clinical topic updates
The Role of Gene Expression Profiling in Breast Cancer Treatment Selection
Gene expression profiling is an emerging tool to help guide treatment decisions in patients with breast cancer. In particular, it has been used to predict which postmenopausal patients are likely to benefit from adjuvant chemotherapy.
Matthew P. Goetz, MD
Consultant and Erivan K. Haub Family Professorship in Cancer Research Honoring Richard F. Emslander, M.D.
" . . . there is a lot of interest in trying to identify the patients who can do well with endocrine therapy alone without the need for chemotherapy.”
The utility of gene expression profiles has been to identify those tumors that not only have a higher risk for recurrence but also would benefit from adjuvant chemotherapy. We know that the benefits of adjuvant endocrine therapy in hormone receptor–positive (HR+) breast cancer are substantial, whereas the benefits of chemotherapy in HR+ disease appear to be somewhat less. Additionally, there are the obvious toxicities associated with chemotherapy to consider. Thus, there has been great interest in trying to identify the patients who can do well with endocrine therapy alone without the need for chemotherapy.
The 21-gene recurrence score assay (ie, the Oncotype DX Breast Recurrence Score assay [Exact Sciences Corporation]) is known to be prognostic and also predictive of chemotherapy benefit. For example, based on the phase 3 TAILORx study in HR+/human epidermal growth factor receptor 2–negative (HER2-), node-negative breast cancer and the phase 3 RxPONDER trial in HR+/HER2-, node-positive disease, it is fairly clear that there is no adjuvant chemotherapy benefit in postmenopausal patients with low-to-intermediate recurrence scores.
However, the situation for premenopausal patients is not as clear. For example, in the RxPONDER trial among premenopausal women with 1 to 3 positive lymph nodes, those with a recurrence score of 25 or lower who received chemoendocrine therapy had fewer recurrences than those who received endocrine-only therapy. Furthermore, chemotherapy benefit did not differ according to recurrence score (0-10 and 11-24). There is some concern, however, that the benefit of chemotherapy in premenopausal patients enrolled in RxPONDER was likely larger than expected, as these individuals were not treated with optimal endocrine therapy (most were treated with tamoxifen monotherapy). For example, we now know that adding ovarian function suppression (OFS) to tamoxifen therapy improves disease-free survival and that an aromatase inhibitor plus OFS provide even greater benefit. So, there remains some controversy regarding the optimal management of premenopausal women with HR+/HER2- early-stage breast cancer. To provide guidance on this question, a prospective clinical trial (NRG-BR009) is planned that will randomize premenopausal patients with HR+/HER2- breast cancer with low-to-intermediate recurrence scores to either chemotherapy followed by endocrine therapy or to endocrine therapy alone. In this study, all women will receive an aromatase inhibitor plus OFS.
Similar findings have been reported with another commonly used gene expression profile, the 70-gene signature MammaPrint [Agendia]). This profile has also been shown to be prognostic and can identify genomically low-risk postmenopausal patients who likely do not benefit from chemotherapy. However, the same issue regarding menopausal status was observed with this assay, wherein genomically low-risk premenopausal patients in the MINDACT trial still appeared to derive some benefit from adjuvant chemotherapy.
Braun M, Kriegmair A, Szeterlak N, et al. Validation of the 21-gene recurrence score assay in patients with hormone receptor–positive, HER2-negative breast cancer and 0 to 3 positive lymph nodes: risk pattern and outcomes on a community level. Breast Care (Basel). 2022;17(3):288-295. doi:10.1159/000521096
Davey MG, Kerin MJ. Using menopause status and 21-gene expression assay to inform chemotherapy benefit in node-positive breast cancer. Breast Cancer Res Treat. 2022;195(1):83-84. doi:10.1007/s10549-022-06671-8
Kalinsky K, Barlow WE, Gralow JR, et al. 21-gene assay to inform chemotherapy benefit in node-positive breast cancer. N Engl J Med. 2021;385(25):2336-2347. doi:10.1056/NEJMoa2108873
Mamounas T. Report from the Breast Cancer Working Group meeting. Session presented at: NRG Oncology Summer Meeting; July 21-23, 2022; Chicago, IL.
Markopoulos C, Hyams DM, Gomez HL, et al. Multigene assays in early breast cancer: insights from recent phase 3 studies. Eur J Surg Oncol. 2020;46(4 Pt A):656-666. doi:10.1016/j.ejso.2019.10.019
Nitz U, Gluz O, Clemens M, et al; West German Study Group PlanB Investigators. West German Study PlanB trial: adjuvant four cycles of epirubicin and cyclophosphamide plus docetaxel versus six cycles of docetaxel and cyclophosphamide in HER2-negative early breast cancer. J Clin Oncol. 2019;37(10):799-808. doi:10.1200/JCO.18.00028
Piccart M, van 't Veer LJ, Poncet C, et al. 70-gene signature as an aid for treatment decisions in early breast cancer: updated results of the phase 3 randomised MINDACT trial with an exploratory analysis by age. Lancet Oncol. 2021;22(4):476-488. doi:10.1016/S1470-2045(21)00007-3
Sparano JA, Gray RJ, Makower DF, et al. Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer. N Engl J Med. 2018;379(2):111-121. doi:10.1056/NEJMoa1804710
Speers CW, Symmans WF, Barlow WE, et al. Evaluation of the sensitivity to endocrine therapy index and 21-gene breast recurrence score in the SWOG S8814 trial. J Clin Oncol. 2023;41(10):1841-1848. doi:10.1200/JCO.22.01499
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