CHAPTER 11 Breast Cancer Metastases to the Neural Axis

Breast cancer is the second most common primary tumor to metastasize to the central nervous system (CNS), after lung cancer.^1,^2,³ Breast cancer metastases to the neural axis typically occur late in the disease, with lung, liver, or bone metastases preceding the diagnosis of CNS metastases. The median interval between the diagnosis of breast cancer and brain metastases is 34 months. The historical 1-year survival rate after diagnosis of brain metastases is 20%.³

CNS metastases can be a challenging management issue. Brain metastases are often more debilitating and more rapidly fatal if untreated than metastases to other organ systems.

Based on data from the 1960s and 1970s, the incidence of clinically apparent brain metastases in women with stage IV breast cancer is 10% to 16%. However, autopsy data show the incidence to be greater and has been reported to be as high as 30%.¹

Younger patients are at higher risk for CNS metastases. In an autopsy series of 1044 breast cancer patients, the median age of patients with CNS metastases was 5 years younger than patients without CNS metastases.¹

Studies suggest a relationship between hormone receptor status and the incidence of CNS metastases.^1,^3,⁴ A study of 217 breast cancer patients found a difference in the rate of brain metastases between estrogen receptor–negative and –positive tumors (10% versus 4%). In a multivariate model, HER-2/neu overexpression was the strongest predictor of CNS relapse, with a 10-fold increase in the incidence of brain metastases (4.3% versus 0.4%). However, it is unclear whether HER-2/neu positive patients are actually at higher risk for CNS metastases or whether the natural history of their disease is affected by more effective systemic disease control with trastuzumab (Herceptin). HER-2 amplification occurs in 25% to 30% of breast cancers and correlates with decreased disease-free and overall survival rates. Treatment with Herceptin improves systemic disease control and overall survival of HER-2/neu positive patients with metastatic breast cancer. However, it does not cross the blood-brain barrier. The theory is that the natural history of the disease may be changed as a result of improved extra-CNS systemic disease control from Herceptin therapy, resulting in an increase in the incidence of CNS metastases. Circumstantial evidence for this includes the statistic that the incidence of CNS metastases in stage IV breast cancer patients who are treated with Herceptin is higher than historical norms, and ranges from 28% to 43%.

DISTRIBUTION OF CRANIAL METASTASES

Brain metastases result from hematogenous spread. Their predilection for the gray-white matter junction is thought to result from decreased vessel caliber at this level acting as a trap for embolized clumps of tumor cells. Similarly, there is a predilection of metastases to occur at intracranial vascular watershed levels. The distribution of metastases within brain compartments is roughly proportionate to the blood supply, with about 80% occurring in the cerebrum, 15% in the cerebellum, and 5% in the brainstem. Metastases occur most commonly at the junction of gray and white matter in the cerebral hemispheres, followed by deep gray matter (basal ganglia, thalami), intraventricular (choroid plexus), and cerebellum.^3,⁶

CNS metastases can be categorized as intra-axial, extra-axial, or cerebrospinal fluid (CSF) dissemination. Breast cancer more commonly involves multiple compartments (parenchyma, meninges, bone) than other tumors. It is the solid tumor most commonly associated with leptomeningeal involvement, although this is considerably less common than parenchymal metastases, occurring in 5% to 16% of patients at autopsy.¹ Breast cancer also metastasizes to the eye at a higher rate than other tumors. A small percentage of breast cancer metastases target the meninges or the skull diploic space. Growth of such lesions may be intracranial and can compress the brain surface, whereas metastases to the skull base dura or bone can exert mass effect on the brainstem or cranial nerves.

The most common imaging manifestation of intracranial metastatic disease is multiple intra-axial brain masses.⁶ These vary in size, shape, and enhancement patterns; the amount of associated edema can range from negligible to intense. Lesions can be solid and enhance uniformly (Figure 1), or can be cystic (Figure 2) or necrotic, with peripheral rim enhancement. Rim enhancement can be thin, thick, uniform, or irregular (Figure 3). Identifying single or multiple intracranial mass lesions in a breast cancer patient is highly suspicious for intracranial metastases, although it has mimicks with other diagnoses, including other neoplasms (metastases from other primaries, brain primary neoplasia, and CNS lymphoma), demyelinating disorders such as multiple sclerosis, multifocal infectious or granulomatous processes, and multifocal ischemic or vasculitic lesions.⁶

FIGURE 1 Enhanced T1-weighted axial MRI from a 68-year-old woman with metastatic breast cancer shows multiple, scattered, rounded, uniformly enhancing masses. Most are peripheral in location, near the brain surface.

FIGURE 2 Enhanced T1-weighted axial MRI from a 63-year-old woman with metastatic breast involvement shows a cystic midbrain lesion with an enhancing rim of variable thickness. The patient presented with new onset of ataxia. Brain metastases were identified 3 years after diagnosis of breast cancer and 1 year after development of thoracic and bone recurrent disease.

FIGURE 3 A 52-year-old woman with metastatic breast cancer to pleura and peritoneum, who developed numbness of the lips and slurred speech. Her original diagnosis of infiltrating ductal carcinoma was 14 years before, with axillary recurrence at 5 years. Brain MRIs (A, axial fluid attenuated inversion recovery (FLAIR); B, enhanced T1-weighted axial; C, coronal, fat-saturated enhanced T1-weighted) show a single brain metastasis to the left paramedian frontal lobe, adjacent to the falx. On FLAIR, the lesion itself is isointense to mildly hyperintense to brain parenchyma, but is outlined by the associated edema. Contrast-enhanced sequences show thick and irregular peripheral enhancement, which suggests central necrosis.

Extra-axial mass lesions may be formed by metastases to the skull or dura. Dural-based metastatic masses can be nodular and mass-like (Figure 4) or elongated and plaque-like (Figure 5). The underlying cerebral cortex may be compressed and edema incited in the underlying parenchyma. Morphologically, dural-based metastases may mimic meningiomas, or subdural collections.⁶

FIGURE 4 Enhanced axial T1-weighted MRI of a 51-year-old woman with metastatic breast cancer shows an enhancing, lobular, dural- and bone-based mass centered on the left sphenoid wing. The component extending into the left middle cranial fossa mimics a meningioma, being dural based and extra-axial, with well-defined margins and an enhancing dural tail. The underlying brain is compressed and edematous. Enhancing tumor also replaces the sphenoid wing bones, and on other levels, extended into the left orbit (not shown). See additional images from the same patient in Case 6 in this chapter.

FIGURE 5 A 47-year-old woman with new-onset expressive aphasia and prior gamma knife therapy 7 months before for right posterior parietal metastasis. Enhanced axial T1-weighted MRI shows a localized region of plaque-like metastatic dural enhancement over the left cerebrum. Additional images on this case can be seen in Case 7 in this chapter.

Leptomeningeal tumor consists at pathologic studies of sheet-like growth of tumor on the brain, spinal cord, or nerve root surfaces. Three mechanisms are postulated for CSF dissemination of tumors.³ Tumor cells may rupture out of the subarachnoid space or pial vessels. Growing metastases in the brain cortex or pia may contact and be bathed by CSF, and thereby shed cells into it. Alternatively, hematogenous metastases to the choroid plexus may seed the CSF. Lobular carcinoma has been noted in clinical and autopsy series to be more likely to manifest as leptomeningeal tumor than ductal carcinoma. The diagnosis can be suggested by characteristic imaging findings on gadolinium-enhanced MRI or can be established by CSF cytology. The imaging hallmarks are enhancement of the leptomeninges (pia and arachnoid) on the brain or cord surface, which can be confluent and sheet-like or nodular, with extension into sulci or along cranial nerves or around the cauda equina (Figure 6).

FIGURE 6 A 51-year-old woman with metastatic breast cancer to liver, bone, and brain, imaged for progressive symptoms, with new perineal numbness, worsening weakness, and urinary incontinence. Based on prior evaluations for headache, the patient was known to have predominantly infratentorial brain parenchymal metastases, diagnosed 5 months before and treated with whole-brain radiation. Her original diagnosis of breast cancer was 9 years before, treated with mastectomy, radiation, and chemotherapy. She had been known to have liver metastases for 6 years and bone involvement for 2 years at the time of identification of brain metastases. A, Sagittal, enhanced (double-dose technique), high-resolution, T1-weighted, gradient echo image shows an enhancing inferior vermis metastasis. In the upper cervical spine included here, linear surface enhancement is seen on the cord (arrow). B, Fat-saturated, enhanced, T1-weighted sagittal view of the thoracic spine shows evidence of known spine and liver metastases. The cord surface also shows linear surface enhancement, compatible with leptomeningeal tumor (arrows). C, Fat-saturated, enhanced, T1-weighted sagittal view of the lumbar spine also shows foci of linear enhancement of cauda equina roots (arrows).

DETECTION OF CNS METASTASES BY IMAGING

Gadolinium-chelate contrast-enhanced MRI is acknowledged to be the most sensitive imaging modality for the diagnosis of neural axis metastases.^7,⁹ Enhanced MRI is superior to enhanced CT for both brain parenchymal and brain and spine leptomeningeal disease due to its higher soft tissue contrast, higher sensitivity to contrast enhancement, direct multiplanar capability, and lack of artifacts related to bone. It particularly excels in demonstration of lesions in the posterior fossa and brainstem, where beam-hardening artifacts can be problematic on CT. MRI is also superior to CT in identifying multiple lesions, which is helpful in the differential diagnosis.⁶

The role of brain PET is limited in evaluating for metastases. Although brain metastases can be seen occasionally on whole-body PET scans (see Case 4 in this chapter), the sensitivity of PET for detection of brain metastases is inferior to MRI and is size dependent. The likelihood of detecting a 1-cm lesion with PET is reported to be about 40%. On a retrospective evaluation of whole-body PET performance in identifying brain metastases, Rohren and colleagues found that PET detected only 61% of lesions found by MRI.⁵

INDICATIONS FOR IMAGING

CNS metastases may be heralded clinically by focal neurologic symptoms, seizure activity, or symptoms reflecting increased intracranial pressure, such as headache, nausea, vomiting, and mental status changes.^1,³ Focal neurologic symptoms may result from tumor-induced chemical changes causing neuron dysfunction and swelling, or from mass effect from compression of normal tissue. Tumor-induced electrical dysfunction can lead to seizure activity. Increased intracranial pressure may result from obstructive hydrocephalus, such as from mass effect from a parenchymal metastasis to the posterior fossa, or from communicating hydrocephalus due to leptomeningeal metastases.

The most common presenting symptom for brain parenchymal metastases is headache, followed by mental status changes and cognitive disturbances. Less common manifestations of CNS metastases include visual and sensory disturbances, focal weakness, seizure, ataxia, and nausea and vomiting. Leptomeningeal disease more often presents with nonlocalizing symptoms of headache or neck or back pain, although cranial neuropathies may result.

TREATMENT OPTIONS

After corticosteroid treatment for edema, therapeutic choices for brain metastases include whole-brain radiation therapy (WBRT), neurosurgery, stereotactic radiosurgery (SRS), and chemotherapy.^1,^2,³ If there are multiple metastases, WBRT has been shown to improve survival and quality of life compared with corticosteroids alone. Median survival is 4 to 5 months. Most patients (75% to 85%) will have improvement of symptoms, with best palliation achieved of seizures and headache. Imaging responses to effective radiation therapy range from complete resolution to shrinkage in size of lesions, to decreased number of identifiable lesions, to alterations of morphology, with improved mass effect and associated edema (Figure 7).

FIGURE 7 A 43-year-old woman with metastatic breast cancer to bone developed headaches. Her breast cancer had been diagnosed 3 years before, and bone metastases were identified 8 months before evaluation for headache. Whole-brain radiation was given for palliation, with improvement in the patient’s symptoms. A, Axial, enhanced, T1-weighted brain MRI at a supratentorial level shows multiple scattered, uniformly enhancing, round newly diagnosed metastases at the gray-white matter junction. B, Enhanced head CT, 4 months later, after whole-brain radiation, shows tiny scattered, smaller residual enhancing metastases, which have shrunk in response to radiation therapy. C, Seven months later, the patient presented with a new seizure. Repeat brain MRI showed progressive disease, with interval growth of several lesions and increased associated edema. A right frontal lesion has grown, and now displays ring enhancement. D, Axial FLAIR of the same lesion shows the associated edema, as well as edema associated with a left paramedian frontal lesion. E, Unenhanced head CT scan, 2 months later, after gamma knife therapy of the same lesion. Calcification is now seen of the treated lesion.

A single metastasis to the brain can be treated either neurosurgically or with SRS. The major advantage of neurosurgery is immediate relief of mass effect from debulking. The decision making is highly dependent on the lesion location.

Surgery can be beneficial to treat a solitary brain metastasis if the breast cancer history is remote (e.g., there is a long tumor-free interval between diagnosis and development of brain metastasis), and there is no other evidence of metastases. Survival is improved in patients undergoing surgery and WBRT for solitary brain metastasis than for those treated with radiation alone. Average survival after resection of a solitary brain metastasis and WBRT is about 1 year.

Selected patients with brain metastases from a variety of primary types (single lesions, better performance status, controlled extra-CNS disease) have better outcomes with surgery than with WBRT. Postoperative external-beam radiation is usually given after gross total tumor excision to treat microscopic residual disease. The addition of WBRT does not appear to confer a survival advantage, although there is improved local control with lower rates of relapse. The major risk of WBRT is progressive dementia.

Single or few metastases can also be treated noninvasively with SRS. Decision making is based on the size and location of the lesion. Ideal lesions for SRS are less than 3 cm in diameter. Stereotactic radiosurgery involves many radiation beams intersecting at a point, resulting in the delivery of a high additive lethal dose to a target tumor, while largely sparing the surrounding brain. Typically, SRS is given as a single, outpatient treatment. Gamma knife is one form of SRS. Contraindications are tumors of large size (>3 cm) and those with significant edema because the treatment can be expected to incite further edema. It is an option to consider for surgically inaccessible metastases (e.g., the brainstem) and can be used to treat multiple tumors.

These treatment options can also be combined. There is evidence that administration of WBRT after SRS reduces the risk for CNS relapse.

There appears to be no clear survival advantage between surgery and SRS in appropriately selected patients. Either treatment confers a survival advantage over WBRT alone.

Chemotherapy plays a lesser role in treatment of breast cancer brain metastases. Most agents used do not cross an intact blood-brain barrier; however, the blood-brain barrier may be dysfunctional with brain metastases, and responses have been reported with agents that do not cross the intact barrier.

Because CSF metastatic disease most commonly manifests as hydrocephalus, and less commonly with carcinomatous meningitis, treatment is directed toward relief of hydrocephalus with shunting, and intrathecal chemotherapy may be considered, administered either by lumbar punctures or Ommaya reservoir.

SPINAL METASTASES

Metastases that compress the spinal cord most commonly present with pain at that level. With increased compression, symptoms progress to numbness below that level and eventually to difficulty ambulating. If untreated, there can be progression to paralysis. Bowel and bladder dysfunction may occur late.

Metastases to the cauda equina produce back pain and, variably, radicular symptoms.⁹

REFERENCES

1 Lin NU, Bellon JR, Winer EP. CNS metastases in breast cancer. J Clin Oncol. 2004;22:3608-3617.

2 Chang EL, Lo S. Diagnosis and management of central nervous system metastases from breast cancer. Oncologist. 2003;8:398-410.

3 Parker EC, Kelly PJ. Brain metastases from breast cancer. In: Roses DF, editor. Breast Cancer. Philadelphia: Elsevier Churchill Livingstone; 2005:633-643.

4 Bendell JC, Domchek SM, Burstein HJ, et al. Central nervous system metastases in women who receive trastuzumab-based therapy for metastatic breast carcinoma. Cancer. 2003;97(12):2972-2977.

5 Rohren EM, Provenzale JM, Barboriak DP, et al. Screening for cerebral metastases with FDG PET in patients undergoing whole-body staging of non–central nervous system malignancy. Radiology. 2003;226:181-187.

6 Yock DH. Magnetic Resonance Imaging of CNS Disease: A Teaching File. St. Louis: Mosby, 2002;2-19. 101, 439

7 Sze G, Milano E, Johnson C, et al. Detection of brain metastases: comparison of contrast-enhanced MR with unenhanced MR and enhanced CT. AJNR Am J Neuroradiol. 1990;11:785.

8 Davis PC, Hudgins PA, Peterman SB, et al. Diagnosis of cerebral metastases: double-dose delayed CT vs contrast-enhanced MR imaging. AJNR Am J Neuroradiol. 1991;12:293.

9 Douglas AF, Cooper PR. Spinal column metastases from breast cancer. In: Roses DF, editor. Breast Cancer. Philadelphia: Elsevier Churchill Livingstone; 2005:644-652.

CASE 1 Multilocular thalamic cystic metastasis

A 43-year-old woman with metastatic breast cancer to the thorax developed nausea, one episode of vomiting, progressive headache, confusion, and speech difficulty.

Her diagnosis of stage T2N1 breast cancer was 5 years before, a 4.5-cm poorly differentiated adenocarcinoma, with one positive lymph node. She underwent bilateral mastectomy and received adjuvant Cytoxan, methotrexate, 5-fluorouracil (CMF) chemotherapy and tamoxifen. Her prior medical history was notable for treatment of Hodgkin’s lymphoma at age 17 with radiation and chemotherapy.

Lung and nodal breast cancer metastases had been identified the year before with PET and CT evaluation for rising tumor markers. The diagnosis of recurrent breast cancer was confirmed by a lung nodule biopsy, which showed malignant adenocarcinoma, consistent with breast primary. The patient was begun on a regimen of docetaxel (Taxotere) and Gemzar. This was eventually discontinued because of pulmonary toxicity (see Case 12 in Chapter 10) and disease progression. The patient’s regimen was changed to capecitabine (Xeloda) for six cycles, with a good initial response, but subsequent regrowth.

When the patient developed symptoms of headache, nausea, and mental status changes, a noncontrast head CT scan was obtained (Figure 1). The head CT identified a lesion and suggested that secondary hydrocephalus was developing. Unenhanced head CT excluded a hemorrhage. Brain MRI was obtained next, which better showed the internal structure of the mass, which was solitary (Figure 2).