Oncology
HER2+ Breast Cancer
Current and Future Roles of Next-Generation Sequencing in HER2+ Breast Cancer
Overview
Next-generation sequencing (NGS) can be a powerful tool to identify patients with actionable genomic alterations. In human epidermal growth factor receptor 2–positive (HER2+) breast cancer, applications for NGS are currently somewhat limited; however, ongoing research on HER2+ metastatic breast cancer and resistance to anti-HER2 therapies might yield additional uses for NGS in the future.
Expert Commentary
Joseph A. Sparano, MD, FACP
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“Should more effective and less toxic agents targeting the PI3K/AKT/mTOR pathway become available that may be safely combined with HER2-directed agents, NGS will have a much greater role in HER2+ metastatic breast cancer.”
Somatic NGS testing of the tumor or cell-free DNA derived from the blood does not currently have a prominent role in guiding therapy for HER2+ breast cancer. If performed in this setting, it is most often in the context of patients who have metastatic disease and have exhausted standard treatment options, or those who are being screened for clinical trials testing novel targeted agents.
Somatic NGS testing, whether of the tumor or circulating tumor DNA, generally shows a spectrum of somatic variants seen in other breast cancer subtypes, such as TP53 alterations, that are currently not actionable. Although alterations in the PI3K/AKT/mTOR pathway are common and are associated with resistance to anti-HER2 therapy, combining anti-HER2 therapy with drugs targeting this pathway has been associated with more toxicity but not greater efficacy. Should more effective and less toxic agents targeting the PI3K/AKT/mTOR pathway become available that may be safely combined with HER2-directed agents, NGS will have a much greater role in HER2+ metastatic breast cancer. Tracking circulating tumor DNA in the blood may prove to have a role in monitoring patients for disease recurrence or in replacing or complementing imaging studies on monitoring the effectiveness of therapy for metastatic disease.
Germline testing for pathogenic germline variants associated with breast cancer is routinely recommended for younger women and for those with a strong family history of breast and/or ovarian cancer. However, HER2+ breast cancer tends to occur less often in patients who have pathogenic germline variants such as BRCA1, BRCA2, and PALB2. These germline mutations tend to be associated more with triple-negative disease.
References
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Hurvitz SA, André F, Jiang Z, et al. Combination of everolimus with trastuzumab plus paclitaxel as first-line treatment for patients with HER2-positive advanced breast cancer (BOLERO-1): a phase 3, randomized, double-blind, multicentre trial. Lancet Oncol. 2015;16(7):816-829. doi:10.1016/S1470-2045(15)00051-0
Laderian B, Hsu R, Sandoval A, et al. Utilization of next generation sequencing (NGS)-guided therapy in breast cancer (BC): Single-institution retrospective analysis of 315 patients [abstract P4-10-19]. Abstract presented at: 2019 San Antonio Breast Cancer Symposium; December 10-14, 2019; San Antonio, TX.
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Rasti AR, Guimaraes-Young A, Datko F, et al. PIK3CA mutations drive therapeutic resistance in human epidermal growth factor receptor 2-positive breast cancer. JCO Precis Oncol. 2022;6:e2100370. doi:10.1200/PO.21.00370
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