Advancing precision oncology in breast cancer: the FDA approval of elacestrant and guardant 360CDx: a correspondence

Abstract

Highlights Breast cancer is the most frequently diagnosed and the second most common mortality-causing cancer among women worldwide. It is induced by the clonal proliferation of ductal epithelial cells with genetic abnormality caused either by exposure to hormones or inherited susceptibility genes. Over the years, treatment options have advanced and survival rates for breast cancer patients have improved significantly. Resistance to hormonal therapy triggered by the mutations in the estrogen receptor gene ligand-binding domain region (ESR1-LBD) poses a serious hindrance to a positive outcome in the treatment plan. ESR1-LBD mutations, although less common in primary tumors (0–3%), may have a high prevalence of up to 55% in metastatic endocrine therapy-resistant breast cancer lesions4. The resistance of ESR1-LBD mutated breast cancers to standard treatment by endocrine therapy is lethal as it leads to uncontrolled proliferation of the disease. Advancements should also be made to use biofluids other than blood, such as saliva, tears, and urine, in liquid biopsy to make this test as minimally invasive as possible. Ensuring the safety, accessibility, and affordability of the test should be the utmost priority. Large-scale research and clinical trials in this area should be called to establish clinical relevance as well as standardization to ensure consistent results. Breast cancer is the most frequently diagnosed and the second most common mortality-causing cancer among women worldwide1. It is induced by the clonal proliferation of ductal epithelial cells with genetic abnormality caused either by exposure to hormones or inherited susceptibility genes2. Over the years, treatment options have advanced, and survival rates for breast cancer patients have improved significantly. The specific treatment regimen may differ based on the type and stage of cancer, as well as the patient’s overall health and personal preferences. Surgery, radiation therapy, chemotherapy, and hormone therapy are all different treatments adopted for breast cancer. Targeted endocrine therapies (also called hormonal therapy), such as aromatase inhibitors and selective estrogen receptor (ER) modulators, are sanctioned as the standard treatment option3. However, resistance to hormonal therapy triggered by the mutations in the estrogen receptor gene ligand-binding domain region (ESR1-LBD) poses a serious hindrance to a positive outcome in the treatment plan. ESR1-LBD mutations, although less common in primary tumors (0–3%), may have a high prevalence of up to 55% in metastatic endocrine therapy-resistant breast cancer lesions4. The resistance of ESR1-LBD mutated breast cancers to standard treatment by endocrine therapy is lethal as it leads to uncontrolled proliferation of the disease. We write this correspondence to provide information on the latest advances in ESR1-LBD breast cancer treatment, including U.S. Food and Drug Administration (FDA)-approved therapies, and to provide recommendations to enhance their potential impact on the future of breast cancer treatment. To overcome the resistance offered by ESR1-LBD, selective estrogen receptor degraders (SERDs) were developed. To date, fulvestrant is the only FDA-approved SERD for the treatment of endocrine-resistant breast cancers5. However, its use was limited due to poor oral bioavailability, intramuscular administration, the need to administer clinically unachievable doses, and suboptimal receptor occupation6. These limitations influenced the development of a new generation of orally bioavailable non-steroidal SERDs. Elacestrant is a novel, oral SERD that demonstrated promising results. Phase III clinical trials have shown that elacestrant is the first oral SERD with the potential of significantly improving progression-free survival in patients with advanced ER+/HER2− breast cancer with ESR1 mutations as compared to the traditional hormone therapy. Elacestrant has not only shown significant activity against tumors resistant to hormone therapy but even displayed superiority over the prior FDA-approved SERD, fulvestrant7. As these pharmaceutical requirements are catered, the diagnostic limitations continue to loom. The orthodox tissue biopsy once considered the gold evaluation standard, has failed to live up to esteem considering its invasive nature, procedural costs, and risk factors, in addition to the deficit in detecting heterogeneity in metastatic patients. Liquid biopsies are gaining tremendous attention on account of their minimally invasive approach, wherein samples can be procured comfortably and repeatedly8. A recent advancement in this area is the Guardant360 CDx. It is a platform for the isolation and detection of circulating tumor DNA (ctDNA) specific to cancers. This blood-based liquid biopsy test is simple, noninvasive, feasible, and has a cost and time-effective character. Additionally, it offers comprehensive genetic profiling by detecting even a small amount of ctDNA from a blood sample. In recent years, it has been experimented to detect ctDNAs specific to breast cancers, provide longitudinal monitoring of ESR1 mutations, and exquisite susceptivity to genetic heterogeneity, encouraging an optimistic perspective for clinical utility9. Since being introduced, the Guardant360 CDx test has been widely employed for blood-based comprehensive genomic profiling of various conditions. However, recently, FDA, for the first time, approved it as a companion diagnostic for ER+/HER2− metastatic breast cancer with ESR1 mutation. FDA’s recent approval of the first-ever blood-based liquid biopsy by Guardant360 CDx for the diagnosis of breast cancer and elacestrant (SERD) for its treatment is promising10. This FDA approval presents as a beacon of hope for breast cancer patients with ESR1 mutations, who now, for the first time, have an approved treatment for their specific type of cancer accompanied by a blood-based companion diagnostic. Guardant360 CDx, although a breakthrough in the diagnosis of advanced breast cancer, has some limitations. Some studies suggest that chances of false results are overhanging due to varying amounts of ctDNA shed from a tumor into plasma and clonal hematopoiesis, etc. The use of technology and artificial intelligence should be considered to overcome these limitations and increase the sensitivity of the test. Advancements should also be made to use biofluids other than blood, such as saliva, tears, and urine, in liquid biopsy to make this test as minimally invasive as possible. Ensuring the safety, accessibility, and affordability of the test should be the utmost priority. Large-scale research and clinical trials in this area should be called to establish clinical relevance as well as standardization to ensure consistent results. Ethical approval and consent to participate Not applicable. Consent for publication Not applicable. Sources of funding None. Author contribution H.Q.A. and A.M.: conceptualization of ideas; H.Q.A. and A.M.: manuscript preparation; H.Q.A. and A.M.: writing of initial drafts; A.M.K. and S.S.: review and editing; M.O.O.: critical review and comments; A.M.K.: data curation. All authors approved the final manuscript – final draft. Conflicts of interest disclosure There are no conflicts of interest. Guarantor Polyne Nafula Wechuli, Jomo Kenyatta University of Agriculture and Technology, Kenya, E-mail: [email protected], Orcid: https://orcid.org/0000-0001-9478-3824. Data availability statement No new data were generated.

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