Stereotactic radiosurgery with concurrent lapatinib is associated with improved local control for HER2-positive breast cancer brain metastases

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OBJECTIVE

With increasing survival for patients with human epidermal growth factor receptor 2-positive (HER2+) breast cancer in the trastuzumab era, there is an increased risk of brain metastasis. Therefore, there is interest in optimizing intracranial disease control. Lapatinib is a small-molecule dual HER2/epidermal growth factor receptor inhibitor that has demonstrated intracranial activity against HER2+ breast cancer brain metastases. The objective of this study was to investigate the impact of lapatinib combined with stereotactic radiosurgery (SRS) on local control of brain metastases.

METHODS

Patients with HER2+ breast cancer brain metastases who underwent SRS from 1997–2015 were included. The primary outcome was the cumulative incidence of local failure following SRS. Secondary outcomes included the cumulative incidence of radiation necrosis and overall survival.

RESULTS

One hundred twenty-six patients with HER2+ breast cancer who underwent SRS to 479 brain metastases (median 5 lesions per patient) were included. Among these, 75 patients had luminal B subtype (hormone receptor-positive, HER2+) and 51 patients had HER2-enriched histology (hormone receptor-negative, HER2+). Forty-seven patients received lapatinib during the course of their disease, of whom 24 received concurrent lapatinib with SRS. The median radiographic follow-up among all patients was 17.1 months. Concurrent lapatinib was associated with reduction in local failure at 12 months (5.7% vs 15.1%, p < 0.01). For lesions in the ≤ 75th percentile by volume, concurrent lapatinib significantly decreased local failure. However, for lesions in the > 75th percentile (> 1.10 cm3), concurrent lapatinib did not significantly improve local failure. Any use of lapatinib after development of brain metastasis improved median survival compared to SRS without lapatinib (27.3 vs 19.5 months, p = 0.03). The 12-month risk of radiation necrosis was consistently lower in the lapatinib cohort compared to the SRS-alone cohort (1.3% vs 6.3%, p < 0.01), despite extended survival.

CONCLUSIONS

For patients with HER2+ breast cancer brain metastases, the use of lapatinib concurrently with SRS improved local control of brain metastases, without an increased rate of radiation necrosis. Concurrent lapatinib best augments the efficacy of SRS for lesions ≤ 1.10 cm3 in volume. In patients who underwent SRS for HER2+ breast cancer brain metastases, the use of lapatinib at any time point in the therapy course was associated with a survival benefit. The use of lapatinib combined with radiosurgery warrants further prospective evaluation.

ABBREVIATIONS BBB = blood-brain barrier; EGFR = epidermal growth factor receptor; HER = human EGFR; IQR = interquartile range; SRS = stereotactic radiosurgery; WBRT = whole-brain radiation therapy.

Article Information

Correspondence John H. Suh: Cleveland Clinic, Cleveland, OH. suhj@ccf.org.

INCLUDE WHEN CITING Published online February 8, 2019; DOI: 10.3171/2018.10.JNS182340.

Disclosures Dr. Chao reports receiving an honorarium from Varian Medical Systems. Dr. Kotecha reports receiving monetary compensation from Chrysalis BioTherapeutics, Inc., Elsevier PracticeUpdate, Accuray, Inc., and Elekta. Dr. Ahluwalia reports being a consultant for Monteris Medical, Inc., AstraZeneca, Varian Medical Systems, Flatiron, Abbvie, BMS, and Kadmon Pharmaceuticals; having ownership in CBT Pharmaceuticals; having direct stock ownership in Mimivax and Doctible; receiving support of non–study-related clinical or research effort from Novartis, BMS, AstraZeneca, Incyte, Novocure, Pharmacyclics, and Abbvie; and serving on the Data Safety and Monitoring Board for VBI Vaccines. Dr. Barnett reports being a consultant for Monteris Medical, Inc., and receiving royalty interests for Mako Surgical Corp. and Roche. Dr. Vogelbaum reports having a fiduciary role, equity, and royalty interests in Infuseon Therapeutics, Inc. Dr. Peereboom reports being a co-principal investigator for Novartis on an NRG trial that uses lapatinib.

© AANS, except where prohibited by US copyright law.

Headings

Figures

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    Cumulative incidence of local failure stratified by volume quartile of metastasis: 1st, 2nd, 3rd, and 4th quartile correspond to 0–0.07, 0.07–0.24, 0.24–1.10, and > 1.10 cm3.

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    Cumulative incidence of local failure (LF) stratified by use of SRS with or without the use of concurrent lapatinib.

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    Cumulative incidence of local failure for lesions ≤ 75th percentile in volume.

  • View in gallery

    Cumulative incidence of local failure stratified by concurrent lapatinib use for lesions in the > 75th percentile.

  • View in gallery

    Overall survival of patients with brain metastases in patients from HER2+ breast cancer treated with SRS. The dashed line indicates patients who received lapatinib at any time point during the disease course, whereas the solid line indicates patients who were treated with SRS alone.

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