Targeted therapies in HER2 negative breast cancer
Missed the other parts?
Part 1: An introduction to the different subtypes of breast cancer can be found here.
Part 2: Targeted therapies in HER2 positive breast cancer can be found here.
Part 4: Targeted therapies in triple negative breast cancer can be found here.
HER2 negative breast cancer is harder to treat than HER2 positive cancer and there are fewer approved therapies. Endocrine therapy might be suitable for patients with HR-positive, HER2-negative metastatic BC [Ref 1], but endocrine agents have also now been studied in combination with inhibitors of cyclin-dependent kinases (CDK) 4 and 6. DNA damage repair targeting therapies such as olaparib and talazoparib, both PARP inhibitors, also show great promise in treating HER2 negative breast cancers for patients who present inactivating mutations in the BRCA1/2 genes.
Pfizer’s Ibrance (palbociclib) was first approved in 2015. This oral drug targets a protein in breast cancer cells called CDK4/6, which may stimulate cancer cell growth. Used along with the Aromatase inhibitor letrozole, the drug is an option for women who have been through menopause and have HR positive, HER2 negative metastatic breast cancer. Palbociclib can also be used with Faslodex (fulvestrant) if the cancer has worsened after receiving other hormonal therapy. Palbociclib generally has few side effects. It can lower the number of white blood cells. But it does not appear to increase the risk of serious infections that are linked to low numbers of white blood cells.
Kisqali (ribociclib) from Novatis was first approved in 2017. This oral drug also targets CDK4/6. Used with an aromatase inhibitor or Faslodex (fulvestrant), it is an option for women who have been through menopause and have ER positive, HER2 negative metastatic breast cancer. Side effects of ribociclib can include low numbers of white blood cells, increases in enzymes linked with liver damage, and changes in heart rhythms. In the phase III MONALEESA-2 trial, an analysis of overall survival with an additional 11 months of follow-up demonstrated a median PFS of 25.3 months for Kisqali plus letrozole and 16.0 months for letrozole and a placebo. According to Novartis, Kisqali has characteristics that make it distinct from other CDK4/6 inhibitors: in particular, Kisqali shows especially strong inhibition against CDK4. In pre-clinical data, Kisqali is four- to five-fold more potent against CDK4 compared to CDK6. CDK4 is likely the dominant CDK in breast cancer and a pivotal driver of disease progression, the company suggests.