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Reassuring Results Observed with Shorter Duration of Adjuvant Trastuzumab in HER2-positive Early Breast Cancer

Non-inferiority with the short- versus long-term adjuvant trastuzumab could not be claimed
07 May 2021
Anticancer agents & Biologic therapy;  Breast cancer

Long-term findings presented at the ESMO Breast Cancer Virtual Congress 2021, held 5 to 8 May, showed that similar disease-free survival (DFS) benefit was obtained with 9 weeks versus one-year of adjuvant trastuzumab in patients with HER2-positive early breast cancer and low to intermediate risk for disease recurrence, which may reassure patients who must discontinue adjuvant trastuzumab earlier than one year due to cardiac adverse events.

Prof. Pier Franco Conte of the Department of Surgery, Oncology and Gastroenterology, University of Padova in Padova, Italy presented long-term data from the ShortHER study (EUDRACT 2007-004326-25; NCT00629278) regarding the co-primary endpoint of overall survival (OS) as well as updated DFS curves. DFS was evaluated according to hormone receptor status and 3 risk categories: low risk (defined as pT< 2cm and pN0), intermediate risk (pT < 2cm and 1-3 pN+ or pT > 2cm and 0-3 pN+), and high risk (any pT and 4+ pN+).

Previous reports described the design, patient characteristics, and event-driven DFS analysis of the study, which was designed to demonstrate the non-inferiority of short versus long administration of adjuvant trastuzumab. However, at the event driven analysis, the hazard ratio (HR) for DFS was 1.13 (90% confidence interval [CI] 0.89-1.42), which did not meet the non-inferiority margin of DFS < 1.29.1

In ShortHER, 1254 patients with HER2-positive early breast cancer were randomly assigned to chemotherapy followed by either 9 weeks (short arm n=626) or one year (long arm n=627) of adjuvant trastuzumab.

With median follow-up of 8.7 years, 121 DFS events occurred with 9 weeks of treatment compared to 116 with one year of adjuvant trastuzumab (HR 1.09; 90% CI 0.88-1.35).

DFS was similar with 9 weeks and one-year of trastuzumab in patients with low and intermediate risk

The evaluation according to post-hoc risk groups demonstrated in 37.2% of the study population that was at low risk HR for DFS of 0.91 (90% CI 0.60-1.38), in intermediate risk patients which comprised 46.7% of the study population HR 0.88 (90% CI 0.63-1.21), and in high risk patients (15.2% of the study population) HR 2.06 (90% CI 1.36-3.13) with short versus long treatment duration of trastuzumab.

Regarding DFS per hormone receptor status, in hormone receptor positive patients receiving the short and long treatment HR 1.11 (90% CI 0.85-1.46) compared to HR 1.06 (90% CI 0.75-1.50) in hormone receptor negative patients.

A total of 109 deaths were reported representing 58 with the short treatment, and 51 with the one-year trastuzumab treatment. In the respective arms, the 9-year OS was 90% with short versus 91% with one-year of trastuzumab (HR 1.18; 90% CI 0.86-1.62).

Dr. Evandro de Azambuja of the Jules Bordet Institute in Brussels, Belgium who discussed the study findings said that short duration is less cardiotoxic, but one-year trastuzumab remains the standard at the present. Nevertheless, a shorter trastuzumab administration could be an option to be tested in patients with a low risk of relapse or to reassure patients who experience cardiac events before the end of therapy. However, low risk patients have been de-escalated on chemotherapy (APT trial). Intermediate risk includes N1-3, and those patients benefit from dual blockade with pertuzumab plus trastuzumab. Short regimen can facilitate the access to trastuzumab to patients with low risk of relapse living in countries with limited resources. He suggested food for thoughts: combining pathologic features with biomarkers to identify these patients who could benefit from this de-escalated strategy. 

Conclusions

The investigators stated that the updated DFS and OS analysis of the ShortHER study confirms the favourable long term results obtained with 9 weeks of adjuvant trastuzumab in the patients with low and intermediate risk factors who represented the majority (83.9%) of the ShortHER study population and reflect most of the patients treated in daily practice.

Although one year of trastuzumab remains standard for adjuvant therapy, the authors recommend that these findings suggest that a shorter trastuzumab administration could be an option in the case of limited access to trastuzumab.

They concluded that their data are also reassuring for patients who have to discontinue trastuzumab due to a decline in left ventricular ejection fraction.

The study was funded by the Agenzia Italiana del Farmaco (AIFA).

Citation

1. Conte P, Frassoldati A, Bisagni G et al. Nine weeks versus 1 year adjuvant trastuzumab in combination with chemotherapy: final results of the phase III randomized Short-HER study. Annals of Oncology 2018;29(12):2328-2333. doi: 10.1093/annonc/mdy414.

Reference

41O – Conte PF, Frassoldati A, Bisagni G, et al. Nine weeks vs 1 year adjuvant trastuzumab: long term outcomes of the ShortHER randomised trial. ESMO Breast Cancer Virtual Congress 2021 (5-8 May).

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