How would you approach a post-menopausal female with both a previously HR+ HER2- breast cancer and HR- HER2+ breast cancer with new brain metastasis?

The treatment of brain metastasis from breast cancer depends on a number of factors:  number of metastases, biology of the cancer, status of extracranial disease, and performance status.  From the question, it sounds like her performance status is good and she does not have progressive extracranial disease, so I will limit the discussion to this case.

For someone with a small number of brain metastases, stereotactic radiosurgery or surgery followed by stereotactic radiosurgery to the resection bed and residual sites of disease is preferable.  I use surgery when there are symptoms or impending symptoms from a large metastasis, when I need confirmation of the diagnosis, such as the first presentation of metastatic disease, or when I need tissue for molecular characterization.  In this case, the original cancer and the axillary recurrences have different biologies for both ER and HER2.  It would be useful to know which is in the brain, so surgery is appropriate, if it can be done safely.  

There is no survival benefit to whole brain radiation after surgery or SRS, as shown by EORTC 22952-26001 and subsequent trials.  The number of lesions that can be safely treated with SRS is an area of ongoing research and seems to rise every year, but depends greatly on the comfort of the local radiation oncologist.

Systemic therapy can play a role when there is a brain penetrant agent of high efficacy.  If the brain disease is truly ER-negative/HER2-positive, then capecitabine with laptinib or neratinib has a RR of 50-65% depending on whether there has been prior radiation, but the responses are often not durable, with PFS medians of less than 6 months in the relevant phase 2 trials.  Similarly, ado-trastuzumab has a response rate in the brain of ~25% with about a 30% stable disease rate, though the durability is less clear due to a lack of high quality prospective trials.  Thus, I reserve all of these options for when SRS is no longer an option.

Thus, for this patient with what sounds like a small number of brain metastases and no systemic disease, I would favor removing one to confirm the biology and then treating all lesions with SRS.  I would then defer systemic treatment for later relapses.