Current Sequence of Treatment for Metastatic HER2+ Breast Cancer

Therapeutic Options for HER2⁺ mBC

Despite advances in the treatment of early breast cancer, 20-30% of patients initially treated with curative intent develop distant metastases over the course of the disease. Additionally, BC is diagnosed at a metastatic stage in 5-10% of cases. In about 20% of breast tumors, there is an overexpression/amplification of the HER2 receptor gene. This serves as both a prognostic and predictive marker, and the introduction of anti-HER2 therapy in the past 20 years has significantly improved outcomes for this subgroup, making them comparable or even better than those of patients with HER2-negative tumors.

Pharmacotherapeutic modalities include monoclonal antibodies (trastuzumab, pertuzumab, margetuximab), tyrosine kinase inhibitors (lapatinib, tucatinib, neratinib, pyrotinib), and antibody-drug conjugates (trastuzumab emtansine, trastuzumab deruxtecan). Margetuximab and pyrotinib are not yet registered in the Czech Republic. Despite the availability of HER2-targeted therapies, HER2⁺ metastatic breast cancer (mBC) is not curable, but it is manageable.

First-Line Standard of Treatment

After the publication of the CLEOPATRA study results, the combination of trastuzumab with pertuzumab and a taxane became the standard of care in the 1st line treatment of HER2⁺ mBC. In this study, involving 808 patients with HER2⁺ mBC, the combination of trastuzumab + docetaxel + pertuzumab was compared to trastuzumab + docetaxel + placebo. The arm with pertuzumab showed a significant prolongation of median progression-free survival (PFS: 18.7 vs. 12.4 months; hazard ratio [HR] 0.69; p < 0.0001) and overall survival (OS: 57.1 vs. 40.8 months; HR 0.69; p < 0.0001). The most significant adverse events in the pertuzumab arm were diarrhea, rash, and neutropenia; however, there was no increase in cardiotoxicity when pertuzumab was added to the treatment regimen.

Change in Second-Line Treatment Standard

Until recently, trastuzumab emtansine was the standard of 2nd line treatment based on results from the EMILIA study. In this study involving 991 patients with advanced HER2⁺ BC who had progressed during or after trastuzumab + taxane therapy, this antibody-drug conjugate significantly prolonged median PFS and OS compared to the then-standard combination of lapatinib + capecitabine (PFS: 9.6 vs. 6.4 months; HR 0.65; p < 0.001; OS: 30.9 vs. 25.1 months; HR 0.68; p < 0.001). Grade 3/4 adverse events were significantly more frequent in the lapatinib + capecitabine group. The most common adverse events in the trastuzumab emtansine arm were thrombocytopenia and elevated aspartate aminotransferase (AST) levels.

However, following the publication of the DESTINY-Breast03 study results, trastuzumab deruxtecan has become the recommended 2nd line treatment. Trastuzumab emtansine has moved to higher lines of therapy in the guidelines. DESTINY-Breast03 compared trastuzumab deruxtecan with trastuzumab emtansine in the 2nd line treatment of HER2⁺ mBC after failure of trastuzumab + taxane (± pertuzumab). Patients treated with trastuzumab deruxtecan reached significantly better outcomes—median PFS of 28.8 months compared to 6.8 months with trastuzumab emtansine (HR 0.33; p < 0.0001). Objective response was achieved in 79% of patients compared to 35% in the control arm. Trastuzumab deruxtecan also reduced the risk of death from any cause by 36% compared to trastuzumab emtansine (HR 0.64; p = 0.0037), and this benefit was observed across all subgroups regardless of the presence of brain or visceral metastases at study entry, expression of endocrine receptors, and prior pertuzumab therapy. Trastuzumab deruxtecan can also be considered in cases of brain metastases following the results of the DEBRAH and TUXEDO-1 studies and a subset analysis from DESTINY-Breast03.

Third-Line Treatment

There is currently no standard 3rd line treatment for HER2⁺ mBC, although many patients remain fit enough to continue therapy. Several therapeutic options are available. After 2nd line treatment with trastuzumab deruxtecan, tucatinib, trastuzumab emtansine, trastuzumab + chemotherapy, lapatinib, neratinib, or margetuximab may be used. In the presence of brain metastases, tucatinib is preferred, although there is no evidence of its benefit after trastuzumab deruxtecan therapy.

HER2⁺ Tumors with Hormone Receptor Expression

The concurrent expression of HER2 and hormone receptors allows for the combination of anti-HER2 agents and hormonal therapy in the 1st line treatment of this type of breast cancer. Dual HER2 blockade combined with hormonal therapy is a valid option for HER2⁺ ER⁺ tumors when chemotherapy is not indicated or as maintenance therapy after completing chemotherapy. In later lines, hormonal therapy is considered mainly for patients who poorly tolerate chemotherapy. The clinical benefit largely comes from impacting the HER2 receptor pathway.

Conclusion

New anti-HER2 agents and continued HER2 blockade strategies after progression of HER2⁺ mBC have led to improved outcomes, including prolonged OS (exceeding 60 months in some studies) and better quality of life with acceptable therapy toxicity. Some drugs show efficacy even in the presence of brain metastases. Numerous clinical studies are evaluating further therapeutic options for patients with HER2⁺ mBC.

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Source: Dempsey N., Sandoval A., Mahtani R. Metastatic HER2-positive breast cancer: Is there an optimal sequence of therapy? Curr Treat Options Oncol 2023 Sep; 24 (9): 1120−1137, doi: 10.1007/s11864-023-01108-w.