A phase III randomized clinical trial comparing 9 weeks versus 1 year of adjuvant trastuzumab in patients with HER2-positive early breast cancer has published its 10-year follow-up results. The ShortHER trial, conducted in Italy, was unable to demonstrate non-inferiority of the shorter trastuzumab regimen, but found only small numerical differences in outcomes between the two arms for patients with lower-risk disease.
The study results were published on September 25, 2023 in the Journal of Clinical Oncology. The trial was funded by a research grant from the Italian Medicines Agency (Agenzia Italiana del Farmaco).
The ShortHER trial was designed to assess whether a shorter 9-week course of adjuvant trastuzumab could produce non-inferior outcomes compared to the standard 1-year regimen in early HER2-positive breast cancer. Trastuzumab, a monoclonal antibody targeting HER2, has been a cornerstone of treatment for HER2-positive breast cancer since pivotal trials showed it reduced the risk of recurrence and death by about one-third when given for 1 year. However, the optimal duration of trastuzumab therapy has remained an open question, with shorter regimens potentially offering reduced toxicity and costs.
This multicenter, open-label, randomized phase III trial enrolled 1,254 women with surgically resected, HER2-positive early breast cancer between 2007 and 2013. Eligible patients were 18-75 years old and had node-positive disease or, if node-negative, at least one additional high-risk feature such as tumor size >2 cm, grade 3 histology, lymphovascular invasion, Ki-67 >20%, age <35 years, or hormone receptor-negative status.
Patients were randomized 1:1 to receive either 1 year of trastuzumab (long arm) or 9 weeks of trastuzumab (short arm) in combination with chemotherapy. The chemotherapy regimen differed between arms:
- Long arm: 4 cycles of anthracycline-based therapy (AC or EC) followed by 4 cycles of taxane (paclitaxel or docetaxel), with trastuzumab starting with the taxane and continuing for a total of 18 doses given every 3 weeks.
- Short arm: 3 cycles of docetaxel followed by 3 cycles of FEC (fluorouracil, epirubicin, cyclophosphamide), with weekly trastuzumab given for 9 weeks concurrently with docetaxel.
The primary endpoint was disease-free survival (DFS), with overall survival (OS) as a co-primary endpoint. The trial was designed as a non-inferiority study, with a hazard ratio of 1.29 set as the non-inferiority margin.
Baseline characteristics were well-balanced between arms. The median age was 55 years, 64% of patients were under age 60, 64% were postmenopausal, 54% were node-negative, 30% had 1-3 positive nodes, 16% had ≥4 positive nodes, and 68% had hormone receptor-positive disease.
The current publication reports outcomes at a median follow-up of 9 years. For the co-primary endpoint of overall survival, the 10-year OS rate was 89% in the long arm versus 88% in the short arm (HR 1.15, 90% CI 0.85-1.56). The updated 10-year DFS rate was 77% in the long arm versus 78% in the short arm (HR 1.06, 90% CI 0.86-1.31).
While the overall results did not meet the pre-specified criteria for non-inferiority of the shorter regimen, subgroup analyses showed differences in outcomes based on nodal status:
- For node-negative patients: 10-year DFS was 81% vs 85% and 10-year OS was 89% vs 95% in the long vs short arms, respectively.
- For patients with 1-3 positive nodes: 10-year DFS was 77% vs 79% and 10-year OS was 92% vs 89% in the long vs short arms.
- For patients with ≥4 positive nodes: 10-year DFS was 63% vs 53% and 10-year OS was 84% vs 64% in the long vs short arms.
These results suggest that while patients with higher-risk disease (≥4 positive nodes) derived clear benefit from 1 year of trastuzumab, the differences were minimal for lower-risk patients.
The study had some important limitations. Most notably, it was underpowered due to lower-than-planned accrual, with only 56% power to detect clinically meaningful differences between arms. The original sample size target was reduced by about half due to slow enrollment. Additionally, the chemotherapy regimens differed between arms, which may have impacted outcomes beyond the trastuzumab duration.
In their discussion, the study authors acknowledge that these results are unlikely to change standard practice, as guidelines continue to recommend 1 year of trastuzumab (often with pertuzumab) for most patients with HER2-positive early breast cancer. However, they note that the long-term data may provide reassurance to clinicians and patients in cases where trastuzumab is discontinued early due to toxicity or other factors, particularly for lower-risk patients.
The authors also highlight the potential global impact of these findings. While 1-year trastuzumab remains the standard of care in high-income countries, access to this regimen is limited in many parts of the world due to cost. A recent survey found that trastuzumab was available to only 15% of patients in low- and middle-income countries, and its use would result in catastrophic expenses for 68% of patients globally. The ShortHER results suggest that a 9-week course of trastuzumab may provide meaningful benefit in settings where 1 year of therapy is not feasible.
From a clinical perspective, these results are unlikely to dramatically alter practice in regions where 1-year trastuzumab is the established standard. However, they may impact decision-making in several ways:
1. For patients who discontinue trastuzumab early due to cardiac or other toxicity, particularly those with node-negative or low-volume node-positive disease, these data provide reassurance that outcomes may not be substantially compromised.
2. In cases where the cost of 1-year trastuzumab is prohibitive, clinicians may consider a shorter course as an alternative to foregoing anti-HER2 therapy entirely.
3. For elderly patients or those with significant comorbidities, where the risks of extended therapy may outweigh the benefits, a shorter trastuzumab course could be considered.
4. In the neoadjuvant setting, where some patients achieve a pathologic complete response after just a few months of therapy, these data may support de-escalation strategies in select patients.
The results also highlight the ongoing need for better risk stratification tools in HER2-positive breast cancer. While nodal status provided some indication of who benefited most from extended trastuzumab, more precise biomarkers are needed to guide individualized treatment decisions.
It's worth noting that the landscape of HER2-positive breast cancer treatment has evolved significantly since this trial was conducted. Dual HER2-blockade with pertuzumab is now standard for higher-risk patients, and the antibody-drug conjugate trastuzumab emtansine (T-DM1) has shown benefit in patients with residual disease after neoadjuvant therapy. How the ShortHER results apply in the context of these newer regimens is unclear.
Additionally, several other de-escalation strategies have been studied in HER2-positive disease, including shortened chemotherapy regimens. The APT trial, for instance, showed excellent outcomes with 12 weeks of paclitaxel and 1 year of trastuzumab in node-negative, small tumors. Future research will need to determine the optimal way to tailor both chemotherapy and HER2-targeted therapy duration based on individual patient and tumor characteristics.
In conclusion, while the ShortHER trial did not meet its statistical threshold for non-inferiority of 9 weeks versus 1 year of trastuzumab, it provides valuable long-term data on outcomes with shortened anti-HER2 therapy. The results suggest that carefully selected patients with lower-risk disease may achieve similar outcomes with a much shorter course of trastuzumab. However, patients with higher-risk features, particularly those with extensive nodal involvement, clearly benefit from the full year of therapy.
These findings are unlikely to supplant 1-year trastuzumab as the standard of care where it is already established, but they may inform decision-making in cases where the full course of therapy is challenging due to toxicity, cost, or other factors. Perhaps most importantly, they provide a framework for improving global access to this life-saving targeted therapy in regions where extended treatment duration is not feasible.
As personalized medicine continues to advance in oncology, studies like ShortHER highlight the importance of tailoring treatment intensity to individual patient risk. Future research should focus on identifying robust biomarkers to guide these decisions and on integrating shortened trastuzumab strategies with newer HER2-targeted agents. Ultimately, the goal remains to optimize outcomes while minimizing unnecessary treatment burden for patients with HER2-positive breast cancer.
References
Conte P, Bisagni G, Piacentini F, et al. Nine-Week Versus One-Year Trastuzumab for Early Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: 10-Year Update of the ShortHER Phase III Randomized Trial. J Clin Oncol. 2023;41(32):4976-4981. doi:10.1200/JCO.23.00790
