phase I and II, single-arm, basket trial presented at the 2023 ESMO Annual Meeting, SKB264 demonstrated an ORR of 36.8 percent, a DCR of 89.5 percent, a six-month sustained response rate of 80 percent, and a median PFS of 11.1 months in treatment-experienced HR-positive, HER-2-negative MBC [25]. This suggests that SKB264 has a manageable safety profile and good efficacy, so SKB264 has been granted Breakthrough Therapy Designation by the Center for Drug Evaluation (CDE) of the China Medical Products Administration (NMPA) for patients with locally advanced or metastatic HR-positive, HER-2-negative breast cancer who have received at least second-line chemotherapy.
3. Endocrine therapy
HR-positive patients account for about 80% of breast cancers. Endocrine therapy has become the cornerstone of comprehensive treatment for early and advanced HR-positive breast cancer, as well as its extensive clinical practice and good patient compliance. In recent years, the targeted combined endocrine therapy model represented by CDK4/6 inhibitors has created a new pattern of diagnosis and treatment of early and advanced HR-positive and HER-2-negative breast cancer, and has become a new standard for the treatment of patients with HR-positive and HER-2-negative breast cancer. However, there are still many questions to be addressed regarding endocrine therapy, and these questions have been further explored in multiple published clinical trials in 2023.
3.1 Early endocrine therapy
The MonarchE study, the first phase III clinical study to achieve positive results in the adjuvant therapy of HR-positive, HER-2-negative and high-risk early breast cancer, confirmed that the CDK4/6 inhibitor abeciclib in combination with endocrine therapy showed the ability to survive invasive disease-free in the adjuvant treatment of HR-positive, HER-2-negative, node-positive patients with high-risk early-stage breast cancer survival, iDFS) [26]. At the 2023 ESMO Annual Meeting, the five-year follow-up milestone results were further announced, showing an absolute benefit of 7.6 percent in the five-year iDFS rate and a 32 percent reduction in the risk of iDFS events in patients receiving abeciclib plus endocrine therapy compared with endocrine therapy [27]. The results show the continuous benefits of abeciclib combined with endocrine therapy, further consolidate the status of abeciclib as standard adjuvant therapy, and bring more opportunities for clinical cure for these patients.
The NATALEE study, which evaluated the efficacy and safety of reboxiclib in combination with nonsteroidal aromatase inhibitors (NSAI) in early-stage HR-positive, HER-2-negative breast cancer, was included in the study,5 The primary endpoint of 101 patients with stage II or III breast cancer at risk of recurrence was reported at the 2023 ASCO Annual Meeting: rebociclib in combination with endocrine therapy was associated with a 25.2 percent reduction in the risk of a three-year iDFS event, a 26 percent reduction in the risk of a three-year distant disease-free survival event, and a well-tolerated three-year rebociclib regimen starting at 400 mg with no new safety signals [28]. The results of its key subgroup analysis were further presented at the 2023 ESMO Annual Meeting: in all clinically relevant subgroups (including disease stage, lymph node metastasis, prior chemotherapy or chemotherapy, menopause, age, etc.), the iDFS benefit of rebociclib in combination with NSAI alone was consistent, and the combination group consistently had a more pronounced iDFS benefit, consistent with the results observed in the overall population, and in the node-negative subgroup, the iDFS was 94% in the rebociclib group , which was only 89 percent in the endocrine therapy group, suggesting that rebociclib significantly improves survival in node-negative patients [29]. The results of this study further support the use of rebociclib in combination with NSAI as a new treatment option for patients with HR-positive and HER-2-negative early-stage breast cancer (including patients with stage II. and III disease, including patients with node-negative disease).
3.2 Late endocrine therapy
Although most current international guidelines recommend first-line use of CDK4/6 inhibitors, long-term toxicity and cost increase compared with second-line use. There is a lack of evidence that first-line treatment is superior to second-line treatment. A randomized, investigator-initiated, phase III SONIA trial was reported at the 2023 ASCO Annual Meeting to evaluate the optimal timing of adding a CDK4/6 inhibitor to endocrine therapy in patients with HR-positive, HER-2-negative advanced breast cancer [30]. Patients will be randomized 1:1: group 1 will receive NSAI+CDK4/6 inhibitor in the first line and fulvestrant in the second line, and group 2 will receive NSAI in the first line and CDK4/6 inhibitor + fulvestrant in the second line. The primary endpoint of the study was median CNS PFS time after second-line therapy, with secondary endpoints including median OS time, safety, quality of life, and cost-effectiveness. The results showed that at a median follow-up of 37.3 months, the median PFS time of subgroup 1 was 24.7 months and 16.1 months (HR=0.59, P<0.000 1), and the median PFS time of subgroup 2 was 31.0 months and 26.8 months (HR=0.87, P=0.01), respectively, and the median OS time was similar between the two groups (HR=0.98, P=0.83). PFS analysis of subgroup 2 showed that patients who had not received prior neoadjuvant therapy, were diagnosed late, had no visceral metastases, had only bone metastases, and received palbociclib showed a more pronounced trend of benefit in the first-line setting, with 42% more ≥-grade 3 TRAEs in the first-line treatment group compared with the second-line treatment group. The study showed that in patients with HR-positive and HER-2-negative advanced breast cancer, first-line CDK4/6 inhibitor + endocrine therapy compared with second-line treatment resulted in no improvement in efficacy and increased toxicity and treatment costs. However, there is still some controversy about the conclusions of this study, which needs to be confirmed by further research.
In addition, although the combination of CDK4/6 inhibitors and endocrine therapy has become the standard first-line treatment for patients with endocrine-sensitive HR-positive, HER-2-negative advanced breast cancer, the optimal treatment after CDK4/6 inhibitor progression remains unknown. The PALMIRA trial explored whether palbociclib could improve second-line antitumor activity in patients with HR-positive, HER-2-negative advanced breast cancer [31]. The study included a total of 198 patients with HR-positive, Patients with HER-2-negative advanced breast cancer were randomized to palbociclib plus second-line endocrine therapy (combination therapy) and second-line endocrine therapy alone (treatment alone) in a 2:1 ratio, and after a median follow-up of 8.7 months, the median PFS duration was 4.2 months in the combination and treatment alone groups (HR=0.8, P=0.206), which was consistent with the results of all stratified subgroups, and the 6-month PFS rate was 40.9 in the combination and treatment alone, respectivelyAmong the 138 patients with evaluable lesions, the ORR (6.4%vs. 2.3%) and clinical benefit rate (33.0%vs. 29.5%) were similar between the combination therapy group and the treatment alone group, and the incidence of grade 3 and 4 TRAEs was higher in the combination therapy group than in the treatment alone group, and no new safety signals appeared. The study suggests that palbociclib maintenance therapy combined with second-line endocrine therapy did not significantly improve PFS in patients with HR-positive, HER-2-negative advanced breast cancer after progression on previous palbociclib-based therapy.
The Phase III LEONARDA-1 clinical study was reported at the 2023 ASCO Annual Meeting evaluating the efficacy and safety of the CDK4/6 inhibitor lerocyclib in combination with fulvestrant (in combination) versus fulvestrant as a monotherapy (monotherapy) in patients with HR-positive, HER-2-negative, locally advanced or metastatic breast cancer who have progressed on prior endocrine therapy [32]. A total of 275 patients were enrolled in the study, and the median PFS time in the combination group and the single agent group was 11.07 months and 5.49 months respectively (HR=0.458, P<0.001), and the ORR and complete response rate were 26.9% and 2.5% in the combination group, which was significantly higher than that in the single agent group (9.9%) and 0, and the observed benefits in premenopausal or perimenopausal patients in the combination group were consistent with those observed in postmenopausal patients; the most common TRAEs in the combination group and the monotherapy group were neutropenia (90.5%vs. 4.3%), leukopenia (86.9%vs. 6.5%), anemia (34.3%vs. 10.1%), thrombocytopenia (19.7%vs. 3.6%), and diarrhea (19.7%vs. 3.6%), and 46.7% of patients in the combination group3. Grade 4 TRAEs did not ≥occur in the single-agent group, while there were no grade 3 TRAEs in the single-agent group, and there ≥were no grade 3 severe diarrhea events in either group. The study confirmed that for endocrine-resistant patients with HR-positive and HER-2-negative advanced breast cancer, the use of lerosiclib combined with fulvestrant therapy can significantly improve the efficacy of patients, and the safety and tolerability are within the controllable range.
In addition, although previous phase III studies have demonstrated that the addition of palbociclib to endocrine therapy (aromatase inhibitors or fulvestrant) can improve the patient's PFS time. However, the efficacy and safety of palbociclib in combination with tamoxifen in patients with different menopausal states remain to be explored. Key results from a randomized, double-blind Phase III clinical study (NCCH1607/PATHWAY trial) were presented at the 2023 ASCO Annual Meeting investigating the efficacy and safety of palbociclib + tamoxifen ± goserelin in Asian patients with HR-positive, HER-2-negative advanced breast cancer [33]. The study enrolled patients randomized 1:1 to receive palbociclib or placebo in combination with tamoxifen as first- or second-line therapy, and premenopausal or perimenopausal patients to receive ovarian suppression with goserelin, with the primary endpoint PFS, with secondary endpoints including OS, ORR, safety, and patient-reported outcomes. A total of 184 patients were included in the study, and the median PFS was 24.4 months for palbociclib + tamoxifen and 11.1 months for placebo + tamoxifen (HR = 0.602, unilateral P = 0.002), with HR = 0.521 for first-line patients and 0.707 for second-line patients, HR = 0.378 for premenopausal or perimenopausal patients and 0.677 for postmenopausal patients, and although OS data were not yet mature, preliminary analysis showed a reduction of 27 in palbociclibThe incidence of grade 3 TRAEs was 93.4% and 20.4% ≥ palbociclib + tamoxifen versus placebo + tamoxifen, respectively, with neutropenia being the most common (89.0% in the palbociclib + tamoxifen group and 1.1% in the placebo + tamoxifen group). The study met its primary endpoint, suggesting a significant and clinically meaningful improvement in PFS in patients with HR-positive, HER-2-negative advanced breast cancer treated with palbociclib + tamoxifen compared with placebo + tamoxifen, with a tolerable safety profile.
4. Immunotherapy
Immunotherapy has revolutionized the paradigm of cancer treatment and has become one of the most important treatments at present. In breast cancer, TNBC was previously considered to be the most immunogenic subtype, making it an important area for the development of tumor immunotherapy. In 2023, a series of important advances have also been made in the research of early and late TNBC immunotherapy. In addition, two phase III randomized controlled studies on immunotherapy for early-stage HR-positive and HER-2-negative breast cancer reported at the 2023 ESMO Annual Meeting [34-35] have officially opened a new era of immunotherapy for HR-positive and HER-2-negative breast cancer, and have become an important node in the progress of breast cancer immunotherapy.
4.1 TNBC
4.1.1 In the early TNBC KEYNOTE-522 study, pembrolizumab was significantly improved in patients with early-stage TNBC who were treated with pembrolizumab in addition to chemotherapy [36-37]. Based on this, pembrolizumab has been approved by the National Medical Products Administration (NMPA) for the treatment of early-stage TNBC with a combined positive score (CPS) of >20. The updated EFS results after a median follow-up of approximately five years were further reported at the 2023 ESMO Annual Meeting [38]. The results showed that the EFS of the pembrolizumab + chemotherapy group was significantly better than that of the placebo group, with 60-month EFS rates of 81.3% and 72.3%, respectively (HR=0.63), and the median was not reached in either group, the most common event was distant recurrence, of which 9.2% in the pembrolizumab + chemotherapy group and 14.1% in the placebo + chemotherapy group, and the OS rate without distant recurrence was 84.4% in the pembrolizumab + chemotherapy group at 60 months, which was better than the 76.8% in the chemotherapy group (HR=0.64). Exploratory analysis showed that the 5-year EFS rates were 92.2% and 88.2% in the pembrolizumab + chemotherapy and placebo + chemotherapy groups for patients who achieved pCR, respectively, while the 5-year EFS rates for patients who did not achieve pCR were 62.6% and 52.3%, respectively, and OS follow-up was still ongoing. The study suggests that in patients with early-stage TNBC, adjuvant pembrolizumab + chemotherapy neoadjuvant therapy followed by adjuvant pembrolizumab improves EFS compared with neoadjuvant chemotherapy alone, regardless of pCR outcome.
The NeoTRIP study is a phase III study evaluating the efficacy and safety of atezolizumab in combination with chemotherapy in the neoadjuvant treatment of patients with early-stage high-risk and locally advanced TNBC, including a total of 280 patients with early-stage high-risk or locally advanced TNBC, who were treated with neoadjuvant carboplatin + nab-paclitaxel with or without atezolizumab for 4 cycles of anthracycline therapy after surgery, with the primary endpoint of EFS. Previous results showed an increase in pCR rates with atezolizumab compared with neoadjuvant chemotherapy alone, but not statistically significant (48.6 versus 44.4 percent, P=0.48), with a 7.6 percent increase in patients with programmed cell death ligand 1 (PD-L1)-positive tumors [39]. At the 2023 ESMO Annual Meeting, NeoTRIP's 5-year data were presented: the addition of neoadjuvant atezolizumab to carboplatin and nab-paclitaxel did not improve EFS in patients with TNBC, with a median follow-up of 54 months, with a 5-year EFS of 70.6% for patients treated with atezolizumab and 74.9% for patients not treated with atezolizumab; PD-L1 expression and higher tumor stromal infiltrating lymphocytes at baseline are associated with better EFS but do not predict the benefit of atezolizumab [40]. Extensive biomarker analysis is being performed using imaging mass spectrometry [41], transcriptome sequencing techniques, and whole-exome sequencing to identify cases that could benefit from atezolizumab treatment. No new safety signals related to atezolizumab emerged during the follow-up period.
4.1.2 The results of the TORCHLIGHT study, the first phase III study in China to achieve positive results in the field of immunotherapy for advanced TNBC, were reported at the 2023 ASCO Annual Meeting [42]. In this study, the efficacy and safety of toripalimab plus nab-paclitaxel versus placebo combined with nab-paclitaxel in patients with first-diagnosed stage IV or recurrent metastatic TNBC showed that toripalimab plus nab-paclitaxel in patients with first-diagnosed stage IV or recurrent metastatic TNBC significantly prolonged PFS in PD-L1-positive populations, with median PFS of 8.4 months and 6.0 months, respectively (HR=0.65, P=0.0102), compared with chemotherapy alone, and in the intention-to-treat (ITT) populationA clear trend of OS benefit was observed in both PD-L1-positive and ITT populations, with median OS duration of 32.8 months and 19.5 months in the PD-L1-positive group (HR=0.62), 33.1 months and 23.5 months in the ITT population (HR=0.69), and ≥ grade 3 TRAE (56.4%) in the two groups, respectively. 54.3%) and fatal events (0.6% to 3.4%) were similar, and no new safety signals were identified. In addition, the most common TRAEs (incidence ≥20%) and immune-related TRAEs (incidence ≥2%) were largely consistent between the two groups.
In conclusion, for patients with PD-L1-positive first-diagnosis stage IV or recurrent metastatic TNBC, the combination of toripalimab on the basis of nab-paclitaxel can significantly improve PFS with a good safety profile, and no new safety signals have been observed. Based on the results of this study, the NMPA has accepted the New Indication Application for toripalimab in combination with nab-paclitaxel for the treatment of treatment-naïve metastatic or relapsed metastatic TNBC with PD-L1-positive (CPS≥1) in May 2023.
A Bayesian adaptive randomized Bayesian-based multicenter phase II study was reported at the 2023 San Antonio Breast Cancer Symposium Annual Meeting to explore the efficacy and safety of toripalimab in combination with metronomic chemotherapy in patients with HER-2-negative metastatic breast cancer [43]. The study included 103 patients with HER2-negative advanced breast cancer who had received ≤ 1 line of standard chemotherapy and were randomly divided into five treatment cohorts: vinorelbine oral beat (NVB single agent group), vinorelbine beat oral + toripalimab (NVB group), vinorelbine beat oral + cisplatin + toripalimab (DDP group), vinorelbine beat oral + bevacizumab + toripalimab (bevacizumab group), Vinorelbine + cyclophosphamide + capecitabine beats oral + toripalimab (VEX group), the primary endpoint was DCR. The study showed that in the total population, the VEX group and the DDP group had the highest DCR, which were 69.7% and 73.7%, respectively. Patients in the VEX group had the longest median PFS of 6.6 months. Among them, the results for the TNBC subgroup (n=48) were similar to those of the general population, with patients in the toripalimab plus VEX group having the highest DCR (74.1%) and the longest median PFS time (9.8 months). In terms of safety, 66% of patients had adverse events (AEs), of which 5.6% had grade ≥3 AEs and 9.0% had immune-related AEs.
4.2 HR＋/HER-2-乳腺癌
CheckMate7FL is the first prospective phase III randomized trial to evaluate nivolumab + neoadjuvant chemotherapy (NACT) + adjuvant endocrine therapy in early-stage, high-risk estrogen receptor (ER)-positive, HER-2-negative breast cancer [34]. Patients in this study were randomized in a 1:1 ratio to receive NACT (paclitaxel + anthracycline + cyclophosphamide) + nivolumab (nivolumab + chemotherapy group), or NACT+placebo treatment (placebo + chemotherapy group), and postoperative patients received nivolumab (nivolumab + chemotherapy group) or placebo (placebo + chemotherapy group) + endocrine therapy. The results of the study were reported at the 2023 ESMO Annual Meeting: the pCR rate of nivolumab + chemotherapy group was significantly higher than that of placebo + chemotherapy group (24.5%vs. 13.8%, P=0.0021), and the pCR rate of patients in the nivolumab + chemotherapy group was also significantly higher than that in the placebo + chemotherapy group (30.7%vs. 8.1%);PD and nivolumab in patients with positive -L1 positivity brought significant pCR benefit (44.3%vs. 20.2%) and residual cancer burden0, Overall improvement in grade 1 rates (especially in PD-L1-positive patients). In the NACT phase of the study, the incidence of grade 3 and 4 TRAEs was similar in the nivolumab + chemotherapy group and placebo + chemotherapy group (35%vs. 32%), and two deaths (pneumonia, hepatitis) in the nivolumab + chemotherapy group were associated with the study drug, and the incidence of immune-related TRAEs in the nivolumab + chemotherapy group was higher than that in the placebo + chemotherapy group. Compared with NACT alone, nivolumab in combination with NACT significantly improved the pCR rate and residual cancer burden grade 0 and 1 rates in patients with early-stage high-risk ER+/HER-2- breast cancer (especially in PD-L1-positive patients), but the incidence of immune-related TRAEs increased, and the overall safety profile was consistent with nivolumab and chemotherapy.
The KEYNOTE-756 study, a global, Phase III clinical study to evaluate the efficacy and safety of endocrine therapy ± adjuvant pembrolizumab after neoadjuvant therapy with chemotherapy ± pembrolizumab in patients with early-stage, high-risk ER-positive, HER-2-negative breast cancer, reported results from the primary endpoint pCR rate at the 2023 ESMO Annual Meeting [35]. A total of 1 278 patients were included in the study, including 635 patients in the pembrolizumab + chemotherapy group and 643 patients in the placebo + chemotherapy group, with a median follow-up of 33.2 months, and the pCR rate in the pembrolizumab + chemotherapy group was significantly improved compared with the placebo + chemotherapy group in the ITT population (24.3%vs. 15.6%, P=0.000). 05), and the benefits were consistent in the predefined subgroup: in the neoadjuvant treatment phase, the incidence of grade ≥3 TRAE was 52.5% in the pembrolizumab + chemotherapy group, 46.4% in the placebo + chemotherapy group, and 1 patient died due to acute myocardial infarction in the pembrolizumab + chemotherapy group. In conclusion, pembrolizumab combined with chemotherapy significantly increased the pCR rate in patients with early-stage high-risk ER-positive, HER-2-negative breast cancer, and the safety profile was consistent with the known features of pembrolizumab and chemotherapy.
5. Summary and outlook
In 2023, a number of breakthroughs have been made in clinical and translational research on breast cancer drug therapy, and new treatment concepts are emerging. Chemotherapy remains the cornerstone of the treatment of various molecular subtypes of breast cancer, and new studies aim to explore the efficacy and safety of different combination strategies such as various doses and combination modalities. Continuous improvements in endocrine therapy are also aimed at maximizing the treatment modality of patients with HR-positive, HER-2-negative breast cancer. A series of advances in targeted therapy and immunotherapy will maximize the precision diagnosis and treatment of breast cancer patients and the extension of survival. However, there are still many issues that need to be addressed, such as the precise selection of beneficiary patients and the management of TRAE. With the development of single-cell multiomics technology and the cross-interaction of multiple disciplines, it will bring new inspiration to breast cancer research. This will help to reveal more mechanisms and potential therapeutic targets for the occurrence and development of breast cancer, thereby promoting the improvement of comprehensive treatment of breast cancer and the development of anti-tumor drugs, further prolonging the survival time of patients and improving the quality of life of patients.
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