Immunotherapy in Estrogen Receptor Positive (ER+) Breast Cancer
Current Technologies and Challenges Targeting ESR1 mutations
DOI:
https://doi.org/10.58445/rars.1984Keywords:
Immunotherapy, Breast Cancer, cancer mutationsAbstract
Metastatic breast cancer remains without a cure and ESR1 mutations have emerged as potential contributors in metastatic ER+ breast cancer. Immunotherapy harnesses the immune system to fight cancer and is utilized for various cancer types. However, the effectiveness and use of immunotherapy are limited when it comes to ER+ breast cancer. This subtype has been considered immunologically “cold,” meaning that the tumor is able to suppress the immune response and prevent T cells from attacking and killing tumor cells. Recent studies have shown a subset of ER+ metastatic breast cancer patients have an increased likelihood of response to immunotherapy often associated with the presence of common ESR1 mutations D538G, Y537S, and E380Q. Emerging data shows that these mutations confer a basal-like phenotype that is more similar to that of triple-negative breast cancer, a subtype more sensitive to immunotherapy, which indicates that the mutant ER cells may be responsive. ESR1 mutants have been shown to produce neoepitopes that are being explored as potential drug targets. This intersection of traits could suggest that ESR1 mutations may confer some sensitivity to traditional immunotherapy in some ER+ metastatic breast cancer. This review will consolidate the recent findings in the field of immunotherapeutic targeting, where the generation of ESR1 mutant neoepitopes for novel targeting and the phenotypic shift toward more basal-like traits combined with new understandings and technologies shine light on possibilities for the future.
References
Ahn, S.G., Bae, S.J., Kim, Y., Ji, J.H., Chu, C., Kim, D., Lee, J., Cha, Y.J., Lee, K.-A. and Jeong, J. (2022). Primary endocrine resistance of ER+ breast cancer with ESR1 mutations interrogated by droplet digital PCR. npj Breast Cancer, 8(1). doi:https://doi.org/10.1038/s41523-022-00424-y.
American Cancer Society (2022). CAR T-cell Therapy and its side effects. [online] www.cancer.org. Available at: https://www.cancer.org/cancer/managing-cancer/treatment-types/immunotherapy/car-t-cell1.html.
Bates, A.M., O’Leary, K.A., Emma, S., Nystuen, E., Sumiec, E.G., Schuler, L.A. and Morris, Z.S. (2020). Abstract 2255: Enhancing immunogenicity in immunologically cold ER+ breast cancer using estrogen receptor blockade and radiation therapy. Cancer Research, [online] 80(16_Supplement), pp.2255–2255. doi:https://doi.org/10.1158/1538-7445.am2020-2255.
Brett, J.O., Spring, L.M., Bardia, A. and Wander, S.A. (2021). ESR1 mutation as an emerging clinical biomarker in metastatic hormone receptor-positive breast cancer. Breast Cancer Research, 23(1). doi:https://doi.org/10.1186/s13058-021-01462-3.
Cancer Research UK (2021). Monoclonal antibodies (MABs) | Immunotherapy | Cancer Research UK. [online] www.cancerresearchuk.org. Available at: https://www.cancerresearchuk.org/about-cancer/treatment/immunotherapy/types/monoclonal-antibodies.
Cleveland Clinic (2020). Immunotherapy: Cancer Treatment, CAR T-Cell Therapy, Types, Risks. [online] Cleveland Clinic. Available at: https://my.clevelandclinic.org/health/treatments/11582-immunotherapy.
Cleveland Clinic (2023). Breast Cancer Recurrence: Symptoms & Treatment. [online] Cleveland Clinic. Available at: https://my.clevelandclinic.org/health/diseases/8328-breast-cancer-recurrence.
Cleveland Clinic (2024). What Is ER-Positive (ER+) Breast Cancer? [online] Cleveland Clinic. Available at: https://my.clevelandclinic.org/health/diseases/er-positive-breast-cancer.
Dailey, G.P., Rabiola, C.A., Lei, G., Wei, J., Yang, X.-Y., Wang, T., Liu, C.-X., Gajda, M., Hobeika, A.C., Summers, A., Marek, R.D., Morse, M.A., Lyerly, H.K., Crosby, E.J. and Hartman, Z.C. (2024). Vaccines targeting ESR1 activating mutations elicit anti-tumor immune responses and suppress estrogen signaling in therapy resistant ER+ breast cancer. Human Vaccines & Immunotherapeutics, [online] 20(1). doi:https://doi.org/10.1080/21645515.2024.2309693.
Dunn, G.P. (n.d.). Cancer Vaccines - Cancer Research Institute (CRI). [online] Cancer Research Institute. Available at: https://www.cancerresearch.org/treatment-types/cancer-vaccines.
Fanning, S.W., Mayne, C.G., Dharmarajan, V., Carlson, K.E., Martin, T.A., Novick, S.J., Toy, W., Green, B., Panchamukhi, S., Katzenellenbogen, B.S., Tajkhorshid, E., Griffin, P.R., Shen, Y., Chandarlapaty, S., Katzenellenbogen, J.A. and Greene, G.L. (2016). Estrogen receptor alpha somatic mutations Y537S and D538G confer breast cancer endocrine resistance by stabilizing the activating function-2 binding conformation. eLife, 5. doi:https://doi.org/10.7554/elife.12792.
Gatti-Mays, M.E., Balko, J.M., Gameiro, S.R., Bear, H.D., Prabhakaran, S., Fukui, J., Disis, M.L., Nanda, R., Gulley, J.L., Kalinsky, K., Abdul Sater, H., Sparano, J.A., Cescon, D., Page, D.B., McArthur, H., Adams, S. and Mittendorf, E.A. (2019). If we build it they will come: targeting the immune response to breast cancer. npj Breast Cancer, [online] 5(1), pp.1–13. doi:https://doi.org/10.1038/s41523-019-0133-7.
Goldberg, J., Qiao, N., Guerriero, J.L., Gross, B., Yagiz Meneksedag, Lu, Y.F., Philips, A.V., Rahman, T., Funda Meric-Bernstam, Roszik, J., Chen, K., Rinath Jeselsohn, Tolaney, S.M., Peoples, G.E., Gheath Alatrash and Mittendorf, E.A. (2024). Estrogen Receptor Mutations as Novel Targets for Immunotherapy in Metastatic Estrogen Receptor-Positive Breast Cancer. Cancer Research Communications, [online] 4(2), pp.496–504. doi:https://doi.org/10.1158/2767-9764.crc-23-0244.
Li, Z., McGinn, O., Wu, Y., Bahreini, A., Priedigkeit, N.M., Ding, K., Onkar, S., Lampenfeld, C., Sartorius, C.A., Miller, L., Rosenzweig, M., Cohen, O., Wagle, N., Richer, J.K., Muller, W.J., Buluwela, L., Ali, S., Bruno, T.C., Vignali, D.A.A. and Fang, Y. (2022). ESR1 mutant breast cancers show elevated basal cytokeratins and immune activation. Nature Communications, [online] 13(1), p.2011. doi:https://doi.org/10.1038/s41467-022-29498-9.
O’Leary, K.A., Bates, A.M., Won Jong Jin, Burkel, B.M., Sriramaneni, R.N., Emma, S.E., Nystuen, E.J., Sumiec, E.G., Ponik, S.M., Morris, Z.S. and Schuler, L.A. (2023). Estrogen receptor blockade and radiation therapy cooperate to enhance the response of immunologically cold ER+ breast cancer to immunotherapy. Breast Cancer Research, [online] 25(1). doi:https://doi.org/10.1186/s13058-023-01671-y.
Pennmedicine.org. (2023). Metastatic Breast Cancer. [online] Available at: https://www.pennmedicine.org/cancer/types-of-cancer/breast-cancer/types-of-breast-cancer/metastatic-breast-cancer#:~:text=Metastatic%20breast%20cancer%20is%20always.
Ross, D.S., Zehir, A., Brogi, E., Konno , F., Krystel-Whittemore, M., Edelweiss, M., Berger, M.F., Toy, W., Chandarlapaty , S., Razavi, P., Baselga, J. and Wen, H.Y. (2019). Immunohistochemical analysis of estrogen receptor in breast cancer with ESR1 mutations detected by hybrid capture-based next-generation sequencing. [online] ScienceDirect. Available at: https://doi.org/10.1038/s41379-018-0116-5.
Schettini, F., Barbao, P., Brasó-Maristany, F., Galván, P., Martínez, D., Paré, L., De Placido, S., Prat, A. and Guedan, S. (2021). Identification of cell surface targets for CAR-T cell therapies and antibody-drug conjugates in breast cancer. ESMO open, [online] 6(3), p.100102. doi:https://doi.org/10.1016/j.esmoop.2021.100102.
Shatsky, R.A. (n.d.). Immunotherapy for Breast Cancer. [online] Cancer Research Institute. Available at: https://www.cancerresearch.org/cancer-types/breast-cancer.
Turner, N.C., Swift, C., Kilburn, L., Fribbens, C., Beaney, M., Garcia-Murillas, I., Budzar, A.U., Robertson, J.F.R., Gradishar, W., Piccart, M., Schiavon, G., Bliss, J.M., Dowsett, M., Johnston, S.R.D. and Chia, S.K. (2020). ESR1 Mutations and Overall Survival on Fulvestrant versus Exemestane in Advanced Hormone Receptor–Positive Breast Cancer: A Combined Analysis of the Phase III SoFEA and EFECT Trials. Clinical Cancer Research, 26(19), pp.5172–5177. doi:https://doi.org/10.1158/1078-0432.ccr-20-0224.
Williams, M.M., Spoelstra, N.S., Arnesen, S., O’Neill, K.I., Christenson, J.L., Reese, J., Torkko, K.C., Goodspeed, A., Rosas, E., Hanamura, T., Sams, S.B., Li, Z., Oesterreich, S., Riggins, R.B., Jacobsen, B.M., Elias, A., Gertz, J. and Richer, J.K. (2021). Steroid Hormone Receptor and Infiltrating Immune Cell Status Reveals Therapeutic Vulnerabilities of ESR1-Mutant Breast Cancer. Cancer Research, 81(3), pp.732–746. doi:https://doi.org/10.1158/0008-5472.can-20-1200.
www.breastcancer.org. (n.d.). Learn About Breast Cancer Recurrence Risk. [online] Available at: https://www.breastcancer.org/treatment/planning/risk-of-recurrence.
Zundelevich, A., Dadiani, M., Kahana-Edwin, S., Itay, A., Sella, T., Gadot, M., Cesarkas, K., Farage-Barhom, S., Saar, E.G., Eyal, E., Kol, N., Pavlovski, A., Balint-Lahat, N., Dick-Necula, D., Barshack, I., Kaufman, B. and Gal-Yam, E.N. (2020). ESR1 mutations are frequent in newly diagnosed metastatic and loco-regional recurrence of endocrine-treated breast cancer and carry worse prognosis. Breast Cancer Research, 22(1). doi:https://doi.org/10.1186/s13058-020-1246-5.
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