Editor’s Note: Breast cancer remains the leading cause of cancer-related deaths among women worldwide, with hormone receptor-positive, HER2-negative (HR+/HER2-) breast cancer being the most common molecular subtype. In recent years, targeted therapies, antibody-drug conjugates (ADCs), and selective estrogen receptor degraders (SERDs) have propelled this subtype into the era of precision medicine. Looking back at 2024, what breakthroughs and conceptual shifts have occurred in the systemic treatment of HR+/HER2- breast cancer? Oncology Frontier invited Academician Binghe Xu from the Cancer Hospital Chinese Academy of Medical Sciences and the Chinese Academy of Engineering to provide an overview and summary.

Early-Stage and (Neo)Adjuvant Therapy

Treatment strategies for early-stage HR+/HER2- breast cancer have centered around a “step-up and step-down” approach, intensifying treatment for high-risk patients while sparing chemotherapy or opting for less toxic regimens in low-to-moderate-risk cases.

CDK4/6 inhibitors (CDK4/6i) have emerged as a novel option for enhancing adjuvant endocrine therapy. Following the positive results of the Phase III monarchE trial, the Phase III NATALEE study reported its primary endpoint in 2024, as published in the New England Journal of Medicine. This trial included patients with Stage IIA (e.g., N0 with Grade 2 tumors and Ki-67 ≥20%, RS score ≥26, or genomic high-risk features; N0 with Grade 3), Stage IIB, and Stage III HR+/HER2- early breast cancer. Ribociclib combined with a nonsteroidal aromatase inhibitor (NSAI) significantly improved invasive disease-free survival (iDFS) compared to NSAI alone, with a 3-year iDFS improvement of 3.3% (90.4% vs. 87.1%, HR 0.75, 95% CI: 0.62–0.91, P=0.003).

The 2024 ASCO conference presented subgroup results for N0 patients, showing a 3-year iDFS absolute benefit of 2.6% (93.2% vs. 90.6%, HR 0.72, 95% CI: 0.41–1.27). At the 2024 ESMO conference, 4-year follow-up data revealed that the difference in iDFS between the two groups had grown to 4.9% (88.5% vs. 83.6%, HR 0.715, 95% CI: 0.609–0.840, P<0.0001).

Multigene assays, such as the 21-gene Oncotype DX and the 70-gene MammaPrint, have been widely used to identify low-to-moderate-risk patients who can safely avoid chemotherapy. However, for high-risk patients, the potential to further de-escalate chemotherapy has also been explored. At the 2024 ASCO conference, the FLEX study categorized early HR+/HER2- breast cancer patients into ultra-low-risk, low-risk, high-risk (H1), and ultra-high-risk (H2) groups based on the 70-gene assay. Results showed no significant difference in pathologic complete response (pCR) rates (7.7% vs. 7.0%) or 3-year recurrence-free survival (RFS: 97.1% vs. 95.3%) between H1 patients treated with docetaxel + cyclophosphamide (TC) or anthracycline-based AC-T regimens. However, H2 patients demonstrated higher pCR rates (32.0% vs. 0%) and 3-year RFS (97.7% vs. 86.4%) with AC-T. These findings suggest that while high-risk patients can benefit from “anthracycline-free” regimens, ultra-high-risk patients still require anthracycline-based regimens to improve outcomes.

Adjuvant endocrine therapy has also been a focus of de-escalation strategies. At the 2024 SABCS conference, a combined analysis of the NRG Oncology/RTOG 9804 and ECOG-ACRIN E5194 studies highlighted the role of tamoxifen (TAM) in patients undergoing breast-conserving surgery for low-risk ductal carcinoma in situ (DCIS). TAM significantly reduced the 15-year ipsilateral breast recurrence rate (IBR: 19.0% vs. 11.4%, P=0.001), primarily through a reduction in invasive disease recurrence (11.5% vs. 6.0%, P=0.005). However, TAM did not significantly impact DCIS recurrence rates (8.1% vs. 5.5%, P=0.09). These findings suggest that for low-risk DCIS patients, sparing both adjuvant radiotherapy and TAM may be worth exploring, potentially identifying patients who could benefit from treatment de-escalation.

First-Line Treatment with CDK4/6 Inhibitors

CDK4/6 inhibitors (CDK4/6i) have become the cornerstone of first-line treatment for HR+/HER2- advanced breast cancer (ABC). Research progress in 2024 brought both controversies and breakthroughs regarding their optimal use.

One key question is whether CDK4/6i should be used as first- or second-line therapy. A Phase III trial from the Netherlands, the SONIA study, published in Nature in October 2024, explored this issue. Patients with previously untreated advanced breast cancer were randomized into two groups: one receiving first-line CDK4/6i combined with a nonsteroidal aromatase inhibitor (NSAI) followed by fulvestrant upon progression, and the other receiving NSAI followed by second-line CDK4/6i plus fulvestrant. The results showed no significant differences in second progression-free survival (PFS2: 31.0 vs. 26.8 months, HR 0.87, 95% CI: 0.74–1.03, P=0.10) or overall survival (OS: 45.9 vs. 53.7 months, HR 0.98, 95% CI: 0.80–1.20, P=0.83) between the two groups. However, first-line CDK4/6i treatment resulted in higher costs (€47,959 vs. €20,881) and more adverse events (Grade ≥3 AEs: 2,763 vs. 1,591). These results, which predominantly reflect the use of palbociclib in 91% of cases, suggest that for patients with low tumor burden or poor CDK4/6i tolerance, endocrine therapy alone may still be a viable first-line option.

Another debate centers on the choice of CDK4/6i. The PALMARES-2 study, presented at the 2024 ASCO conference, compared the real-world effectiveness of palbociclib, abemaciclib, and ribociclib in first-line settings. This study included 1,850 patients: 750 on palbociclib, 424 on abemaciclib, and 676 on ribociclib. Results showed that both abemaciclib (HR 0.71, 95% CI: 0.56–0.90, P=0.005) and ribociclib (HR 0.81, 95% CI: 0.65–0.99, P=0.048) had better real-world PFS (rwPFS) compared to palbociclib, while there was no significant difference between abemaciclib and ribociclib (HR 0.91, 95% CI: 0.70–1.19, P=0.505). Future data on OS and safety are eagerly awaited to guide CDK4/6i selection further.

For aggressive diseases, can CDK4/6i replace chemotherapy? The final results of the Phase II RIGHT Choice study, published in JCO in August 2024, addressed this question in patients with HR+/HER2- ABC and visceral crisis, symptomatic visceral metastases, or rapid disease progression. Ribociclib combined with endocrine therapy significantly improved PFS (21.8 vs. 12.8 months, HR 0.61, 95% CI: 0.43–0.87, P=0.03) compared to chemotherapy, with comparable objective response rates (ORR: 66.1% vs. 61.8%) and time to response (4.9 vs. 3.2 months, HR 0.76, 95% CI: 0.55–1.06). Subgroup analyses presented at the SABCS 2024 conference showed consistent benefits across Luminal A, Luminal B, and HER2-enriched subtypes. Additionally, the Phase II ABIGAIL and Phase IV PADMA studies, reported at ESMO and SABCS 2024, supported the use of CDK4/6i in aggressive HR+/HER2- ABC. The ABIGAIL study demonstrated that abemaciclib combined with endocrine therapy improved ORR (58.8% vs. 40.2%, P=0.0193) compared to paclitaxel-based chemotherapy in patients with high-risk features. The PADMA study showed that palbociclib plus endocrine therapy significantly extended the time to treatment failure (TTF: 17.2 vs. 6.1 months, HR 0.46, 95% CI: 0.31–0.69, P<0.001) and PFS (18.7 vs. 7.8 months, HR 0.45, 95% CI: 0.29–0.70, P<0.001) compared to chemotherapy in high-risk patients.

The potential for combining CDK4/6i with other targeted therapies is also a topic of active research. The Phase III INAVO120 study, published in NEJM in October 2024, evaluated the addition of the PI3K inhibitor inavolisib to palbociclib plus endocrine therapy in patients with PIK3CA-mutant HR+/HER2- ABC who progressed during or shortly after adjuvant endocrine therapy. The triple combination significantly improved PFS (15.0 vs. 7.3 months, HR 0.43, 95% CI: 0.32–0.59, P<0.001) and showed a trend toward OS benefit (HR 0.64, 95% CI: 0.43–0.97, P=0.03, not reaching the pre-specified significance threshold of P<0.0098). While Grade ≥3 adverse events were similar between the triple (88.3%) and double therapy groups (82.1%), severe adverse events were more common in the triple therapy arm (24.1% vs. 10.5%). This study offers a new treatment option for patients with endocrine-resistant, PIK3CA-mutant HR+/HER2- breast cancer.

Third: Second- and Later-Line Treatments for Advanced Breast Cancer

The landscape of second- and later-line treatment for HR+/HER2- advanced breast cancer (ABC) is marked by diverse and innovative strategies. In 2024, research progress spanned across CDK4/6 inhibitors (CDK4/6i), inhibitors targeting the PI3K-AKT-mTOR (PAM) pathway, selective estrogen receptor degraders (SERDs), antibody-drug conjugates (ADCs), and immunotherapy, showcasing a vibrant field of advancements.

CDK4/6 Inhibitors in Second- and Later-Line Therapy

The postMONARCH trial, presented at the 2024 ASCO conference, investigated HR+/HER2- ABC patients progressing on prior CDK4/6i therapy. Patients received fulvestrant with or without abemaciclib. The results showed a significantly improved median progression-free survival (PFS) in the abemaciclib + fulvestrant group (6.0 vs. 5.3 months; HR 0.73, 95% CI: 0.57–0.95, P=0.02), with consistent benefits observed across subgroups, including those with ESR1 or PIK3CA mutations. Additionally, the BRIGHT-2 trial, led by the Cancer Hospital Chinese Academy of Medical Sciences , examined the efficacy of the novel selective CDK4/6i pyrrolocyclinib combined with fulvestrant in patients who had failed endocrine therapy and had received no more than one prior line of chemotherapy. Pyrrolocyclinib significantly improved PFS (12.94 vs. 7.29 months; HR 0.561, 95% CI: 0.393–0.799, P=0.0012).

PAM Pathway Inhibitors

The Phase III CAPItello-291 trial evaluated capivasertib, an AKT inhibitor, in patients with prior CDK4/6i exposure. Earlier reports showed significant PFS benefits in both the overall population (7.2 vs. 3.6 months; HR 0.60, 95% CI: 0.51–0.71, P<0.001) and in patients with PIK3CA/AKT1/PTEN mutations (7.3 vs. 3.1 months; HR 0.50, 95% CI: 0.38–0.65, P<0.001). Data presented at the 2024 ESMO BC conference further demonstrated improved second progression-free survival (PFS2) in both the overall cohort (14.7 vs. 12.5 months; HR 0.70, 95% CI: 0.57–0.86) and the mutation subgroup (15.5 vs. 10.8 months; HR 0.52, 95% CI: 0.38–0.71). A patient-reported outcomes (PRO) analysis, published in The Lancet Oncology in August 2024, highlighted delayed deterioration in overall health status/quality of life with capivasertib, though diarrhea was more common in the treatment group.

Selective Estrogen Receptor Degraders (SERDs)

Elacestrant, a SERD, has shown promise in CDK4/6i-pretreated patients. The Phase III EMERALD trial demonstrated significant PFS benefits in the overall population (2.8 vs. 1.9 months; HR 0.70, 95% CI: 0.55–0.88, P=0.002) and in patients with ESR1 mutations (3.8 vs. 1.9 months; HR 0.55, 95% CI: 0.39–0.77, P<0.001). A subgroup analysis published in CCR in 2024 revealed that among patients with ≥12 months of prior CDK4/6i + ET treatment, elacestrant extended PFS to 8.6 months compared to 1.9 months with standard therapy (HR 0.41, 95% CI: 0.26–0.63, P<0.014).

The EMBER-3 trial, reported at SABCS 2024 and published in NEJM, evaluated imlunestrant, another SERD, in three arms: imlunestrant alone, standard ET (fulvestrant or exemestane), and imlunestrant + abemaciclib. Results showed significant PFS improvement in ESR1-mutant patients treated with imlunestrant versus standard ET (5.5 vs. 3.8 months; HR 0.62, 95% CI: 0.46–0.82, P<0.001) and in the combination arm compared to imlunestrant monotherapy (9.4 vs. 5.5 months; HR 0.57, 95% CI: 0.44–0.73, P<0.001).

The SERENA-2 trial, published in The Lancet Oncology, assessed camizestrant, a novel oral SERD and complete ERα antagonist. Both 75 mg (7.2 vs. 3.7 months; HR 0.59, 95% CI: 0.42–0.82) and 150 mg doses (7.7 vs. 3.7 months; HR 0.64, 95% CI: 0.46–0.89) significantly improved PFS compared to fulvestrant, with greater benefits in ESR1-mutant patients.

Antibody-Drug Conjugates (ADCs)

The DESTINY-Breast06 trial, presented at ASCO 2024 and published in NEJM, evaluated trastuzumab deruxtecan (T-DXd) in HR+/HER2-low or HER2-ultralow metastatic breast cancer. T-DXd significantly improved PFS across subgroups, including the intention-to-treat population (13.2 vs. 8.1 months; HR 0.63, 95% CI: 0.53–0.75, P<0.001), HER2-low (13.2 vs. 8.1 months; HR 0.62, 95% CI: 0.51–0.74, P<0.001), and HER2-ultralow (13.2 vs. 8.3 months; HR 0.78, 95% CI: 0.50–1.21). T-DXd also improved ORR compared to chemotherapy.

The EVER-132-002 trial, led by the Cancer Hospital Chinese Academy of Medical Sciences  and published in Nature Medicine, explored sacituzumab govitecan (SG), a TROP2-targeting ADC, in Asian HR+/HER2- ABC patients who had undergone 2–4 prior lines of systemic chemotherapy. SG significantly improved PFS (4.3 vs. 4.2 months; HR 0.67, 95% CI: 0.52–0.87, P=0.0028) and OS (21.0 vs. 15.3 months; HR 0.64, 95% CI: 0.47–0.88, P=0.0061).

Immunotherapy

Progress in immunotherapy for HR+/HER2- ABC remains limited. The Phase II SACI-IO HR+ trial, presented at ASCO 2024, investigated SG alone or combined with pembrolizumab. Neither PFS (8.12 vs. 6.22 months; HR 0.81, 95% CI: 0.51–1.28, P=0.37) nor OS (18.52 vs. 17.96 months; HR 0.65, 95% CI: 0.33–1.28, P=0.21) showed significant differences, even in PD-L1-positive subgroups. Future efforts should focus on strategies to enhance immune responses or identify sensitive populations.