Treatment Intensity Should Be Personalized in Women with HER2-positive Breast Cancer, Study Says

Personalized treatment intensity is crucial to the success of less toxic and demanding therapies for women with HER2-positive breast cancer, according to a spokesperson from the European Society for Medical Oncology (ESMO).

The remarks by Carmen Criscitiello, MD, PhD, accompanied updated results from the PERNETTA trial (EudraCT number 2012-002556-17), a study assessing the consequences of removing chemotherapy as a first-line treatment for women with HER2-positive breast cancer. The presentation was made at the ESMO Breast Cancer Congress 2019, May 2–4 in Berlin, Germany.

The findings of the study, “Pertuzumab (P) trastuzumab (T) with or without chemotherapy both followed by T-DM1 in case of progression in patients with HER2-positive metastatic breast cancer (MBC) – The PERNETTA trial (SAKK 22/10), a randomized open label phase II study (SAKK, UNICANCER, BOOG),” were presented by Jens Huober, MD, a professor at the University Hospital Ulm in Germany.

“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,” Criscitiello said in a press release, Criscitiello also is a senior physician at the European Institute of Oncology in Milan, Italy. “However, the priority is to identify which patients might be spared some toxic therapies without worsening the survival benefit.”

The new findings were in agreement with previous results from the trial presented last year at the ESMO 2018 Congress. Those results showed that women who did not receive chemotherapy as a first-line therapy had identical overall survival, but had significantly shorter progression-free survival compared to those who had. Progression-free survival refers to the time patients lived without their disease worsening.

Between May 2013 and January 2016, the randomized Phase 2 trial enrolled a total of 210 women with HER2-positive metastatic breast cancer. The group had a median age of 58, and were assigned randomly to receive either a combination therapy of Herceptin (trastuzumab) plus Perjeta (pertuzumab) (T P), or T P together with chemotherapy, until disease progression.

Patients receiving chemotherapy were treated with either paclitaxel or Navelbine (vinorelbine) once a week. After cancer progression, all patients received Kadcyla (ado-trastuzumab emtansine, or T-DM1), as a second-line therapy.

The trial’s primary goal was to assess patients’ overall survival at two years. Secondary goals included progression-free survival and treatment adverse events (side effects).

Results showed that 77% of women treated with T P, and 76% of those receiving T P together with chemotherapy, achieved the trial’s primary outcome of overall survival at two years.

However, women treated with chemotherapy lived significantly longer without their disease worsening, compared to women who had not undergone chemotherapy (23.3 months versus 8.4 months).

These results were identical for women with hormone receptor (HR) positive or negative tumors.

During first-line therapy, the overall quality of life was similar in both groups. However, women receiving T P alone experienced fewer treatment side effects, including hair loss, nausea, fatigue, and mouth sores, compared to those treated with chemotherapy.

“We looked at two-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,” Huober explained. “However, a Phase 3 trial is needed for definitive proof that patients are not at risk of early death if they start with antibodies alone.”

Investigators are now using the PAM50 test to profile tumors of patients participating in the trial to identify women whose progression-free survival is less likely to be affected by the lack of chemotherapy during first-line therapy, and may therefore, benefit from a combination therapy of T P alone.

“There was no biological selection of patients in the PERNETTA trial,” Criscitiello said. “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 if denying a treatment which is 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,” she said.