Trastuzumab deruxtecan and the evolving HER2-low breast cancer landscape 

VJOncology is excited to present the latest data and developments in the HER2-low breast cancer field, with comments from experts Paolo Tarantino, Mattia Rediti, and Rani Bansal

Practice-changing results of the DESTINY-Breast04 trial (NCT03734029) presented at the American Society of Clinical Oncology (ASCO) 2022 Annual Meeting in June 2022 led to the approval of the human epidermal growth factor receptor 2 (HER2)-targeting antibody-drug conjugate (ADC) trastuzumab deruxtecan (T-DXd) for patients with unresectable or metastatic HER2-low breast cancer in August.1 

The approval of the first therapy for patients with HER2-low breast cancer, defined as cancer that is immunohistochemically (IHC) 1+ or 2+ but lacks HER2 gene amplification as measured by in situ hybridization (ISH),2 has garnered a large amount of interest, as HER2-low cancer accounts for 50-55% of all primary breast tumors.3 Previously HER2 status was considered either positive or negative; HER2+ defined as IHC 2+ or 3+ with ISH measurable HER2 gene amplification, and HER2- as IHC0, 1+ or 2+ and ISH negative,4 with HER2-targeted agents used only in the former3,5.

The randomized, multicenter, open-label Phase III DESTINY-Breast04 trial enrolled 557 adult patients with unresectable or metastatic HER2-low breast cancer, of which 494 were hormone receptor-positive (HR+) and 63 hormone receptor-negative (HR-).6 373 were randomized to receive T-DXd by intravenous infusion every three weeks while 184 received physician’s choice of chemotherapy.6 

In all patients, the median progression-free survival (PFS) was 9.9 months versus 5.1 months for T-DXd and physician’s choice, respectively (hazard ratio [HR] = 0.50; P<0.001), and overall survival (OS) was 23.4 months and 16.8 months, respectively, (HR = 0.64; P=0.001).6 In the HR+ group the median PFS was 10.1 months versus 5.4 months, respectively, (HR = 0.51; P<0.001), and OS 23.9 months versus 17.5 months, respectively (HR = 0.64; P=0.003).6 

The most common reported adverse events in patients receiving T-DXd are nausea, fatigue, alopecia, vomiting, constipation, decreased appetite, musculoskeletal pain, and diarrhea.1 The prescribing information includes a boxed warning on the risk of interstitial lung disease (ILD) and embryo-fetal toxicity, thus it is not recommended for women who are pregnant.1 

Drug-related ILD/pneumonitis is a significant adverse event related to T-DXd, with a recent pooled analysis of nine Phase I and II monotherapy studies involving a total of 1150 heavily pretreated patients, 510 (44.3%) of whom had breast cancer, suggesting the overall incidence of adjudicated drug-related ILD/pneumonitis was 15.4%.7 Such cases were predominantly low grade with 77.4% of cases being grade 1 or 2, and just 2.2% of cases grade 5.7 Overall, 87.0%  of these events occurred within 12 months of starting TDX-d, with a median time to onset of 5.4 months (range, <0.1-46.8 months). Notably, the median time to grade 5 onset was shorter, at 3.2 months (range, <0.1-20.8 months).7 

Incidences of ILD/pneumonitis in the recently reported Phase III randomized DESTINY-Breast03 trial, evaluating T-DXd as a second-line treatment in patients with HER2-positive metastatic breast cancer, were lower than those reported in the pooled analysis; 10.5% of patients (27/257) treated with T-DXd experienced adjudicated drug-related ILD/pneumonitis, 92.6% of cases were grade 1 or 2 and there were no grade 4 or 5 events.7,8 Possible reasons for this posited by the authors of the pooled analysis include that increasing awareness about this adverse event has resulted in the implementation of ILD/pneumonitis monitoring, diagnosis, and management guidelines, and that there may be a lower rate of ILD/pneumonitis in patients who are less heavily pretreated.8 

The approval brings forward the question of whether HER2-low breast cancer is a distinct biologic and prognostic subtype. According to research published by Tarantino et al., the answer is likely no.9 In their cohort study of 5235 patients with HER2- breast cancer, 2917 patients (55.7%) and 2318 patients (44.3%) had HER2-low and HER-0 (IHC 0) tumors, respectively. The results showed expression of HR was significantly more common among HER2-low cancers (2643 patients [90.6%] versus 1895 patients [81.8%], respectively; P<0.001), with the rate of HER2-low tumors increasing progressively with estrogen receptor (ER) expression (40.1% of ER-negative, 46.3% of ER-low, 55.2% of ER-moderate, 57.8% of ER-high and 62.1% of ER-very high tumors).9 

There were no statistically significant differences in pathologic complete response (pCR) rates between HER2-low and HER2-0 tumors when separately analyzing tumors based on HR expression.9 There were also no reported differences in disease-free survival, distant disease–free survival, or OS. This led the investigators to conclude that most clinicopathologic differences were associated with HR expression, that HER2-low expression has no prognostic significance when adjusting for HR status and therefore the data do not support HER2-low as a distinct biologic subtype of breast cancer.9 

“What we are learning basically is that HER2-low breast cancer is not a distinct subtype of breast cancer. The biology is really related to, among non-amplified tumors, the hormone receptor expressions and so triple-negative tumors have similar biology, similar PAM50 profile, regardless of HER2-low expression,”

stated Paolo Tarantino, MD, Dana-Farber Cancer Institute, Boston, MA, one of the study authors at the European Society for Medical Oncology (ESMO) 2022 Congress. PAM50 is a 50-gene signature that classifies breast cancer into five molecular intrinsic subtypes, each with its individual biological properties and prognoses.10 

Similar results were recently reported from the Metastatic breast cancer (MBC)-Registry of the Austrian Study Group of Medical Tumor Therapy (AGMT), in which low HER2 expression did not significantly influence OS in either the HR+ (HR 0.89; 95% CI 0.74–1.05; P=0.171) nor the TNBC subgroup (HR 0.92; 95% CI 0.68–1.25; P = 0.585) when compared to HER2-0 disease.3 The study included 1,973 patients. 

Moreover, at the San Antonio Breast Cancer Symposium (SABCS) 2022, Rani Bansal, MD, Duke Cancer Center, Durham, NC presented an investigation into the genomic and transcriptomic landscape of HER2-low breast cancer involving 4,000 samples from the Caris Life Sciences database. She commented:

“We looked at all those samples to see if there were any differences in the genomic landscape or mutation differences between HER2-low samples versus HER2-0, and we actually saw that there really wasn’t significant differences in terms of mutational burden or even markers of immune response… Overall our data supports that HER2-low is not a separate entity and all the samples were pretty similar in terms of their genomic landscape.” 

Regardless of whether HER2-low is or is not a distinct subtype, the DESTINY-Breast04 trial in patients with HER2-low cancer highlights that HER2-low is a critical biomarker of response to T-DXd, as outcomes were not affected by patient history or disease characteristics, including prior lines of chemotherapy or CDK4/6 inhibitor treatment and baseline central nervous system (CNS) metastases.11 

The approval has also presented a further challenge; whether IHC is reliable enough for the identification and selection of HER2-low breast cancer patients for treatment with targeted agents, including T-DXd.12 HER2 is expressed on all breast cancer and normal breast cells, so to differentiate between malignancy and regular tissue, IHC assays are calibrated to detect HER2-amplified tumors with high expression levels13 100–10,000 fold above normal breast samples.10 Xu et al. recently published research based on mRNA expression suggesting that tumors with no detectable HER2 by IHC (ie, IHC 0) have a range of HER2 mRNA expression, with some ICH 0 tumors having mRNA levels greater than or equal to some IHC 1+ or 2+ cancers.13 Moreover, they noted that the range of HER2 mRNA expression exceeded the limited range detectable by IHC and thus they suggest a molecular method of defining HER2-low cancers may better serve treatment decision-making. 13  

There have also been concerns raised about the inter-observer agreement on HER2 scoring by IHC, especially in the 0 and 1+ cases, with a recently published study from the College of American Pathologists finding just 26% concordance between ICH 0 and 1+ on breast cancer biopsies, versus 58% concordance between ICH 2+ and 3+.14 This result led the investigators to conclude that, using a current standard HER2 IHC assay, the scoring accuracy in the low range (ICH 0 and 1+) was poor and could lead to the misassignment of many patients for treatment with T-DXd.14 

Commenting on HER2-low breast cancer at the ESMO 2022 Congress, Mattia Rediti, MD, Institut Jules Bordet, Anderlecht, Belgium, stated:

“As a subtype I think it is very fluid and would be modified by other testing, because for the moment we are simply testing the immunohistochemistry, but I believe that integrating this with gene expression, for instance, would improve the selection of the patients and probably expand, even, this population that may benefit from treatment.” 

A further trial, Phase III DESTINY-Breast06 (NCT04494425), is also now investigating T-DXd versus investigator’s choice chemotherapy in patients with ultra-low HER2 breast cancer, defined as those who score IHC-0 with incomplete and faint staining in ≤10% of tumor cells.15 The trial is based on reports that subsets of HER2- patients have benefited from anti-HER2 therapy, which some experts suggest may be due to ultra-low HER2 expression, while others postulate it may be the result of intra-tumor heterogeneity.15 

Overall, the approval of T-DXd brings hope for HER2-low breast cancer patients. Yet it also presents challenges, particularly around patient selection and testing, that must be overcome to maximize the potential benefit in this population.  


  1. FDA Approves First Targeted Therapy for HER2-Low Breast Cancer [Internet]. U.S. Food and Drug Administration; 2022 [cited 2022Dec8]. Available from:  
  1. Zhang H, Katerji H, Turner BM, Hicks DG. HER2-Low Breast Cancers: New Opportunities and Challenges. American Journal of Clinical Pathology. 2021Sep14;157(3):328–36.  
  1. Gampenrieder SP, Rinnerthaler G, Tinchon C, et al. Landscape of her2-low metastatic breast cancer (MBC): Results from the Austrian AGMT_MBC-registry. Breast Cancer Research. 2021Dec14;23(1).  
  1. Wolff AC, Hammond ME, Allison KH, 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. Archives of Pathology & Laboratory Medicine. 2018May30;142(11):1364–82.  
  1. Fehrenbacher L, Cecchini RS, Geyer Jr CE, 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+. Journal of Clinical Oncology. 2020Feb10;38(5):444–53.  
  1. Modi S, Jacot W, Yamashita T, et al. Trastuzumab Deruxtecan in previously treated HER2-low advanced breast cancer. New England Journal of Medicine. 2022Jul7;387(1):9–20.  
  1. Powell CA, Modi S, Iwata H, Takahashi S, Smit EF, Siena S, et al. Pooled analysis of drug-related interstitial lung disease and/or pneumonitis in nine trastuzumab deruxtecan monotherapy studies. ESMO Open. 2022Aug11;7(4):100554.   
  1. Cortés J, Kim S-B, Chung W-P, Im S-A, Park YH, Hegg R, et al. Trastuzumab Deruxtecan versus Trastuzumab Emtansine for breast cancer. New England Journal of Medicine. 2022Mar24;386(12):1143–54.   
  1. Tarantino P, Jin Q, Tayob N, et al. Prognostic and biologic significance of erbb2-low expression in early-stage breast cancer. JAMA Oncology. 2022Jun23. 
  1. Kensler KH, Sankar VN, Wang J, et al. PAM50 molecular intrinsic subtypes in the nurses’ health study cohorts. Cancer Epidemiology, Biomarkers & Prevention. 2019Apr1;28(4):798–806.  
  1. Harbeck N, Modi S, Jacot W, et al. Trastuzumab deruxtecan vs treatment of physician’s choice in patients with HER2-low unresectable and/or metastatic breast cancer: subgroup analyses from DESTINY-Breast04. Presented at 2022 San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX. LBA-3. 
  1. Baez-Navarro X, Salgado R, Denkert C, et al. Selecting patients with HER2-low breast cancer: Getting out of the tangle. European Journal of Cancer. 2022Sep19;175:187–92.  
  1. Xu K, Bayani J, Mallon E, et al. Discordance between immunohistochemistry and ERB-B2 receptor tyrosine kinase 2 mrna to determine human epidermal growth factor receptor 2 low status for breast cancer. The Journal of Molecular Diagnostics. 2022May5;24(7):775–83.  
  1. Fernandez AI, Liu M, Bellizzi A, et al. Examination of low ERBB2 protein expression in breast cancer tissue. JAMA Oncology. 2022Feb3;8(4):607.   
  2. Venetis K, Crimini E, Sajjadi E, et al. HER2 low, ultra-low, and novel complementary biomarkers: Expanding the spectrum of HER2 positivity in breast cancer. Frontiers in Molecular Biosciences. 2022Mar15;9. 

Written by Blanka Awtani