DNA mutations in tumors are sometimes known as driver mutations and when they alter proteins the encode can impart a cancer-like characteristic such as an accelerated growth rate, ability to invade and spread or resistance to cancer drug therapies.
Many of these mutations, known to be present in certain tumors at the time of diagnosis, are termed truncal mutations, whereas others can be acquired over time — especially those that result in resistance to the drug the patient is taking. Drugs targeting the estrogen receptor (ER) have been a staple of the treatment of ER-positive breast cancer, which make up about 75% of all cases.
Because estrogen can induce production of growth factors that spur tumor cell proliferation, ER overexpression is one of the shortest pathways to developing breast cancer.
Once these cancers are established, they are dependent on ER, so treatments that lower estrogen levels, such as aromatase inhibitors, are often effective initially. But cancer cells have a high mutation rate, so mutations that happen to be in the ESR1 gene and that allow ER to be activated in the absence of estrogen, so those cells continue to divide, taking over the tumor cell populations.
ESR1 mutations are rarely present in untreated breast cancers (less than 1%), but after exposure to aromatase inhibitors, resistant tumors that progress and exhibit an ESR1 mutation becomes present in 40% of cases. The discovery of ESR1 mutations allowed scientists to develop a new class of drugs called oral selective estrogen receptor degraders (SERDs), some of which have been shown to be very effective against cancers harboring these alterations.
The first randomized trial completed compared a SERD known as Orserdu (elacestrant) to Faslodex (fulvestrant), an older SERD given by injection, and Orserdu was found to significantly improve progressionfree survival, particularly in cases with ESR1 mutations. As a result of these data, the drug was approved by the Food and Drug Administration on Jan. 27, 2023, specifically in the presence of this mutation after progression on endocrine therapy.
This augurs in a new era for treating refractory hormonally driven breast cancer. Even newer ER-degrading drugs such as PROTACS (proteolysis targeting chimeras) are in early phases of testing and will offer an array of options that have fewer side effects than chemotherapy, which has been the long-standing option after resistance to hormonal therapies. There are many other examples of acquired mutations to cancer therapies involving other cancer-driving genes through a variety of mechanisms and this is facilitating the development of many new strategies that will continue to change the landscape of targeted therapeutics.
DEBU TRIPATHY, M.D.
EDITOR-IN-CHIEF
Professor of Medicine Chair, Department of Breast Medical Oncology
The University of Texas MD Anderson Cancer Center
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