Dramatic Recovery of Vision after Trastuzumab Deruxtecan Treatment of HER2-Positive Breast Cancer with Pituitary Metastasis

Brain metastases (BMs) occur in 15% of women with metastatic breast cancer. BM is more frequent in patients with human epidermal growth factor receptor 2 (HER2)-positive and triple-negative breast cancer. In particular, 31% of HER2-positive metastatic breast cancer had BM [1]. Currently, the prognosis of BM remains poor, and the median overall survival of patients with HER2-positive breast cancer and BM is approximately 12 months. Local therapy, including radiation and surgery, is commonly employed for BM; however, novel HER2-targeted therapies are being developed to improve BM prognosis. Recent studies report that using anti-HER2 drugs improves the outlook of patients with HER2-positive breast cancer and BM. In this report, we describe a case of visual impairment due to recurrent HER2-positive breast cancer with pituitary metastasis that was successfully treated with the HER2-targeted drug trastuzumab deruxtecan (T-DXd), resulting in the restoration of visual acuity. Although T-DXd has been known to be effective in treating BM, it is rare for drug therapy to markedly improve visual loss due to BM, as in this case. The CARE Checklist has been completed by the authors for this case report and is attached as online supplementary material at https://doi.org/10.1159/000531164.

A 64-year-old woman presented with a sharp decline in performance status (PS) and cognitive function. There was an unknown family history of cancer. The patient underwent breast conserving surgery and radiotherapy for left-sided ductal carcinoma of the breast with microinvasion at the age of 52 years. Details of perioperative systemic therapy were unknown because the patient had been treated previously at a different hospital. At 57 years of age, she underwent a total mastectomy due to the recurrence of an ipsilateral breast tumor, which was an invasive ductal carcinoma. Immunohistochemical staining revealed estrogen receptor-borderline, progesterone receptor-negative, and HER2-positive (IHC: 3+) tumor. Lung and adrenal metastases were identified at the age of 60, after which anti-HER2 therapy was administered. Trastuzumab, pertuzumab, and docetaxel were administered as the 1st line of treatment for 4 months. After the disease was stabilized, docetaxel was replaced with anastrozole for 9 months as maintenance therapy. Due to increased lung metastases, the patient was moved to the 2nd line of treatment and received trastuzumab emtansine (T-DM1) for 9 months. With further disease progression, the patient was switched to lapatinib and capecitabine as the 3rd line of therapy and was treated for 16 months. At 63 years of age, she presented with rapid memory and judgment loss and restlessness 2 months after the commencement of trastuzumab, pertuzumab, and eribulin as the 4th line of treatment.

At the time of the initial examination in December 2020, the patient had a Glasgow Coma Scale (GCS) score of 15 (E4V5M6), PS1, right upper- and lower-extremity paraplegia, a manual muscle testing (MMT) grade of 5 in both upper and lower extremities, and a Mini-Mental State Examination (MMSE) score of 26/30. A brain computed tomography scan revealed hydrocephalus; consequently, urgent VP shunting was performed. Thereafter, cognitive function and performance status improved. After the shunt operation, the patient came to our hospital for continued treatment. Vision in the right eye was almost lost (Fig. 1a) with indirect light reflection and no direct contralateral light reflection 1 month before the start of T-DXd treatment. Brain MRI showed pituitary and other BM (Fig. 2a) and that visual impairment was caused by optic nerve compression from the pituitary metastases. Blood tests to evaluate pituitary dysfunction revealed the following concentrations: thyroid stimulating hormone was 0.041 mIU/L (normal range; 0.37–4.2 mIU/L), free thyroxine was 0.09 pmol/L (normal range; 0.09–0.19 pmol/L), cortisol was 1.0 μg/dL (normal range; 4.5–21.1 μg/dL), and growth hormone was 0.70 ng/mL (normal range; 0.13–9.88 ng/mL). The patient was diagnosed with secondary hypothyroidism and adrenal insufficiency and received levothyroxine (50 μg p.o. once daily) and hydrocortisone (15 mg p.o. once daily). Following whole-brain irradiation of 30 Gy/10 fr for multiple BM, T-DXd treatment (5.4 mg/kg every 3 weeks) was commenced in February 2021 as the 5th line of therapy. We immediately initiated this regimen as systemic therapy because lung metastases had rapidly increased. Visual acuity improved after the second dose of T-DXd (Fig. 1b), and the response was confirmed by MRI after the sixth dose (Fig. 2b). The 25th dose was administered in December 2022. An issue with the shunt tube (VP shunt exposed on body surface, tube removed and replaced with LP shunt) temporarily interrupted the treatment course. Nevertheless, cognitive and visual functioning were maintained over the treatment duration of 22 months without any serious T-DXd-related adverse events.

In the present case, T-DXd therapy was initiated after whole-brain irradiation for BM. The patient’s vision recovered quickly after T-DXd administration commenced, and no new BM appeared during the treatment course. After local treatment of BM in HER2-positive metastatic breast cancer, it is standard practice to shift to systemic treatment if there are metastases in other organs [2, 3]. In this case, radiation therapy was performed before the start of T-DXd. Steroids have also been concomitantly administered for secondary adrenal insufficiency. Therefore, it is difficult to evaluate the efficacy of T-DXd alone. However, lung metastases also responded quickly to T-DXd, and all metastatic lesions, including BMs, continued treatment for more than 20 months without progression. These can be considered an effect of T-DXd.

In addition, the case is notable for its significant improvement from the prognosis predicted by the Graded Prognostic Assessment (GPA) score. Prognostic prediction of breast cancer with BM can be stratified using the GPA index [4]. Breast cancer-specific GPA is based on age, general condition, subtype, number of BM, and presence of other metastases. The expected median survival of this patient was 13 months, according to a breast cancer-specific GPA of 1.5 (KPS 50%, 64 years of age, HER2 positive, more than two BM, metastases other than the brain). However, after 22 months of successful 5th line treatment with T-DXd, the disease has not progressed, and the prognosis is significantly better than predicted. This suggests that the anti-tumor effect of T-DXd is highly effective in this case.

Owing to advances in drug therapy, the prognosis of breast cancer with BM, especially that of HER2-positive cases, is improving. The DESTINY-Breast01 trial: a phase 2 trial reported a response rate of 60.9% (95% CI: 53.4–68.0) and a median progression-free survival of 16.4 months for patients with HER2-positive advanced or recurrent breast cancer previously treated with T-DM1. Subgroup analysis of patients with BM showed antitumor efficacy comparable to that of the larger study population [5]. The DESTINY-Breast03 trial: a phase 3 trial compared T-DXd and T-DM1 as second-line therapies in patients with recurrent or metastatic HER2-positive breast cancer previously administered with trastuzumab and taxanes. Both progression-free survival and overall response rates in the subgroup of patients with BM were better in the T-DXd than in the T-DM1 group, indicating that T-DXd has a greater anti-tumor effect on BM [6]. Additionally, in the TUXEDO-1 trial: a phase 2 trial, the intracranial response rate of patients treated with T-DXd with BM previously treated with trastuzumab or pertuzumab was 73.3% (95% CI: 48.1–89.1). This finding illustrates that T-DXd is also expected to respond to intracranial lesions. Furthermore, the study showed that cognitive dysfunction, which can be a problem during WBRT, did not occur during T-DXd administration, and the quality of life was maintained [7]. Given the previous trial findings, these beneficial effects of T-DXd are expected, even in the presence of intracranial lesions. This success is expected to be maintained after local therapy. The results of these studies confirm the efficacy of T-DXd in this case. These findings support the use of T-DXd as a standard therapy for patients with previously treated HER2-positive metastatic breast cancer.

In this case, the symptoms were different from those seen in common pituitary tumors. First, the hydrocephalus persisted even after the pituitary tumor had decreased in size, requiring a VP shunt or LP shunt. Cerebrospinal fluid cytology performed after transfer to our hospital was negative; therefore, meningeal dissemination was ruled out as a cause of hydrocephalus. Elevated protein levels in the spinal fluid led us to speculate that the disorder of a cerebrospinal fluid absorption might be causing the hydrocephalus. Right-eye blindness did not improve after the VP shunt placement. Second, bilateral hemianopsia is a common visual field disturbance seen with pituitary tumors [8]; however, the patient in this case had right-eye blindness. This is because the pituitary tumor was present in a position to overlie the right optic nerve. Although small tumors were also present in the occipital lobe, there is no homonymous hemiblindness, which is typical with the disorder of the occipital lobe. Therefore, we consider the pituitary tumor to be the responsible lesion in this case of vision loss.

A patient with visual impairment due to postoperative recurrence of HER2-positive breast cancer responded to T-DXd administration after local therapy for BM, resulting in tumor shrinkage and symptomatic improvement. This is the first case report of dramatic vision recovery caused by an intracranial response to T-DXd. This is an interesting case that also shows the characteristics of T-DXd, which can achieve a high intracranial response. Hopefully, the increase in the use of T-DXd will establish an effective treatment strategy for multiple BM in the future.

We would like to thank Editage (www.editage.com) for English language editing.

Written informed consent was obtained from the patient for publication of this case report and any accompanying images. Ethical approval is not required for this study in accordance with local or national guidelines.

Shibata N. reports consulting or advisory roles for Kyowa Kirin Co., Ltd.; has received speakers’ bureau from Kyowa Kirin Co., Ltd., Chugai Pharmaceutical Co., Ltd., Pfizer Japan Inc., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., Yakult Honsha Co., Ltd., Taiho Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Nippon Kayaku Co., Ltd., MSD K.K., Merck Biopharma Co., Ltd., and Becton, Dickinson and Company; and research funding from Daiichi Sankyo Co., Ltd., Ono Pharmaceutical Co., Ltd., and MSD K.K. Kikawa Y. has received speakers’ bureau from Eisai Co., Ltd., Pfizer Japan Inc., Novartis Pharma K.K., AstraZeneca K.K., Taiho Pharmaceutical Co., Ltd., and Daiichi Sankyo Co., Ltd. Sugie T. has received speakers’ bureau from Chugai Pharmaceutical Co., Ltd., and MSD K.K.

No research support for this study.

Matsui C. and Shibata N. wrote the case report and contributed to analysis and/or interpretation of data. Shibata N., Hirai C., Tada M., Kikawa Y., and Sugie T. contributed to the clinical management of this patient. Matsui C., Shibata N., Kikawa Y., and Sugie T. contributed to drafting of the manuscript. Kikawa Y. and Sugie T. contributed to critical review of the manuscript for important intellectual content.

All data generated or analyzed during this study are included in this article and its online supplementary material. Further inquiries can be directed to the corresponding author.