What about tumor evolution, given the growing body of evidence that biomarker status in MBC can change over time?
Patients with MBC often have several active areas of cancer, and these areas will evolve differently. During each line of treatment, some metastases will develop resistance and others won’t. For instance, if my patient’s liver metastases start to grow, I will change therapy immediately. If, however, a single bone metastasis begins to grow and the liver metastases have responded well, I might consider local therapy — such as radiation — to target that bone metastasis, though this particular approach hasn’t been formally studied.
Ultimately, we can expect tumors to change over time as they become more biologically aggressive or resistant to current therapy. The most common biomarker change is probably loss of ER or PR expression, but the frequency of ER, PR, or HER2 biomarker changes is still not well understood.
Resistance mutations can also happen. When, for instance, activating mutations in ESR1 occur, the estrogen receptor becomes independent of estrogen and tumors then develop resistance to endocrine therapies. We see a similar problem arise in metastatic prostate cancer. With chronic testosterone deprivation, eventually the androgen receptor evolves to become independent of testosterone in a stage known as castrate-resistant prostate cancer.
Which biomarkers or combinations of biomarkers can be paired with an approved treatment?
We have a range of treatments targeting ER-positive and HER2-positive MBC in particular. For tumors harboring additional targetable mutations, preliminary data suggest that HER2-targeted tyrosine kinase inhibitors (TKIs), such as tucatinib and neratinib, are effective against activating mutations in ERBB2.
The PI3K inhibitor alpelisib in combination with fulvestrant has been approved for patients with ER-positive, HER2-negative MBC and mutations in PIK3CA. The mTOR inhibitor everolimus plus exemestane is an option for patients with ER-positive, HER2-negative. And for those with activating mutations in ESR1, I switch patients to a selective estrogen receptor degrader, such as fulvestrant.
PARP inhibitors, including olaparib or talazoparib, target metastatic HR-positive disease or TNBC with deleterious germline BRCA1 or BRCA2 mutations. Sacituzumab govitecan has been approved for treating metastatic TNBC and targets the cell surface protein TROP2, expressed in almost 90% of TNBC tumors.
What targets, on the other hand, are less informative for treatment choice?
When we order next-generation sequencing, we also will get a list of possible targets for which there are currently no therapeutic options, but there may be in the future. I find this knowledge is helpful. For example, an activating mutation in KRAS tells me that the cancer has a very strong oncogenic driver that I won›t be able to target. I know that activating KRAS mutations in lung cancer and colon cancer portend a poorer prognosis, which helps me to prepare the patient and family.
Atezolizumab in combination with paclitaxel has been FDA-approved for PD-L1 TNBC in the first-line setting, though data show that immune checkpoint inhibitors may be effective even without PD-L1 expression. Although cell surface protein TROP2 has emerged as a target in recent years, its expression is so common in TNBC that confirmatory testing for TROP2 expression is not required to prescribe sacituzumab govitecan.
What factors do you weigh when selecting among the large number of tests available for tumor testing?
We have many biomarker tests available, but the National Comprehensive Cancer Network does not have guidelines for tumor genetics testing in breast cancer. That means insurance does not have to cover the cost, and many companies don’t. Ultimately, though, drug companies and some testing companies have an incentive to cover the cost themselves because a companion diagnostic might be linked to their drug — therascreen PIK3CA RGQ PCR kit for alpelisib, for instance.