Approximately 15% to 20% of BC patients in the U.S. are HER2+, and of these patients, about one-half are also HR+ BC. These patients are at a gradual increased risk of recurrence following anti-HER2 treatment.

For patients with stage IV metastatic HR+/HER2+ BC, therapeutic options include anti-HER2 therapy with chemotherapy or endocrine therapy (ET) with or without anti-HER2 therapy. Anti-HER2 therapy plus chemotherapy has prolonged survival. Single-target combination therapy with ET has been associated with increased progression-free survival (PFS) and overall survival (OS; 4.8 to 14.1 months and 28.5 to 33.3 months, respectively). Dual combinations with ET have been associated with an increase in PFS of 5.7 to 18.9 months.

However, it is unclear which therapeutic regimens are the safest and most efficacious due to small sample sizes and a lack of information on combination regimens in metastatic HER2+ BC in the original trials.

To help address these concerns, investigators conducted a Bayesian network meta-analysis to provide evidence-based data on the optimal management of stage IV metastatic HR+/HER+ BC.

A literature search was conducted of seven databases (PubMed, the Cochrane Library, Web of Science, EMBASE, Sinomed, CNI, and WANFANG) between January 1, 2000, and November 23, 2022. To be eligible for inclusion in this meta-analysis, patients enrolled in the studies had to be diagnosed with advanced/metastatic BC confirmed by histopathology; the studies had to be controlled trials; and one of following outcomes had to be measured—objective response rate (ORR), PFS, OS, and the incidence rate for grade III/IV adverse events (AEs). Ongoing studies without sufficient data, meta-analyses, letters, cases reports, reviews, and duplicative studies were excluded. Multiple treatment options were compared using the surface under the cumulative ranking curve (SUCRA). A higher SUCRA value indicates a more appropriate treatment option.

A total of 25 randomized, controlled trials involving 5,958 patients were included in the Bayesian network analysis. About one-third (32%) of studies (N = 8) involved patients with advanced line 1 disease (i.e., those who had received no prior antitumor treatment in the advanced BC stage), and four studies included patients with line >3 disease (i.e., any line greater than line 1 was defined as having completed at least one prior systemic antitumor treatment in the advanced stage).

Investigators found that the combination of dual-target therapy with ET (anastrozole, fulvestrant, and letrozole) was the most effective treatment combination. Dual anti-HER2 monoclonal antibodies (trastuzumab and pertuzumab) with ET had the highest SUCRA value (87.9%) for PFS indicating that it was the optimal treatment option. For ORR and OS, anti-HER2 monoclonal antibody therapy and tyrosine kinase inhibitors (TKIs; i.e., afatinib, lapatinib, neratinib, pyrotinib, and tucatinib) plus ET and dual anti-HER2 monoclonal antibodies (mABs) plus ET demonstrated the best outcomes. The researchers found that the combination of anti-HER2 therapy with ET, especially dual-target therapy, produced the best outcomes in patients with HR+/HER2+ metastatic BC.

Additional beneficial treatment options included dual anti-HER2 mAB therapy and chemotherapy (capecitabine, docetaxel, doxorubicin, paclitaxel, MD choice chemo, taxane, vinorelbine); anti-HER2 mAB therapy plus CDK4/6 inhibitors (abemaciclib, palbociclib) and ET; and anti-HER2 mAB + TKI + chemotherapy are the preferred options.

For safety, anti-HER2 mAB + CDK4/6 inhibitor + ET (SUCRA 15.3%) was the least effective regimen in reducing the incidence rate of grade III/IV AEs. Whereas, aside from radiation, anti-HER2 mAB + ET therapy was associated with the greatest effect of reducing grade III/IV AEs.

This study provides pharmacists who treated patients with HR+/HER2+ metastatic BC with evidence-based medicine to support the most effective and safe treatment options in this population.

Efficacy was assessed based on PFS, OS, and ORR.

• PFS: double-target combined ET (anastrozole, fulvestrant, letrozole) and dual HER2-mABs (pertuzumab, trastuzumab; HR = 0.38; 95% credible interval [CrI], 0.16-0.88) and HER2-mAB + HER2-TKI (afatinib, lapatinib, neratinib, pyrotinib, and tucatinib) + ET (HR 0.45; 95% CrI, 0.23-0.89). Takeaway point: double-target combined ET significantly improved PFS compared with ET monotherapy
• PFS: single-target combined ET-HER2-TKI + ET (HR = 0.65; 95% CrI, –0.39 to 1.06) and HER2-mABs + ET (HR = 0.69; 95% CrI, 0.45-1.05) did not significantly improve PFS compared with ET alone
• PFS: SUCRA ranked dual HER2-mAB + ET (87.9%) > HER2-mAB + HER2-TKI + ET (79.1%), HER2-TKI + ET (44.1%) > HER2-mAB + ET (36.3%) > ET (2.5%)
• PFS: dual HER2-mABs + chemotherapy (capecitabine, docetaxel, doxorubicin, paclitaxel, medical doctor–choice chemotherapy, taxane, vinorelbine; HR 0.76; 95% CrI, 0.6-0.96) and HER2-mAB + HER2-TKI + chemotherapy (HR = 0.48; 95% CrI, 0.29-0.81) significantly improved PFS compared with HER2-mAB + chemotherapy
• PFS: dual HER2-mABs + chemotherapy (HR = 0.65; 95% CrI, 0.46-0.91) and HER2-mAB + HER2-TKI + chemotherapy (HR = 0.41; 95% CrI, 0.23-0.73) significant improved PFS compared with HER2-TKI + chemotherapy
• PFS: all dual-targeted combined chemotherapy showed notable PFS improvements compared with single-target combined chemotherapy
• PFS: HER2–antibody-drug conjugates (ADCs; HR = 0.75; 95% CrI, 0.57-1) and HER2-mAB + HER2-ADCs (trastuzumab deruxtecan, trastuzumab, and emtansine; HR = 0.63; 95% CrI, 0.42-0.95) significantly improved PFS compared with HER2-TKI + chemotherapy
• PFS: SUCRA ranked HER2-mAB + HER2-TKI + chemotherapy (95.3%) > HER2-mAB + HER2-ADC (71.1%) > dual HER2-mAB + chemotherapy (69.2%) > HER2-mAB + cyclin-dependent kinase (CKD) 4/6 inhibitor + ET (60.0%) > HER2-ADC (49.0%)
• OS: HER2-TKI + ET, HER2-mAB + ET, and HER2-mAB + HER2-TKI + ET had a tendency towards improved OS compared with ET alone; this was not statistically significant (NSS)
• OS: dual-target combined ET-HER2-mAB + HER2-TKI + ET had improved OS compared with HER2-TKI + ET and HER2-mAB + ET; single-target combination ET had lower OS benefit, but this was NSS
• OS: SUCRA ranked HER2-mAB + HER2-TKI + ET (92.2%) > HER2-mAB + ET (52.2%) > HER2-TKI +ET (50.5%) > ET (5.1%)
• OS: dual combination chemotherapy—dual HER2-mAB + chemotherapy (HR = 0.71; 95% CrI, 0.43-1.18) and HER2-mAB + HER2-TKI + chemotherapy (HR = 0.85; 95% CrI, 0.49-1.47); increased trend in OS benefit, but NSS compared with HER2-mAB and chemotherapy
• OS: SUCRA ranked dual mABs + chemotherapy (72.4%), HER2-mAB + CDK4/6 inhibitor (abemaciclib, palbociclib; 67.0%), HER2-mAB + CDK4/6 inhibitor + ET (64.4%), HER2-mAB + HER2-TKI + chemotherapy (50.3%), HER2-mAB + chemotherapy (26.5%), and chemotherapy (19.3%)
• ORR: HER2-TKI + ET (OR = 3.26; 95% CrI, 1.13-10.17), HER2-mAB + ET (odds ratio [OR] = 2.81; 95% CrI, 1.08-8.18) and HER2-mAB + HER2-TKI + ET (OR = 7.37; 95% CrI, 1.81-33.72) significantly improved OR compared with ET
• ORR: dual-target combined ET (HER2-mAB + HER2-TKI + ET) had greater benefit in ORR compared with single-target combined ET (HER2-mAB + ET, HER2-TKI + ET), but was NSS
• ORR: SUCRA ranked HER2-mAB + HER2-TKI + ET (95.5%), HER2-TKI+ ET (56.3%), HER2-mAb + ET (46.7%), ET (1.4%)
• ORR: SUCRA ranked HER2-mAB + chemotherapy (64.6%), HER2-mAB + CDK 4/6 (62.3%), HER2-mAB + CDK4/6 inhibitor + ET (23.9%)
• ADEs: dual mABs + chemotherapy reached statistical significance
• ADEs: SUCRA for reducing the incidence of grade III/IV adverse events (AEs); endocrine therapy (ET; 94.4%), HER2-mAB + ET (72.3%), dual HER2-mABs + ET (69.2%), HER2-TKI + ET (52.8%), HER2-mAB + HER2-TKI + ET (49.2%), HER2-mAB + CDK4/6 inhibitor + ET (15.3%); latter is least effective in reducing the incidence rate of grade III/IV AEs.

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