In a patient with de novo stage IV breast carcinoma harboring an RB1 Q395* (nonsense) mutation, would treatment with a CDK4/6 inhibitor be appropriate, or should it be avoided due to likely resistance?

HR+/HER2- with baseline RB1Q395* nonsense mutation.

This is one of those incredibly tough, "data-free zone" scenarios where standard guidelines fail us, and we have to rely heavily on clinical judgment and the underlying biology. In a de novo metastatic setting, our reflex is always to reach for a C...

Thank you for bringing up this question. As I outlined below, it makes sense based on the evidence available that CDK4/6 inhibitors are less effective or ineffective in patients with tumors harboring Rb LOF mutations. There is, however, little guidance from clinical trials or guidelines to lead us t...

Excellent question. We generally think of Rb-mutated tumors as resistant to CDK46i. However, breast cancer is a heterogeneous disease in the metastatic setting, and it may be worth a brief trial if the disease is not too bulky or the progression too rapid.

First line therapy is usually the longest therapy. CDK 4/6 inhibitors increase treatment toxicity and are quite expensive. As the SONIA trial suggests there is no overall survival advantage of upfront versus second line CDKi therapy, and given that the value of a CDKi in this patient is questionable...

My understanding of RB mutations is that they are rare and occur with prior exposure to CDK4/6 inhibitors. Therefore, testing with biomarkers (i.e., liquid biopsy) is vital to identify these mutations. Thankfully, these mutations may not routinely influence our therapy as many of us switch therapy t...