ER+/PR+ HER2+ Breast Cancer With Brain Metastases

Presentation, Workup, and Diagnosis

After palpating a breast mass, a 45-year-old patient undergoes a right breast diagnostic mammogram and an ultrasound, which reveal a large area of architectural distortion with calcifications and a corresponding irregular mass measuring at least 3.5 x 1.2 x 2.0 cm. The right axillary ultrasound reveals an abnormal-appearing lymph node measuring 1.0 x 1.1 x 1.6 cm with cortical thickening, in addition to a few other abnormal enlarged lymph nodes. A core biopsy of the right breast mass shows invasive ductal carcinoma that is ER+ (95%)/PR+ (70%)/HER2+ (IHC 3+/no FISH done). A biopsy of the axillary node is positive for carcinoma.

At the time of diagnosis, the patient also reports left lower rib pain. A staging CT shows a lytic lesion in the thoracic spine and multiple liver lesions between 1.4 and 3.8 cm. A nuclear bone scan shows uptake in the right acetabulum, right iliac crest, bilateral shoulders, clavicles, ribs with fractures, and multiple vertebral bodies. A brain MRI shows a 5-mm benign pituitary lesion.

Initial Treatment

The patient begins first-line therapy with paclitaxel (2 weeks on, 1 week off) and trastuzumab/pertuzumab every 3 weeks, in addition to zoledronic acid. After completion of chemotherapy, PET/CT shows resolved liver lesions, sclerosis in bones without hypermetabolism, and a right breast mass with mild hypermetabolism. She continues trastuzumab/pertuzumab alone and adds tamoxifen. Two months later, she undergoes bilateral salpingo-oophorectomy and switches to anastrozole. Her restaging scans continue to show stable disease.

Follow-Up and Subsequent Treatment

The patient reports having headaches 18 months later. A brain MRI shows new enhancing foci in the right superior cerebellum, left superior parietal lobule, and left posterior superior frontal gyrus, with the largest at 1.1 cm. She then undergoes radiosurgery to the three lesions, while continuing treatment with trastuzumab/pertuzumab and anastrozole.

Every-3-month brain MRIs show resolved brain lesions, until 2 years later, when imaging shows an increased sized focus in the medial right cerebellar hemisphere with significantly increased sized surrounding T2/FLAIR hyperintensity, now measuring 2.3 x 1.6 cm (previously 1.0 x 0.8 cm). A new small focus of susceptibility within the enhancing lesion suggests a new hemorrhagic component. Radiation oncology recommends an arterial spin labeling (ASL) brain MRI to determine if these findings represent progression of disease versus sequelae of prior radiosurgery. The ASL brain MRI shows a similarly sized enhancing right cerebellar lesion with diminished surrounding edema. There is no elevated cerebral blood flow on perfusion imaging. Findings were felt to be compatible with evolving post-treatment effect and not progressive metastases. 

Nine months later, a brain MRI shows progressive interval enlargement of the hyperperfusing right cerebellar enhancing lesion with increasing surrounding vasogenic edema. Neurosurgery and radiation oncology conclude this to be progression. The patient then undergoes radiosurgery again to the right cerebellar metastasis, while continuing treatment with trastuzumab/pertuzumab and anastrozole.

One year later, another brain MRI again shows significantly increased size of enhancement in the superior right cerebellum and vermis with associated hyperperfusion, now measuring 4.1 x 1.3 x 1.2 cm, with mass effect on the fourth ventricle with partial effacement. The patient is started on oral dexamethasone to reduce the swelling. Pertuzumab and anastrozole are stopped, and she continues on trastuzumab with the addition of tucatinib 300 mg BID and capecitabine 2000 mg/m² per day (this patient started with a 1500 mg BID dose) 2 weeks on, 1 week off.

Six months later, a brain MRI shows increased size of treated metastasis in the right cerebellum with imaging characteristics (peripheral nodularity and elevated perfusion), which favor progressive tumor over evolving post-treatment change. The patient undergoes partial brain radiation. She continues tucatinib, capecitabine, and trastuzumab.

Eight months later, a brain MRI shows an interval increase in size of treated heterogeneously enhancing metastasis in the right cerebellum, measuring approximately 4.9 x 1.8 cm in axial (compared to 4.4 x 1.5 cm previously). An increase in associated vasogenic edema is noted, now extending to the vermis with increased mass effect on the right superior cerebellar peduncle and increased effacement of the fourth ventricle. The patient begins a 2-month course of bevacizumab, after which she undergoes a resection of the brain lesion. This shows metastatic adenocarcinoma, consistent with a breast primary, ER-/PR-, HER2 2+ IHC, FISH 31/3.1, ratio 10.

Four months post-brain lesion resection, a brain MRI shows interval enlargement of nodular enhancing tumor at the superomedial aspect of the resection cavity, now measuring 2.8 x 1.7 x 2.1 cm (previously 2.1 x 1.4 x 1.5 cm), demonstrating elevated perfusion. The patient then begins treatment with trastuzumab deruxtecan.

Discussion

In breast cancer, brain metastases are most common among patients with more aggressive disease types, including HER2-positive disease.¹ Oral and intravenous therapies for brain metastases are limited due to the challenges in crossing the blood–brain barrier.² For this reason, patients may have poor response to these therapies in the brain but very well controlled disease elsewhere.²

In the HER2CLIMB trial, combination treatment with tucatinib, capecitabine, and trastuzumab was shown to increase progression-free survival in patients with HER2-positive breast cancer with brain metastases when compared to capecitabine and trastuzumab alone (7.6 months and 5.4 months, respectively [HR 0.48; 95% CI, 0.34 to 0.69; p<0.001]), paving the way for the FDA approval of this combination therapy.³ In DESTINY-Breast03, trastuzumab deruxtecan was shown to improve progression-free survival when compared to T-DM1 in patients with stable brain metastases (15.0 months vs 5.7 months, respectively; HR 0.38; 95% CI, 0.23-0.64).⁴ The TUXEDO-1 trial later demonstrated 14-month progression-free survival among patients with active brain metastases.⁵

Radiation has been a mainstay in treating brain metastases and can be given as radiosurgery, partial brain radiation, or whole brain radiation—each covering increasing amounts of tissue. Radiosurgery, which affects very little healthy tissue, is recommended as it is well tolerated and has minimal side effects.⁶ However, for patients with more than 10 brain metastases not eligible for local treatment and for patients with new lesions not eligible for radiosurgery, whole-brain radiation is indicated.⁶ Surgical resection is reserved for patients with good performance status, few lesions, or large symptomatic lesions (≥3 cm).⁶ Radiation can result in necrosis and edema at the treated sites, which can sometimes cause symptoms. Bevacizumab has been shown to reduce radiation necrosis.⁷

The general approach in breast cancer is that if the disease in the body is well controlled by a patient’s treatment and the disease in the brain is not, the brain can be treated with radiation while continuing the same intravenous and oral therapy. However, with newer, more effective medical therapies that cross the blood–brain barrier, this may change in the future.

References

1. Pasquier D, Darlix A, Louvel G, et al. Treatment and outcomes in patients with central nervous system metastases from breast cancer in the real-life ESME MBC cohort. Eur J Cancer. 2020;125:22-30.
2. Garcia-Alvarez A, Papakonstantinou A, Oliveira M. Brain metastases in HER2-positive breast cancer: Current and novel treatment strategies. Cancers (Basel). 2021;13(12):2927.
3. Murthy RK, Loi S, Okines A, et al. Tucatinib, Trastuzumab, and Capecitabine for HER2-positive metastatic breast cancer [published correction appears in N Engl J Med. 2020 Feb 6;382(6):586]. N Engl J Med. 2020;382(7):597-609.
4. Cortés J, Kim SB, Chung WP, et al. Trastuzumab deruxtecan versus trastuzumab emtansine for breast cancer. N Engl J Med. 2022;386(12):1143-1154.
5. Bartsch R, Berghoff AS, Furtner J, et al. Trastuzumab deruxtecan in HER2-positive breast cancer with brain metastases: a single-arm, phase 2 trial. Nat Med. 2022;28(9):1840-1847.
6. Bailleux C, Eberst L, Bachelot T. Treatment strategies for breast cancer brain metastases. Br J Cancer. 2021;124(1):142-155.
7. Zhuang H, Shi S, Yuan Z, Chang JY. Bevacizumab treatment for radiation brain necrosis: mechanism, efficacy and issues. Mol Cancer. 2019;18(1):21. Published 2019 Feb 7.