China Oncology ›› 2023, Vol. 33 ›› Issue (2): 181-190.doi: 10.19401/j.cnki.1007-3639.2023.02.012
• Review • Previous Articles
Received:
2022-05-26
Revised:
2022-11-21
Online:
2023-02-28
Published:
2023-03-22
Contact:
ZHANG Jian
CLC Number:
GUO Qing, ZHANG Jian. Advances in targeted therapy for HER2-low breast cancer[J]. China Oncology, 2023, 33(2): 181-190.
Tab. 1
Summary of anti-HER2 agents and the related clinical trials of HER2-low breast cancer"
Drug | Clinical trials | Phase | Inclusion criteria | Primary outcome | Results |
---|---|---|---|---|---|
ADC | |||||
RC48-ADC | NCT04400695 | Ⅲ | Participants with HER2-low, unresectable, locally advanced, or metastatic breast cancer who had previously been treated with an anthracycline and received 1 or 2 systemic chemotherapy regimens after relapse or metastasis | PFS | Ongoing |
ARX788 | NCT05018676 | Ⅱ | Unresectable and/or metastatic HER2-low breast cancer. Patients with recurrent or metastatic disease should receive≥2 lines of systemic chemotherapy regimens; Hormone receptor-positive objects need to have received ≥2-line endocrine therapy±targeted therapy (including neoadjuvant/adjuvant therapy) | ORR | Ongoing |
A166 | CTR20181301 | Ⅰ | Patients with HER2-expressing locally advanced or metastatic solid tumors (51 HER2-positive (3+ or 2+/ISH+), 6 HER2-low (1+ or 2+/ISH-) | ORR | The efficacy of 36 HER2-positive breast cancer patients with measurable disease was evaluated; the best ORR was 59.1% (13/22) and 71.4% (10/14) in the 4.8 and 6.0 mg/kg cohorts, respectively. Corneal epitheliopathy (73.7%), blurred vision (59.6%), peripheral sensory neuropathy (26.3%), dry eye (21.1%), anemia (19.3%), and hyponatremia (19.3%) were the most common TRAEs. Corneal epitheliopathy (17.5%), hypophosphatemia (5.3%), and dry eye (5.3%) were the most common grade 3 TRAEs |
Bispecific antibody | |||||
KN026 | NCT04165993 | Ⅱ | Patients with HER2-low and hormone receptor positive MBC failed standard chemotherapy and hormone therapy; patients with HER2-low and hormone receptor negative/weak positive MBC failed standard chemotherapy | ORR; DOR | Ongoing |
ZW25 | NCT02892123 | Ⅰ | Patients with HER2-expressing cancer that was locally advanced (unresectable) or metastatic | DLTs | Ongoing |
Ertumaxomab | NCT00522457 | Ⅱ | Enrolled patients had advanced breast cancer that was ER and/or PgR positive with low HER2 expression (IHC 1+ or 2+ and FISH negative). Patients were required to have PD after hormonal therapy that included at least one aromatase inhibitor, but no prior chemotherapy for advanced disease | ORR | The evaluable population's median TTP was 65.5 days (95% CI: 43-98). Pyrexia (74.1%), headache (40.7%), chill (33.3%), and vomitting (29.6%) were the most frequently observed AEs. The majority (73.8%) of AEs were mild or moderate in severity and resolved within one day |
Vaccine | |||||
Nelipepimut-S | NCT01479244 | Ⅲ | Patients with HER2/neu-positive, node-positive, or high-risk node-negative breast cancer | Disease recurrence | At the interim analysis with the median follow-up (16.8 months), there was no discernible between-arms difference in DFS events. Imaging identified 54.1% of recurrence episodes in NP-S participants as opposed to 29.2% in the placebo group (P = 0.069). Injection-related erythema (84.3%), induration (55.8%), and pruritus (54.9%) were the most prevalent |
GP2 | NCT00524277 | Ⅱ | Breast cancer patients with tumors expressing HER2 (IHC 1-3+) who were clinically disease-free, node-positive, and high-risk node-negative were enrolled | Disease recurrence | The 5-year DFS rate in the ITT analysis was 88% (95% CI: 78%-94%) in the vaccine-eligible patients versus 81% (95% CI: 69%-89%) (P = 0.43), in the control group |
AE37 | NCT00524277 | Ⅱ | Patients with tumors expressing any level of HER2 (IHC 1-3+) who were node-positive and high-risk node-negative for breast cancer and were clinically disease-free | Disease recurrence | Relative risk decreased 12%, HR = 0.885, 95% CI: 0.472-1.659, P = 0.70; recurrence rate in the immunized group was 12.4% against 13.8% in the control group. Vaccinated patients had a 5-year DFS rate of 80.8%, compared to 79.5% for control patients. The 5-year DFS was 77.2% in patients who received the vaccine (n = 76) compared to 65.7% in those who received a placebo (n = 78) in planned subset analyses of patients with IHC 1+/2+ HER2-expressing tumors (P = 0.21). DFS was 77.7% in the vaccinated patients (n = 25) against 49.0% in the control patients (n = 25) in patients with TNBC (HER2 IHC 1+/2+ and hormone receptor negative) (P = 0.12) |
[1] |
SUNG H, FERLAY J, SIEGEL R L, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2021, 71(3): 209-249.
doi: 10.3322/caac.v71.3 |
[2] |
REN X Y, SONG Y, ZHANG Y N, et al. Prognostic significance of different molecular typing methods and immune status based on RNA sequencing in HR-positive and HER2-negative early-stage breast cancer[J]. BMC Cancer, 2022, 22(1): 548.
doi: 10.1186/s12885-022-09656-4 pmid: 35568835 |
[3] |
DENKERT C, SEITHER F, SCHNEEWEISS A, et al. Clinical and molecular characteristics of HER2-low-positive breast cancer: pooled analysis of individual patient data from four prospective, neoadjuvant clinical trials[J]. Lancet Oncol, 2021, 22(8): 1151-1161.
doi: 10.1016/S1470-2045(21)00301-6 pmid: 34252375 |
[4] |
SESHADRI R, FIRGAIRA F A, HORSFALL D J, et al. Clinical significance of HER-2/neu oncogene amplification in primary breast cancer. The South Australian Breast Cancer Study Group[J]. J Clin Oncol, 1993, 11(10): 1936-1942.
doi: 10.1200/JCO.1993.11.10.1936 pmid: 8105035 |
[5] |
SHUI R H, LIANG X Z, LI X M, et al. Hormone receptor and human epidermal growth factor receptor 2 detection in invasive breast carcinoma: a retrospective study of 12, 467 patients from 19 Chinese representative clinical centers[J]. Clin Breast Cancer, 2020, 20(1): e65-e74.
doi: 10.1016/j.clbc.2019.07.013 |
[6] |
PONDÉ N, BRANDÃO M, EL-HACHEM G, et al. Treatment of advanced HER2-positive breast cancer: 2018 and beyond[J]. Cancer Treat Rev, 2018, 67: 10-20.
doi: S0305-7372(18)30062-8 pmid: 29751334 |
[7] |
WOLFF A C, HAMMOND M E H, ALLISON K H, 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[J]. J Clin Oncol, 2018, 36(20): 2105-2122.
doi: 10.1200/JCO.2018.77.8738 pmid: 29846122 |
[8] | FEHRENBACHER L, CECCHINI R S, GEYER C E Jr, 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]. J Clin Oncol, 2020, 38(5): 444-453. |
[9] |
PINHEL I, HILLS M, DRURY S, et al. ER and HER2 expression are positively correlated in HER2 non-overexpressing breast cancer[J]. Breast Cancer Res, 2012, 14(2): R46.
doi: 10.1186/bcr3145 |
[10] |
SCHETTINI F, CHIC N, BRASÓ-MARISTANY F, et al. Clinical, pathological, and PAM50 gene expression features of HER2-low breast cancer[J]. NPJ Breast Cancer, 2021, 7(1): 1.
doi: 10.1038/s41523-020-00208-2 pmid: 33397968 |
[11] |
ZHANG G C, REN C Y, LI C, et al. Distinct clinical and somatic mutational features of breast tumors with high-, low-, or non-expressing human epidermal growth factor receptor 2 status[J]. BMC Med, 2022, 20(1): 142.
doi: 10.1186/s12916-022-02346-9 pmid: 35484593 |
[12] |
TARANTINO P, HAMILTON E, TOLANEY S M, et al. HER2-low breast cancer: pathological and clinical landscape[J]. J Clin Oncol, 2020, 38(17): 1951-1962.
doi: 10.1200/JCO.19.02488 pmid: 32330069 |
[13] |
SLAMON D J, LEYLAND-JONES B, SHAK S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2[J]. N Engl J Med, 2001, 344(11): 783-792.
doi: 10.1056/NEJM200103153441101 |
[14] |
ARTEAGA C L. Can trastuzumab be effective against tumors with low HER2/Neu (ErbB2) receptors?[J]. J Clin Oncol, 2006, 24(23): 3722-3725.
pmid: 16847283 |
[15] |
ITHIMAKIN S, DAY K C, MALIK F, et al. HER2 drives luminal breast cancer stem cells in the absence of HER2 amplification: implications for efficacy of adjuvant trastuzumab[J]. Cancer Res, 2013, 73(5): 1635-1646.
doi: 10.1158/0008-5472.CAN-12-3349 pmid: 23442322 |
[16] |
PAIK S, KIM C, WOLMARK N. HER2 status and benefit from adjuvant trastuzumab in breast cancer[J]. N Engl J Med, 2008, 358(13): 1409-1411.
doi: 10.1056/NEJMc0801440 |
[17] |
PEREZ E A, REINHOLZ M M, HILLMAN D W, et al. HER2 and chromosome 17 effect on patient outcome in the N9831 adjuvant trastuzumab trial[J]. J Clin Oncol, 2010, 28(28): 4307-4315.
doi: 10.1200/JCO.2009.26.2154 pmid: 20697084 |
[18] |
SEIDMAN A D, BERRY D, CIRRINCIONE C, et al. Randomized phase Ⅲ trial of weekly compared with every-3-weeks paclitaxel for metastatic breast cancer, with trastuzumab for all HER-2 overexpressors and random assignment to trastuzumab or not in HER-2 nonoverexpressors: final results of cancer and leukemia group B protocol 9840[J]. J Clin Oncol, 2008, 26(10): 1642-1649.
doi: 10.1200/JCO.2007.11.6699 |
[19] |
SCHNEEWEISS A, PARK-SIMON T W, ALBANELL J, et al. Phase Ⅰb study evaluating safety and clinical activity of the anti-HER3 antibody lumretuzumab combined with the anti-HER2 antibody pertuzumab and paclitaxel in HER3-positive, HER2-low metastatic breast cancer[J]. Invest New Drugs, 2018, 36(5): 848-859.
doi: 10.1007/s10637-018-0562-4 |
[20] |
WYNN C S, TANG S C. Anti-HER2 therapy in metastatic breast cancer: many choices and future directions[J]. Cancer Metastasis Rev, 2022, 41(1): 193-209.
doi: 10.1007/s10555-022-10021-x |
[21] |
GEYER C E, FORSTER J, LINDQUIST D, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer[J]. N Engl J Med, 2006, 355(26): 2733-2743.
doi: 10.1056/NEJMoa064320 |
[22] |
WORTHYLAKE R, OPRESKO L K, STEVEN WILEY H. ErbB-2 amplification inhibits down-regulation and induces constitutive activation of both ErbB-2 and epidermal growth factor receptors[J]. J Biol Chem, 1999, 274(13): 8865-8874.
doi: 10.1074/jbc.274.13.8865 pmid: 10085130 |
[23] |
PRESS M F, FINN R S, CAMERON D, et al. HER-2 gene amplification, HER-2 and epidermal growth factor receptor mRNA and protein expression, and lapatinib efficacy in women with metastatic breast cancer[J]. Clin Cancer Res, 2008, 14(23): 7861-7870.
doi: 10.1158/1078-0432.CCR-08-1056 pmid: 19047115 |
[24] |
COSTA R L B, CZERNIECKI B J. Clinical development of immunotherapies for HER2+ breast cancer: a review of HER2-directed monoclonal antibodies and beyond[J]. NPJ Breast Cancer, 2020, 6: 10.
doi: 10.1038/s41523-020-0153-3 |
[25] |
DRAGO J Z, MODI S N, CHANDARLAPATY S. Unlocking the potential of antibody-drug conjugates for cancer therapy[J]. Nat Rev Clin Oncol, 2021, 18(6): 327-344.
doi: 10.1038/s41571-021-00470-8 pmid: 33558752 |
[26] |
CORTI C, GIUGLIANO F, NICOLÒ E, et al. Antibody-drug conjugates for the treatment of breast cancer[J]. Cancers, 2021, 13(12): 2898.
doi: 10.3390/cancers13122898 |
[27] |
ENGEBRAATEN O, YAU C, BERG K, et al. RAB5A expression is a predictive biomarker for trastuzumab emtansine in breast cancer[J]. Nat Commun, 2021, 12(1): 6427.
doi: 10.1038/s41467-021-26018-z pmid: 34741021 |
[28] | BURRIS H A 3rd, RUGO H S, VUKELJA S J, et al. Phase Ⅱ study of the antibody drug conjugate trastuzumab-DM1 for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer after prior HER2-directed therapy[J]. J Clin Oncol, 2011, 29(4): 398-405. |
[29] |
KROP I E, LORUSSO P, MILLER K D, 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]. J Clin Oncol, 2012, 30(26): 3234-3241.
doi: 10.1200/JCO.2011.40.5902 |
[30] |
OGITANI Y, AIDA T, HAGIHARA K, et al. DS-8201a, A novel HER2-targeting ADC with a novel DNA topoisomerase Ⅰ inhibitor, demonstrates a promising antitumor efficacy with differentiation from T-DM1[J]. Clin Cancer Res, 2016, 22(20): 5097-5108.
doi: 10.1158/1078-0432.CCR-15-2822 |
[31] |
TALUKDAR A, KUNDU B, SARKAR D, et al. Topoisomerase Ⅰ inhibitors: challenges, progress and the road ahead[J]. Eur J Med Chem, 2022, 236: 114304.
doi: 10.1016/j.ejmech.2022.114304 |
[32] |
OGITANI Y, HAGIHARA K, OITATE M, et al. Bystander killing effect of DS-8201a, a novel anti-human epidermal growth factor receptor 2 antibody-drug conjugate, in tumors with human epidermal growth factor receptor 2 heterogeneity[J]. Cancer Sci, 2016, 107(7): 1039-1046.
doi: 10.1111/cas.2016.107.issue-7 |
[33] |
DOI T, SHITARA K, NAITO Y, et al. Safety, pharmacokinetics, and antitumour activity of trastuzumab deruxtecan (DS-8201), a HER2-targeting antibody-drug conjugate, in patients with advanced breast and gastric or gastro-oesophageal tumours: a phase 1 dose-escalation study[J]. Lancet Oncol, 2017, 18(11): 1512-1522.
doi: S1470-2045(17)30604-6 pmid: 29037983 |
[34] |
MODI, PARK H, MURTHY R K, 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]. J Clin Oncol, 2020, 38(17): 1887-1896.
doi: 10.1200/JCO.19.02318 |
[35] | DIÉRAS V, DELUCHE E, LUSQUE A, et al. Trastuzumab deruxtecan (T-DXd) for advanced breast cancer patients (ABC), regardless HER2 status: a phase Ⅱ study with biomarkers analysis (DAISY)[J]. Cancer Res, 2022, 82(4_suppl): PD8-2. |
[36] |
MODI S N, JACOT W, YAMASHITA T, et al. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer[J]. N Engl J Med, 2022, 387(1): 9-20.
doi: 10.1056/NEJMoa2203690 |
[37] | ENHERTU® significantly improved both progression-free and overall survival in DESTINY-Breast04 trial in patients with HER2 low metastatic breast cancer[EB/OL]. [2022-06-06] https://www.daiichisankyo.com/media/press_release/detail/index_4098.html. |
[38] |
TARANTINO P, CURIGLIANO G, TOLANEY S M. Navigating the HER2-low paradigm in breast oncology: new standards, future horizons[J]. Cancer Discov, 2022, 12(9): 2026-2030.
doi: 10.1158/2159-8290.CD-22-0703 |
[39] | SAURA C, THISTLETHWAITE F, BANERJI U, et al. A phase Ⅰ expansion cohorts study of SYD985 in heavily pretreated patients with HER2-positive or HER2-low metastatic breast cancer[J]. J Clin Oncol, 2018, 36(15). |
[40] |
HU X C, ZHANG J, LIU R J, et al. Phase Ⅰ study of A166 in patients with HER2-expressing locally advanced or metastatic solid tumors[J]. J Clin Oncol, 2021, 39(15_suppl): 1024.
doi: 10.1200/JCO.2021.39.15_suppl.1024 |
[41] | CARDOSO F, DIRIX L, CONTE P F, et al. Phase Ⅱ study of single agent trifunctional antibody ertumaxomab (anti-HER2 & anti-CD3) in HER2 low expressing hormone-refractory advanced breast cancer patients (ABC)[J]. Cancer Res, 2010, 70(24_suppl): P3-14-21. |
[42] |
MITTENDORF E A, LU B, MELISKO M, et al. Efficacy and safety analysis of nelipepimut-S vaccine to prevent breast cancer recurrence: a randomized, multicenter, phase Ⅲ clinical trial[J]. Clin Cancer Res, 2019, 25(14): 4248-4254.
doi: 10.1158/1078-0432.CCR-18-2867 |
[43] |
MITTENDORF E A, ARDAVANIS A, LITTON J K, et al. Primary analysis of a prospective, randomized, single-blinded phase Ⅱ trial evaluating the HER2 peptide GP2 vaccine in breast cancer patients to prevent recurrence[J]. Oncotarget, 2016, 7(40): 66192-66201.
doi: 10.18632/oncotarget.v7i40 |
[44] |
MITTENDORF E A, ARDAVANIS A, SYMANOWSKI J, et al. Primary analysis of a prospective, randomized, single-blinded phase Ⅱ trial evaluating the HER2 peptide AE37 vaccine in breast cancer patients to prevent recurrence[J]. Ann Oncol, 2016, 27(7): 1241-1248.
doi: 10.1093/annonc/mdw150 |
Viewed | ||||||
Full text |
|
|||||
Abstract |
|
|||||
沪ICP备12009617
Powered by Beijing Magtech Co. Ltd