Breast cells have hormone receptors for estrogen and progesterone. When these hormones bind to the receptors, it signals to the cells to grow. Breast cancer cells may have hormone receptors (denoted as “positive”) or not have hormone receptors (denoted as “negative”). When a breast tumor is hormone receptor-positive, the hormones in the body fuel the growth of the cancer.[1] Hormone therapy is used for hormone receptor-positive breast cancers to stop the hormones from binding to the receptors. The main types of hormone therapies are selective estrogen receptor modulators (SERMs), selective estrogen receptor degraders (SERDs), and aromatase inhibitors (AIs).[2] Additional targeted therapies such as CDK4/6 inhibitors, PI3K inhibitors, and mTOR inhibitors can make hormone therapy more effective.[3]

Cyclin-dependent kinases (CDKs) are proteins that promote cell division. CDK4/6 inhibitors block these proteins (CDK4 and CDK6 specifically), stopping cancer cells from dividing. Phosphoinositide 3-kinases (PI3Ks) are a family of proteins that promote cell growth.4 PI3K inhibitors block these proteins, stopping the growth of cancer cells. Mammalian target of rapamycin (mTOR) is a protein that promotes cell proliferation.5 mTOR inhibitors block these proteins, stopping the proliferation of cancer cells.[3] Some targeted therapies for hormone receptor positive breast cancer are:

CDK4/6 inhibitors are used to treat advanced breast cancer that is hormone receptor-positive and HER2-negative.3 HER2 (human epidermal growth factor receptor 2), a protein encoded by the HER2 gene, promotes growth; therefore, breast cancers with an excess of this protein tend to grow and spread quickly. However, HER2-negative breast cancers cannot be treated with HER2-targeted therapies[MB1].[6] Palbociclib, ribociclib, and abemaciclib are taken orally, usually once or twice a day. These three drugs can be used with AIs or SERDs (fulvestrant) for postmenopausal women. For premenopausal or perimenopausal women, palbociclib, ribociclib, and abemaciclib can be used with AIs or fulvestrant, but ovarian suppression [MB2] must be done as well. Abemaciclib may also be used by itself in women who have already been treated with hormone therapy and chemotherapy.[3]

Alpelisib, which is taken orally once a day, can be used with fulvestrant to treat advanced breast cancer that is hormone receptor-positive and HER2-negative in postmenopausal women with a PIK3CA mutation. It is often used if a woman’s cancer grew during or shortly after being treated with an AI.3 About 30-40% of breast cancers have a mutated PIK3CA gene.[3] The PIK3CA gene contains the instructions for making the protein p110α. This protein promotes cell growth and division.[7] Alpelisib targets this mutation to stop cancer cells from growing and dividing.3 Breast cancers with a PIK3CA mutation tend to not respond as well to hormone therapies, so PI3K inhibitors are useful for treating these cancers.[3,7] This mutation can be tested for by taking a sample of blood or breast tissue.[7]

Besides blocking mTOR proteins to stop cancer cell proliferation, everolimus can also stop tumors from producing new blood vessels, limiting their growth. Everolimus, which is taken orally once a day, is used to treat advanced breast cancer that is hormone receptor-positive and HER2-negative in postmenopausal women. It is used with the AI exemestane for women whose cancer grew during or shortly after taking the AIs letrozole or anastrozole.[3]

References

1.     Hormone Receptor Status https://www.breastcancer.org/symptoms/diagnosis/hormone_status (accessed Jun 15, 2021).

2.     Hormone Therapy for Breast Cancer https://www.cancer.org/cancer/breast-cancer/treatment/hormone-therapy-for-breast-cancer.html (accessed Jun 11, 2021).

3.     Targeted Drug Therapy for Breast Cancer https://www.cancer.org/cancer/breast-cancer/treatment/targeted-therapy-for-breast-cancer.html (accessed Jun 11, 2021).

4.     Madsen, R. R.; Vanhaesebroeck, B. Cracking the context-specific PI3K signaling code https://stke.sciencemag.org/content/13/613/eaay2940 (accessed Jun 14, 2021).

5.     Zou, Z.; Tao, T.; Li, H.; Zhu, X. mTOR signaling pathway and mTOR inhibitors in cancer: progress and challenges https://cellandbioscience.biomedcentral.com/articles/10.1186/s13578-020-00396-1 (accessed Jun 14, 2021).

6.     What are CDK4/6 Inhibitors? https://www.breastcancer.org/treatment/targeted_therapies/cdk46-inhibitors (accessed Jun 14, 2021).

7.     Doctor Discussion Guide: Tips for Discussing PIK3CA Mutation with Your Doctor https://www.healthline.com/health/metastatic-breast-cancer/doctor-discussion-guide-tips-for-discussing-pik3ca-mutation-with-your-doctor (accessed Jun 14, 2021).

 [MB1]Link to ‘HER2-targeted therapies’ article

 [MB2]More info on ovarian suppression in ‘hormone therapy’ article