Targeting the Sanctuary Site: Options when Breast Cancer Metastasizes to the Brain

ABSTRACT: Brain metastasis is a poor prognostic factor in breast cancer progression, and traditional treatment options have shown minimal response with overall low median survival rates. The incidence of brain metastasis has been increasing despite and, in part, due to advancements in treatment as a result of prolongation of survival. Targeted therapy such anti-HER2 agents have a lower efficacy in this setting compared to metastases elsewhere; however, novel therapies are emerging in this regard. In this comprehensive review, we discuss risk per subtype, special considerations for therapy selection, current focal and systemic treatments, and recent advancements and potential future targets for success. We present our treatment paradigm and multidisciplinary approach to brain metastases arising from breast cancer based on the available evidence, incorporating molecular characteristics.

Introduction

Breast cancer has the second highest incidence of brain metastasis among all malignancies. There are few systemic therapies that penetrate the blood-brain barrier (BBB).[1,2] Brain metastasis carries a very poor prognosis, is often associated with a decline in cognition, and may affect sensory and motor function.[3] In this review, we discuss the current management of brain metastasis in breast cancer including focal therapies as well as systemic options for specific populations, including emerging and novel therapies.

Risk per subtype

The risk of developing brain metastases arising from breast cancer varies by subtype as a result of the natural history of each. Basal tumors (estrogen receptor [ER]/progesterone receptor [PR]-/anti-human epidermal growth factor receptor 2 [HER2]-) and HER2-positive tumors (ER/PR-/HER2+) have an increased risk of developing brain metastases ranging from 25% to 27% and 11% to 20%, respectively. Luminal tumors are least likely to metastasize to the brain, with luminal A (ER/PR+/HER2-) at lowest risk of 0.7%, while luminal B (ER/PR+/HER2+ or ER/PR+ or -/HER2-) is slightly higher at 12%, due to the HER2 positivity.[4–6] Figure 1 demonstrates the risk of developing brain metastasis in accordance with the subtype of breast cancer.[6] The recognition of molecular subtypes has improved the understanding of the genomic landscape and heterogeneity of the disease, which has been and continues to be one of the important obstacles to advancements in the prognosis and treatment of the disease.

Special/molecular considerations for therapy selection

HER 2 positive breast cancer

Approximately 25% of patients with HER2-positive breast cancer will develop brain metastases.[7] Those with HER2-positive disease have demonstrated a significant survival benefit with the use of systemic anti-HER2 therapy.[8] One proposed mechanism behind the propensity of HER2-positive disease to metastasize to the brain is the inability of trastuzumab to cross the BBB.[9]

HER2-directed therapies for breast cancer can be classified into three subgroups: monoclonal antibodies such as trastuzumab and pertuzumab, small-molecule tyrosine kinase inhibitors (TKIs) such as lapatinib and neratinib, and the antibody-drug conjugate ado-trastuzumab emtansine (T-DM1). The American Society of Clinical Oncology has recommendations on disease management for advanced HER2-positive breast cancer and brain metastases, which we have outlined in Table 1.[10]

Trastuzumab was the first developed recombinant monoclonal antibody directed against the HER2 oncoprotein. Like most other monoclonal antibodies, it is too large to cross an intact BBB, making the brain a safe haven or “sanctuary site” for any cells able to hematogenously disseminate there. The brain is increasingly reported as the first site of distant relapse in HER2-positive patients, especially those who are treated with trastuzumab. The exact mechanism is unclear but is possibly linked to the increased survival in this subset of patients since the emergence of HER2-targeted therapy. It is speculated that there is sufficient opportunity to develop brain metastasis as a result of prolongation of survival.[11,12]

Although pertuzumab is also unable to cross the BBB, dual HER2 targeting appears to delay the onset of brain metastases. Table 2 highlights some of the key clinical trials upon which systemic therapy recommendations for the treatment of brain metastases in breast cancer are based.[12–21] The CLEOPATRA trial demonstrated a significant increase in time to development of brain metastases with the addition of pertuzumab to trastuzumab and docetaxel from 11.9 months to 15 months (P = .0049).[8] The current standard clinical practice is to combine 2 anti-HER2 agents with a taxane for patients with untreated HER2-positive disease who did not receive adjuvant treatment at diagnosis.

The role for TKIs for use in brain metastases is of interest due to their increased BBB permeability. Lapatinib is a dual TKI of the HER1 and HER2 receptors. It was analyzed with capecitabine in a phase II trial in the first-line setting to delay whole-brain radiotherapy (WBRT). This study enrolled 45 patients with metastatic breast cancer and brain metastases; 29 patients had a partial response to treatment. The most common grade 3 or 4 toxicities included diarrhea and hand-foot syndrome.[9] Single-agent lapatinib has some activity in patients with progressive HER2-positive brain metastases after progression from radiation and trastuzumab; however, it is traditionally used along with capecitabine due to increased response rates (RR) of 21.4% for the combination compared to lapatinib alone with an RR of 7.2 %.[13,15]

Lapatinib with capecitabine is considered a treatment option for progressive brain metastasis (after trastuzumab and T-DM1 failure) and when local therapy has failed, or re-radiation is not feasible, especially when an oral systemic treatment option is preferred. More recently, the TKI neratinib was studied in a phase II trial among 40 patients with HER2-positive breast cancer with brain metastases who had progressed after at least one line of therapy. The intracranial response rates were modest at 8% with this agent.[12]

T-DM1 is an antibody-drug conjugate of trastuzumab and a cytotoxic agent, DM1.[22,23] In an exploratory analysis of the EMILIA trial, median overall survival (OS) with T-DM1 was significantly higher compared to lapatinib with capecitabine in those with brain metastases (26.8 months vs 12.9 months; P = .008).[23] In a subgroup analysis, the incidence of CNS progression was comparable with the lapatinib-capecitabine combination; however, T-DM1 patients had a longer OS.[23] In the randomized phase III TH3RESA trial, 602 patients with locally advanced or metastatic breast cancer, pretreated with at least 2 anti-HER2 agents, were randomized to either T-DM1 or physician’s choice. Crossover was allowed. This study demonstrated a significant improvement in the T-DM1 arm in terms of median progression-free survival (PFS) (6.2 months vs 3.3 months; stratified hazard ratio [HR], 0.53; 95% CI, 0.42–0.66) and median OS (22.7 months vs 15.8 months; HR, 0.68; 95% CI, 0.54–0.85).[24] Currently, we use this active agent for patients who progress after initial trastuzumab and taxane or following both trastuzumab and lapatinib/capecitabine regimens.

Triple-negative breast cancer (TNBC)

The backbone of therapy in this subset of triple-negative breast cancer (TNBC) is cytotoxic chemotherapy, as there are no targetable receptors. There is some evidence of CNS response with chemotherapy. Agents demonstrating efficacy include cisplatin-based regimens and single-agent capecitabine.[25,26] Rosner et al in 1986 described various regimens combining cyclophosphamide, methotrexate, anthracyclines, and fluorouracil for objective responses up to 50%.[27] Temozolomide, an oral alkylating agent, has shown activity in brain metastases arising from breast cancer in combination with other chemotherapy such as cisplatin, capecitabine, or etoposide.[25,28]

Although recent developments in the field have shown promising results, there is a need for new therapeutics with BBB penetration to improve CNS control. In Figure 2 and Figure 3, we outline our recommendations on systemic therapy for the various subgroups.

BRCA mutated breast cancer

BRCA mutations, particularly BRCA1, increase the likelihood of developing brain metastases. Up to 5% of patients with breast cancer harbor a germline BRCA mutation.[31] Poly (ADP-ribose) polymerase (PARP) inhibitors that disrupt DNA repair mechanisms have been developed as an effective therapy in germline BRCA-mutated breast cancers.[32] The OlympiAD and EMBRACA trials for PARP inhibition in patients with germline BRCA mutation demonstrated a significant survival advantage with olaparib and talazoparib, respectively. Olaparib was studied in first or second progression, compared with standard therapy. Median PFS benefit was 2.8 months with a decrease of 42% in disease progression and a more favorable safety profile.[33] Similarly, talazoparib was shown to have a 3-month PFS benefit compared to standard therapy.[34] Another indication for PARP inhibition in most malignancies includes a germline deficiency or somatic loss of function of genes responsible for DNA repair. Repair of both single-strand and double-strand DNA breaks can be blocked using PARP inhibitors, making them particularly useful in those with homologous recombination deficiency.

ER/PR expressing breast cancer

Randomized trials are lacking in this area and only low-level evidence exists in the form of case reports to support the activity of endocrine therapy in brain metastases. The overall incidence of brain metastasis in the hormone receptor (HR) positive subtype is much less frequent. Case report data suggest responses to tamoxifen[35] and aromatase inhibition[36]. Patients with HR positive brain metastases have shown significant responses to cytotoxic chemotherapy. Niwinska et al. demonstrated an improvement in the median survival ranging from 3-14 months with the addition of chemotherapy in luminal breast cancer subtypes.[37] Therapy selection for brain metastases arising from HR positive breast cancer emphasizes local control followed by systemic chemotherapy or in select cases endocrine therapy if extracranial disease is stable.

Focal treatment of brain metastases

Focal treatment including surgery, WBRT, and stereotactic radiosurgery (SRS) is indicated for the treatment of intracranial metastases across all intrinsic subtypes of breast cancer. However, the type of focal treatment strategy depends upon the extent of CNS disease and other disease- and patient-specific characteristics. An individualized approach is preferred, assimilating the above variables with clinical presentation. The approach to focal treatment of brain metastases in breast cancer is also based upon the intrinsic subtype of breast cancer and should be decided on a case-by-case basis. For example, salvage radiation is likely a first line-therapy among those with TNBC due to limited systemic options. However, a patient with HER2-positive disease may benefit from aforementioned systemic therapy options and may be able to forgo focal therapy.

Surgery

In the case of a solitary brain metastasis, preferred treatment options include surgical resection or SRS, although surgical resection may be limited by anatomic site. Neurosurgical resection is also helpful in relieving mass effect in patients with large symptomatic lesions. Due to the high risk of recurrence after surgery, typically postoperative SRS is offered.

WBRT

In recent years, the use of WBRT has decreased due to the development of less neurotoxic treatment options for focal disease. However, WBRT remains the therapy of choice in those with multiple metastases (typically > 4–5).

SRS

SRS is a noninvasive technique for local control of brain metastasis. The technique of SRS involves intersected beams to deliver a high dose of radiotherapy to a target volume in order to generate a significant local effect while sparing the surrounding normal tissue. It may be delivered in single or multiple fractions. There are no prospective studies comparing surgery with SRS for the treatment of limited brain metastases. SRS is typically performed for a limited number of lesions and is preferred over WBRT to avoid the adverse neurocognitive impact that can be seen after WBRT. SRS is typically used for a limited number of metastatic foci, usually 4 to 5 or fewer, and < 3 cm in largest diameter.[39] s a non-invasive technique for local control of brain metastasis. The technique of SRS involves intersected beams to deliver a high dose of radiotherapy to a target volume in order to generate a significant local effect while sparing the surrounding normal tissue. It may be delivered in single or multiple fractions. There are no prospective studies comparing surgery with SRS for the treatment of limited brain metastases. SRS is typically performed for a limited number of lesions and is preferred over WBRT to avoid the adverse neurocognitive impact that can be seen after WBRT. SRS is typically used for a limited number of metastatic foci, usually four to five or fewer, and < 3 cm in largest diameter.[39]

Prognosis

Development of brain metastases in breast cancer has a poor overall prognosis, with a median survival between 2 and 27 months without treatment.[3,40] In addition, they are often associated with neurocognitive deficits, functional decline, and impaired quality of life. Fortunately, recent advances in the management of brain metastases with systemic therapy have improved this prognosis, particularly for those with targetable mutations.

There are validated prognostic scoring systems for these patients. The most helpful and specific prognostication tool for breast cancer brain metastases is the diagnosis-specific graded prognostic assessment (GPA), which includes age, performance status, and breast cancer subtype. Median survival varies with GPA score, with a score of 0 to 1 predicting a survival of 3.4 months to a score of 3.5 to 4 predicting a median survival of as high as 25.3 months (Table 3).[41]

Ongoing trials and future prospects

Current trials include a focus on immunotherapy. From clinical trials in melanoma and lung cancer, we are aware that immunotherapy does have an impact on brain metastases. Hoping to unleash an abscopal effect using radiation in addition to immunotherapy, there are ongoing trials combining the two. Investigators are pursuing a phase II trial with the programmed death ligand 1 inhibitor atezolizumab in combination with SRS in TNBC with brain metastasis (NCT03483012). Another phase II clinical trial is evaluating neratinib with capecitabine in HER2-positive patients. Subsequently, another arm in this trial has been added to include neratinib plus T-DM1 (NCT01494662).

Some of the other noteworthy trials in HER2-positive disease include a phase II randomized controlled trial of a new oral HER2 inhibitor, tucatinib, in combination with trastuzumab and capecitabine (NCT02614794). Some other interesting future prospects include phosphoinositide 3-kinase/mammalian target of rapamycin (PI3K/mTOR) inhibitors and cyclin-dependent kinase (CDK) 4/6 inhibitors.[42]

Conclusion

Brain metastasis in breast cancer is a major cause of morbidity and mortality. Increasing evidence supports using an individualized treatment strategy in these patients due to disease heterogeneity. There are a large number of ongoing randomized trials evaluating targeted agents and most recently immunotherapy in the treatment of brain metastasis in breast cancer.

Financial Disclosures:The Authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

PERSPECTIVE

Internal server error