2.2.1.1 Neoadjuvant therapy

HR-positive, HER2-positive breast cancer (triple-positive breast cancer [TPBC]) tends to respond clinically to neoadjuvant targeted therapy more often than HR-negative, HER2-positive breast cancer due to crosstalk between HER2 and hormone receptor (HR) signaling pathways. The MUKDEN01 single-arm phase II trial evaluated oral, chemotherapy-free neoadjuvant therapy with pyrotinib, letrozole and dalpiciclib in patients with TPBC. Among the 61 TPBC patients enrolled, the total pathologic complete response rate (tpCR) was 29.5% (18/61 patients), and the objective response rate (ORR) was as high as 88.5% [5], which was comparable to the double HER2 blockade in TPBC patients with standard chemotherapy [46, 47]. During the COVID-19 epidemic, neoadjuvant therapy with pyrotinib, letrozole and dalpiciclib in TPBC patients not only has good efficacy and manageable side effects, but also is more convenient.

2.2.1.2 Adjuvant therapy

The APHINITY phase III trial has demonstrated that the dual anti-HER2 with trastusumab and pertusumab as adjuvant treatment significantly improved iDFS among patients with HER2-positive early breast cancer [48]. Updated results from the APHINITY trial with a median follow-up of 8.4 years, was presented at the 2022 ESMO congress. For the primary endpoint, the addition of pertuzumab revealed a 2.6% absolute benefit for 8-year invasive disease-free survival (iDFS) (88.4% vs. 85.8%, HR = 0.77; 95% CI = 0.66–0.91), especially in lymph node-positive cohort [6]. Higher 8-year OS (92.7% vs. 92.0%, HR = 0.83; p = 0.078) was observed with the pertusumab-based regimen; however, this increase has not yet reached a statistical significance. The updated data confirmed the survival benefit of adding pertuzumab to trastuzumab plus chemotherapy in HER2-positive early breast cancer.

T-DM1 is an HER2-targeted ADC comprised of trastuzumab and the cytotoxic microtubule inhibitor mertansine (DM1) by a noncleavable linker according to a drug-to-antibody ratio (DAR) of 3.5. The 2022 San Antonio Breast Cancer Symposium (SABCS) reported the updated 5-year survival results of the ATEMPT trial, which was designed to compare the efficacy of adjuvant T-DM1 versus paclitaxel plus trastuzumab (TH) for stage I HER2-positive breast cancer. Among the 497 patients, the 5-year iDFS for T-DM1 was 97.8%, higher than 91.3% in TH group, while the 5-year OS for T-DM1 and TH groups were 97.8% and 97.9%, respectively [7]. This study indicated that T-DM1 monotherapy was effective and well-tolerated in patients with stage I HER2-positive breast cancer.

2.2.1.3 HER2 positive MBC

Pyrotinib, an irreversible oral pan-HER tyrosine kinase inhibitor (TKI) plus capecitabine, has shown promising efficacy as a second-line therapy for HER2-positive MBC [49]. The PHILA phase III trial reported the efficacy and safety of the dual anti-HER2 regimen of pyrotinib plus trastuzumab and docetaxel (THPy) versus placebo plus trastuzumab and docetaxel in untreated HER2-positive MBC [8]. In terms of safety, THPy was well tolerated, with diarrhea clinically manageable and no new identifiable safety signals. Notably, the median PFS assessed by an independent review of the THPy regimen has reached 33.0 months, the longest median PFS reported in the first-line treatment of HER2-positive MBC. The results represented in this study are expected to change the landscapes of first-line treatment of HER2-positive MBC.

Trastuzumab deruxtecan (T-DXd) is a novel HER2-targeting ADC consisting of an anti-HER2 antibody, a cleavable tetrapeptide-based linker and a cytotoxic topoisomerase I inhibitor (exatecan derivative, also known as DXd) [50]. At 2022 SABCS, the DESTINY‑Breast 02 study compared the efficacy of T-DXd with physician's choice treatment in patients with HER2-positive MBC previously treated with T-DM1. In this study, T-DXd significantly improved PFS (median: 17.8 vs. 6.9 months, HR = 0.36, p < 0.0001) and OS (median: 39.2 vs. 26.5 months, HR = 0.66, p = 0.0021) compared with physician's choice treatment for patients with HER2-positive MBC before T-DM1 [9], with no new safety signals observed. In addition, the updated OS data of DESTINY‑Breast 03 was presented at 2022 SABCS. Compared with T-DM1, T-DXd showed significantly improvement in OS (HR = 0.64, p = 0.0037) in patients with HER2-positive MBC [10]. This updated results demonstrated remarkable survival benefit and tolerable safety for T-DXd, supporting the T-DXd as the second-line standard treatment in patients with HER2-positive MBC.

2.2.1.4 HER2-low MBC

As a new generation ADC, T-DXd has a high DAR and cytotoxic bystander effect, allowing to target HER2-heterogeneous tumors. A phase Ib study (DS8201-A-J101) initially demonstrated good antitumor activity and good tolerability of T-DXd in patients with advanced HER2-low breast cancer [51]. This study was followed by the DESTINY-Breast 04 phase III randomized study comparing T-DXd with the investigator's choice of chemotherapy in HER2-low breast cancer, which recently met its primary endpoints. This first phase III trial found that T-DXd significantly improved PFS (9.9 vs. 5.1 months, HR = 0.50, 95% CI: 0.40–0.63, p < 0.001) and OS (23.9 vs. 17.5 months, HR = 0.64, 95% CI: 0.48–0.86, p = 0.0028) compared with chemotherapy in HER2-low breast cancer patients [11]. In terms of adverse reactions, the incidence of grade ≥3 adverse events in the T-DXd group was significantly lower than that in the chemotherapy group (52.6% vs. 67.4%). Notably, the incidence of interstitial lung disease (ILD) in the T-DXd group was 12.1%, but most cases (10.0%) were grade 1/2 ILD. Based on the promising results of DB-04, the National Comprehensive Cancer Network (NCCN) guidelines [52] recommend T-DXd for HER2-low MBC patients who have received at least one chemotherapy (HR-positive patients should be resistant to endocrine therapy).

2.2.1.5 Breast cancer brain metastases

Approximately 30%–50% of patients with HER2-positive MBC develop brain metastases. Breast cancer with brain metastases has a poor prognosis and represents the greatest clinical challenge in the treatment of HER2-positive breast cancer. In the DESTINY-Breast 01 study, which included 24 patients with stable brain metastases, the ORR in the T-DXd group was 58.3%, and the median PFS was 18.1 months [12]. The Phase II TUXEDO-1 study investigated the efficacy and safety of T-DXd in patients with active brain metastases. Among the 15 patients with brain metastases from HER2-positive breast cancer, the T-DXd intracranial response rate was 73.3% (11/15 cases), the clinical benefit rate (CBR) was 86.7% (13/15 cases), and the median PFS was 14 months [13]. No new safety issues were observed during treatment, and overall quality of life as well as cognitive function was maintained [53], thus demonstrating the favorable efficacy of T-DXd in patients with active brain metastases. Moreover, the DAISY study reported the efficacy of T-DXd in patients with HER2-low MBC and brain metastases. A total of 24 patients were divided into 3 cohorts, including cohort 1 (HER2 overexpressing: 12 patients), cohort 2 (HER2-low: 10 patients) and cohort 3 (HER2-IHC0: 2 patients), with best objective response rates of 91.7%, 30%, and 50%, respectively, and a median PFS of 13 months, 4.1 months and was not reached [14]. Overall, T-DXd showed good antitumor activity in patients with brain metastases, which deserves further study.

Previous studies have evaluated the efficacy of TKIs in the treatment of brain metastases [54, 55]. Tucatinib is a highly selective HER2-targeting TKI. The HER2CLIMB study demonstrated the efficacy of tucatinib in the treatment of brain metastases from HER2-positive breast cancer [15]. Results of the final overall survival analysis showed that tucatinib plus trastuzumab and capecitabine significantly prolonged OS, both in all 291 patients with brain metastases (21.6 vs. 12.5 months) and in 174 patients with active brain metastases (21.4 vs. 11.8 months) [56], which provides convincing evidence for the use of TKIs in patients with HER2-positive breast cancer and brain metastases.

2.3.3.1 Selective estrogen receptor modulators and degraders

Approximately 30%–40% of breast cancer patients treated with AI may develop gene mutations. Among them, the ESR1 gene is the most mutated gene. Mutations in ESR1 may lead to aberrant estrogen-independent ER activation, which is a major cause of AI resistance. Lasofoxifene is a third-generation oral selective estrogen receptor modulator. The ELAINE 1 study explored whether lasofoxifene has better antitumor activity than fulvestrant in advanced breast cancer patients with ESR1 mutation after progression on CDK4/6 inhibitors combined with AI therapy. The results showed that the median PFS was 4.04 months for fulvestrant and 6.04 months for lasofoxifene (p = 0.138). Moreover, ORR and CBR were not significantly different (p = 0.12) [23]. The efficacy of lasofoxifene needs to be explored on a larger scale.

As a kind of SERD, fulvestrant is an important choice for endocrine therapy of breast cancer. However, because the type of injection may limit the use of such therapies, oral SERD, including giredestrant, have been developed. A phase Ib study suggested that giredestrant showed good efficacy in advanced ER-positive, HER2-negative breast cancer [66]. The phase II acelERA BC trial enrolled patients with advanced ER-positive, HER2-negative breast cancer who had progressed after 1–2 lines of systemic therapy. Patients were randomly assigned to receive either giredestrant or physician's choice of endocrine monotherapy (fluoxetine or AI). The median PFS in the two groups was 5.6 months and 5.4 months, respectively (p = 0.18). CBR (31.8% vs. 21.1%) and ORR (12.6% vs. 7.2%) were higher in the giredestrant group than in the physician's choice group. Notably, the PFS benefit was more pronounced in patients with ESR1 mutations (median: 5.3 vs. 3.5 months, p = 0.061) [24]. Therefore, giredestrant showed a promising survival benefit in ESR1 mutations, but needs to be validated by larger studies.

Elacestrant is a novel oral SERD. In patients with ER-positive, HER2-negative MBC following progression on prior endocrine and CDK4/6 inhibitor therapy, the EMERALD trial demonstrated significantly prolonged PFS for elacestrant versus standard of care endocrine therapy (SoC). Benefits were observed in all patients and in patients with ESR1 mutant MBC [67]. In this trial, patients were randomized 1:1 to elacestrant or SoC (investigator's choice of aromatase inhibitor or fulvestrant). At SABCS in 2022, researchers reported the impact of duration of prior CDK4/6 inhibitors on PFS. The duration of prior CDK4/6 inhibitor in the metastatic setting was positively associated with PFS, the longer the duration of prior CDK4/6 inhibitor in the metastatic setting, the longer the PFS on elacestrant versus SoC. For patients that had been on a CDK4/6 inhibitor for at least 12 months, the median PFS was 3.78 months in the elacestrant group, compared with 1.91 months in the SoC group (HR = 0.613, 95% CI: 0.453–0.828). For patients with ESR1 mutations that had been on a CDK4/6 inhibitor for at least 12 months, the median PFS was 8.61 months in the elacestrant group and 1.91 months in the SoC group, with a 59% lower risk of progression or death (HR = 0.410, 95% CI: 0.262–0.634). Elacestrant was well tolerated with significantly longer PFS versus SoC, highlighting its potential role as a therapeutic option for patients with ER-positive, HER2-negative MBC [25].

2.3.3.2 Combination with CDK4/6 inhibitors

CDK4/6 inhibitors combined with endocrine therapy have become the standard treatment strategy for HR-positive, HER2-negative advanced breast cancer. Currently, studies such as PALOMA-2, MONALEESA-2, MONARCH 3, and MONALEESA-7 have confirmed that CDK4/6 inhibitors combined with endocrine therapy can significantly reduce the risk of disease progression compared with endocrine therapy alone [68].

Palbociclib is the first CDK4/6 inhibitor approved for HR-positive, HER2-negative advanced breast cancer. The PALOMA-2 trial showed that palbociclib plus letrozole can significantly improve PFS compared with placebo plus letrozole in the first-line treatment of ER-positive, HER2-negative advanced breast cancer (median: 24.8 vs. 14.5 months) [69]. The 2022 ASCO Annual Meeting reported the results of the final analysis of OS. Median OS was longer in the ITT population with palbociclib plus letrozole compared with placebo plus letrozole, but the results were not statistically significant (53.9 vs. 51.2 months, stratified one-sided p = 0.3378) [26]. The PALOMA-2 trial met its primary endpoint of improved PFS but not its secondary endpoint of improved OS. Furthermore, fulvestrant is one of the standard first- and second-line endocrine therapy drugs for HR-positive MBC. The results of the FUTURE study showed that the combination of palbociclib and fulvestrant beyond disease progression to fulvestrant monotherapy can further improve the survival of patients, achieving a median PFS benefit of 9.4 months [27].

Recent updates from the MONALEESA-2, -3, and -7 trials demonstrated statistically significant PFS and OS benefits for ribociclib in combination with endocrine therapy in HR-positive, HER2-negative advanced breast cancer [70-72]. In general, patients with advanced breast cancer with visceral metastases have a poor prognosis. ESMO Congress 2022 reported pooled survival analysis of the MONALEESA-2, -3, and -7 trials in HR-positive, HER2-negative breast cancer patients with visceral metastases, including those with liver metastases. For patients with visceral metastases, ribociclib combination therapy reduced the risk of disease progression by 39.0% (median: 22.1 vs. 12.7 months; HR = 0.61) and the risk of death by 19.0% (median: 49.0 vs. 46.5 months; HR = 0.81) [28]. Ribociclib combined regimen may be an effective strategy for the treatment of patients with visceral metastases. Moreover, the MAINTAIN trial evaluated fulvestrant or exemestane with or without ribociclib plus CDK4/6 inhibition in patients with HR-positive, HER2-negative metastatic breast cancer who had progressed on antiestrogen therapy. Compared with the placebo group, PFS was significantly improved in the fulvestrant or exemestane combined with ribociclib group (median: 5.29 vs. 2.76 months), and the 12-months PFS rate was significantly improved (24.6% vs. 7.4%) [29]. The results showed that patients with HR-positive, HER2-negative MBC whose disease progressed on CDK4/6 inhibitor therapy, gained a significant PFS benefit by switching endocrine therapy and receiving ribociclib.

Abemaciclib in combination with nonsteroidal aromatase inhibitors (NSAIs) is approved as first-line therapy for postmenopausal women with HR-positive, HER2-negative advanced breast cancer based on positive PFS results from the MONARCH 3 trial. The results of the second interim analysis of OS were reported at ESMO Congress 2022. The median OS in the ITT population was 67.1 months for abemaciclib plus NSAI and 54.5 months for placebo plus NSAI (p = 0.0301). Furthermore, the absolute benefit in OS amounted to 12.6 months. However, statistical significance has not yet been reached (preset p ≤ 0.018). Final OS data are expected to be available in the next year [30]. The previous monarcHER trial demonstrated that trastuzumab plus abemaciclib plus fulvestrant significantly improved PFS in patients with HR-positive, HER2-positive advanced breast cancer compared with trastuzumab plus chemotherapy [73]. Updated data showed that the median OS of the trastuzumab plus abemaciclib plus fulvestrant was nearly 1 year longer than that of trastuzumab combined with chemotherapy (20.7 vs. 31.1 months) [31].

Dalpiciclib is the first self-developed new highly selective CDK4/6 inhibitor in China. The DAWNA-1 trial explored the efficacy and safety of dalpiciclib plus fulvestrant in patients with HR-positive, HER2-negative advanced breast cancer whose disease had progressed after prior endocrine therapy. Based on the efficacy of the interim analysis [74], it has been approved by the National Medical Products Administration in 2021. The latest follow-up data were reported at ESMO Congress 2022. Median PFS was 16.6 months for dalpiciclib plus fulvestrant and 7.2 months for placebo plus fulvestrant, respectively. Compared with placebo, dalpiciclib reduced the risk of disease progression or death by 50% (one-sided p < 0.0001) [32]. The results support dalpiciclib plus fulvestrant as a new option for patients who have progressed on prior endocrine therapy. Furthermore, the DAWNA-2 trial evaluated the efficacy and safety of dalpiciclib plus letrozole or anastrozole in the first-line treatment of HR-positive, HER2-negative advanced breast cancer. Median PFS was 30.6 months in the dalpiciclib plus letrozole/anastrozole group, which was significantly longer than placebo plus letrozole/anastrozole group by 12.4 months; in addition, the risk of disease progression or death was reduced by 49.0% [33]. The results further support this regimen as a new option for first-line treatment.

2.3.3.3 Combination with PI3K/AKT/mTOR inhibitors

The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) (PI3K/AKT/mTOR) signaling pathway is the most commonly mutated pathway in HR-positive breast cancer, and abnormal activation of this pathway is highly correlated with resistance to endocrine therapy [75].

Capivasertib is the first highly selective oral small molecule AKT inhibitor that selectively inhibits three AKT isoforms (AKT1/2/3). The FAKTION trial explored the efficacy and safety of fulvestrant combined with capivasertib in patients with ER-positive MBC who had progressed on AI threrapy [76]. The 2022 ASCO Annual Meeting reported that fulvestrant combined with capivasertib can significantly improve OS and PFS. The median OS of the fulvestrant plus capivasertib group and the fulvestrant plus placebo group were 29.3 months and 23.4 months, respectively (HR = 0.66, p = 0.035), and the median PFS were 10.3 months and 4.8 months, respectively (HR = 0.56, p = 0.002). In addition, the researchers found through next-generation sequencing-based biomarker analysis that patients with altered PIK3CA/AKT/PTEN signaling pathways benefited more from fulvestrant combioned with capivasertib [34].

CAPItello-291 trial investigated the efficacy and safety of capivasertib combined with fulvestrant in patients with AI-resistant HR-positive, HER2-negative advanced breast cancer. Patients were randomized 1:1 to receive fulvestrant with either placebo or capivasertib. 2022 SABCS reported PFS results. The median PFS was 7.2 months in capivasertib group and 3.6 months in placebo group (HR = 0.60, p < 0.001). In patients with AKT pathway-altered tumors, median PFS was 7.3 months in the capivasertib group and 3.1 months in the placebo group (HR = 0.50, p < 0.001). Capivasertib combined with fulvestrant significantly improved PFS compared to fulvestrant alone in the overall population, and in patients with AKT pathway-altered tumors, and may become a future treatment option in this setting [35].