clinical topic updates
The Importance of Next-Generation Sequencing in Guiding Therapy Selection
Our understanding of the genetic and molecular alterations associated with hormone receptor–positive (HR+)/human epidermal growth factor receptor 2–negative (HER2-) breast cancer is improving. Next-generation sequencing (NGS) may help shed light on mechanisms of treatment resistance.
Matthew P. Goetz, MD
Consultant and Erivan K. Haub Family Professorship in Cancer Research Honoring Richard F. Emslander, M.D.
"In patients who are treated with aromatase inhibitors, acquired ESR1 mutations drive endocrine resistance and are a focal point for research into new approaches to hormone therapy.”
NGS has become a standard approach for the management of HR+/HER2- metastatic breast cancer (MBC). Approximately 30% to 40% of these patients exhibit a PIK3CA mutation. These tend to be truncal mutations, meaning that they are present from the start of the tumor's development. Additional mutations that are targetable include BRCA/PALB2 mutations (poly [ADP-ribose] polymerase inhibitors) and ESR1 mutations (elacestrant).
For patients with newly diagnosed estrogen receptor–positive (ER+)/HER2- MBC who are eligible to begin therapy with a CDK4/6 inhibitor and in whom a large survival benefit has been observed with ribociclib, a common question is: Should the presence or absence of a germline or somatic alteration alter the recommendation away from a CDK4/6 inhibitor in favor of a targeted approach such as alpelisib for PIK3CA-mutated disease or olaparib for BRCA-mutated disease? The answer is that there are no data suggesting that we should be substituting these targeted approaches for a CDK4/6 inhibitor. However, a critical question is determining whether we can identify biomarkers for patients at risk for primary endocrine resistance. For these individuals, targeted approaches against PI3K/AKT/mTOR and/or BRCA mutations may lead to better outcomes compared with those associated with CDK4/6 inhibitor therapy.
For patients with a PIK3CA mutation, alpelisib, a selective inhibitor of PI3Kα, was tested in the phase 3 SOLAR-1 study and following a CDK4/6 inhibitor in the phase 2 BYLieve trial. In the SOLAR-1 trial, patients with PIK3CA-mutated, HR+/HER2- advanced breast cancer that had progressed during or after treatment with endocrine therapy exhibited significantly longer progression-free survival (PFS) when they received alpelisib plus fulvestrant compared with placebo plus fulvestrant, with researchers reporting an estimated 35% lower risk of progression or death. In the BYLieve trial, the median PFS was 7.3 months.
In the phase 3 CAPItello-291 trial, patients with endocrine-resistant ER+/HER2- breast cancer who had progressed on endocrine therapy were randomized to capivasertib, a pan-AKT inhibitor, plus fulvestrant vs fulvestrant alone. In this study, there were dual end points (ie, PFS overall and in the AKT-altered cohort). Capivasertib plus fulvestrant significantly improved PFS compared with fulvestrant alone, both overall and in the AKT-altered subset (PIK3CA, PTEN loss, or AKT mutations). Importantly, prior CDK4/6 inhibitor therapy was a stratification factor, and the benefit was seen in all subgroups, including those on prior CDK4/6 inhibitors.
In patients who are treated with aromatase inhibitors, acquired ESR1 mutations drive endocrine resistance and are a focal point for research into new approaches to hormone therapy. The recently US Food and Drug Administration–approved selective estrogen receptor degrader (SERD) elacestrant improved PFS compared with fulvestrant in patients with MBC with prior progression on a CDK4/6 inhibitor and an ESR1 mutation. Other SERDs, such as camizestrant, imlunestrant, giredestrant, and ARV-471, as well as the selective estrogen receptor modulator (SERM) lasofoxifene, have demonstrated preliminary evidence of antitumor activity in this same setting. Ongoing studies will be evaluating these novel SERDs and SERMs in combination with CDK4/6 inhibitors and other targeted approaches.
Finally, NGS may also identify a variety of rare mutations, such as NTRK translocations. Moreover, tumor mutation burden identified by NGS may allow patients with HR+ breast cancer to be eligible for the drug pembrolizumab.
Alves CL, Ditzel HJ. Drugging the PI3K/AKT/mTOR pathway in ER+ breast cancer. Int J Mol Sci. 2023;24(5):4522. doi:10.3390/ijms24054522
André F, Ciruelos E, Rubovszky G, et al; SOLAR-1 Study Group. Alpelisib for PIK3CA-mutated, hormone receptor-positive advanced breast cancer. N Engl J Med. 2019;380(20):1929-1940. doi:10.1056/NEJMoa1813904
Bidard F-C, Kaklamani VG, Neven P, et al. Elacestrant (oral selective estrogen receptor degrader) versus standard endocrine therapy for estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: results from the randomized phase III EMERALD trial. J Clin Oncol. 2022;40(28):3246-3256. doi:10.1200/JCO.22.00338
Bruzas S, Kuemmel S, Harrach H, et al. Next-generation sequencing-directed therapy in patients with metastatic breast cancer in routine clinical practice. Cancers (Basel). 2021;13(18):4564. doi:10.3390/cancers13184564
Damodaran S, Plourde PV, Moore HCF, Churchill Anderson I, Portman DJ. Open-label, phase 2, multicenter study of lasofoxifene (LAS) combined with abemaciclib (Abema) for treating pre- and postmenopausal women with locally advanced or metastatic ER+/HER2− breast cancer and an ESR1mutation after progression on prior therapies. J Clin Oncol. 2022;40(suppl 16):1022. doi:10.1200/JCO.2022.40.16_suppl.1022
Emens LA, Adams S, Cimino-Mathews A, et al. Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of breast cancer [published correction appears in J Immunother Cancer. 2021;9(12):e002597corr1]. J Immunother Cancer. 2021;9(8):e002597. doi:10.1136/jitc-2021-002597
Goetz MP, Plourde P, Stover DG, et al. LBA20 Open-label, randomized study of lasofoxifene (LAS) vs fulvestrant (Fulv) for women with locally advanced/metastatic ER+/HER2- breast cancer (mBC), an estrogen receptor 1 (ESR1) mutation, and disease progression on aromatase (AI) and cyclin-dependent kinase 4/6 (CDK4/6i) inhibitors. Ann Oncol. 2022;33(suppl 7):S1387-S1388. doi:10.1016/j.annonc.2022.08.015
Kakati RT, Kim H, Whitman A, Spanheimer PM. High expression of the RET receptor tyrosine kinase and its ligand GDNF identifies a high-risk subset of estrogen receptor positive breast cancer. Breast Cancer Res Treat. 2023 Apr 15. doi:10.1007/s10549-023-06937-9
Nourieh M, Vibert R, Saint-Ghislain M, Cyrta J, Vincent-Salomon A. Next-generation sequencing in breast pathology: real impact on routine practice over a decade since its introduction. Histopathology. 2023;82(1):162-169. doi:10.1111/his.14794
Rugo HS, Lerebours F, Ciruelos E, et al. Alpelisib plus fulvestrant in PIK3CA-mutated, hormone receptor-positive advanced breast cancer after a CDK4/6 inhibitor (BYLieve): one cohort of a phase 2, multicentre, open-label, non-comparative study [published correction appears in Lancet Oncol. 2021;22(5):e184]. Lancet Oncol. 2021;22(4):489-498. doi:10.1016/S1470-2045(21)00034-6
Servetto A, Napolitano F, De Angelis C, et al. A review of the use of next generation sequencing methodologies to identify biomarkers of resistance to CDK4/6 inhibitors in ER+/HER2- breast cancer. Crit Rev Oncol Hematol. 2021;157:103191. doi:10.1016/j.critrevonc.2020.103191
Shastry M, Hamilton E. Novel estrogen receptor-targeted agents for breast cancer. Curr Treat Options Oncol. 2023 May 2. doi:10.1007/s11864-023-01079-y
Sturgill EG, Misch A, Lachs R, et al. Next-generation sequencing of patients with breast cancer in community oncology clinics. JCO Precis Oncol. 2021;5:1297-1311. doi:10.1200/PO.20.00469
Tung NM, Robson ME, Ventz S, et al. TBCRC 048: phase II study of olaparib for metastatic breast cancer and mutations in homologous recombination-related genes. J Clin Oncol. 2020;38(36):4274-4282. doi:10.1200/JCO.20.02151
Turner N, Oliveira M, Howell SJ, et al. Capivasertib and fulvestrant for patients with aromatase inhibitor-resistant hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer: results from the phase III CAPItello-291 trial [abstract GS3-04]. Abstract presented at: 2022 San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX.
Turner S, Chia S, Kanakamedala H, et al. Effectiveness of alpelisib + fulvestrant compared with real-world standard treatment among patients with HR+, HER2-, PIK3CA-mutated breast cancer. Oncologist. 2021;26(7):e1133-e1142. doi:10.1002/onco.13804