New emerging data on adjuvant systemic therapy for stage I HER2 positive breast cancer
Editorial Commentary

New emerging data on adjuvant systemic therapy for stage I HER2 positive breast cancer

Hossameldin Abdallah1, Susanne Crocamo2, Bruno de Paula3

1Clinical Research Fellow in Cancer Early Phase Clinical Trials, Cambridge Clinical Research Centre (CCRC), University Hospitals of Cambridge NHS Foundation Trust, Cambridge, UK; 2Núcleo de Pesquisa Clínica, Hospital do Câncer III, Instituto Nacional de Câncer - INCA, , Brazil; 3School of Biosciences, Faculty of Health and Medical Sciences, University of Surrey, Guilford, UK

Correspondence to: Hossameldin Abdallah, MBBCh, MRCP (UK), PGCert Oncology. Clinical Research Fellow in Cancer Early Phase Clinical Trials, Oncology Department, Cambridge Clinical Research Centre (CCRC), University Hospitals of Cambridge NHS Foundation Trust, Keith Day Rd, Cambridge, CB2 0SL, UK. Email: Hossameldin.abdallah@nhs.net.

Comment on: Tarantino P, Tayob N, Villacampa G, et al. Adjuvant Trastuzumab Emtansine Versus Paclitaxel Plus Trastuzumab for Stage I HumanEpidermal Growth Factor Receptor 2-Positive Breast Cancer: 5-Year Results and Correlative Analyses From ATEMPT. J Clin Oncol 2024;42:3652-65.

Keywords: Trastuzumab emtansine (T-DM1); trastuzumab; paclitaxel

Submitted Feb 02, 2025. Accepted for publication May 09, 2025. Published online May 27, 2025.

doi: 10.21037/gs-2025-41

Human epidermal growth factor receptor 2 (HER2)-positive breast cancer is characterised by overexpression of HER2 proteins, which represent about 15–20% of all invasive breast cancer (1). It is associated with poor prognosis, however, the introduction of anti-HER2 directed therapies has revolutionised the treatment with improvement of the survival outcomes (2). Antibody drug conjugates (ADCs) are an innovative therapeutic approach of delivering the cytotoxic agent attached to the monoclonal antibodies improving the selectivity of the cancer cells and sparing the normal tissues (3). The efficacy of the ADCs in different indications of breast cancer treatment has inspired for testing of more ADCs compounds in trials to overcome resistance and enhance efficacy in breast and other tumour types.

Adjuvant paclitaxel in combination with trastuzumab treatment was investigated in the Adjuvant Paclitaxel and Trastuzumab (APT) trial, which was an open-label single-arm study (4). In this study, patients with HER2-positive breast cancer with tumour size up to 3 cm and node-negative were treated with paclitaxel for 12 weeks and trastuzumab for 1 year. It showed that invasive disease-free survival (iDFS) at 3 years, 7 years and 10 years were significantly positive with 98.7% [95% confidence interval (CI), 97.6–99.8%], 93.3% (95% CI, 90.4–96.2%) and 91.3% (95% CI, 88.3–94.4%), respectively (5). Based on these results, adjuvant paclitaxel with trastuzumab was recommended by the St. Gallen expert panel for node-negative, HER2-positive breast cancer with tumours between 0.5 and 2 cm in size (6).

The grade ≥2 adverse event of interest, such as neuropathy, neutropenia, diarrhoea, and allergic reaction, occurred at 13.1%, 10.6%, 13.1% and 8.6% respectively. Two patients (0.5%; 95% CI, 0.1–1.8%) had grade 3 systolic dysfunction of the left ventricle. Alopecia was expected in the majority of the patients, however, exact incidence data were not collected (4). Due to this toxicity profile in the early adjuvant setting, the use of trastuzumab emtansine (T-DM1) in the same setting was explored in the Adjuvant Trastuzumab Emtansine versus Paclitaxel Trastuzumab (ATEMPT) trial.

Designed as a phase II randomised open label study, the aim of the ATEMPT trial was to investigate the use of 1 year treatment of T-DM1 versus paclitaxel + trastuzumab (PH) (paclitaxel for 12 weeks and trastuzumab for 1 year) in patients with HER2 positive stage I (T1N0M0) breast cancer. The study was only powered to compare the clinically relevant toxicities (CRTs) between 2 arms and the efficacy in the T-DM1 arm only (7).

With a longer follow-up of 5 years, the iDFS rate remained high in the T-DM1 group. The 3-year iDFS was 97.8% (95% CI, 96.3–99.3%), and the 5-year iDFS was 97.0% (95% CI, 95.2–98.7%) (8). While this suggests strong efficacy in this patient group, it is important to note that the ATEMPT trial did not include patients with tumours larger than 2 but ≤3 cm, a subgroup that made up approximately 8.9% of the APT study population (4). The 5-year overall survival (OS) was also high at 97.8% (95% CI, 96.3–99.3%), though further follow-up is needed.

In the first published outputs, after a median follow-up of 3.8 years, there was no statistical difference between the incidence of CRTs in both arms [46% in T-DM1 arm and 47% in T-DM1 + trastuzumab arm, P=0.83). However, the toxicity profile differs considerably (Table 1) with more grade ≥2 toxicities in PH arm vs. TDM-1 as follows: neuropathy (23% vs. 11%, P=0.003), neutropenia (13% vs. 3%, P<0.001), alopecia (41% vs. 0%, P<0.001), diarrhoea (9% vs. 4%, P=0.04), and infusion-related reaction (11% vs. 5%, P=0.04). In contrast, grade ≥2 thrombocytopenia (11% vs. 1%, P<0.001) and elevated bilirubin (5% vs. 1%, P=0.04) were more common with T-DM1 (7).

Table 1

Toxicity amongst randomized arms at the ATEMPT trial [adapted from (8)]

T-DM1 arm PH arm P value
Overall CRTs rate 46% 47% 0.83
Adverse events with grade ≥2
   Neuropathy 11% 23% 0.003
   Neutropenia 3% 13% <0.001
   Alopecia 0% 41% <0.001
   Diarrhoea 4% 9% 0.04
   Infusion related reaction 5% 11% 0.04
   Thrombocytopenia 11% 1% <0.001
   Elevated bilirubin 5% 1% 0.04

CRT, clinically relevant toxicities; T-DM1, trastuzumab emtansine; PH, paclitaxel + trastuzumab.

Notably, patients who had at least one dose reduction varied between the 2 arms, with 29% of patients in the T-DM1 arm (at any point of a 1-year treatment) and 17% in PH arm (during paclitaxel 3-month treatment duration) (7). Treatment discontinuation rates due to toxicities were higher with T-DM1 than with PH (17% vs. 6%). Of those who discontinued the T-DM1 treatment, 61% switched to trastuzumab to complete the year of treatment. The probability of T-DM1 discontinuation within the first 6 months was 8.2% compared with 10.7% for discontinuation between months 6 and 12. The most common reasons for T-DM1 discontinuation were elevated liver enzymes or bilirubin (28%), neuropathy (19%), and thrombocytopenia (19%) (7).

As the ATEMPT trial demonstrated that the use of adjuvant T-DM1 in patients with stage I HER2-positive breast cancer was effective, but with differences in toxicity profiles between the 2 treatment arms, with statistically more thrombocytopenia and elevated bilirubin in the T-DM1 arm and more neuropathy, neutropenia and alopecia (currently with satisfactory control using hair cryotherapy or scalp cooling techniques) in the PH arm (9). Nevertheless, it is important to consider that the rate of dose reduction and discontinuation of T-DM1 in the trial was higher than in the PH arm, which might be a worrying fact for the efficacy of the treatment if used on a large scale in this group of patients.

Patient-reported outcome survey scores, Functional Assessment of Cancer Therapy-Breast (FACT-B), were reported to be significantly inferior in the PH arm compared to T-DM1 arm (P<0.01). However, patients were aware of the arm allocation before taking the baseline survey assessment, and said that there were no biases in the results found for overall quality of life (7).

The genomic risk data presented on the ATEMPT trial are compelling. On the other hand, HER2DXÒ (HER2 Diagnostic) genomic testing, while a promising tool for stratifying risk groups in patients with HER2-positive breast cancer, is not yet considered a standard of care due to limited prospective validation (10). The pre-established HER2DXÒ risk score cut-off was 50, which will divide the patients into 2 risk groups: high risk (50–100) and low risk (0–50) (8,11). With this cut-off score, the proportion of HER2DXÒ high- and low-risk diseases in the ATEMPT trial are 6.4% (n=12) and 93.6% (n=175) respectively. Patients with HER2DXÒ low risk showed more favourable survival outcomes with recurrence-free interval (RFI) [5-year 98.1% vs. 81.8%; hazard ratio (HR), 0.10; 95% CI, 0.02 to 0.57; P=0.01] and better iDFS (5-year 96.3% vs. 81.8%; HR, 0.20; 95% CI, 0.04 to 0.98; P=0.047) in comparison to the HER2DXÒ high risk group (8). However, in a retrospective combined analysis of HER2DXÒ tool in APT and ATEMPT trials showed a proportion of HER2DXÒ high-risk score (≥50) is 5.5%. There was a significantly high relapse risk, with HER2DXÒ high-risk disease (HR, 7.33; 95% CI, 2.29–23.47; P<0.001), but the effect on iDFS was non-significant in the same group (HR, 2.78; 95% CI, 0.97–7.95; P=0.057) (11). Hence, further studies are needed to better use the tool.

In a more pragmatic approach, besides clinical toxicities, financial toxicity can be a limiting factor on adopting a treatment widely, but especially for middle/low-income countries. A total course of treatment of adjuvant T-DM1 for 1 year as per ATEMPT trial in an average 70 kg person will cost approximately £72,000 based on the approved prices between the manufacturer company and National Institute for Health and Care Excellence (NICE) (12,13). For a typical patient, a 38-week course of combination therapy costs approximately £15,500 for trastuzumab and £9,600 for paclitaxel with a total cost of £25,100 as published by NICE in March 2002 (14-16).

We expect from the future regimens to be considered based on risk of recurrence, toxicity, and a balanced cost-benefit to be considered. For instance, the sequencing of anti-HER2-directed treatments is currently being explored in the ATEMPT 2 trial. This is an ongoing phase II study aiming to compare use of T-DM1 (every 3 weeks for 6 cycles) followed by trastuzumab (every 3 weeks for 11 cycles) vs. the standard of care of weekly paclitaxel (for 12 weeks to 4 cycles) and trastuzumab (every 3 weeks for 17 cycles) in stage I HER2 positive breast cancer, with expected time to primary completion of the trial is 5/2025. However, it would be interesting to understand if randomization is being balanced according to genomic risk, which could potentially inform future treatment selection (17).

Conclusions

T-DM1 is another option than PH as adjuvant treatment for stage I HER2-positive breast cancer. T-DM1, however, failed to show improvement in the CRTs defined by the ATEMPT trial over PH and is more expensive. It remains unclear if T-DM1 or other regimens should be better indicated for higher risk of recurrence and stage I HER2-positive breast cancer based on genomic testing such as HER2DXÒ. Future prospective trials in HER2-positive patients should incorporate risk assessment platforms, including genomic testing, to better stratify patients for next-generation therapies or optimise treatment intensity.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Gland Surgery. The article did not undergo external peer review.

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gs.amegroups.com/article/view/10.21037/gs-2025-41/coif). B.d.P. is currently employed by AstraZeneca R&D. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

  1. Modi S, Saura C, Yamashita T, et al. Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer. N Engl J Med 2020;382:610-21. [Crossref] [PubMed]
  2. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001;344:783-92. [Crossref] [PubMed]
  3. Verma S, Miles D, Gianni L, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med 2012;367:1783-91. [Crossref] [PubMed]
  4. Tolaney SM, Barry WT, Dang CT, et al. Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer. N Engl J Med 2015;372:134-41. [Crossref] [PubMed]
  5. Tolaney SM, Tarantino P, Graham N, et al. Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer: final 10-year analysis of the open-label, single-arm, phase 2 APT trial. Lancet Oncol 2023;24:273-85. [Crossref] [PubMed]
  6. Curigliano G, Burstein HJ, Winer EP, 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. Ann Oncol 2017;28:1700-12. [Crossref] [PubMed]
  7. Tolaney SM, Tayob N, Dang C, et al. Adjuvant Trastuzumab Emtansine Versus Paclitaxel in Combination With Trastuzumab for Stage I HER2-Positive Breast Cancer (ATEMPT): A Randomized Clinical Trial. J Clin Oncol 2021;39:2375-85. [Crossref] [PubMed]
  8. Tarantino P, Tayob N, Villacampa G, et al. Adjuvant Trastuzumab Emtansine Versus Paclitaxel Plus Trastuzumab for Stage I Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: 5-Year Results and Correlative Analyses From ATEMPT. J Clin Oncol 2024;42:3652-65. [Crossref] [PubMed]
  9. Nangia J, Wang T, Osborne C, et al. Effect of a Scalp Cooling Device on Alopecia in Women Undergoing Chemotherapy for Breast Cancer: The SCALP Randomized Clinical Trial. JAMA 2017;317:596-605. [Crossref] [PubMed]
  10. Tolaney SM, Tung N, Wolff AC, et al. HER2DX genomic test in early-stage HER2-positive breast cancer. ESMO Open 2024;9:103987. [Crossref] [PubMed]
  11. Saez OM, Brasó-Maristany F, Griguolo G, et al. 5P HER2DX risk-score in HER2-positive (HER2+) breast cancer following neoadjuvant and adjuvant anti-HER2-based treatment: An updated survival analysis. ESMO Open 2023;8:101229.
  12. Medicinal forms | Trastuzumab emtansine (Specialist drug) | Drugs | BNF | NICE n.d. Available online: https://bnf.nice.org.uk/drugs/trastuzumab-emtansine-specialist-drug/medicinal-forms/ (accessed January 22, 2025).
  13. 2 Information about trastuzumab emtansine | Trastuzumab emtansine for adjuvant treatment of HER2-positive early breast cancer. Available online:
  14. Medicinal forms | Paclitaxel (Specialist drug). Available online: https://bnf.nice.org.uk/drugs/paclitaxel-specialist-drug/medicinal-forms/ (accessed January 22, 2025).
  15. Medicinal forms | Trastuzumab (Specialist drug). Available online: https://bnf.nice.org.uk/drugs/trastuzumab-specialist-drug/medicinal-forms/ (accessed January 22, 2025).
  16. Overview | Guidance on the use of trastuzumab for the treatment of advanced breast cancer. Available online:
  17. Study Details | ATEMPT 2.0: Adjuvant T-DM1 Vs TH. Available online: https://clinicaltrials.gov/study/NCT04893109 (accessed January 22, 2025).
Cite this article as: Abdallah H, Crocamo S, de Paula B. New emerging data on adjuvant systemic therapy for stage I HER2 positive breast cancer. Gland Surg 2025;14(5):803-806. doi: 10.21037/gs-2025-41

Article Options

Download Citation

Share