In summary, this is a 66-year-old woman with advanced breast cancer, and refractory brain metastases.

She was originally diagnosed with left-sided, early-stage breast cancer in 1993. The tumor was estrogen receptor negative and progesterone receptor negative, and received adjuvant CMF chemotherapy, radiation therapy, and tamoxifen. The tamoxifen was subsequently transitioned to raloxifene. In 2002, she had a right-sided breast cancer, and tumor testing showed that the cancer was ER, PR and HER2 negative. She underwent genetic testing and was found to harbor a deleterious BRCA1 mutation; she has undergone bilateral salpingo-oophorectomy. She received adjuvant AC chemotherapy, and had definitive local treatment with bilateral mastectomy.

In 2005, she had tumor recurrence in the right supraclavicular lymph nodes, and received docetaxel and capecitabine chemotherapy. In 2006, she developed overt metastatic disease with rising tumor markers and pleural nodules. She received cisplatin and vinorelbine chemotherapy. In September 2007, she developed central nervous system metastases with new brain lesions. She was treated with whole-brain irradiation. In January 2008, she developed progressive metastatic disease, with leptomeningeal carcinomatosis. She began capecitabine and temozolamide chemotherapy.

Unfortunately, records now indicate that she has progressive neurological symptoms, and has been placed on corticosteroids as palliative therapy. Additional studies on the tumor have confirmed that it is negative for ER, PR and HER2, and that there is no amplification of the EGFR gene.

Review of her brain imaging from January and March 2008 by Mass. General Hospital suggests multiple hemorrhagic metastatic lesions in the brain. Treatment of breast cancer that has metastasized to the brain is very unsatisfactory.

The experience described here is all too familiar, with patients having modest or minimal cancer burdens outside of the brain, but afflicted by cancer within the central nervous system. Most chemotherapy drugs do not penetrate well into the brain. A recent review by Lin and Winer (Journal of Clinical Oncology, Vol 22, No 17 (September 1), 2004: pp. 3608-3617; available at: lists agents with potential activity within the CNS. These include: 5-fluorouracil, cyclosphosphamide, anthracyclines, platinum salts, and Temozolomide. The patient has had all these classes of chemotherapy already. Chemotherapy drugs such as irinotecan or etoposide may have activity in brain metastases from breast cancer, though the benefits in patients who have had as much treatment as this one are undocumented. It is likely though not certain that the tumor is resistant to many of these agents.

Should the patient be offered additional chemotherapy, it would be her 6th line of treatment, at least. The likelihood of a dramatic clinical response under such circumstances is low. It has been 6 years since the patient had cyclophosphamide or doxorubicin. These agents could be tried again if the patient and medical team thought that more chemotherapy would be warranted. As mentioned, I suspect that the likelihood of major improvement with that treatment would be low. Dexamethasone is a potent steroid, capable of reducing inflammation caused by brain metastases. It often reduces headache and other neurological symptoms. It is a widely used, standard treatment for patients with refractory brain metastases.

The patient has had whole brain irradiation. The notes do not suggest that the current tumor burden would easily be treated with stereotactic radiosurgery. However, if the neuron-oncology team believes that there was a single, dominant CNS mass causing symptoms, then consideration of palliative focal radiation therapy might be of some benefit.

Lapatinib has been studied in patients with brain metastases and with tumors that are HER2 overexpressing. Lapatinib targets the EGFR and the HER2 growth factor receptors. In our clinical trial experience treating 39 patients with HER2+ metastatic breast cancer and brain metastases, there was one response (response rate: 2.5%; Lin, et al. J Clin Oncol 2008, in press). To date, there are no compelling data that lapatinib has activity in HER2 negative breast cancer. Thus, I would not anticipate that lapatinib would have any clinical benefit.

Many sites are beginning clinical trials for brain metastases. However, the patient would not be eligible for the studies that I am currently aware of, owing to the extent of her prior treatments.

The patient inquires about the Klinik St. George in Germany. I have no direct familiarity with this clinic. I did an internet search and reviewed comments on this clinic. They are offered radio-frequency and hyperthermia based treatments, among a variety of other “natural” treatments for cancer. I am not aware of any meaningful data that such treatments would help this patient.

Specific recommendations :

1. Consideration of possible additional chemotherapy, with recognition of likely modest benefits, at best.
2. Consideration of stereotactice radiosurgery if the brain MRI suggests it would be feasible and helpful.
3, Continuation of dexamethasone and palliative care services.


Electronically signed
Harold Burstein, MD