Advanced HER2-positive breast tumors expressed variable amounts of protein—a measurement which had a significant correlation with survival, a biomarker analysis of a large clinical trial showed.

Women with the highest levels of HER2 expression had a median overall survival of almost 3 years when treated with trastuzumab emtansine (T-DM1, Kadcycla), as compared with 2 years for patients treated with lapatinib (Tykerb) and capecitabine (Xeloda), Jose Baselga, MD, reported at the American Association for Cancer Research meeting here.

Among patients with lower HER2 expression, median overall survival declined to 26.5 months with T-DM1 and 23.7 months with lapatinib-capecitabine, he reported.

The findings have potentially major implications for treatment of HER2-positive breast cancer, including the possibility of treating some women without conventional chemotherapy.

“In the HER2-positive tumors, we think there is a group that is hypersensitive,” Baselga, of Memorial Sloan-Kettering Cancer Center in New York City, said during a press briefing. “I think we are going to see a group of HER2-positive tumors that will not need chemotherapy because HER2 therapies are going to be so effective by themselves.

“In some neoadjuvant studies that we have done with pertuzumab (Perjeta) and trastuzumab (Herceptin), there is a proportion of patients who had complete remissions without chemotherapy. We suspect these are going to be the (hypersensitive) ones. It’s very exciting because we think we will be able to identify these hypersensitive tumors, and lots of indications suggest they are going to be these super-HER2 expressors.”

The biomarker analysis also showed that mutations in PI3KCA (a member of the PI3 kinase family) blunted the efficacy of the lapatinib-capecitabine combination but not the activity of T-DM1, pointing to another possible step toward more effective use of targeted therapies.

New Analysis of EMILIA

The results came from a new analysis of the phase III randomized EMILIA trial involving 991 patients with advanced or metastatic, HER2-positive breast cancer previously treated with trastuzumab (Herceptin) and taxane-based chemotherapy.

Patients received the antibody-drug conjugate T-DM1 or the lapatinib-capecitabine combination and were treated until disease progression, unacceptable toxicity, or withdrawal from the study. The primary endpoint was progression-free survival (PFS).

As previously reported, the initial results showed a statistically significant 3-month improvement in PFS with T-DM1. A follow-up report showed that patients in the T-DM1 arm had a 4-month advantage in overall survival.

The trial protocol included several biomarker analyses, said Baselga. One objective was to determine whether the amount of HER2 messenger RNA (mRNA) produced by a tumor influenced response to treatment. Investigators also wanted to see whether activating mutations in PIK3CA (a member of the PI3 kinase family) affected efficacy or survival.

Patients in both treatment arms were stratified by mRNA production. HER2 mRNA levels at or below the median concentration ratio of 13 were defined as low expression, and a concentration ratio above the median was considered high expression.

The results showed that greater HER2 expression was associated with improved outcomes in both treatment groups.

T-DM1-treated patients with high HER2 expression had a median PFS of 10.6 months compared with 6.9 months in the lapatinib-capecitabine arm (HR 0.65, 95% CI 0.50-0.85), the investigators found. A low HER2 mRNA concentration ratio was associated with a median PFS of 8.2 months with T-DM1, versus 6.4 months with lapatinib-capecitabine (HR 0.64, 95% 0.50-0.82).

Repeating the analysis for overall survival, Baselga and colleagues found that the survival advantage with T-DM1 had increased to almost 10 months in the high-expression patients (34.1 versus 24.8 months, HR 0.53, 95% CI 0.37-0.76).

‘Remarkable’ Increase in Survival

“We are talking about an overall survival of 34 months in patients who were in second-line therapy,” said Baselga. “That is remarkable.”

Moreover, median overall survival among low-expression patients treated with T-DM1 was similar to that of patients with high HER2 expression treated with lapatinib-capecitabine (26.5 versus 24.8 months). Median overall survival with lapatinib-capecitabine was similar in patients with high and low HER2 expression (23.7 months).

HER2-positive tumors with mutations in PIK3CA do not respond well to conventional anti-HER-2 therapies, said Baselga. To see whether the adverse effect held up in treatment with T-DM1, the investigators identified a subgroup of 79 patients who had PIK3CA mutations: 39 in the lapatinib-capecitabine arm and 40 in the T-DM1 arm.

The results showed a median PFS of 4.3 months in patients with PIK3CA-mutated tumors treated with lapatinib-capecitabine versus 10.9 months with T-DM1. In contrast, 87 lapatinib-capecitabine patients with wild-type PIK3CA had a median PFS of 6.4 months, whereas 93 patients with wild-type PIK3CA had a median PFS of 9.8 months with T-DM1, no different from PFS among patients with PIK3CA mutations.

Median overall survival overall survival was 17.3 months with PIK3CA mutations and 27.8 months with wild-type PIK3CA in the lapatinib-capecitabine group but had not been reached in the T-DM1 group.