Abstract

Leptomeningeal disease (LMD) is known to have exceptionally poor prognosis with few viable treatment options in patients with cancer. HER2+ breast cancer in particular has a predilection for leptomeningeal dissemination relative to other primary malignancies. In this case report, we detail the treatment of a patient with aggressive HER2+ breast carcinoma with leptomeningeal metastases who had remarkable sustained clinical response to systemic and intrathecal (IT) trastuzumab, with correlative cytologic and molecular spinal fluid studies that showed eradication of disease after targeted molecular treatment. This case emphasizes the therapeutic value of IT trastuzumab in a patient with HER2+ breast cancer associated LMD and the need to further explore this specific treatment approach in this patient population for whom treatment options remain very limited.

Keywords: Trastuzumab; Leptomeningeal Disease; HER2+ breast cancer

Introduction

Leptomeningeal disease (LMD) is a rare and devastating complication of breast cancer occurring in less than 5% of breast cancers patients; it portends an unfavorable prognosis with median survival of approximately 4 months after diagnosis [1]. No clear treatment guidelines exist, although a combination of radiotherapy, systemic chemotherapy, and intrathecal chemotherapy is typically utilized, with intrathecal trastuzumab more recently being recognized as a potential agent that can prolong survival in this patient population [2]. We present a case of a 52-year-old female with HER2+, ER-, PR- breast adenocarcinoma with progressive brain and leptomeningeal metastases who after treatment with systemic and intrathecal trastuzumab, in conjunction with radiotherapy and chemotherapy, sustained a durable clinical and radiologic remission of greater than a decade after initial treatment.

Case Presentation

A 52-year-old woman presented in December 2011 to the Neuro-oncology clinic for management of newly diagnosed leptomeningeal disease. She was initially diagnosed with invasive ductal carcinoma of the left breast, estrogen receptor (ER) and progesterone receptor (PR) negative, and HER2neu positive in July 2005. She underwent bilateral mastectomy with left axillary dissection and the pathology staging confirmed a T2 N2 M0 tumor. She received adjuvant chemotherapy with doxorubicin and cyclophosphamide (AC) followed by paclitaxel and trastuzumab which she continued for one year in conjunction with radiation therapy (RT) to the left chest and axilla. She was disease free until October 2009 when she developed right sided neck pain and persistent headache. Subsequent brain MRI revealed 2 brain metastases, one in the right vermis and a second in the right cerebellar hemisphere adjacent to the tentorium and extending into the right occipital lobe. The patient underwent surgical resection of the right cerebellar tumor with pathology positive for metastatic adenocarcinoma with HER-2/neu gene amplification. Thereafter, she received stereotactic radiosurgery to both metastases. She then was initiated on dual chemotherapy with capecitabine and lapatinib for 6 cycles followed by single agent lapatinib for 4 cycles. One year later, in December 2010 the patient was found to have recurrent disease in the cerebellum for which she received 30 Gy palliative radiation. She was stable until 04/2011 when the brain MRI revealed a new metastasis in the left occipital lobe which was treated with gamma knife radiosurgery. Thereafter, she resumed chemotherapy with capecitabine and lapatinib. In late August 2011 she developed low back pain, pain in her right gluteus muscle, and perianal numbness which slowly progressed over the next 3-4 months with associated bowel and bladder dysfunction, at which time she was diagnosed with cauda equina syndrome. The PET/CT scan revealed multiple foci of increased uptake within the spinal canal at the lumbar spine and upper sacrum; the lumbo-sacral MRI revealed subarachnoid leptomeningeal lesions within the lower thoracic spine from T11 through L2 with patchy enhancement of nerve roots of the cauda equina (Figure 1). Cerebrospinal fluid (CSF) showed elevated protein of 515 MG/DL, 71 white blood cells and malignant cells consistent with metastatic adenocarcinoma originating from her primary breast malignancy. She completed 27 Gy radiation therapy and subsequently underwent an Ommaya reservoir placement in preparation for intrathecal (IT) therapy. In January 2012 she was initiated on IT trastuzumab 40 mg weekly and continued systemic treatment with capecitabine and lapatinib. After one cycle of treatment with 4 weekly doses of IT trastuzumab, the brain MRI revealed more obvious nodular enhancement coating the right lateral pons worrisome for tumor progression. Clinically the patient was improving with no back pain, less tightness in the right thigh and less perianal numbness. Repeat CSF cytology revealed only rare atypical cells with normal white cell number and minimally elevated protein (Figure 2). Her IT trastuzumab dose was increased to 80 mg weekly and IT topotecan 0.4 mg was added. Her systemic chemotherapy was changed to trastuzumab and vinorelbine. Between 02/2012 and 10/2019 the patient received IT trastuzumab 100 mg and topotecan 0.4 mg every 4 weeks with durable clinical, radiographic, and CSF cytologic response with no adverse effects from the IT chemotherapy. The PET/CT scan from 3/09/2012 demonstrated that the nodular hypermetabolism in the spinal canal and surrounding the sacral roots had completely resolved. Concurrently, the spine MRI revealed significant improvement of the leptomeningeal disease, and follow up spine MRIs showed no evidence of disease (Figure 1). Her systemic treatment included trastuzumab and vinorelbine from early 2012 until December 2013, followed by single agent trastuzumab until 2014, conjugated trastuzumab-emtansine from 2014 to 2018 and trastuzumab and pertuzumab from 2014-2019. In August 2017 brain MRI revealed progression of the right cerebellar metastasis and the patient received a Laser interstitial Thermal therapy (LITT) therapy. A second LITT procedure was performed in November 2018 for recurrent disease in the right cerebellum. In October 2019 CSF cytology revealed malignant cells and IT topotecan was switched to cytarabine with consistent negative CSF cytology to date. Her systemic therapy was switched to tucatinib from 2019 to 2021 and since 2021 the patient has been receiving trastuzumab-deruxtecan.

Figure 1: Top panel: Left, FDG PET/CT Multiple foci of increased up-take within the spinal canal at the lumbar spine and upper sacrum.. Right: FDG PET/CT Complete resolution of the leptomenigeal hypermetabolic in spinal canal. Bottom panel, Left, a Lumbo-sacral spine MRI12/14/11, before and after (Right lower panel) Lumbo-sacral spine MRI therapy.

Figure 2: Top Panel demonstrates CSF findings with numerous malignant cells pre-treatment as compared to rare atypical cells post-IT Trastuzumab.