De-Escalating Treatment in Metastatic HER2+ Breast Cancer: Is it Safe?

Omitting chemotherapy from a treatment regimen involving dual blockade with pertuzumab and trastuzumab resulted in a substantially reduced progression-free survival among patients with metastatic HER2-positive breast cancer, but no significant difference with regard to overall survival, according to a randomized phase II trial. The results suggest a more personalized approach to therapy de-escalation may be needed in this setting.

“Trials of HER2-positive breast cancer in the neoadjuvant setting have shown that the HER2 enriched subtype is the most sensitive to anti-HER2 therapy,” said Jens Huober, MD, of the University Hospital Ulm in Germany, according to a press release. “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.”

Huober presented results of the PERNETTA trial at the European Society for Medical Oncology (ESMO) Breast Cancer Congress, held May 2–4 in Berlin. The trial randomized 210 patients with metastatic HER2-positive breast cancer to receive either pertuzumab plus trastuzumab (P+T) alone or in combination with paclitaxel or vinorelbine followed by maintenance P+T until progression. Following progression, both groups received trastuzumab emtansine as a second-line therapy.

In the P+T-alone group, the median progression-free survival was 8.4 months, compared with 23.3 months in the group that also received chemotherapy. This did not result in a difference in overall survival, however. At 2 years, the overall survival rate in both groups was 76.2%, and hormone receptor status did not appear to influence the results.

The overall quality-of-life scores in the study were also similar, though patients in the P+T-alone group had small improvements during first-line therapy while those receiving chemotherapy had stable scores. Patients in the P+T-alone group did report lower rates of hair loss, mouth sores, nausea, and fatigue.

“Omitting chemotherapy in the first line could be discussed as an option with patients who have a low to intermediate tumor burden,” Huober said. “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.”

A more personalized approach to de-escalation is likely needed, and the researchers plan to use the PAM50 assay to profile the tumors in this trial and search for potential markers of outcome. “There was no biological selection of patients in the PERNETTA trial,” said Carmen Criscitiello, MD, PhD, of the European Institute of Oncology in Milan, Italy, who commented on the study for ESMO. She noted that the sample size in the trial is too small to capture overall survival differences, and the 2-year endpoint may be too short as well.

“Avoiding chemotherapy in HER2-positive disease is appealing for patients and investigators, but it has to be done safely,” she said.