Long-term analysis of the Short-HER trial showed that 9 weeks of adjuvant trastuzumab conveyed benefits comparable to a 1-year course in patients with early HER2-positive breast cancer deemed to be at low or intermediate risk for disease recurrence. High-risk patients, however, derived considerably more benefit from the conventional longer course, and the study did not meet the noninferiority threshold of significance, Short-HER investigators reported at the ESMO Breast Cancer Virtual Congress 2021 (Abstract 410).
“Patients classified as low- and intermediate-risk represented 84.6% of the study population. In the follow-up analysis, both disease-free and overall survival curves for those groups were superimposable,” said lead investigator Pierfranco Conte, MD, of the University of Padua in Italy.
For a large proportion of real-world patients with HER2-positive early breast cancer, [less treatment may be acceptable.]— Pierfranco Conte, MD
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While 1 year of adjuvant trastuzumab remains the standard, he said, “For a large proportion of real-world [patients with] HER2-positive early breast cancer,” less treatment may be acceptable.
About Short-HER
The Short-HER trial randomly assigned 1,254 patients with HER2-positive early breast cancer to chemotherapy plus 9 weeks vs 1 year of adjuvant trastuzumab. More than half the patients had node-negative disease and therefore were at low risk for recurrence, Dr. Conte noted.
Chemotherapy in the long-treatment arm was doxorubicin or epidoxorubicin plus cyclophosphamide for four courses followed by a taxane for four courses; trastuzumab was given every 3 weeks for 18 doses. Chemotherapy in the short-treatment arm was docetaxel for three courses followed by fluorouracil, epidoxorubicin, and cyclophosphamide for three courses; trastuzumab was given for 9 weeks.
The study was designed to assess whether a shorter trastuzumab course is noninferior to a conventional 1-year course with respect to disease-free survival. A hazard ratio (HR) of < 1.29 was set as a noninferiority margin.
At the event-driven analysis, previously reported in 2018 in Annals of Oncology, after a median follow up of 6 years, disease-free survival events numbered 95 (15%) in the long arm and 105 (17%) in the short arm. This yielded 5-year disease-free survival rates of 88% and 85%, respectively (HR = 1.13, 90% confidence interval [CI] = 0.89–1.42), with the upper limit of the confidence interval crossing the noninferiority margin set at 1.29. Noninferiority, therefore, could not be claimed at that time, said Dr. Conte.
Shorter treatment was associated with less cardiotoxicity; grade ≥ 2 cardiac adverse events were observed in 4.3% of patients in the short arm and 13.1% of the long arm, yielding a risk ratio of 0.33 favoring shorter treatment (P < .001). Time to cardiac events showed consistent results (HR = 0.32, P < .0001).
Long-Term Follow-up
At the ESMO Breast Cancer Virtual Congress 2021, Dr. Conte presented the overall survival analysis (the co-primary endpoint of the study) and the updated disease-free survival according to hormone receptor status and the three risk categories:
- Low risk (pT < 2 cm and pN0), which was 38% of the population
- Intermediate risk (pT < 2 cm and 1–3 pN+ or pT > 2 cm and 0–3 pN+), which was 47% of the population
- High risk (any pT and 4+ pN+), which was 15% of the population.
At a median follow up of 8.7 years, disease-free survival events numbered 121 in the short treatment arm and 116 in the long arm, respectively (HR = 1.09, 90% CI = 0.88–1.35). The HRs by risk category were comparable between the arms, except for in the high-risk category:
- Low risk: HR = 0.91
- Intermediate risk: HR = 0.88
- High risk: HR = 2.06.
Five-year disease-free survival rates were as follows for the three categories:
- Low risk: short treatment = 91%, long treatment = 91%
- Intermediate risk: short treatment = 89%, long treatment = 88%
- High risk: short treatment = 64%, long treatment = 82%.
By hormone receptor status, HRs were 1.11 for hormone receptor–positive patients and 1.06 for hormone receptor–negative patients.
At 9 years, overall survival rates were 90% after 9 weeks of trastuzumab and 91% with 1 year of treatment (HR = 1.18, 90% CI = 0.86–1.62), Dr. Conte reported.
He said that because outcomes are good with 9 weeks of trastuzumab, a short course could be an option in populations with limited access to trastuzumab.
“Our data are also reassuring for patients who have to discontinue trastuzumab due to a decline in left ventricular ejection fraction,” he added.
Disclosure: Dr. Conte disclosed financial relationships with Roche, Novartis, Merck kga, AstraZeneca, and Lilly. For full disclosures of the study authors, visit oncologypro.esmo.org.
