I am seeing a 55yo female with heavily pretreated, metastatic HER2+ breast cancer. She has received THP, TDM1, herceptin+lapatinib, herceptin+tucatinib+capecitabine, TDXd, and is currently on eribulin with herceptin (treatments in chronological order). She developed a solitary brain metastasis while on TDXd that was resected and she received radiation to the resection cavity. No current evidence of brain metastasis. She has been re-biopsied three times along the way, always showing ER0PR0HER2 3+ (most recently in the lungs when she progressed on TDXd). She has an excellent performance status ECOG=0 and no comorbid conditions. (1) what treatment would you recommend upon progression? (2) what role does further genetic testing play here ie: foundation? she has not had germline testing. (3) are there promising clinical trial options you would recommend pursuing?
You have clearly treated her with the appropriate and best therapies available. It would be interesting to see which regimens led to the longest PFS/TTP. In terms of standard therapy, I would consider margetuximab next mainly because it is a slightly different anti-HER2 molecule and seems to have benefit in the minority of patients who carry the homozygous V158 allele in CD16A which is the high affinity binding molecule. However, there is no commercial test available for this testing to my knowledge. Margetuximab or other trastuzumab like molecule would need to be paired with a chemo agent. In my experience, navelbine has been the best next agent to pair after taxanes, so I would use this next. I would go ahead and get a foundationone liquid biopsy to see if there is anything actionable rather than do another tissue biopsy at this point. neratinib has shown modest activity if there is an activating HER2 mutation which could be driving resistance. In terms of clinical trials, several ADCs are in varying stages of development and they would be the best bet. However, if the patient had a very short time on TDxd, would not think other ADCs would be necessarily better, but it is possible.
