Shorter Duration of Adjuvant Trastuzumab Shows Long-Term Survival Benefit in Select HER2+ Early Breast Cancer

Updated survival data from the phase 3 Short-HER trial (NCT00629278) presented during the ESMO Breast Cancer Virtual Congress 2021 confirm the promising long-term results obtained with 9 weeks of adjuvant trastuzumab (Herceptin) in patients with HER2-positive early breast cancer who have low and intermediate risk factors, a population that is representative of most patients seen in clinical practice.¹

After a median follow-up of 8.7 years, patients who received 1 year of trastuzumab had a 5-year disease-free survival (DFS) rate of 87.9% vs 85.8% those who received it for 9 weeks (hazard ratio [HR], 1.09; 90% CI, 0.88-1.35). Moreover, patients had a 5-year overall survival (OS) rate of 95.1% in both arms, respectively (HR, 1.18; 90% CI, 0.86-1.62).

“Patients classified as low/intermediate risk on the basis of [tumor] size and nodal status represent 84.6% of the Short-HER study population. In this patient population, long-term DFS and OS are superimposable between the 2 treatment arms,” Pier Franco Conte, MD, a full professor of oncology at the University of Padova, Italy; director of the Division of Medical Oncology at the Istituto Oncologico Veneto in Padova; and chairman of Rete Oncologica Veneta, said in a presentation on the findings. “Although 1 year of trastuzumab remains a standard, de-escalation of treatment is a reasonable option for a large proportion of a real-world population of [patients with] HER2-positive early breast cancer.”

The superiority of combining 1 year of trastuzumab with adjuvant chemotherapy over chemotherapy alone in patients with HER2-positive early breast cancer was demonstrated in the phase 3 HERA (NCT00045032), Joint Analysis B31-N9831, and N9831 trials.^2-4 In November 2006, trastuzumab was approved by the FDA as an adjuvant therapy for patients with HER2-positive, node-positive breast cancer as part of a treatment regimen containing doxorubicin, cyclophosphamide, and paclitaxel.⁵

“It was very clear at the time that the choice of a 1-year duration of trastuzumab administration was based empirically and that a similar degree of benefit had already been reported with the small FinHER study with 9 weeks of trastuzumab,” Conte noted.

The Short-HER trial, which was an investigator-driven, noninferiority study, started off with an initial sample size of 2500 patients; however, as of February 2011, this was amended to 1250 patients. The study was conducted across 82 investigational sites in Italy and had a recruitment period that ran from December 2007 to October 2013. The primary analysis was completed after 189 DFS events at 5.2 years median follow-up.

The trial enrolled patients with HER2-positive, node positive, or high-risk node-negative disease. “Patients were then randomized to receive either 1 year of trastuzumab plus chemotherapy, which included 4 courses of doxorubicin and cyclophosphamide, followed by 4 courses of a taxane, vs 3 courses of docetaxel combined with 9 weeks of weekly trastuzumab followed by 3 courses of fluorouracil, epirubicin hydrochloride, and cyclophosphamide,” Conte said. Stratification factors included hormone receptor status and nodal status. Patients who were aged 65 years or older received docetaxel at 80 mg/sqm dose of docetaxel. Eleven percent of patients who received the longer duration of trastuzumab were given paclitaxel at 175 mg/sqm.

The overall patient population had a median age of 55 years (range, 25-78), and 64.0% were postmenopausal. Moreover, 40.6% of patients had stage I disease, 43.8% had stage II disease, and 15.2% had stage III disease. Most patients were node negative (53.5%), although 30.7% of patients had 1 to 3 positive nodes and 15.8% had at least 4 positive nodes. Additionally, 68.2% of patients had hormone receptor–positive status.

The DFS reported in the primary analysis of the trial showcased a HR of 1.13 (90%, CI, 0.89-1.42). Investigators reported that the probability that the shorter duration of treatment would be noninferior to that of the longer duration was 78% .6 Moreover, the primary analysis identified an association between a longer duration of treatment and a longer and higher incidence of cardiac events. The incidence of grade 2 or higher cardiac events was 13.1% in the long-duration treatment arm vs 4.3% in the short-duration treatment arm.

The updated results of the study had a median follow-up of 8.7 years with 237 DFS events and 109 deaths.

Investigators also examined DFS and OS outcomes with respect to risk category. “The high-risk group clearly has worse outcomes in terms of both DFS and OS, while both low- and intermediate-risk groups had very good DFS and OS estimates,” Conte said.

Patients in the low-risk group experienced a 5-year DFS of 91% in both treatment arms (HR, 0.91). In the intermediate-risk group, those who were treated with the longer duration of treatment had a 5-year DFS rate of 88% vs 89% with the shorter duration (HR, 0.88); the 5-year DFS rates in the high-risk group for the longer and shorter treatment durations were 82% and 64%, respectively (HR, 2.06).

Additionally, the 5-year OS rate for patients in the low-risk group who received the longer duration of treatment was 97% vs 99% with the shorter duration (HR, 0.57). In the intermediate-risk group, these rates were 96% and 95%, respectively (HR, 1.14), while they were 95% ad 91%, respectively, in the high-risk group (HR, 1.09).

References

1. Conte P, Frassoldati A, Bisagni G, et al. Nine weeks vs 1 year adjuvant trastuzumab: long term outcomes of the Short-HER randomized trial. Presented at: ESMO Breast Cancer Virtual Congress 2021. May 5-8, 2021; Virtual. Abstract 401.
2. Herceptin (Trastuzumab) in treating women with human epidermal growth factor receptor (HER) 2-positive primary breast cancer (HERA). ClinicalTrials.org. Updated April 27, 2017. Accessed May 7, 2021. https://clinicaltrials.gov/ct2/show/NCT00045032
3. Doxorubicin and cyclophosphamide plus paclitaxel with or without trastuzumab in treating women with node-positive breast cancer that overexpresses HER2. ClinicalTrials.gov. Updated April 29, 2021. Accessed May 7, 2021. https://clinicaltrials.gov/ct2/show/NCT00004067
4. Doxorubicin hydrochloride, cyclophosphamide, and paclitaxel with or without trastuzumab in treating women with HER2-positive node-positive or high-risk node-negative breast cancer. ClinicalTrials.gov. Updated August 2020. Accessed May 7, 2021. https://clinicaltrials.gov/ct2/show/NCT00005970
5. FDA approves Herceptin for the adjuvant treatment of HER2-positive node-positive breast cancer. News release. FDA. November 16, 2006. Accessed May 7, 2021. https://bit.ly/3vNSNpX
6. Conte P, Bisagni G, Frassoldati A, et al. Final analysis of the phase III multicentric Italian study Short-HER: 9 weeks vs 1 year adjuvant trastuzumab for HER21 early breast cancer. Ann Oncol. 2017;28(suppl 6):vi1-vi2. doi:10.1093/annonc/mdx421