De-escalation approaches in the treatment of women with HER2-positive breast cancer need to be personalized, according to a European Society for Medical Oncology (ESMO) spokesperson Carmen Criscitiello, MD, PhD, of the European Institute of Oncology in Milan, Italy. Dr. Criscitello commented on the presentation of updated research results at the inaugural ESMO Breast Cancer Congress 2019.
“The introduction of anti-HER2 therapies has brought a huge survival benefit in early and advanced HER2-positive breast cancer, thus, there is now a need for reducing the intensity and side effects of the treatment administered,” said Dr. Criscitiello. “However, the priority is to identify which patients might be spared some toxic therapies without worsening the survival benefit.”
A de-escalation strategy omitting chemotherapy in the first-line treatment of HER2-positive metastatic breast cancer was attempted in the PERNETTA trial (Abstract 288PD). As previously reported, the strategy did not worsen 2-year overall survival, but significantly shortened progression-free survival.
The phase II trial randomly allocated 210 patients to trastuzumab plus pertuzumab alone vs trastuzumab plus pertuzumab combined with chemotherapy until disease progression. After progression, both groups received ado-trastuzumab emtansine (T-DM1) as second-line therapy.
The primary endpoint of overall survival at 2 years was reached by 77% of patients receiving antibodies alone and 76% of those who also had chemotherapy. Progression-free survival after first-line therapy was 8.4 months with antibodies alone and 23.3 months in the antibodies-plus-chemotherapy group.
New findings presented at the ESMO Breast Cancer Congress (Abstract 150O_PR) showed that results were similar regardless of hormone receptor status, and overall quality of life was also similar between groups during first-line treatment. However, according to analyses of adverse events and patient-reported symptoms, those receiving antibodies alone had less hair loss, mouth sore development, nausea, and fatigue.
The difference in progression-free survival between groups has prompted the investigators to look for predictive factors to identify patients who could receive targeted therapy alone with little or no detriment in progression-free survival. They are using the PAM50 test to profile tumors of all patients in the trial.
First study author Jens Huober, MD, of the University Hospital Ulm, Germany, said, “Trials of HER2-positive breast cancer in the neoadjuvant setting have shown that the HER2-enriched [disease] subtype is the most sensitive to anti-HER2 therapy. Our hypothesis is that this also applies to the metastatic setting. If the progression-free survival difference is smaller in this subtype, then omitting chemotherapy in the first line may be a good option for these patients.”
Dr. Huober noted that the trial was conducted to determine whether it is safe to omit chemotherapy from the first-line treatment of patients with HER2-positive metastatic breast cancer who receive dual anti-HER2 therapy followed by T-DM1. “We looked at 2-year overall survival because physicians are afraid they will lose patients early if they don’t give the maximum treatment. Progression-free survival was shorter, but did not seem to affect overall survival in the long run. Omitting chemotherapy in the first line could be discussed as an option with patients who have a low to intermediate tumor burden. However, a phase III trial is needed for definitive proof that patients are not at risk of early death if they start with antibodies alone.”
Dr. Criscitiello emphasized that it is important for studies in this field to select a specific population in which to attempt treatment intensity optimization. She agreed that using the PAM50 test to select patients with the HER2 enrichment subtype may be an effective approach.
“There was no biological selection of patients in the PERNETTA trial,” noted Dr. Criscitiello, who also highlighted the choice of the primary endpoint. “Here, we have a progression-free survival that is almost two times less than that achieved with chemotherapy. The short overall survival endpoint did not capture whether denying a treatment demonstrated to be meaningfully most effective impacts on long-term survival. In addition, the sample size is very small to detect a difference in overall survival. Avoiding chemotherapy in HER2-positive disease is appealing for patients and investigators, but it has to be done safely.”
Disclosure: For full disclosures of the study authors, visit cslide.ctimeetingtech.com/breast2019.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.