Higher HER2 Expression Leads to Better Outcomes with T-DM1 in Patients with Metastatic Breast Cancer

Phoebe Starr

May 2013, Vol 4, No 4 - Personalized Medicine


Washington, DC—Among women with HER2-positive metastatic breast cancer, patients with the highest expression of HER2 had the best outcomes in treatment with ado-trastuzumab emtansine (T-DM1; Kadcyla), according to a biomarker analysis of the phase 3 EMILIA trial which was presented at the 2013 American As­sociation for Cancer Research annual meeting. Furthermore, the analysis showed that T-DM1 achieved superior outcomes in all patients who were enrolled in the trial versus patients who received capecitabine (Xeloda) plus lapatinib (Tykerb).

The presence of PI3 kinase mutations (PI3KCA) had no effect on treatment with T-DM1, but these mutations compromised the effectiveness of capecitabine plus lapatinib and are known to interfere with the effectiveness of trastuzumab.

“HER2-positive breast cancer is the same in all patients. The data of our biomarker analysis will help personalize therapy for individuals with HER2-positive breast cancer and make informed treatment decisions,” stated José Baselga, MD, PhD, Physician-in-Chief at Memorial Sloan-Kettering Cancer Center, New York.

T-DM1 is the first antibody-drug conjugate to be approved by the US Food and Drug Administration. The drug links the antibody trastuzumab to a highly potent toxic chemotherapy called emtansine. Trastuzumab attaches to the HER2 protein expressed in HER2-positive breast cancers and triggers the release of emtansine into the tumors, thereby killing tumor cells. Emtansine could not otherwise be administered to patients, because it is so toxic, Dr Baselga noted.

EMILIA was designed to compare the effectiveness of T-DM1 versus lapatinib plus capecitabine in patients with metastatic HER2-positive breast cancer who previously received trastuzumab plus taxane chemotherapy. T-DM1 significantly improved progression-free survival (PFS) and overall survival (OS) compared with capecitabine plus lapatinib.

Tumor samples were collected prospectively to study biomarkers. PFS and OS were correlated with biomarkers such as epidermal growth factor receptor, HER2 mRNA, and PI3KCA. Median HER2 mRNA concentration ratios and PI3KCA mutation frequencies were similar across all treatment arms at baseline.

T-DM1 achieved superior PFS and OS in all biomarker subgroups. How­ever, high expressors of HER2 mRNA levels derived even more benefit from T-DM1 than those with lower levels of expression. In the high expressors, median PFS was 34.1 months with T-DM1 versus 24.8 months with capecitabine plus lapatinib.

The presence of PI3KCA mutations had no effect on PFS or on OS in patients treated with T-DM1, but in the capecitabine plus lapatinib arm, the presence of PI3KCA mutations led to worse outcomes than with the PI3KCA wild type. “T-DM1 is PI3KCA mutation-neutral,” Dr Baselga said.
At present, the working hypothesis is that tumors with high HER2 overexpression are hypersensitive to anti- HER2 therapies and may not need additional chemotherapy. “But this is speculation at this point,” he explained.

T-DM1 is currently being studied earlier in the course of disease as adjuvant therapy and as first-line therapy for metastatic disease.

Novel antibody-drug conjugates are in development for other types of cancer, Dr Baselga noted.