Document Type : Review Article(s)

Authors

1 Department of Oncology, Mediclinic Hospital, Dubai, United Arab Emirates

2 Department of Oncology, Cairo University, Cairo, Egypt

3 Department of Oncology, Almoosa Specialist Hospital, Oncology Center, Al Mubarraz, Saudi Arabia

4 The Medical Oncology Centre of Rosebank, Johannesburg, South Africa

5 Department of Immunology, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa

6 Department of Medical Oncology, Bayindir Hospital, Ankara, Turkey

7 Department of Oncology, Sheikh Khalifa Specialty Hospital, Abu Dhabi, United Arab Emirates

8 Department of Oncology, Royal Preston Hospital, Sharoe Green Lane, Fulwood, Preston, United Kingdom

9 College of Medicine, Al-Faisal University, Riyadh, Saudi Arabia

10 Department of Oncology, Chellah University, Rabat, Morocco

11 Department of Oncology, Baskent University, Ankara, Turkey

12 Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon

10.30476/mejc.2024.103586.2143

Abstract

Approximately 50 to 67% of breast cancers (BCs), traditionally categorized as human epidermal growth factor receptor 2 (HER2)-negative, but demonstrating low HER2 expression, are now being defined as a new HER2-low subset or HER2-low category of BC. For metastatic BC (mBC), standard therapy options include targeted approaches, such as cyclin-dependent kinase 4/6 inhibitors, phosphoinositide 3-kinase inhibitors, poly (adenosine diphosphate-ribose) polymerase inhibitors, and anti-programmed death-ligand 1 agents, depending on tumor type and its molecular profile. Recent clinical trials reported significant clinical benefits from novel anti‑HER2 antibody‑drug conjugates, such as trastuzumab deruxtecan in HER2‑low mBC. Novel treatment options have increased the complexity of the clinical decision‑making process, particularly for treatment sequencing for each clinical setting. A regional expert committee meeting was held to discuss the challenges, overcome limitations, and present recommendations to enhance HER2 reporting as well as treatment of patients with HER2‑low mBC in the Middle East and Africa region.

Highlights

Shaheenah Dawood (PubMed)

Nagi S. El-Saghir (Google Scholar)

Keywords

Main Subjects

This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination, and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.30476/mejc.2024.103586.2143

  1. The Global Cancer Observatory: Factsheets. Breast Cancer. [Internet]. 2020 [cited 2022 Aug 11]. Available from: http://gco.iarc.fr/today/home
  2. American Cancer Society. Breast Cancer Facts & Figures 2019-2020. Atlanta: American Cancer Society, Inc. 2019. [Internet]. [cited 2022 Aug 11]. Available from: https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/breast-cancer-facts-and-figures/breast-cancer-facts-and-figures-2019-2020
  3. Loibl S, Gianni L. HER2-positive breast cancer. Lancet. 2017;389(10087):2415-29. doi: 10.1016/S0140-6736(16)32417-5. PMID: 27939064.
  4. Zekri J, Saadeddin A, Alharbi H. Frequency and clinical characteristics of HER2 over-expressed breast cancer in Saudi Arabia: a retrospective study. BMC Womens Health. 2021;21(1):10. doi: 10.1186/s12905-020-01159-3. PMID: 33407382; PMCID: PMC7788710.
  5. Nicolò E, Boscolo Bielo L, Curigliano G, Tarantino P. The HER2-low revolution in breast oncology: steps forward and emerging challenges. Ther Adv Med Oncol. 2023;15:17588359231152842. doi: 10.1177/17588359231152842. PMID: 36844387; PMCID: PMC9943960.
  6. Eiger D, Agostinetto E, Saúde-Conde R, de Azambuja E. The exciting new field of HER2-low breast cancer treatment. Cancers (Basel). 2021;13(5):1015. doi: 10.3390/cancers13051015. PMID: 33804398; PMCID: PMC7957750.
  7. Wolff AC, Somerfield MR, Dowsett M, Hammond MEH, Hayes DF, McShane LM, et al. Human epidermal growth factor receptor 2 testing in breast cancer. Arch Pathol Lab Med. 2023;147(9):993-1000. doi: 10.5858/arpa.2023-0950-SA. PMID: 37303228.
  8. Viale G, Basik M, Niikura N, Tokunaga E, Brucker S, Penault-Llorca F, et al. Retrospective study to estimate the prevalence and describe the clinicopathological characteristics, treatments received, and outcomes of HER2-low breast cancer. ESMO Open. 2023;8(4):101615. 10.1016/j.esmoop.2023.101615. PMID: 37562195; PMCID: PMC10515285.
  9. Finn RS, Martin M, Rugo HS, Jones S, Im SA, Gelmon K, et al. Palbociclib and letrozole in advanced breast cancer. N Engl J Med. 2016;375(20):1925-36. doi: 10.1056/NEJMoa1607303. PMID: 27959613.
  10. Tripathy D, Im SA, Colleoni M, Franke F, Bardia A, Harbeck N, et al. Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive, advanced breast cancer (MONALEESA-7): a randomised phase 3 trial. Lancet Oncol. 2018;19(7):904-15. doi: 10.1016/S1470-2045(18)30292-4. PMID: 29804902.
  11. Sledge GW, Toi M, Neven P, Sohn J, Inoue K, Pivot X, et al. MONARCH 2: Abemaciclib in combination with fulvestrant in women with HR+/HER2- advanced breast cancer who had progressed while receiving endocrine therapy. J Clin Oncol. 2017;35(25):2875-84. doi: 10.1200/JCO.2017.73.7585. PMID: 28580882.
  12. Gennari A, André F, Barrios CH, Cortés J, de Azambuja E, DeMichele A, et al. ESMO Clinical Practice Guideline for the diagnosis, staging and treatment of patients with metastatic breast cancer. Ann Oncol Off J Eur Soc Med Oncol. 2021;32(12):1475-95. doi: 10.1016/j.annonc.2021.09.019. PMID: 34678411.
  13. Li S, Bao C, Huang L, Wei JF. Current therapeutic strategies for metastatic triple-negative breast cancer: From pharmacists’ perspective. J Clin Med. 2022;11(20):6021. doi: 10.3390/jcm11206021. PMID: 36294342. PMCID: PMC9604829.
  14. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Breast Cancer V.2.2024.© National Comprehensive Cancer Network, Inc. 2024. All rights reserved. Accessed April 11, 2024. To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.
  15. Tarantino P, Hamilton E, Tolaney SM, Cortes J, Morganti S, Ferraro E, et al. HER2-Low breast cancer: pathological and clinical landscape. J Clin Oncol. 2020;38(17):1951-62. doi: 10.1200/JCO.19.02488. PMID: 32330069.
  16. Nakada T, Sugihara K, Jikoh T, Abe Y, Agatsuma T. The latest research and development into the antibody-drug conjugate, [fam-] trastuzumab deruxtecan (DS-8201a), for HER2 cancer therapy. Chem Pharm Bull (Tokyo). 2019;67(3):173-85. 10.1248/cpb.c18-00744. PMID: 30827997.
  17. Modi S, Park H, Murthy RK, Iwata H, Tamura K, Tsurutani J, et al. Antitumor activity and safety of trastuzumab deruxtecan in patients with HER2-low-expressing advanced breast cancer: results from a phase Ib study. J Clin Oncol. 2020;38(17):1887-96. doi: 10.1200/JCO.19.02318. PMID: 32058843; PMCID: PMC7280051
  18. Tamura K, Tsurutani J, Takahashi S, Iwata H, Krop IE, Redfern C, et al. Trastuzumab deruxtecan (DS-8201a) in patients with advanced HER2-positive breast cancer previously treated with trastuzumab emtansine: a dose-expansion, phase 1 study. Lancet Oncol. 2019;20(6):816-26. doi: 10.1016/S1470-2045(19)30097-X. PMID: 31047803.
  19. Banerji U, van Herpen CML, Saura C, Thistlethwaite F, Lord S, Moreno V, et al. Trastuzumab duocarmazine in locally advanced and metastatic solid tumours and HER2-expressing breast cancer: a phase 1 dose-escalation and dose-expansion study. Lancet Oncol. 2019;20(8):1124-35. doi: 10.1016/S1470-2045(19)30328-6. PMID: 31257177.
  20. Saura C, Thistlethwaite F, Banerji U, Lord S, Moreno V, MacPherson I, et al. A phase I expansion cohorts study of SYD985 in heavily pretreated patients with HER2-positive or HER2-low metastatic breast cancer. J Clin Oncol. 2018;36(15_suppl):1014. doi: 10.1200/JCO.2018.36.15_suppl.1014.
  21. Modi S, Jacot W, Yamashita T, Sohn J, Vidal M, Tokunaga E, et al. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. N Engl J Med. 2022;387(1):9-20. doi: 10.1056/NEJMoa2203690. PMID: 35665782; PMCID: PMC10561652.
  22. Research C for DE and. FDA approves fam-trastuzumab deruxtecan-nxki for HER2-low breast cancer. FDA [Internet] [cited 2023 Jan 25]; Available from: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-fam-trastuzumab-deruxtecan-nxki-her2-low-breast-cancer
  23. Wolff AC, Hammond MEH, Allison KH, Harvey BE, Mangu PB, Bartlett JMS, et al. Human Epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update. Arch Pathol Lab Med. 2018;142(11):1364-82. doi: 10.5858/arpa.2018-0902-SA. PMID: 29846104.
  24. Miglietta F, Griguolo G, Bottosso M, Giarratano T, Lo Mele M, Fassan M, et al. Evolution of HER2-low expression from primary to recurrent breast cancer. Npj Breast Cancer. 2021;7(1):1-8. doi:10.1038/s41523-021-00343-4. PMID: 34642348; PMCID: PMC8511010.
  25. Venetis K, Crimini E, Sajjadi E, Corti C, Guerini-Rocco E, Viale G, et al. HER2 low, ultra-low, and novel complementary biomarkers: expanding the spectrum of HER2 positivity in breast cancer. Front Mol Biosci. 2022;9:834651. doi: 10.3389/fmolb.2022.834651. PMID: 35372498; PMCID: PMC8965450.
  26. Ahn S, Woo JW, Lee K, Park SY. HER2 status in breast cancer: changes in guidelines and complicating factors for interpretation. J Pathol Transl Med. 2020;54(1):34-44. doi: 10.4132/jptm.2019.11.03. PMID: 31693827;  PMCID: PMC6986968.
  27. Zhang H, Karakas C, Tyburski H, Turner BM, Peng Y, Wang X, et al. HER2-low breast cancers: Current insights and future directions. Semin Diagn Pathol. 2022;39(5):305-12. doi: 10.1053/j.semdp.2022.07.003. PMID: 35872032.
  28. Fehrenbacher L, Cecchini RS, Geyer CE, Rastogi P, Costantino JP, Atkins JN, et al. NSABP B-47/NRG Oncology phase III randomized trial comparing adjuvant chemotherapy with or without trastuzumab in high-risk invasive breast cancer negative for HER2 by FISH and with IHC 1+ or 2. J Clin Oncol. 2020;38(5):444-53. doi: 10.1200/JCO.19.01455. PMID: 31821109;  PMCID: PMC7007289.
  29. Denkert C, Seither F, Schneeweiss A, Link T, Blohmer JU, Just M, et al. Clinical and molecular characteristics of HER2-low-positive breast cancer: pooled analysis of individual patient data from four prospective, neoadjuvant clinical trials. Lancet Oncol. 2021;22(8):1151-61. doi: 10.1016/S1470-2045(21)00301-6. PMID: 34252375.
  30. Won HS, Ahn J, Kim Y, Kim JS, Song JY, Kim HK, et al. Clinical significance of HER2-low expression in early breast cancer: a nationwide study from the Korean Breast Cancer Society. Breast Cancer Res. 2022;24(1):22. doi: 10.1186/s13058-022-01519-x. PMID: 35307014; PMCID: PMC8935777.
  31. Fernandez AI, Liu M, Bellizzi A, Brock J, Fadare O, Hanley K, et al. Examination of low ERBB2 Protein expression in breast cancer tissue. JAMA Oncol. 2022;8(4):1-4. doi: 10.1001/jamaoncol.2021.7239. PMID: 35113160; PMCID: PMC8814969.
  32. Schettini F, Chic N, Brasó-Maristany F, Paré L, Pascual T, Conte B, et al. Clinical, pathological, and PAM50 gene expression features of HER2-low breast cancer. NPJ Breast Cancer. 2021;7(1):1. doi: 10.1038/s41523-020-00208-2. PMID: 33397968; PMCID: PMC7782714.
  33. Pauzi SHM, Masir N, Yahaya A, Mohammed F, Laim NMST, Mustangin M, et al. HER2 testing by immunohistochemistry in breast cancer: A multicenter proficiency ring study. Indian J Pathol Microbiol. 2021;64(4):677. doi: 10.4103/IJPM.IJPM_983_20. PMID: 34673585.
  34. Tarantino P, Jin Q, Tayob N, Jeselsohn RM, Schnitt SJ, Vincuilla J, et al. Prognostic and biologic significance of ERBB2-low expression in early-stage breast cancer. JAMA Oncol. 2022;8(8):1177-83. doi: 10.1001/jamaoncol.2022.2286. PMID: 35737367; PMCID: PMC9227690.
  35. Angerilli V, Galuppini F, Pagni F, Fusco N, Malapelle U, Fassan M. The role of the pathologist in the next-generation era of tumor molecular characterization. Diagnostics. 2021;11(2):339. doi: 10.3390/diagnostics11020339. PMID: 33670699; PMCID: PMC7922586.
  36. Gao JJ, Cheng J, Bloomquist E, Sanchez J, Wedam SB, Singh H, et al. CDK4/6 inhibitor treatment for patients with hormone receptor-positive, HER2-negative, advanced or metastatic breast cancer: a US Food and Drug Administration pooled analysis. Lancet Oncol. 2020;21(2):250-60. doi: 10.1016/S1470-2045(19)30804-6. PMID: 31859246.
  37. Baselga J, Cortés J, Kim SB, Im SA, Hegg R, Im YH, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012;366(2):109-19. doi: 10.1056/NEJMoa1113216. PMID: 22149875; PMCID: PMC5705202.
  38. Filho OM, Viale G, Stein S, Trippa L, Yardley DA, Mayer IA, et al. Impact of HER2 heterogeneity on treatment response of early-stage HER2-positive breast cancer: Phase II neoadjuvant clinical trial of T-DM1 combined with pertuzumab. Cancer Discov. 2021;11(10):2474-87. doi: 10.1158/2159-8290.CD-20-1557. PMID: 33941592; PMCID: PMC8598376.
  39. Lopez G, Costanza J, Colleoni M, Fontana L, Ferrero S, Miozzo M, et al. Molecular insights into the classification of luminal breast cancers: The genomic heterogeneity of progesterone-negative tumors. Int J Mol Sci. 2019;20(3):E510. doi: 10.3390/ijms20030510. PMID: 30691046; PMCID: PMC6386970.
  40. Wang L, Gao S, Li D, Ran X, Sheng Z, Wu W, et al. CDK4/6 inhibitors plus endocrine therapy improve overall survival in advanced HR+/HER2− breast cancer: A meta-analysis of randomized controlled trials. Breast J. 2020;26(7):1439-43. doi: 10.1111/tbj.13703. PMID: 31828901.
  41. Hortobagyi GN, Stemmer SM, Burris HA, Yap YS, Sonke GS, Paluch-Shimon S, et al. Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive, HER2-negative advanced breast cancer. Ann Oncol Off J Eur Soc Med Oncol. 2018;29(7):1541-7. doi: 10.1093/annonc/mdy155. PMID: 29718092.
  42. Goetz MP, Toi M, Campone M, Sohn J, Paluch-Shimon S, Huober J, et al. MONARCH 3: Abemaciclib as initial therapy for advanced breast cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2017;35(32):3638-46. doi: 10.1200/JCO.2017.75.6155. PMID: 28968163.
  43. Cristofanilli M, Turner NC, Bondarenko I, Ro J, Im SA, Masuda N, et al. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Lancet Oncol. 2016;17(4):425-39. doi: 10.1016/S1470-2045(15)00613-0. PMID: 26947331.
  44. Martin M, Zielinski C, Ruiz-Borrego M, Carrasco E, Turner N, Ciruelos EM, et al. Palbociclib in combination with endocrine therapy versus capecitabine in hormonal receptor-positive, human epidermal growth factor 2-negative, aromatase inhibitor-resistant metastatic breast cancer: a phase III randomised controlled trial—PEARL. Ann Oncol. 2021;32(4):488-99. doi: 10.1016/j.annonc.2020.12.013. PMID: 33385521.
  45. Park YH, Kim TY, Kim GM, Kang SY, Park IH, Kim JH, et al. Palbociclib plus exemestane with gonadotropin-releasing hormone agonist versus capecitabine in premenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer (KCSG-BR15-10): a multicentre, open-label, randomised, phase 2 trial. Lancet Oncol. 2019;20(12):1750-9. doi: 10.1016/S1470-2045(19)30565-0. PMID: 31668850.
  46. Dawood SS, Brzozowski K. Efficacy of CDK4/6i in the visceral crisis setting: Result from a real-world database. J Clin Oncol. 2021;39(15_suppl):1047. doi: 10.1200/JCO.2021.39.15_suppl.1047.
  47. SABCS 2022: Primary results from the randomized Phase II RIGHT Choice trial of premenopausal patients with aggressive HR+/HER2− advanced breast cancer treated with ribociclib + endocrine therapy vs physician’s choice combination chemotherapy [Internet]. [cited at: 2023 Apr 26] Available from: https://clin.larvol.com/abstract-detail/SABCS%202022/60535039
  48. El Saghir NS, Yap YS, Eralp Y, Im SA, Azim HA, Rihani J, et al. Outcomes with first-line (1L) ribociclib (RIB) + endocrine therapy (ET) vs physician’s choice combination chemotherapy (combo CT) by age in pre/perimenopausal patients (pts) with aggressive HR+/HER2− advanced breast cancer (ABC): A subgroup analysis of the RIGHT Choice trial. J Clin Oncol. 2023;41(16_suppl):1063. doi: 10.1200/JCO.2023.41.16_suppl.1063.
  49. Yap YS, Im SA, Lu YS, Azim HA, Eralp Y, Kanakasetty GB, et al. First-line (1L) ribociclib (RIB) + endocrine therapy (ET) vs combination chemotherapy (combo CT) in HR+/HER2− advanced breast cancer (ABC): A post hoc analysis of Asian and non-Asian patients (pts) from the phase II RIGHT choice trial. Ann Oncol. 2023;34:S1488. doi: 10.1016/j.annonc.2023.10.192.
  50. Dawood S, Konstantionva M, Dent R, Perazzo F, Kim SB, Villarreal-Garza C, et al. Optimizing treatment selection, and sequencing decisions for management of HR-positive, HER2-negative advanced breast cancer - Proceedings from breast cancer expert group meeting. BMC Proc. 2021;15(Suppl 10):15. doi: 10.1186/s12919-021-00224-5. PMID: 34372853; PMCID: PMC8351081.
  51. Robertson JFR, Bondarenko IM, Trishkina E, Dvorkin M, Panasci L, Manikhas A, et al. Fulvestrant 500 mg versus anastrozole 1 mg for hormone receptor-positive advanced breast cancer (FALCON): an international, randomised, double-blind, phase 3 trial. Lancet Lond Engl. 2016;388(10063):2997-3005. doi: 10.1016/S0140-6736(16)32389-3. PMID: 27908454.
  52. Kalinsky K, Accordino MK, Chiuzan C, Mundi PS, Trivedi MS, Novik Y, et al. A randomized, phase II trial of fulvestrant or exemestane with or without ribociclib after progression on anti-estrogen therapy plus cyclin-dependent kinase 4/6 inhibition (CDK 4/6i) in patients (pts) with unresectable or hormone receptor–positive (HR+), HER2-negative metastatic breast cancer (MBC): MAINTAIN trial. J Clin Oncol. 2022;40(17_suppl):LBA1004. doi: 10.1200/JCO.2022.40.17_suppl.LBA1004.
  53. Turner N, Howell S, Jhaveri K, Gomez H, Toi M, Hu X, et al. A phase III trial of capivasertib and fulvestrant versus placebo and fulvestrant in patients with HR+/HER2− breast cancer (CAPItello-291). Ann Oncol. 2020;31:S388-9. doi: 10.1016/j.annonc.2020.08.452.
  54. Bidard FC, Kaklamani VG, Neven P, Streich G, Montero AJ, Forget F, et al. Elacestrant (oral selective estrogen receptor degrader) versus standard endocrine therapy for estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: Results from the randomized phase III EMERALD trial. J Clin Oncol. 2022;40(28):3246-56. doi: 10.1200/JCO.22.00338.
  55. Helwick C. Camizestrant improves progression-free survival in advanced breast cancer - The ASCO Post. [Internet] [cited at: 2023 Apr 26] Available from: https://ascopost.com/issues/january-25-2023/camizestrant-improves-progression-free-survival-in-advanced-breast-cancer/
  56. Modi S, Jacot W, Iwata H, Park YH, Losada MJV, Li W, et al. Trastuzumab deruxtecan (T-DXd) versus treatment of physician’s choice (TPC) in patients (pts) with HER2-low unresectable and/or metastatic breast cancer (mBC): Updated survival results of the randomized, phase III DESTINY-Breast04 study. Ann Oncol. 2023;34:S334-5. doi: 10.1016/j.annonc.2023.09.553.
  57. Rugo HS, Bardia A, Marmé F, Cortés J, Schmid P, Loirat D, et al. Overall survival with sacituzumab govitecan in hormone receptor-positive and human epidermal growth factor receptor 2-negative metastatic breast cancer (TROPiCS-02): a randomised, open-label, multicentre, phase 3 trial. Lancet Lond Engl. 2023;402(10411):1423-33. doi: 10.1016/S0140-6736(23)01245-X. PMID: 37633306.
  58. Rugo HS, Bardia A, Marmé F, Cortes J, Schmid P, Loirat D, et al. Sacituzumab govitecan in hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2022;40(29):3365-76. doi: 10.1200/JCO.22.01002. PMID: 36027558.
  59. Tutt A, Tovey H, Cheang MCU, Kernaghan S, Kilburn L, Gazinska P, et al. Carboplatin in BRCA1/2-mutated and triple-negative breast cancer BRCAness subgroups: the TNT trial. Nat Med. 2018;24: doi: 10.1038/s41591-018-0009-7. PMID: 29713086; PMCID: PMC6372067.
  60. Telli ML, Timms KM, Reid J, Hennessy B, Mills GB, Jensen KC, et al. Homologous recombination deficiency (HRD) score predicts response to platinum-containing neoadjuvant chemotherapy in patients with triple-negative breast cancers. Clin Cancer Res Off J Am Assoc Cancer Res. 2016;22(15):3764-73. doi: 10.1158/1078-0432.CCR-15-2477. PMID: 26957554; PMCID: PMC6773427.
  61. Schmid P, Rugo HS, Adams S, Schneeweiss A, Barrios CH, Iwata H, et al. Atezolizumab plus nab-paclitaxel as first-line treatment for unresectable, locally advanced or metastatic triple-negative breast cancer (IMpassion130): updated efficacy results from a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2020;21(1):44-59. doi: 10.1016/S1470-2045(19)30689-8. PMID: 31786121.
  62. Cortes J, Cescon DW, Rugo HS, Nowecki Z, Im SA, Yusof MM, et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): a randomised, placebo-controlled, double-blind, phase 3 clinical trial. Lancet. 2020;396(10265):1817-28. doi: 10.1016/S0140-6736(20)32531-9. PMID: 33278935.
  63. Robson ME, Tung N, Conte P, Im SA, Senkus E, Xu B, et al. OlympiAD final overall survival and tolerability results: Olaparib versus chemotherapy treatment of physician’s choice in patients with a germline BRCA mutation and HER2-negative metastatic breast cancer. Ann Oncol. 2019;30(4):558-66. doi: 10.1093/annonc/mdz012. PMID: 30689707; PMCID: PMC6503629.
  64. Litton JK, Hurvitz SA, Mina LA, Rugo HS, Lee KH, Gonçalves A, et al. Talazoparib versus chemotherapy in patients with germline BRCA1/2-mutated HER2-negative advanced breast cancer: final overall survival results from the EMBRACA trial. Ann Oncol. 2020;31(11):1526-35. doi: 10.1016/j.annonc.2020.08.2098. PMID: 32828825; PMCID: PMC10649377.
  65. Miles DW, Diéras V, Cortés J, Duenne AA, Yi J, O’Shaughnessy J. First-line bevacizumab in combination with chemotherapy for HER2-negative metastatic breast cancer: pooled and subgroup analyses of data from 2447 patients. Ann Oncol. 2013;24(11):2773-80. doi: 10.1093/annonc/mdt276. PMID: 23894038.
  66. Bardia A, Messersmith WA, Kio EA, Berlin JD, Vahdat L, Masters GA, et al. Sacituzumab govitecan, a Trop-2-directed antibody-drug conjugate, for patients with epithelial cancer: final safety and efficacy results from the phase I/II IMMU-132-01 basket trial. Ann Oncol. 2021;32(6):746-56. doi: 10.1016/j.annonc.2021.03.005. PMID: 33741442.
  67. Bardia A, Hurvitz SA, Tolaney SM, Loirat D, Punie K, Oliveira M, et al. Sacituzumab govitecan in metastatic triple-negative breast cancer. N Engl J Med. 2021;384(16):1529-41. doi: 10.1056/NEJMoa2028485. PMID: 33882206.
  68. Martín M, Zielinski C, Ruiz-Borrego M, Carrasco E, Ciruelos EM, Muñoz M, et al. Overall survival with palbociclib plus endocrine therapy versus capecitabine in postmenopausal patients with hormone receptor-positive, HER2-negative metastatic breast cancer in the PEARL study. Eur J Cancer. 2022;168:12-24. doi: 10.1016/j.ejca.2022.03.006. PMID: 35429901.
  69. Johnston S, Martin M, Di Leo A, Im SA, Awada A, Forrester T, et al. MONARCH 3 final PFS: a randomized study of abemaciclib as initial therapy for advanced breast cancer. NPJ Breast Cancer. 2019;5:5. doi: 10.1038/s41523-018-0097-z. PMID: 30675515; PMCID: PMC6336880.
  70. Slamon DJ, Neven P, Chia S, Fasching PA, De Laurentiis M, Im SA, et al. Phase III randomized study of ribociclib and fulvestrant in hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: MONALEESA-3. J Clin Oncol. 2018;36(24):2465-72. doi: 10.1200/JCO.2018.78.9909. PMID: 29860922.
  71. Slamon DJ, Neven P, Chia S, Jerusalem G, De Laurentiis M, Im S, et al. Ribociclib plus fulvestrant for postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer in the phase III randomized MONALEESA-3 trial: updated overall survival. Ann Oncol. 2021;32(8):1015-24. doi: 10.1016/j.annonc.2021.05.353. PMID: 34102253.
  72. Lu YS, Im SA, Colleoni M, Franke F, Bardia A, Cardoso F, et al. Updated overall survival of ribociclib plus endocrine therapy versus endocrine therapy alone in pre- and perimenopausal patients with HR+/HER2- advanced breast cancer in MONALEESA-7: A phase III randomized clinical trial. Clin Cancer Res. 2022;28(5):851-9. doi: 10.1158/1078-0432.CCR-21-3032. PMID: 34965945; PMCID: PMC9377723.
  73. Bonneterre J, Thürlimann B, Robertson JF, Krzakowski M, Mauriac L, Koralewski P, et al. Anastrozole versus tamoxifen as first-line therapy for advanced breast cancer in 668 postmenopausal women: results of the Tamoxifen or Arimidex randomized group efficacy and tolerability study. J Clin Oncol. 2000;18(22):3748-57. doi: 10.1200/JCO.2000.18.22.3748. PMID: 11078487.
  74. Nabholtz JM, Buzdar A, Pollak M, Harwin W, Burton G, Mangalik A, et al. Anastrozole is superior to tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: results of a North American multicenter randomized trial. Arimidex Study Group. J Clin Oncol. 2000;18(22):3758-67. doi: 10.1200/JCO.2000.18.22.3758. PMID: 11078488.
  75. Piccart-Gebhart MJ, Burzykowski T, Buyse M, Sledge G, Carmichael J, Lück HJ, et al. Taxanes alone or in combination with anthracyclines as first-line therapy of patients with metastatic breast cancer. J Clin Oncol. 2008;26(12):1980-6. doi: 10.1200/JCO.2007.10.8399. PMID: 18421049.
  76. Royce M, Bachelot T, Villanueva C, Özgüroglu M, Azevedo SJ, Cruz FM, et al. Everolimus plus endocrine therapy for postmenopausal women with estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: A Clinical Trial. JAMA Oncol. 2018;4(7):977-84. doi: 10.1001/jamaoncol.2018.0060. PMID: 29566104; PMCID: PMC5885212.
  77. DeMichele A, Cristofanilli M, Brufsky A, Liu X, Mardekian J, McRoy L, et al. Comparative effectiveness of first-line palbociclib plus letrozole versus letrozole alone for HR+/HER2- metastatic breast cancer in US real-world clinical practice. Breast Cancer Res. 2021;23(1):37. doi: 10.1186/s13058-021-01409-8. PMID: 33761995; PMCID: PMC7989035.
  78. Beck JT, Hortobagyi GN, Campone M, Lebrun F, Deleu I, Rugo HS, et al. Everolimus plus exemestane as first-line therapy in HR+, HER2 advanced breast cancer in BOLERO-2. Breast Cancer Res Treat. 2014;143(3):459-67. doi: 10.1007/s10549-013-2814-5. PMID: 24362951; PMCID: PMC3907668.
  79. Turner NC, Slamon DJ, Ro J, Bondarenko I, Im SA, Masuda N, et al. Overall survival with palbociclib and fulvestrant in advanced breast cancer. N Engl J Med. 2018;379(20):1926-36. doi: 10.1056/NEJMoa1810527. PMID: 30345905.
  80. André F, Ciruelos EM, Juric D, Loibl S, Campone M, Mayer IA, et al. Alpelisib plus fulvestrant for PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: final overall survival results from SOLAR-1. Ann Oncol. 2021;32(2):208-17. doi: 10.1016/j.annonc.2020.11.011. PMID: 33246021.
  81. Robson M, Im SA, Senkus E, Xu B, Domchek SM, Masuda N, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N Engl J Med. 2017;377(6):523-33. doi: 10.1056/NEJMoa1706450. PMID: 28578601.
  82. Litton JK, Rugo HS, Ettl J, Hurvitz SA, Gonçalves A, Lee KH, et al. Talazoparib in patients with advanced breast cancer and a germline BRCA mutation. N Engl J Med. 2018;379(8):753-63. doi: 10.1056/NEJMoa1802905. PMID: 30110579; PMCID: PMC10600918.
  83. Safra T, Kaufman B, Kadouri L, Efrat Ben-Baruch N, Ryvo L, Nisenbaum B, et al. Everolimus plus letrozole for treatment of patients with HR+, HER2- advanced breast cancer progressing on endocrine therapy: An open-label, phase II trial. Clin Breast Cancer. 2018;18(2):e197-203. doi: 10.1016/j.clbc.2017.09.004. PMID: 29097108.
  84. Cazzaniga ME, Airoldi M, Arcangeli V, Artale S, Atzori F, Ballerio A, et al. Efficacy and safety of everolimus and exemestane in hormone-receptor positive (HR+) human-epidermal-growth-factor negative (HER2-) advanced breast cancer patients: New insights beyond clinical trials. The EVA study. Breast Edinb Scotl. 2017;35:115-21. doi: 10.1016/j.breast.2017.06.043. PMID: 28711793.
  85. Tesch H, Stoetzer O, Decker T, Kurbacher CM, Marmé F, Schneeweiss A, et al. Efficacy and safety of everolimus plus exemestane in postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer: Results of the single-arm, phase IIIB 4EVER trial. Int J Cancer. 2019;144(4):877-85. doi: 10.1002/ijc.31738. PMID: 29992557; PMCID: PMC6587781.
  86. Jerusalem G, de Boer RH, Hurvitz S, Yardley DA, Kovalenko E, Ejlertsen B, et al. Everolimus plus exemestane vs everolimus or capecitabine monotherapy for estrogen receptor-positive, HER2-negative advanced breast cancer: The BOLERO-6 randomized clinical trial. JAMA Oncol. 2018;4(10):1367-74. doi: 10.1001/jamaoncol.2018.2262. PMID: 29862411; PMCID: PMC6233772.
  87. Jhaveri KL, Goldman JW, Hurvitz SA, Guerrero-Zotano A, Unni N, Brufsky A, et al. Neratinib plus fulvestrant plus trastzuzumab (N+F+T) for hormone receptor-positive (HR+), HER2-negative, HER2-mutant metastatic breast cancer (MBC): Outcomes and biomarker analysis from the SUMMIT trial. J Clin Oncol. 2022;40(16_suppl):1028. doi: 10.1200/JCO.2022.40.16_suppl.1028.
  88. Sledge GW, Toi M, Neven P, Sohn J, Inoue K, Pivot X, et al. The effect of abemaciclib plus fulvestrant on overall survival in hormone receptor-positive, ERBB2-negative breast cancer that progressed on endocrine therapy-MONARCH 2: A randomized clinical trial. JAMA Oncol. 2020;6(1):116-24. doi: 10.1001/jamaoncol.2019.4782. PMID: 31563959; PMCID: PMC6777264.
  89. Miles D, Gligorov J, André F, Cameron D, Schneeweiss A, Barrios C, et al. Primary results from IMpassion131, a double-blind, placebo-controlled, randomised phase III trial of first-line paclitaxel with or without atezolizumab for unresectable locally advanced/metastatic triple-negative breast cancer. Ann Oncol. 2021;32(8):994-1004. doi: 10.1016/j.annonc.2021.05.801. PMID: 34219000.
  90. Winer EP, Lipatov O, Im SA, Goncalves A, Muñoz-Couselo E, Lee KS, et al. Pembrolizumab versus investigator-choice chemotherapy for metastatic triple-negative breast cancer (KEYNOTE-119): a randomised, open-label, phase 3 trial. Lancet Oncol. 2021;22(4):499-511. doi: 10.1016/S1470-2045(20)30754-3. PMID: 33676601.
  91. Pistilli B, Wildiers H, Hamilton EP, Ferreira AA, Dalenc F, Vidal M, et al. Clinical activity of MCLA-128 (zenocutuzumab) in combination with endocrine therapy (ET) in ER+/HER2-low, non-amplified metastatic breast cancer (MBC) patients (pts) with ET-resistant disease who had progressed on a CDK4/6 inhibitor (CDK4/6i). J Clin Oncol. 2020;38(15_suppl):1037. doi: 10.1200/JCO.2020.38.15_suppl.1037.
  92. Hamilton EP, Petit T, Pistilli B, Goncalves A, Ferreira AA, Dalenc F, et al. Clinical activity of MCLA-128 (zenocutuzumab), trastuzumab, and vinorelbine in HER2 amplified metastatic breast cancer (MBC) patients (pts) who had progressed on anti-HER2 ADCs. J Clin Oncol. 2020;38(15_suppl):3093. doi: 10.1200/JCO.2020.38.15_suppl.3093.
  93. Hamilton E, Shapiro CL, Petrylak D, Boni V, Martin M, Conte GD, et al. Trastuzumab deruxtecan (T-DXd; DS-8201) with nivolumab in patients with HER2-expressing, advanced breast cancer: A 2-part, phase 1b, multicenter, open-label study. Cancer Res. 2021;81(4_Supplement):PD3-07. doi: 10.1158/1538-7445.SABCS20-PD3-07.
  94. Gianni L, Bisagni G, Colleoni M, Del Mastro L, Zamagni C, Mansutti M, et al. Neoadjuvant treatment with trastuzumab and pertuzumab plus palbociclib and fulvestrant in HER2-positive, ER-positive breast cancer (NA-PHER2): an exploratory, open-label, phase 2 study. Lancet Oncol. 2018;19(2):249-56. doi: 10.1016/S1470-2045(18)30001-9. PMID: 29326029.
  95. Chick RC, Clifton GT, Hale DF, Vreeland TJ, Hickerson AT, Kemp Bohan PM, et al. Subgroup analysis of nelipepimut-S plus GM-CSF combined with trastuzumab versus trastuzumab alone to prevent recurrences in patients with high-risk, HER2 low-expressing breast cancer. Clin Immunol. 2021;225:108679. doi: 10.1016/j.clim.2021.108679. PMID: 33485895.
  96. Krop IE, LoRusso P, Miller KD, Modi S, Yardley D, Rodriguez G, et al. A phase II study of trastuzumab emtansine in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer who were previously treated with trastuzumab, lapatinib, an anthracycline, a taxane, and capecitabine. J Clin Oncol Off J Am Soc Clin Oncol. 2012;30(26):3234-41. doi: 10.1200/JCO.2011.40.5902. PMID: 22649126.
  97. Gianni L, Lladó A, Bianchi G, Cortes J, Kellokumpu-Lehtinen PL, Cameron DA, et al. Open-label, phase II, multicenter, randomized study of the efficacy and safety of two dose levels of Pertuzumab, a human epidermal growth factor receptor 2 dimerization inhibitor, in patients with human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2010;28(7):1131-7. doi: 10.1200/JCO.2009.24.1661. PMID: 20124183; PMCID: PMC4979215.
  98. Perez EA, Reinholz MM, Hillman DW, Tenner KS, Schroeder MJ, Davidson NE, et al. HER2 and chromosome 17 effect on patient outcome in the N9831 adjuvant trastuzumab trial. J Clin Oncol. 2010;28(28):4307-15. doi: 10.1200/JCO.2009.26.2154. PMID: 20697084; PMCID: PMC2954132.
  99. AstraZeneca. A Phase 1b multicentre, open-label, modular, dose-finding and dose-expansion study to explore the safety, tolerability, pharmacokinetics and anti-tumour activity of trastuzumab deruxtecan (T-DXd) in combination with other anti-cancer agents in patients with metastatic HER2-low breast cancer (DESTINY-Breast08). [Internet] clinicaltrials.gov; 2022 Oct [cited 2022 Nov 7]. Report No.: NCT04556773. Available from: https://clinicaltrials.gov/ct2/show/NCT04556773
  100. Schmid P, Jung KH, Wysocki PJ, Jassem J, Ma CX, Fernandes R, et al. Datopotamab deruxtecan (Dato-DXd) + durvalumab (D) as first-line (1L) treatment for unresectable locally advanced/metastatic triple-negative breast cancer (a/mTNBC): Initial results from BEGONIA, a phase Ib/II study. Ann Oncol. 2022;33:S199. doi: 10.1016/j.annonc.2022.03.185.
  101. Franchina M, Pizzimenti C, Fiorentino V, Martini M, Ricciardi GRR, Silvestris N, et al. Low and ultra-low HER2 in human breast cancer: An effort to define new neoplastic subtypes. Int J Mol Sci. 2023;24(16):12795. doi: 10.3390/ijms241612795. PMID: 37628975; PMCID: PMC10454084.
  102. MacNeil IA, Burns DJ, Rich BE, Soltani SM, Kharbush S, Osterhaus NG, et al. New HER2-negative breast cancer subtype responsive to anti-HER2 therapy identified. J Cancer Res Clin Oncol. 2020;146(3):605-19. doi: 10.1007/s00432-020-03144-7. PMID: 32036454; PMCID: PMC7039866.
  103. Diéras V, Deluche E, Lusque A, Pistilli B, Bachelot T, Pierga JY, et al. Abstract PD8-02: Trastuzumab deruxtecan (T-DXd) for advanced breast cancer patients (ABC), regardless HER2 status: A phase II study with biomarkers analysis (DAISY). Cancer Res. 2022;82(4_Supplement): PD8-02. doi: 10.1158/1538-7445.SABCS21-PD8-02.
  104. Bose R, Kavuri SM, Searleman AC, Shen W, Shen D, Koboldt DC, et al. Activating HER2 mutations in HER2 gene amplification negative breast cancer. Cancer Discov. 2013;3(2):224-37. doi: 10.1158/2159-8290.CD-12-0349. PMID: 23220880; PMCID: PMC3570596.
  105. Chen Z, Jia H, Zhang H, Chen L, Zhao P, Zhao J, et al. Is HER2 ultra-low breast cancer different from HER2 null or HER2 low breast cancer? A study of 1363 patients. Breast Cancer Res Treat. 2023;202(2):313-23. doi: 10.1007/s10549-023-07079-8. PMID: 37639064; PMCID: PMC10505593.