ADVANCES IN BREAST CANCER DIAGNOSIS AND TREATMENT: ESSENTIALS

Advances in breast cancer diagnosis and treatment Essentials_kapak

ADJUVANT SYSTEMIC THERAPY

Nihan Eren

İstanbul University, Institute of Oncology, Department of Medical Oncology, İstanbul, Türkiye

Eren N. Adjuvant Systemic Therapy. In: Citgez B editor. Advances in Breast Cancer Diagnosis and Treatment Essentials. 1st ed. Ankara: Türkiye Klinikleri; 2025. p.91-100.

ABSTRACT

Adjuvant systemic therapy administered after surgery for early breast cancer is important to prevent cancer recurrence and improve survival. This treatment strategy is built on three key components: chemotherapy, endocrine therapy, and targeted therapy. The treatment plan for each individual is personalized considering many factors including tumor biology and molecular tests. Endocrine therapy is the main treatment in hormone receptor-positive/HER2-negative breast cancer. Tamoxifen and aromatase inhibitors can be used effectively in endocrine therapy. Ovarian function suppression can also be used in combination with either tamoxifen or aromatase inhibitors in high-risk premenopausal patients. The decision to employ chemotherapy is implemented considering factors such as clinical risk, lymph node involvement, and genetic profile. Multigene genomic assays can be helpful in making the decision to add chemotherapy to endocrine therapy, especially in postmenopausal patients with less than four lymph nodes positivity. Anthracycline-based combination chemotherapy followed by taxanes is the standard, but anthracycline-free combinations can also be preferred. Recently developed targeted therapies such as CDK4/6 inhibitors and PARP inhibitors also provide benefit in reducing recurrence and improving survival in high-risk patients. Trastuzumab-based chemotherapy combinations improve survival outcomes in HER2-positive tumors. Chemotherapy combinations with or without anthracyclines can be combined with antiHER2 therapies. Trastuzumab emtansine should be considered in patients who do not achieve complete response with neoadjuvant therapy. Chemotherapy is the mainstay of treatment in triple-negative breast cancer. Anthracycline-based chemotherapy and taxanes with or without platinum combinations are standard. Adjuvant capecitabine improves survival in patients who do not achieve complete response with neoadjuvant therapy. Olaparib can also be used in high-risk patients with hereditary BRCA1/2 mutations. The treatment plan should be determined according to the patient’s vital risk and tumor biology.

Keywords: Breast cancer; Chemotherapy; Adjuvant chemotherapy; Targeted therapy; Immunotherapy

Referanslar

  1. Lohrisch C, Paltiel C, Gelmon K, Speers C, Taylor S, Barnett J, et al. Impact on survival of time from definitive surgery to initiation of adjuvant chemotherapy for early-stage breast cancer. J Clin Oncol. 2006;24(30):4888-4894. [Crossref]  [PubMed]
  2. Curigliano G, Burstein HJ, Winer EP, Gnant M, Dubsky P, Loibl S, et al. De-escalating and escalating treatments for early-stage breast cancer: the St. Gallen International Expert Consensus Conference on the Primary Therapy of Early Breast Cancer 2017 [published correction appears in Ann Oncol. 2018;29(10):2153.
  3. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Breast Cancer. V.4.2025. Philadelphia, PA: National Comprehensive Cancer Network, Inc. 2025.
  4. Loibl S, André F, Bachelot T, Barrios CH, Bergh J, Burstein HJ, et al. Early breast cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2024;35(2):159-182. [Crossref]  [PubMed]
  5. Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials. Lancet. 2015;386(10001):1341-1352. [Crossref]  [PubMed]
  6. Early Breast Cancer Trialists' Collaborative Group (EBCTCG), Davies C, Godwin J, Clarke M, Cutter D, Darby S, et al. Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet. 2011;378(9793):771-784. [Crossref]
  7. Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005;365(9472):1687-1717. [Crossref]  [PubMed]
  8. Davies C, Pan H, Godwin J, Gray R, Arriagada R, Raina V, et al. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial [published correction appears in Lancet. 2013;381(9869):805-816.
  9. Albain KS, Barlow WE, Ravdin PM, Farrar WB, Burton GV, Ketchel SJ, et al. Adjuvant chemotherapy and timing of tamoxifen in postmenopausal patients with endocrine-responsive, node-positive breast cancer: a phase 3, open-label, randomised controlled trial. Lancet. 2009;374(9707):20552063. [Crossref]  [PubMed]
  10. Li YF, Chang L, Li WH, Xiao MY, Wang Y, He WJ, et al. Radiotherapy concurrent versus sequential with endocrine therapy in breast cancer: A meta-analysis. Breast. 2016;27:93-98. [Crossref]  [PubMed]
  11. Cuzick J, Sestak I, Baum M, Buzdar A, Howell A, Dowsett M, et al. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 10-year analysis of the ATAC trial. Lancet Oncol. 2010;11(12):1135-1141. [Crossref]  [PubMed]
  12. Ruhstaller T, Giobbie-Hurder A, Colleoni M, Jensen MB, Ejlertsen B, de Azambuja E, et al. Adjuvant Letrozole and Tamoxifen Alone or Sequentially for Postmenopausal Women With Hormone Receptor-Positive Breast Cancer: Long-Term Follow-Up of the BIG 1-98 Trial. J Clin Oncol. 2019;37(2):105-114. [Crossref]  [PubMed]  [PMC]
  13. Coombes RC, Kilburn LS, Snowdon CF, Paridaens R, Coleman RE, Jones SE, et al. Survival and safety of exemestane versus tamoxifen after 2-3 years' tamoxifen treatment (Intergroup Exemestane Study): a randomised controlled trial [published correction appears in Lancet. 2007;369(9565):906. Lancet. 2007;369(9561):559-570. [Crossref]  [PubMed]
  14. Kaufmann M, Jonat W, Hilfrich J, Eidtmann H, Gademann G, Zuna I, et al. Improved overall survival in postmenopausal women with early breast cancer after anastrozole initiated after treatment with tamoxifen compared with continued tamoxifen: the ARNO 95 Study. J Clin Oncol. 2007;25(19):2664-2670. [Crossref]  [PubMed]
  15. Goss PE, Ingle JN, Martino S, Robert NJ, Muss HB, Piccart MJ, et al. Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: updated findings from NCIC CTG MA.17. J Natl Cancer Inst. 2005;97(17):1262-1271. [Crossref]  [PubMed]
  16. Francis PA, Regan MM, Fleming GF, Láng I, Ciruelos E, Bellet M, et al. Adjuvant ovarian suppression in premenopausal breast cancer. N Engl J Med. 2015;372(5):436-446. [Crossref]  [PubMed]  [PMC]
  17. Pagani O, Regan MM, Walley BA, Fleming GF, Colleoni M, Láng I, et al. Adjuvant exemestane with ovarian suppression in premenopausal breast cancer. N Engl J Med. 2014;371(2):107-118. [Crossref]  [PubMed]  [PMC]
  18. Pagani O, Walley BA, Fleming GF, Colleoni M, Láng I, Gomez HL, et al. Adjuvant Exemestane With Ovarian Suppression in Premenopausal Breast Cancer: Long-Term Follow-Up of the Combined TEXT and SOFT Trials. J Clin Oncol. 2023;41(7):1376-1382. [Crossref]  [PubMed]  [PMC]
  19. Baek SY, Noh WC, Ahn SH, Kim HA, Ryu JM, Kim SI, et al. Adding Ovarian Suppression to Tamoxifen for Premenopausal Women With Hormone Receptor-Positive Breast Cancer After Chemotherapy: An 8-Year Follow-Up of the ASTRRA Trial. J Clin Oncol. 2023;41(31):4864-4871. [Crossref]  [PubMed]
  20. Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Aromatase inhibitors versus tamoxifen in premenopausal women with oestrogen receptor-positive early-stage breast cancer treated with ovarian suppression: a patient-level meta-analysis of 7030 women from four randomised trials [published correction appears in Lancet Oncol. 2022;23(4):e161.
  21. Gray R, Rea D, Handley K, Bowden SJ, Perry P, Earl HM, et al. aTTom: Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years in 6,953 women with early breast cancer [Abstract]. J Clin Oncol 2013;31(Suppl):Abstract 5. [Crossref]
  22. Goss PE, Ingle JN, Pritchard KI, Robert NJ, Muss H, Gralow J, et al. Extending Aromatase-Inhibitor Adjuvant Therapy to 10 Years. N Engl J Med. 2016;375(3):209-219. [Crossref]  [PubMed]  [PMC]
  23. Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Adjuvant bisphosphonate treatment in early breast cancer: meta-analyses of individual patient data from randomised trials [published correction appears in Lancet. 2016 Jan 2;387(10013):30] [published correction appears in Lancet. 2017;389(10088):2472.
  24. Kalinsky K, Barlow WE, Gralow JR, Meric-Bernstam F, Albain KS, Hayes DF, et al. 21-Gene Assay to Inform Chemotherapy Benefit in Node-Positive Breast Cancer. N Engl J Med. 2021;385(25):2336-2347. [Crossref]  [PubMed]  [PMC]
  25. Sparano JA, Gray RJ, Makower DF, Pritchard KI, Albain KS, Hayes DF, et al. Adjuvant Chemotherapy Guided by a 21-Gene Expression Assay in Breast Cancer. N Engl J Med. 2018;379(2):111-121. [Crossref]  [PubMed]  [PMC]
  26. Paik S, Tang G, Shak S, Kim C, Baker J, Kim W, et al. Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer. J Clin Oncol. 2006;24(23):3726-3734. [Crossref]  [PubMed]
  27. Sparano JA, Gray RJ, Makower DF, Pritchard KI, Albain KS, Hayes DF, et al. Adjuvant Chemotherapy Guided by a 21-Gene Expression Assay in Breast Cancer. N Engl J Med. 2018;379(2):111-121. [Crossref]  [PubMed]  [PMC]
  28. Gluz O, Nitz UA, Christgen M, Kates RE, Shak S, Clemens M, et al. West German Study Group Phase III PlanB Trial: First Prospective Outcome Data for the 21-Gene Recurrence Score Assay and Concordance of Prognostic Markers by Central and Local Pathology Assessment. J Clin Oncol. 2016;34(20):2341-2349. [Crossref]  [PubMed]
  29. Albain KS, Barlow WE, Shak S, Hortobagyi GN, Livingston RB, Yeh IT, et al. Prognostic and predictive value of the 21gene recurrence score assay in postmenopausal women with node-positive, oestrogen-receptor-positive breast cancer on chemotherapy: a retrospective analysis of a randomised trial. Lancet Oncol. 2010;11(1):55-65. [Crossref]  [PubMed]
  30. Cardoso F, van't Veer LJ, Bogaerts J, Slaets L, Viale G, Delaloge S, et al. 70-Gene Signature as an Aid to Treatment Decisions in Early-Stage Breast Cancer. N Engl J Med. 2016;375(8):717-729. [Crossref]  [PubMed]
  31. Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Electronic address: bc.overview@ctsu.ox.ac. uk; Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Anthracycline-containing and taxane-containing chemotherapy for early-stage operable breast cancer: a patient-level meta-analysis of 100 000 women from 86 randomised trials. Lancet. 2023;401(10384):1277-1292.
  32. Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Increasing the dose intensity of chemotherapy by more frequent administration or sequential scheduling: a patient-level meta-analysis of 37 298 women with early breast cancer in 26 randomised trials. Lancet. 2019;393(10179):1440-1452.
  33. Jones S, Holmes FA, O'Shaughnessy J, Blum JL, Vukelja SJ, McIntyre KJ, et al. Docetaxel With Cyclophosphamide Is Associated With an Overall Survival Benefit Compared With Doxorubicin and Cyclophosphamide: 7-Year Follow-Up of US Oncology Research Trial 9735. J Clin Oncol. 2009;27(8):1177-1183. [Crossref]  [PubMed]
  34. Johnston SRD, Toi M, O'Shaughnessy J, Rastogi P, Campone M, Neven P, et al. Abemaciclib plus endocrine therapy for hormone receptor-positive, HER2-negative, node-positive, high-risk early breast cancer (monarchE): results from a preplanned interim analysis of a randomised, open-label, phase 3 trial. Lancet Oncol. 2023;24(1):77-90. [Crossref]  [PubMed]
  35. Fasching PA, Stroyakovskiy D, Yardley D, Huang CS, Crown JP, Bardia A, et al. LBA13 Adjuvant ribociclib (RIB) plus nonsteroidal aromatase inhibitor (NSAI) in patients (Pts) with HR+/HER2− early breast cancer (EBC): 4-year outcomes from the NATALEE trial. Ann Oncol. 2024;35(Supplement 2):1207. [Crossref]
  36. Loibl S, Marmé F, Martin M, Untch M, Bonnefoi H, Kim SB, et al. Palbociclib for Residual High-Risk Invasive HR-Positive and HER2-Negative Early Breast Cancer-The Penelope-B Trial. J Clin Oncol. 2021;39(14):1518-1530. [Crossref]  [PubMed]
  37. Gnant M, Dueck AC, Frantal S, Martin M, Burstein HJ, Greil R, et al. Adjuvant Palbociclib for Early Breast Cancer: The PALLAS Trial Results (ABCSG-42/AFT-05/BIG-14-03). J Clin Oncol. 2022;40(3):282-293. [Crossref]  [PubMed]  [PMC]
  38. Geyer CE Jr, Garber JE, Gelber RD, Yothers G, Taboada M, Ross L, et al. Overall survival in the OlympiA phase III trial of adjuvant olaparib in patients with germline pathogenic variants in BRCA1/2 and high-risk, early breast cancer. Ann Oncol. 2022;33(12):1250-1268. [Crossref]  [PubMed]  [PMC]
  39. Early Breast Cancer Trialists' Collaborative group (EBCTCG). Trastuzumab for early-stage, HER2-positive breast cancer: a meta-analysis of 13 864 women in seven randomised trials. Lancet Oncol. 2021;22(8):1139-1150.
  40. Tolaney SM, Barry WT, Dang CT, Yardley DA, Moy B, Marcom PK, et al. Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer [published correction appears in N Engl J Med. 2015;372(2):134-141. [Crossref]  [PubMed]  [PMC]
  41. Slamon D, Eiermann W, Robert N, Pienkowski T, Martin M, Press M, et al. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med. 2011;365(14):1273-1283. [Crossref]  [PubMed]  [PMC]
  42. Loibl S, Jassem J, Sonnenblick A, Parlier D, Winer E, Bergh J, et al. Adjuvant Pertuzumab and Trastuzumab in Early Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer in the APHINITY Trial: Third Interim Overall Survival Analysis With Efficacy Update. J Clin Oncol. 2024;42(31):3643-3651. [Crossref]  [PubMed]
  43. Cortazar P, Zhang L, Untch M, Mehta K, Costantino JP, Wolmark N, et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis [published correction appears in Lancet. 2014;384(9938):164-172. [Crossref]  [PubMed]
  44. Geyer CE Jr, Untch M, Huang CS, Mano MS, Mamounas EP, Wolmark N, et al. Survival with Trastuzumab Emtansine in Residual HER2-Positive Breast Cancer. N Engl J Med. 2025;392(3):249-257. [Crossref]  [PubMed]
  45. Loibl S, Huang CS, Mano MS, Mamounas EP, Geyer CE Jr, Untch M, et al. Adjuvant trastuzumab emtansine in HER2-positive breast cancer patients with HER2-negative residual invasive disease in KATHERINE. NPJ Breast Cancer. 2022;8(1):106. Published 2022 Sep 19. [Crossref]  [PubMed]  [PMC]
  46. Goldhirsch A, Gelber RD, Piccart-Gebhart MJ, de Azambuja E, Procter M, Suter TM, et al. 2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA): an open-label, randomised controlled trial. Lancet. 2013;382(9897):1021-1028. [Crossref]  [PubMed]
  47. Earl HM, Hiller L, Vallier AL, Loi S, McAdam K, Hughes-Davies L, et al. 6 versus 12 months of adjuvant trastuzumab for HER2-positive early breast cancer (PERSEPHONE): 4-year disease-free survival results of a randomised phase 3 non-inferiority trial. Lancet. 2019;393(10191):2599-2612. [Crossref]  [PubMed]
  48. Pivot X, Romieu G, Debled M, Pierga JY, Kerbrat P, Bachelot T, et al. 6 months versus 12 months of adjuvant trastuzumab in early breast cancer (PHARE): final analysis of a multicentre, open-label, phase 3 randomised trial. Lancet. 2019;393(10191):2591-2598. [Crossref]  [PubMed]
  49. Romond EH, Jeong JH, Rastogi P, Swain SM, Geyer CE Jr, Ewer MS, et al. Seven-year follow-up assessment of cardiac function in NSABP B-31, a randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel (ACP) with ACP plus trastuzumab as adjuvant therapy for patients with node-positive, human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol. 2012;30(31):37923799. [Crossref]  [PubMed]  [PMC]
  50. Chan A, Moy B, Mansi J, Ejlertsen B, Holmes FA, Chia S, et al. Final Efficacy Results of Neratinib in HER2-positive Hormone Receptor-positive Early-stage Breast Cancer From the Phase III ExteNET Trial. Clin Breast Cancer. 2021;21(1):80-91.e7. [Crossref]  [PubMed]
  51. Desch CE, McNiff KK, Schneider EC, Schrag D, McClure J, Lepisto E, et al. American Society of Clinical Oncology/ National Comprehensive Cancer Network Quality Measures. J Clin Oncol. 2008;26(21):3631-3637. [Crossref]  [PubMed]
  52. Mason SR, Willson ML, Egger SJ, Beith J, Dear RF, Goodwin A. Platinum-based chemotherapy for early triple-negative breast cancer. Cochrane Database Syst Rev. 2023;9(9):CD014805. Published 2023 Sep 8. [Crossref]  [PubMed]  [PMC]
  53. von Minckwitz G, Untch M, Blohmer JU, Costa SD, Eidtmann H, Fasching PA, et al. Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J Clin Oncol. 2012;30(15):1796-1804. [Crossref]  [PubMed]
  54. Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Increasing the dose intensity of chemotherapy by more frequent administration or sequential scheduling: a patient-level meta-analysis of 37 298 women with early breast cancer in 26 randomised trials. Lancet. 2019;393(10179):1440-1452.
  55. Schmid P, Cortes J, Dent R, McArthur H, Pusztai L, Kümmel S, et al. Overall Survival with Pembrolizumab in Early-Stage Triple-Negative Breast Cancer. N Engl J Med. 2024;391(21):1981-1991. [Crossref]  [PubMed]
  56. Masuda N, Lee SJ, Ohtani S, Im YH, Lee ES, Yokota I, et al. Adjuvant Capecitabine for Breast Cancer after Preoperative Chemotherapy. N Engl J Med. 2017;376(22):2147-2159. [Crossref]  [PubMed]
  57. Shah AN, Flaum L, Helenowski I, Santa-Maria AC, Jain S, Rademaker A, et al. Phase II study of pembrolizumab and capecitabine for triple negative and hormone receptor-positive, HER2-negative endocrine-refractory metastatic breast cancer. J Immunother Cancer. 2020;8(1):e000173. [Crossref]  [PubMed]  [PMC]