Invited discussant of the Short-HER trial, Evandro de Azambuja, MD, PhD, Head of the Medical Support Team at the Institut Jules Bordet, Brussels, acknowledged the good outcomes in low- and intermediate-risk patients treated with either a short or long duration of trastuzumab but said 1 year of the anti-HER2 drug remains the standard.1
Evandro de Azambuja, MD, PhD
The question in HER2-positive early breast cancer, he noted, is whether to escalate treatment in high-risk, fit patients or to de-escalate treatment in low-risk, frail patients, such as those with cardiac comorbidities. “This is always a question of balancing efficacy with safety,” Dr. de Azambuja added.
The Short-HER trial evaluated a shorter duration of trastuzumab in combination with anthracycline-based treatment. The study failed to demonstrate, after 8.7 years of follow-up, that a shorter duration was not inferior to 1 year of trastuzumab in terms of disease-free or overall survival. Short-HER did, however, demonstrate in its primary analysis that patients treated with a shorter duration had less cardiac toxicity, he said.
“What’s interesting in this study is how they categorized patients by risk: low risk (tumors ≤ 2 cm and no positive nodes); intermediate risk (tumors ≤ 2 cm and 1–3 positive nodes or > 2 cm and 0–3 nodes); and high risk (any tumor size and 4+ positive nodes). Patients classified as being at low or intermediate risk represented 84.6% of the study population; although for these patients, the disease-free and overall survival curves did not differ between the arms; “they could not declare the treatments to be equivalent,” Dr. de Azambuja stated. “And, in the high-risk group, we clearly saw a separation of the curves.”
Putting the Data in Context: Other Trials and Contemporary Practice
Dr. de Azambuja put the Short-HER data in context with three other noninferiority trials encompassing almost 11,000 patients. PHARE2 and PERSEPHONE3 evaluated 6 months of trastuzumab, whereas SOLD evaluated 9 weeks of trastuzumab.4 PERSEPHONE alone showed a shorter duration (6 months) to be noninferior to 1 year of trastuzumab. And, of note, the hazard ratios and confidence intervals of that trial were very similar to those found in the negative PHARE trial, he noted.
Dr. de Azambuja also pointed out, and Dr. Conte agreed during the discussion, that the treatment approaches of Short-HER are not in keeping with contemporary practice. “Today, low-risk patients would be eligible for paclitaxel plus trastuzumab (ie, the APT regimen),5 whereas intermediate- and high-risk patients could be candidates for neoadjuvant therapy,” he explained.
“For the low-risk population, we already de-escalate treatment—we don’t give anthracyclines anymore—so I would be a little afraid to de-escalate the duration of trastuzumab as well,” Dr. de Azambuja said. “We know that intermediate-risk patients—those with N1–3 disease—are eligible for neoadjuvant treatment, including dual HER2 blockade with pertuzumab and trastuzumab. Those patients need more treatment, and I would not de-escalate them either.”
Dr. Conte added: “Yes, in most cases, when we de-escalate treatment in our clinics, we use APT—which de-escalates the chemotherapy—but still give 1 year of trastuzumab.
Dr. de Azambuja concluded: “From the final analysis of Short-HER, we can say for sure that shorter durations of trastuzumab are less cardiotoxic; however, 1 year of trastuzumab still remains the standard of care for our patients. Nevertheless, a shorter duration of trastuzumab could be an option for patients with a low risk of relapse and for those who must stop trastuzumab early because of cardiac safety issues. We can ensure these patients can still derive a treatment benefit. A shorter regimen may also facilitate access to trastuzumab in patients with a low risk of relapse in countries with limited resources.”
Potential Role of Tumor-Infiltrating Lymphocytes
According to Dr. de Azambuja, future research should seek to identify subsets who benefit most from longer or shorter durations of trastuzumab. To this end, he advised further exploration of HER2 enrichment and stromal tumor-infiltrating lymphocytes. In fact, tumor-infiltrating lymphocytes were prognostic in the Short-HER trial: Patients with low tumor-infiltrating lymphocytes (< 20%) derived a significant benefit from 1 year of trastuzumab vs 9 weeks (hazard ratio [HR] = 1.75; P = .021, for distant disease–free survival), whereas those with high tumor-infiltrating lymphocytes (≥ 20%) had an excellent prognosis with either approach but numerically higher distant disease–free survival rates with the shorter treatment (HR = 0.23; P = .064; P for interaction = .015).6
The results suggest that tumor-infiltrating lymphocytes may play a role in identifying patients with early HER2-positive disease who might safely undergo de-escalated anti-HER2 treatment in the adjuvant setting. However, Dr. de Azambuja noted, this should be studied in a clinical trial.
DISCLOSURE: Dr. de Azambuja reported financial relationships with Roche/GNE, GSK/Novartis, Seattle Genetics, Libbs, Zodiac, Lilly, and Pierre Fabre.
REFERENCES
1. Conte PF, Frassoldati A, Bisagni G, et al: Nine weeks vs 1 year adjuvant trastuzumab: Long-term outcomes of the Short-HER randomised trial. ESMO Breast Cancer Virtual Congress 2021. Abstract 410. Presented May 7, 2021.
2. Pivot X, Romieu G, Debled M, et al: 6 months versus 12 months of adjuvant trastuzumab in early breast cancer (PHARE): Final analysis of a multicentre, open-label, phase 3 randomised trial. Lancet 393:2591-2598, 2019.
3. Earl HM, Hiller L, Vallier AL, et al: 6 versus 12 months of adjuvant trastuzumab for HER2-positive early breast cancer (PERSEPHONE): 4-year disease-free survival results of a randomised phase 3 non-inferiority trial. Lancet 393:2599-2612, 2019.
4. Joensuu H, Fraser J, Wildiers H, et al: Effect of adjuvant trastuzumab for a duration of 9 weeks vs 1 year with concomitant chemotherapy for early human epidermal growth factor receptor 2-positive breast cancer: The SOLD randomized clinical trial. JAMA Oncol 4:1199-1206, 2018.
5. Tolaney SM, Barry WT, Dang CT, et al: Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer. N Engl J Med 372:134-141, 2015.
6. Dieci MV, Conte P, Bisagni G, et al: Association of tumor-infiltrating lymphocytes with distant disease-free survival in the ShortHER randomized adjuvant trial for patients with early HER2+ breast cancer. Ann Oncol 30:418-423, 2019.
