NEOADJUVANT ENDOCRINE THERAPY FOR PATIENTS WITH ESTROGEN-RECEPTOR-POSITIVE BREAST CANCER

More than 70 % of patients with breast cancer have estrogen-receptor-positive tumors (ER+) and are considered hormone- sensitive. That is why a vast majority of patients with early operable  tumors receive adjuvant endocrine therapy. Patients with metastatic  ER+ breast cancer also receive hormone therapy as first-line  treatment. Patients with ER+/PR+ locally advanced breast cancer  including potentially operable cases (cT2N1, cT3N0M0) are still a  subject to neoadjuvant chemotherapy in most of the oncology  centers in Russia and worldwide. More than 10 years ago, several  trials evaluating the efficacy of neoadjuvant endocrine therapy were  conducted in the Petrov Research Institute of Oncology (aromatase  inhibitors vs tamoxifen, neoadjuvant endocrine therapy vs  neoadjuvant chemotherapy, etc.) The primary endpoint was the  evaluation of pathologic complete/partial response to therapy and  the frequency of breast-conserving surgeries following neoadjuvant  treatment. We now represent 10-year long-term follow-up data on  comparison of neoadjuvant chemotherapy with neoadjuvant  endocrine therapy after retrospective determination of IHC- phenotypes of 239 patients with ER+ breast cancer. The study  results show tendency to better 10-year disease-free survival in  patients with luminal-A breast cancer who received endocrine  therapy compared to neoadjuvant chemotherapy (72.8 % vs 53.9  %, respectively, p=0.062) There were no statistically significant  differences in DFS rates among patients with the luminal B breast  cancer subtype (41 % vs 40 %) The discovery of biomarkers of  potential resistance to endocrine therapy (cycline-dependant kinase  activity [cdk 4/6], estrogenreceptor mutation [ESR1], mTOR  signaling pathway activity, co-expression of the ER and HER2neu  [ER+/ HER2neu3+]) and ways to inhibit the activity of the resistance pathways (palbocyclib, everolimus, etc.) have expanded the  armamentarium of endocrine-therapy for not only metastatic and  locally-advanced but also operable cases of ER+ breast cancer.

1. Semiglazov V.F., Krivorotko P.V., Semiglazova Т.Yu., Nikolaev К.S., Komyakhov А.V., Dashyan G.А., Semiglazov V.V., Palutev R.М. Practical recommendations for the treatment of breast cancer. Moscow: Megapolis. 2017. 168. [in Russian]

2. Goldhirsch A., Winer E.P., Coates A.S., Gelber R.D., Piccart-Gebhart M., Thürlimann B., Senn H.J.; Panel members. 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. 2013 Sep; 24 (9): 2206– 23. doi: 10.1093/annonc/mdt303.

3. Eiermann W., Paepke S., Appfelstaedt J., Llombart-Cussac A., Eremin J., Vinholes J., Mauriac L., Ellis M., Lassus M., Chaudri-Ross H.A., Dugan M., Borgs M.; Letrozole Neo-Adjuvant Breast Cancer Study Group. Preoperative treatment of postmenopausal breast cancer patients with letrozole: a randomized double-blind multicenter study. Ann Oncol. 2001 Nov; 12 (11): 1527–32.

4. Ellis M.J., Coop A., Singh B., Mauriac L., Llombert-Cussac A., Jänicke F., Miller W.R., Evans D.B., Dugan M., Brady C., Quebe- Fehling E., Borgs M. Letrozole is more effective neoadjuvant endocrine therapy than tamoxifen for ErbB-1 and/or ErbB-2- positive, estrogen receptor-positive primary breast cancer: evidence from a phase III randomized trial. J Clin Oncol. 2001 Sep 15; 19 (18): 3808–16. doi: 10.1200/JCO.2001.19.18.3808.

5. Smith I.E., Dowsett M. Comparison of anastozole vs. tamoxifen alone and in combination as neoadjuvant treatment of estrogen receptorpositive (ER+) operable breast cancer in postmenopausal women: the IMPACT trial. Breast Cancer. Res. 2003; 82: S6.

6. Semiglazov V.F., Semiglazov V.V., Dashyan G.A., Ziltsova E.K., Ivanov V.G., Bozhok A.A., Berstein L.M. Phase II randomized trial of primary endocrine therapy chemotherapy in postmenopausal patients with estrogen receptor positive breast cancer. Cancer. 2007, 110 (2): 244–254.

7. Semiglazov V.F., Dashyan G.A., Semiglazov V.V., Petrenko O.L., Komyahov A.V., Paltuev R.M., Matzko D. P198 Prognostic values of breast cancer subtypes : from phase 2 randomized trial of neoadjuvant therapy. The Breast, 2015; 24: S92.

8. Cardoso F., Costa A., Norton L., Senkus E., Aapro M., Andre F., Cardoso M.J. ESO- ESMO 2nd international consensus guidelines for advanced breast Cancer (ABC2). Simultaneous And Annals of Oncology. 2014: 25: 1871–1888.

9. Finn R.S., Crown J.P., Lang I., Boer K., Bondarenko I.M., Kulyk S.O., Ettl J., Patel R., Pinter T., Schmidt M., Shparyk Y., Thummala A.R., Voytko N.L., Fowst C., Huang X., Kim S.T., Randolph S., Slamon D.J. The cyclin – dependent kinase 4/6 inhibitor palbociclib on combination with letrozole versus letrozole alone as first- line treatment of estrogen receptorpositive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomized phase 2 study. Lancet Oncol. 2015 Jan; 16 (1): 25– 35. doi: 10.1016/S1470-2045(14)71159-3.

10. Turner N.C., Huang Bartlett C., Cristofanilli M. Palbociclib in hormone- receptor-positive advanced breast cancer. N Engl J Med. 2015 Oct 22; 373 (17): 1672– 3. doi: 10.1056/NEJMc1510345.

11. Finn R.S., Martin M., Rugo H.S., Jones S.E., Im S.A., Gelmon K.A., Gauthier E.R. PALOMA-2: primary results from a phase III trial of palbociclib (P) with letrozole (L) compared with letrozole alone in postmenopausal women with ERb/HER2e advanced breast cancer (ABC). J Clin Oncol 2016; 34. Abstr 507.

12. Weigel R.J., de Coninck E.C. Transcriptional control of estrogen receptor in estrogen receptor-negative breast carcinoma. Cancer Res. 1993 Aug 1; 53 (15): 3472–4.

13. Fribbens C., O’Leary B., Kilburn L., Hrebien S., Garcia-Murillas I., Beaney M., Cristofanilli M., Andre F., Loi S., Loibl S., Jiang J., Bartlett C.H., Koehler M., Dowsett M., Bliss J.M., Johnston S.R., Turner N.C. Plasma ESR1 mutations and the treatment of estrogen receptor-positive advanced breast cancer. J Clin Oncol. 2016 Sep 1; 34 (25): 2961–8. doi: 10.1200/JCO.2016.67.3061

14. Harbeck N., Iyer S., Turner N., Cristofanilli M., Ro J., André F., Loi S., Verma S., Iwata H., Bhattacharyya H., Puyana Theall K., Bartlett C.H., Loibl S. Quality of life with palbociclib plus full-vestrant in previously treated hormone receptor- positive, HER2-negative metastatic breast cancer: patient-reported outcomes from the PALOMA-3 trial. Ann Oncol. 2016 Jun; 27 (6): 1047–54. doi: 10.1093/annonc/mdw139.

15. Bachelot T., Bourgier C., Cropet C., Ray-Coquard I., Ferrero J.M., Freyer G., Abadie-Lacourtoisie S., Eymard J.C., Debled M., Spaëth D., Legouffe E., Allouache D., El Kouri C., Pujade-Lauraine E. Randomized phase II trial of everolimus in combination with tamoxifen in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer with prior exposure to aromatase inhibitors: a GINECO study. J Clin Oncol. 2012 Aug 1; 30 (22): 2718–24. doi: 10.1200/JCO.2011.39.0708.