WASHINGTON, DC — The effectiveness of trastuzumab emtansine (Kadcyla, Genentech), which was recently approved for the second-line treatment of metastatic HER2-positive breast cancer, is apparently not diminished by tumor mutations in the PIK3CA gene.
This is good news for clinicians because PIK3CA mutations can lead to resistance to conventional HER2-directed therapies, such as trastuzumab (Herceptin, Genentech) and lapatinib (Tykerb, GlaxoSmithKline), said José Baselga, MD, PhD, from the Memorial Sloan-Kettering Cancer Center in New York City.
Dr. Baselga spoke at a press conference here at the American Association for Cancer Research 104th Annual Meeting.
He explained that trastuzumab emtansine, also known as T-DM1, is different from other drugs for HER2-positive disease because it has the mechanisms of action of trastuzumab, a targeted therapy, but also delivers a "very potent" chemotherapy, emtansine, directly to tumors.
Dr. Baselga presented new data from the EMILIA study, which was the basis for the approval of T-DM1 in metastatic disease.
Dr. Baselga reported that, consistent with previous findings, patients treated with T-DM1 had significantly better progression-free survival (9.6 vs 6.4 months) and overall survival (30.9 vs 25.1 months) than patients treated with lapatinib and capecitabine.
In addition, he presented a new subanalysis that examined the relation between treatment efficacy and a number of biomarkers, including the PIK3CA mutation.
"Our findings [on biomarkers] are an important step toward identifying the best therapy for individual patients with HER2-positive breast cancer," said Dr. Baselga in a press statement. "HER2-positive breast cancer is not a uniform disease; each patient is different."
The investigators found that patients treated with T-DM1 had similar outcomes, regardless of their PIK3CA status, but that patients treated with lapatinib and capecitabine did worse if they had the mutation.
These data provide further evidence that mutations in the PIK3CA gene might be important in selecting the appropriate HER2 therapy.
"Our results are not practice changing at this point" because they are retrospective and need confirmation, said Dr. Baselga. "But I think we should start sequencing and checking for the presence of PIK3CA mutations," he added.
Another expert, who is not involved with the study, had similar thoughts and suggested that the testing should be performed for all women with HER2-positive breast cancer.
"In the future, we should test for the PIK3CA mutation because, if you have it, then you may be less sensitive to trastuzumab and lapatinib," said Giuseppe Giaconne, MD, PhD, from the Georgetown Lombardi Comprehensive Cancer Center in Washington, DC, and the National Cancer Institute. When he spoke with Medscape Medical News at the meeting, he emphasized that the findings need to be repeated in a prospective trial.
If testing becomes standard, then treatment decisions for patients with HER2-positive disease would be based, in part, on PIK3CA status, he explained.
This information should pave the way for earlier and wider use of T-DM1 in HER2-positive breast cancer patients, Dr. Giaconne said.
There are now 4 therapies that target HER2-positive metastatic breast cancer, and T-DM1 is the most expensive. According to media reports, trastuzumab costs around $4500 per month, pertuzumab costs around $6000 per month, and T-DM1 costs around $9800 per month. Some clinicians are very concerned about the escalating cost of these therapies.
Amount of HER2 Also Matters
Dr. Baselga and colleagues reviewed data from the 991-patient EMILIA trial to retrospectively look at specific biomarkers, including the PIK3CA mutation, and their possible influence on treatment outcomes.
Tumor tissue collected for HER2 testing was also used to assess PIK3CA in a subset of 259 patients — 133 treated with T-DM1 and 126 treated with lapatinib and capecitabine.
In the T-DM1 group, progression-free survival, the primary study outcome, was somewhat better in the 40 patients with PIK3CA mutations than in the 93 patients with wild-type PIK3CA (10.9 vs 9.8 months). Overall survival was comparable between the 2 groups.
In other words, in the T-DM1 group, PIK3CA mutations did not mean worse outcomes.
This was not the case for the patients treated with lapatinib and capecitabine; PIK3CA mutations meant worse progression-free and overall survival in that group.
Specifically, in the lapatinib and capecitabine group, progression-free survival was worse in the 39 patients with PIK3CA mutations than in the 87 patients with wild-type PIK3CA (4.3 vs 6.4 months). Overall survival was also worse in patients with the mutation.
The investigators also assessed the associaiton between tumor levels of HER2, based on the amount of HER2 messenger (m)RNA, and treatment outcome.
Patients with tumor samples expressing greater than the median amount of HER2 mRNA were considered to have high levels of HER2. Those with tumor samples expressing the median amount of HER2 mRNA or less were considered to have low levels of HER2.
For patients treated with T-DM1, overall survival was better for tumors expressing higher levels of HER2 than for tumors expressing lower levels (34.1 vs 26.5 months).
The study was sponsored by Genentech and Roche. Dr. Baselga reports financial relationships with Roche and other pharmaceutical companies. Dr. Giaconne has disclosed no relevant financial relationships.
American Association for Cancer Research (AACR) 104th Annual Meeting: Abstract LB-63. Presented April 8, 2013.
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Cite this: Mutation Status May Guide Treatment for HER2 Breast Cancer - Medscape - Apr 10, 2013.