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T-DM1 May Overcome Resistance to anti-HER2 Medicines Caused by Gene Mutation

Findings show women with and without PIK3CA mutations similarly benefit from Kadcyla

August 1, 2013

Written By Nicole Katze, MA, Editor and Manager, Publications
Reviewed By Nancy U. Lin, MD

Through a subanalysis of data from EMILIA, the clinical trial that led to FDA approval of T-DM1, researchers found that the amount of HER2 messenger RNA (mRNA) present in HER2 positive, metastatic tumors may predict how well that breast cancer will respond to the medicine. Messenger RNA is a type of molecule that carries genetic information to help make proteins. The more mRNA measured on tumor cells, the more HER2 proteins present, and the more responsive those cells will be to T-DM1.

The study also showed T-DM1 was effective in women with HER2 positive breast cancer regardless of whether or not their tumors carried a mutation in the PIK3CA gene. T-DM1, an antibody-drug conjugate, pairs chemotherapy with a targeted medicine to deliver chemotherapy directly to the tumor, while sparing healthy cells from its toxic effects.

These findings have not yet been published in a peer-reviewed medical journal, but were presented at the 2013 Annual Meeting of the American Association for Cancer Research.

Background

Researchers involved in the EMILIA study found that women with HER2 metastatic breast cancer experienced longer progression-free survival (PFS) and overall survival (OS) than women in the second arm of the research study, who were treated with both capecitabine and lapatinib. However, HER2 positive tumors vary at the molecular level, including in the amount of HER2 proteins expressed and whether gene mutations play a role in their growth.

In order to better understand how HER2 tumors respond to T-DM1, the investigators of the current study explored two factors they believed might help identify who would benefit most from treatment with the medicine.

  • The level of HER2 mRNA expression, which is a method some labs use to determine HER2 status.
  • The presence of a mutation to the PIK3CA gene, which activates the PI3K pathway in cells. Activation of the PI3K pathway is believed to work against other anti-HER2 therapies available, such as trastuzumab (Herceptin).

Design

The investigators tested the 495 tumor samples collected from the T-DM1 treatment arm of the EMILIA trial for level of HER2 mRNA and PIK3CA mutations. Tumors with more than the median amount of HER2 mRNA were categorized as having high levels of HER2; those with the median amount or less were categorized as having low levels of HER2. The researchers then analyzed the progression-free and overall survival data for each group.

EMILIA enrolled 991 people with HER2 positive, locally advanced or metastatic breast cancer whose cancers progressed after treatment with trastuzumab and a taxane. Participants were randomly assigned to T-DM1, given by vein every 3 weeks, or to lapatinib plus capecitabine, taken as a pill twice daily for 14 days every 3 weeks.

Results

Comparing PFS and OS within the two groups, the investigators found that

  • women with high levels of HER2 experienced longer PFS (10.6 vs. 8.2 mos.) and OS (34.1 vs. 26.5 mos.) than women with low levels of HER2, when treated with T-DM1
  • women with and without PIK3CA gene mutations benefitted similarly from T-DM1

What This Means for You

T-DM1 is already a promising, less toxic treatment option for HER2 positive, metastatic breast cancer. The finding that women with higher levels of HER2 respond better to treatment with T-DM1 means that in the future, doctors may be able to choose your treatments in a more individualized fashion. Learning that women with PIK3CA mutations benefit from treatment with T-DM1 as much as women without a mutation is important, because other studies have suggested that PIK3CA mutations might reduce the benefit of anti-HER2 therapies such as trastuzumab.

Though these findings are important, they are unlikely to change your course of treatment today – but they do have the potential to impact future treatments. Even women with lower levels of HER2 experienced over 8 months of disease control with T-DM1, so right now, testing for HER2 level with mRNA is not recommended in routine clinical practice. 

If you are interested in participating in a clinical trial, talk with your doctor to see if any are available in your area and if you are eligible to join.

 Baselga, J, Verma, S, Ro, J. Relationship between tumor biomarkers (BM) and efficacy in EMILIA, a phase III study of trastuzumab emtansine (T-DM1) in HER2-positive metastatic breast cancer (MBC). Paper presented at: American Association for Cancer Research Annual Meeting; April 2013, Washington DC.

Denver, CO  ·  September 13, 2014

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