Trastuzumab and fulvestrant combination therapy showed a median PFS of 6.4 months, median OS of 35.3 months, and 64% DCR, which suggested moderate efficacy in patients with HR + HER2+ metastatic breast cancer. In this study, most patients were heavily pretreated and developed visceral metastasis, including liver and brain metastases, indicating poor prognosis in these patients. The response rate was only 4%, which might be due to the late treatment line of this population; the median number of treatment lines was six, and four patients were treated after the 10th line.

Real-world evidence of treatment after T-DM1 in patients with HER2+ metastatic breast cancer showed that most patients received trastuzumab and chemotherapy after T-DM1, and approximately 5% of the patients received hormone therapy with or without anti-HER2 antibodies [12]. The median PFS after T-DM1 treatment was 6.1 months (95% CI, 5.3–6.7) and median OS was 23.7 (95% CI, 20.7–27.4), which are comparable with the PFS and OS of trastuzumab and fulvestrant combination therapy in the current study. This suggests that trastuzumab and fulvestrant combination therapy is a reasonable treatment option after T-DM1 for patients with HR + HER2+ metastatic breast cancer.

Recently, clinical trials on the addition of a CDK4/6 inhibitor to the combination of fulvestrant and HER2-targeted therapy have been conducted in patients with HR + HER2+ breast cancer [13, 14]. However, the data on fulvestrant and trastuzumab combination therapy that should have been the background for these studies are scarce; hence, our data are considered useful. The monarcHER trial, a phase 2 trial that compared abemaciclib plus trastuzumab plus fulvestrant, abemaciclib plus trastuzumab, and standard-of-care chemotherapy plus trastuzumab, showed better PFS with abemaciclib plus trastuzumab plus fulvestrant than with standard-of-care chemotherapy plus trastuzumab [13]. The median PFS of the abemaciclib plus trastuzumab plus fulvestrant group (n = 79) and that of standard-of-care chemotherapy and trastuzumab group were 8.3 months (95% CI, 5.9–12.6) and 5.7 (95% CI, 5.4–7.0), respectively. The PFS of trastuzumab plus fulvestrant in our study was comparable to that of standard-of-care chemotherapy and trastuzumab in the monarcHER trial. The patient background in our study was also similar to that in the monarcHER trial. For example, patients who received at least two HER2-targeted therapies for advanced breast cancer were included. In the abemaciclib plus trastuzumab plus fulvestrant group, 44% patients had two or three previous systemic therapies for advanced breast cancer and 56% had four or more. Moreover, 73% patients had visceral metastasis, and most patients were heavily pretreated for it. The overall response rate in the abemaciclib plus trastuzumab plus fulvestrant group was 33%, which was higher than that in our survey. This suggests that adding abemaciclib to trastuzumab and fulvestrant combination therapy in this population is effective. Based on these efficacy data, anti-HER2 therapy plus endocrine plus CDK4/6 inhibitor combination is a promising strategy in this patient population and phase 3 trials are ongoing. For example, DETECT V/CHEVENDO trial is recruiting patients, which is a randomized phase III study comparing the safety and efficacy of trastuzumab plus pertuzumab and the ribociclib, CDK4/6 inhibitor, along with either endocrine therapy or chemotherapy and includes trastuzumab plus pertuzumab plus ribociclib plus fulvestrant arm (NCT02344472). Another phase III trial, PATINA, is evaluating the efficacy of adding palbociclib to the anti-HER2 therapy plus endocrine therapy after 4 to 8 cycles of induction treatment (NCT02947685).

There has recently been remarkable progress in the development of new drugs for HER2+ metastatic breast cancer [15]. These new drugs include novel antibody–drug conjugates (trastuzumab deruxtecan) and tyrosine kinase inhibitors (neratinib and tucatinib). Some of these agents are being developed in clinical trials as combination therapy with fulvestrant; however, there are no control efficacy data on trastuzumab and fulvestrant combination therapy. This study contributes to understanding the efficacy of trastuzumab and fulvestrant combination therapy and further development of anti-HER2 agents plus hormone therapy.

We recognized several imitations of this study. First, this is a single-center retrospective study, which makes it difficult to appropriately evaluate adverse events or toxicity. Second, only 14% patients previously received treatment containing pertuzumab. The records include patients since 2001, which implies that most patients received anti-HER2 treatment before pertuzumab approval. Finally, the number of patients who received trastuzumab and fulvestrant was small, which requires careful interpretation of the results.

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