Preoperative Hormone Therapy in the Treatment of Breast Cancer: What Do We Know So Far?

Breast cancer is the most common malignant disease in the world. One of the methods of treating breast cancer is neoadjuvant chemotherapy. Neoadjuvant chemotherapy (NCT) is now the standard of care for locally advanced breast cancer. Patients with HER2-positive and triple-negative breast cancer subtypes benefi t the most from NCT, with a 50–60 % chance of achieving pCR, while patients with hormone-sensitive, HER2-negative breast cancer subtypes have an average chance of achieving pCR of 10–20 %. For patients with locally advanced, hormone-sensitive Her2neu-negative breast cancer, neoadjuvant hormone therapy contributes to a tumor downstaging and an increasing rate of organ-preserving surgery. However, neoadjuvant hormone therapy is still not used routinely. There are a limited number of clinical guidelines that describe the choice of the optimal drugs, the optimal duration of hormone therapy and the criteria for selecting patients for preoperative hormone therapy. This is the first literature review in Russia that includes a systematization of the evidence regarding the effectiveness of neoadjuvant hormone therapy, a comparison of hormone therapy with neoadjuvant chemotherapy, comparison of hormonal drug groups, optimal duration of hormone therapy, attempts to combine hormone therapy with drugs of the group of selective CDK4/6 cyclin-dependent kinase inhibitors and phosphatidylinositol 3-kinase inhibitors for women with locally advanced hormone-sensitive Her2neu-negative breast cancer. The possibilities of using modern commercial multigene panels to assess the feasibility of identifying the cohort of patients for whom neoadjuvant hormone therapy would be most effective are also considered.

1. Sung H., Ferlay J., Siegel R.L., Laversanne M., Soerjomataram I., Jemal A., et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71(3):209–49. DOI: 10.3322/caac.21660

2. Australian Institute of Health and Welfare 2019. Cancer in Australia 2019. Cancer series no.119. Cat. no. CAN 123. Canberra: AIHW; 2019.

3. Puglisi F., Follador A., Minisini A.M., Cardellino G.G., Russo S., Andreetta C., et al. Baseline staging tests after a new diagnosis of breast cancer: Further evidence of their limited indications. Ann. Oncol. 2005;16:263–6. DOI: 10.1093/annonc/mdi063

4. Liedtke C., Mazouni C., Hess K.R., André F., Tordai A., Mejia J.A., et al. Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. J. Clin. Oncol. 2008;26:1275–81. DOI: 10.1200/JCO.2007.14.4147

5. Cortazar P., Zhang L., Untch M., Mehta K., Costantino J.P., Wolmark N., et al. Pathological complete response and long-term clinical benefit in breast cancer: The CTNeoBC pooled analysis. Lancet. 2014;384:164–72. DOI: 10.1016/S0140-6736(13)62422-8

6. Gianni L., Pienkowski T., Im Y.-H., Roman L., Tseng L.-M., Liu M.-C., et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): A randomised multicentre, open-label, phase 2 trial. Lancet Oncol. 2012;13:25–32. DOI: 10.1016/S1470-2045(11)70336-9

7. Korde L.A., Somerfield M.R., Carey L.A., Crews J.R., Denduluri N., Hwang E.S., et al. Neoadjuvant chemotherapy, endocrine therapy, and targeted therapy for breast cancer: ASCO Guideline. J Clin Oncol. 2021;39(13):1485–505. DOI: 10.1200/JCO.20.03399

8. van Ramshorst M.S., van der Voort A., van Werkhoven E.D., Mandjes I.A., Kemper I., Dezentjé V.O., et al. Neoadjuvant chemotherapy with or without anthracyclines in the presence of dual HER2 blockade for HER2-positive breast cancer (TRAIN-2): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2018;19(12):1630–40. DOI: 10.1016/S1470-2045(18)30570-9

9. Zhang D., Lu W., Zhuo Z., Mei H., Wu X., Cui Y. Construction of a breast cancer prognosis model based on alternative splicing and immune infiltration. Discov Oncol. 2022;13(1):78. DOI: 10.1007/s12672-022-00506-0

10. Fujii T., Kogawa T., Dong W., Sahin A.A., Moulder S., Litton J.K., et al. Revisiting the definition of estrogen receptor positivity in HER2-negative primary breast cancer. Ann Oncol. 2017;28(10):2420–8. DOI: 10.1093/annonc/mdx397

11. Schneeweiss A., Chia S., Hickish T., Harvey V., Eniu A., Hegg R., et al. Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: A randomized phase II cardiac safety study (TRYPHAENA) Ann. Oncol. 2013;24:2278–84. DOI: 10.1093/annonc/mdt182

12. Sikov W.M., Berry D.A., Perou C.M., Singh B., Cirrincione C.T., Tolaney S.M., et al. Impact of the addition of carboplatin and/or bevacizumab to neoadjuvant once-per-week paclitaxel followed by dose-dense doxorubicin and cyclophosphamide on pathologic complete response rates in stage II to III triple-negative breast cancer: CALGB 40603 (Alliance) J. Clin. Oncol. 2015;33:13–21. DOI: 10.1200/jco.2014.57.0572

13. Ellis M.J., Ma C. Letrozole in the neoadjuvant setting: the P024 trial. Breast Cancer Res Treat. 2007;105(Suppl 1):33–43. DOI: 10.1007/s10549-007-9701-x

14. Smith I.E., Dowsett M., Ebbs S.R., Dixon J.M., Skene A., Blohmer J.U., et al. Neoadjuvant treatment of postmenopausal breast cancer with anastrozole, tamoxifen, or both in combination: the Immediate Preoperative Anastrozole, Tamoxifen, or Combined with Tamoxifen (IMPACT) multicenter double-blind randomized trial. J Clin Oncol. 2005;23(22):5108–16. DOI: 10.1200/JCO.2005.04.005

15. Cataliotti L., Buzdar A.U., Noguchi S., Bines J., Takatsuka Y., Petrakova K., et al. Comparison of anastrozole versus tamoxifen as preoperative therapy in postmenopausal women with hormone receptor-positive breast cancer: the Pre-Operative “Arimidex” Compared to Tamoxifen (PROACT) trial. Cancer. 2006;106(10):2095–103. DOI: 10.1002/cncr.21872

16. Ellis M.J., Suman V.J., Hoog J., Lin L., Snider J., Prat A., et al. Randomized phase II neoadjuvant comparison between letrozole, anastrozole, and exemestane for postmenopausal women with estrogen receptor-rich stage 2 to 3 breast cancer: clinical and biomarker outcomes and predictive value of the baseline PAM50-based intrinsic subtype--ACOSOG Z1031. J Clin Oncol. 2011;29(17):2342–9. DOI: 10.1200/JCO.2010.31.6950

17. Spring L.M., Gupta A., Reynolds K.L., Gadd M.A., Ellisen L.W., Isakoff S.J., et al. Neoadjuvant endocrine therapy for estrogen receptor-positive breast cancer: a systematic review and meta-analysis. JAMA Oncol. 2016;2(11):1477–86. DOI: 10.1001/jamaoncol.2016.1897

18. Semiglazov V.F., Semiglazov V.V., Dashyan G.A., Ziltsova E.K., Ivanov V.G., Bozhok A.A., et al. Phase 2 randomized trial of primary endocrine therapy vs chemotherapy in postmenopausal patients with estrogen receptor-positive breast cancer. Cancer. 2007;110:244–54. DOI: 10.1002/cncr.22789

19. Alba E., Calvo L., Albanell J., De La Haba J.R., Lanza A.A., Chacon J.I., et al. Chemotherapy (CT) and hormonotherapy (HT) as neoadjuvant treatment in luminal breast cancer patients: Results from the GEICAM/2006-03, a multicenter, randomized, phase-II study. Ann. Oncol. 2012;23:3069–74. DOI: 10.1093/annonc/mds132

20. Murray N., Francis P., Zdenkowski N., Wilcken N., Boyle F., Gebski V., et al. Randomized trial of neoadjuvant chemotherapy with or without concurrent aromatase inhibitor therapy to downstage ER+ve breast cancer: Breast Cancer Trials Group ANZ 1401 ELIMINATE trial. Ann Oncol. 2022;33(3):164–5. DOI: 10.1016/j.annonc.2022.03.107

21. Krainick-Strobel U.E., Lichtenegger W., Wallwiener D., Tulusan A.H., Janicke F., Bastert G., et al. Neoadjuvant letrozole in postmenopausal estrogen and/or progesterone receptor positive breast cancer: a phase IIb/III trial to investigate optimal duration of preoperative endocrine therapy. BMC Cancer. 2008;8:62. DOI: 10.1186/1471-2407-8-62

22. Llombart-Cussac A., Guerrero A., Galan A., Caranana V., Buch E., Rodriguez-Lescure A., et al. Phase II trial with letrozole to maximum response as primary systemic therapy in postmenopausal patients with ER/PgR[+] operable breast cancer. Clin Transl Oncol. 2012;14(2):125–31. DOI: 10.1007/s12094-012-0771-9

23. Carpenter R., Doughty J.C., Cordiner C., Moss N., Gandhi A., Wilson C., et al. Optimum duration of neoadjuvant letrozole to permit breast conserving surgery. Breast Cancer Res Treat. 2014;144(3):569–76. DOI: 10.1007/s10549-014-2835-8

24. Prat A., Saura C., Pascual T., Hernando C., Munoz M., Pare L., et al. Ribociclib plus letrozole versus chemotherapy for postmenopausal women with hormone receptor-positive, HER2-negative, luminal B breast cancer (CORALLEEN): an open-label, multicentre, randomised, phase 2 trial. Lancet Oncol. 2020;21(1):33–43. DOI: 10.1016/S1470-2045(19)30786-7

25. Goldhirsch A., Winer E.P., Coates A.S., Gelber R.D., Piccart-Gebhart M., Thurlimann B., et al. Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013. Ann Oncol. 2016;24(9):2206–23. DOI: 10.1093/annonc/mdt303

26. Harbeck N., Thomssen C., Gnant M. St. Gallen 2013: brief preliminary summary of the consensus discussion. Breast Care (Basel). 2013;8(2):102–9. DOI: 10.1159/000351193

27. Burstein H.J., Curigliano G., Loibl S., Dubsky P., Gnant M., Poortmans P., et al. Estimating the benefits of therapy for early-stage breast cancer: the St. Gallen International Consensus Guidelines for the primary therapy of early breast cancer 2019. Ann Oncol. 2019;30(10):1541–57. DOI: 10.1093/annonc/mdz235

28. Burstein H.J., Curigliano G., Thürlimann B., Weber W.P., Poortmans P., Regan M.M., et al. Customizing local and systemic therapies for women with early breast cancer: the St. Gallen International Consensus Guidelines for treatment of early breast cancer 2021. Ann Oncol. 2021;32(10):1216–35. DOI: 10.1016/j.annonc.2021.06.023

29. Lin M., Jin Y., Zhang J. Expert review on systemic treatment in the St. Gallen International Breast Cancer Conference 2021. Transl Breast Cancer Res 2021;2:17. DOI: 10.21037/tbcr-21-7

30. Jackisch C. Overcoming endocrine resistance in neoadjuvant endocrine therapy for early breast cancer. Lancet Oncol. 2019;20(9):1185–7. DOI: 10.1016/S1470-2045(19)30500-5

31. Saura C., Hlauschek D., Oliveira M., Zardavas D., Jallitsch-Halper A., de la Pena L., et al. Neoadjuvant letrozole plus taselisib versus letrozole plus placebo in postmenopausal women with oestrogen receptor-positive, HER2-negative, early-stage breast cancer (LORELEI): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol. 2019;20(9):1226–38. DOI: 10.1016/S1470-2045(19)30334-1

32. Johnston S., Puhalla S., Wheatley D., Ring A., Barry P., Holcombe C., et al. Randomized phase II study evaluating palbociclib in addition to letrozole as neoadjuvant therapy in estrogen receptor-positive early breast cancer: PALLET trial. J Clin Oncol. 2019;37(3):178–89. DOI: 10.1200/JCO.18.01624

33. Cottu P., D'Hondt V., Dureau S., Lerebours F., Desmoulins I., Heudel P.E., et al. Letrozole and palbociclib versus chemotherapy as neoadjuvant therapy of high-risk luminal breast cancer. Ann Oncol. 2018;29(12):2334–40. DOI: 10.1093/annonc/mdy448

34. Sestak I., Buus R., Cuzick J., Dubsky P., Kronenwett R., Denkert C., et al. Comparison of the performance of 6 prognostic signatures for estrogen receptor-positive breast cancer: a secondary analysis of a randomized clinical trial. JAMA Oncol. 2018;4(4):545–53. DOI: 10.1001/jamaoncol.2017.5524

35. Jaber M.I., Song B., Taylor C., Vaske C.J., Benz S.C., Rabizadeh S., et al. A deep learning image-based intrinsic molecular subtype classifier of breast tumors reveals tumor heterogeneity that may affect survival. Breast Cancer Res. 2020;22(1):12. DOI: 10.1186/s13058-020-1248-3

36. Andre F., Ismaila N., Allison K.H., Barlow W.E., Collyar D.E., Damodaran S., et al. Biomarkers for adjuvant endocrine and chemotherapy in early-stage breast cancer: ASCO Guideline Update. J Clin Oncol. 2022;40(16):1816–37. DOI: 10.1200/JCO.22.00069

37. Wu H.J., Chu P.Y. Recent discoveries of macromolecule- and cell-based biomarkers and therapeutic implications in breast cancer. Int J Mol Sci. 2021;22(2):636. DOI: 10.3390/ijms22020636

38. Goto-Yamaguchi L., Yamamoto-Ibusuki M., Yamamoto Y., Fujiki Y., Tomiguchi M., Sueta A., et al. Therapeutic predictors of neoadjuvant endocrine therapy response in estrogen receptor-positive breast cancer with reference to optimal gene expression profiling. Breast Cancer Res Treat. 2018;172(2):353–62. DOI: 10.1007/s10549-018-4933-5

39. Gao J.J., Swain S.M. Luminal a breast cancer and molecular assays: a review. Oncologist. 2018;23(5):556–65. DOI: 10.1634/theoncologist.2017-0535

40. Cardoso F., Kyriakides S., Ohno S., Penault-Llorca F., Poortmans P., Rubio I.T., et al. Early breast cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2019;30(10):1674. DOI: 10.1093/annonc/mdz173

41. Selli C., Turnbull A.K., Pearce D.A., Li A., Fernando A., Wills J., et al. Molecular changes during extended neoadjuvant letrozole treatment of breast cancer: distinguishing acquired resistance from dormant tumours. Breast Cancer Res. 2019;21(1):2. DOI: 10.1186/s13058-018-1089-5

42. Inda M.A., Blok E.J., Kuppen P.J.K., Charehbili A., den Biezen-Timmermans E.C., van Brussel A., et al. Estrogen Receptor pathway activity score to predict clinical response or resistance to neo-adjuvant endocrine therapy in primary breast cancer. Mol Cancer Ther. 2019;19(2):680–89. DOI: 10.1158/1535-7163.MCT-19-0318

43. Ueno T., Saji S., Masuda N., Iwata H., Kuroi K., Sato N., et al. Changes in recurrence score by neoadjuvant endocrine therapy of breast cancer and their prognostic implication. ESMO Open. 2019;4(1):e000476. DOI: 10.1136/esmoopen-2018-000476

44. Vendrell J.A., Solassol J., Gyorffy B., Vilquin P., Jarlier M., Donini C.F., et al. Evaluating ZNF217 mRNA expression levels as a predictor of response to endocrine therapy in ER+ breast cancer. Front Pharmacol. 2018;9:1581. DOI: 10.3389/fphar.2018.01581

45. Bear H.D., Wan W., Robidoux A., Rubin P., Limentani S., White R.L. Jr, et al. Using the 21-gene assay from core needle biopsies to choose neoadjuvant therapy for breast cancer: a multicenter trial. J Surg Oncol. 2017;115(8):917–23. DOI: 10.1002/jso.24610

46. Sparano J.A., Gray R.J., Makower D.F., Pritchard K.I., Albain K.S., Hayes D.F., et al. Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer. N Engl J Med. 2018;379(2):111–21. DOI: 10.1056/NEJMoa1804710

47. Russnes H.G., Lingjaerde O.C., Borresen-Dale A.L., Caldas C. Breast cancer molecular stratification: from intrinsic subtypes to integrative clusters. Am J Pathol. 2017;187(10):2152–62. DOI: 10.1016/j.ajpath.2017.04.022

48. Giridhar K.V., Liu M.C. Available and emerging molecular markers in the clinical management of breast cancer. Expert Rev Mol Diagn. 2019;19(10):919–28. DOI: 10.1080/14737159.2019.1664901

49. Gyorffy B., Hatzis C., Sanft T., Hofstatter E., Aktas B., Pusztai L. Multigene prognostic tests in breast cancer: past, present, future. Breast Cancer Res. 2017;17:11. DOI: 10.1186/s13058-015-0514-2

50. Iwata H., Masuda N., Yamamoto Y., Fujisawa T., Toyama T., Kashiwaba M., et al. Validation of the 21-gene test as a predictor of clinical response to neoadjuvant hormonal therapy for ER+, HER2-negative breast cancer: the TransNEOS study. Breast Cancer Res Treat. 2019;173(1):123–33. DOI: 10.1007/s10549-018-4964-y