Resistance to fulvestrant commonly develops due to mutations in ESR1, the gene that encodes the ER protein. Until recently, fulvestrant was the only available FDA-approved treatment that worked by destroying ER. Therefore, patients whose tumors become resistant to it were left with limited treatment options. The FDA approval of elacestrant (Orserdu) in January 2023 brings new hope to these patients. Elacestrant, which also works by destroying the ER, was approved for postmenopausal women or adult men with ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer with disease progression following at least one line of endocrine therapy. Unlike fulvestrant, which is delivered through intramuscular injections, elacestrant is administered orally, making it more convenient for patients to receive the treatment. The approval was based on results from a phase III, randomized clinical trial showing that among patients with ESR1 mutations, those treated with elacestrant had a 45 percent lower risk of death or disease progression than those treated with other endocrine therapies (399). Personalizing Treatment for Patients with a Rare Solid Tumor Rare cancer is defined by the National Cancer Institute as cancer that occurs in fewer than 15 out of 100,000 people each year. Rare cancers can be challenging for researchers to study and for physicians to treat (see Sidebar 36, p. 90). During the 12 months covered by this report, August 1, 2022, to July 31, 2023, the FDA approved molecularly targeted therapeutics and immunotherapeutics for treating several rare cancers, bringing the promise of precision medicine to patients, such as Isabella (Bella) Snow Fraser, p. 110, and Alexis Browning, p. 112, who often have few treatment options. Bile duct cancer, also known as cholangiocarcinoma, is a rare but aggressive disease in which cancer arises from cells in the bile ducts. Cholangiocarcinoma is often diagnosed at an advanced stage. There are two types of bile duct cancer: intrahepatic, where cancer forms in the bile ducts inside the liver; and extrahepatic, where cancer forms in the bile ducts outside the liver. Less than 8,000 new cases of bile duct cancer are estimated to be diagnosed in the United States in 2023 and only a small number of bile duct cancers are intrahepatic (28). While rare, the incidence of intrahepatic cholangiocarcinoma is increasing worldwide (400). Surgery is the main curative treatment option for patients with intrahepatic cholangiocarcinoma. However, up to two thirds of patients have disease recurrence and patients with intrahepatic cholangiocarcinoma have a 5-year overall survival rate of less than eight percent (400). Alterations in fibroblast growth factor receptor 2 (FGFR2), a protein involved in many cellular processes including multiplication, migration, and survival, are associated with several cancers including bile duct cancers. Nearly 14 percent of patients with intrahepatic cholangiocarcinoma have fusions or rearrangements in the FGFR2 gene (see Sidebar 7, p. 30) (400). FDA had previously approved two molecularly targeted therapeutics, pemigatinib (Pemazyre) and infigratinib (Truseltiq), which block the function of FGFR2 proteins, for the treatment of patients with cholangiocarcinoma with confirmed FGFR2 fusions or rearrangements (389,401). While these agents are benefiting many patients with bile duct cancer, their efficacy has been somewhat limited due to the development of treatment resistance (400). The Challenge of Treatment Resistance Diversity, or heterogeneity, among cancer cells within and between tumors is a major cause of treatment resistance. Some examples of heterogeneity are as follows: Not all cells in a tumor may be rapidly dividing; those that are not, are insensitive to treatments targeting rapidly dividing cells such as cytotoxic chemotherapeutics. Some cancer cells in a tumor may have or may acquire mutations in the target of a given treatment that render the treatment ineffective in those cells and their progeny. Some cancer cells in a tumor may have or may acquire molecular or cellular differences other than changes in the treatment target that render the treatment ineffective. Redundancies among signaling pathways fueling proliferation can enable cancer cells to become resistant to a treatment even if one of the pathways is effectively blocked. Differences in tumor microenvironment components can render a treatment ineffective. Adapted from (67). SIDEBAR 35 continued on page 90 Advancing the Frontiers of Cancer Science and Medicine AACR Cancer Progress Report 2023 87
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