Since the first targeted cancer therapy, tamoxifen, was approved for treating breast cancer more than two decades ago, the goal of developing effective drugs that specifically attack cancer cells while sparing healthy cells has increasingly become a reality. As investigators learn more about the molecular changes that induce normal cells to become cancerous, the tool kit of targeted therapies for a variety of cancers continues to expand.
Several studies presented at this week’s American Association for Cancer Research (AACR) annual meeting in Washington, DC, demonstrate the promise of using new targeted therapies for the treatment of breast cancer. José Baselga, Memorial Sloan-Kettering’s newly appointed Physician-in-Chief, contributed to three of these studies.
The largest was a multicenter, phase III trial of a drug called trastuzumab emtansine (T-DM1 or KadcylaTM), which was approved by the US Food and Drug Administration in February 2013 for the treatment of certain types of advanced breast cancer. Dr. Baselga was the lead author of the study, which reported on how particular molecular changes within tumor cells can affect a patient’s response to the new therapy.
“There has already been a lot of excitement about this drug because it is superior in terms of survival compared with other treatments, and it is virtually devoid of side effects,” Dr. Baselga says. “It’s a fantastic leap forward in the field.”
(The drug is currently approved for use in metastatic breast cancer after other drugs have failed. Although T-DM1 has been shown to extend survival in these patients, most people in the phase III study eventually died because their disease was so advanced.)
A New Class of Drug
T-DM1 is known as an antibody-conjugate drug: It is made up of a targeted antibody coupled with a chemotherapy drug. The antibody homes in on cancer cells and carries with it a toxic chemotherapy agent, which destroys the cells upon delivery. T-DM1 is the first such drug approved for the treatment of a solid tumor, but similar drugs have been developed for leukemia and lymphoma.
The antibody component of T-DM1 is called trastuzumab, which works by binding to and inactivating HER2, a protein that is overproduced on the surface of cancer cells in about one-quarter of breast cancers. In the current study, all 495 women had overexpression of HER2, but Dr. Baselga and his team found that those who had higher levels of the protein had a greater response to the drug.
The investigators also tested the patients’ tumors for mutations in the gene PIK3CA, which are present in about one-third of patients who have HER2-positive disease.
“With other drugs targeted at HER2, patients who also have PIK3CA mutations usually have worse outcomes,” Dr. Baselga says. “This is because PIK3CA occurs ‘downstream’ from HER2, which means that blocking HER2 is not enough to turn off the cancer pathway.”
With T-DM1, however, investigators observed that even patients with PIK3CA mutations responded to the drug. “It makes sense because T-DM1 delivers a very potent toxin. Once it’s internalized, it kills the cells, and it doesn’t matter if the cells had that additional mutation or not,” Dr. Baselga notes. “This finding is important because it further identifies the population of patients who might benefit from this drug.”
Offering the Drug to More Patients
Other trials for T-DM1 are already planned at Memorial Sloan-Kettering and other centers. One will evaluate the drug earlier in treatment in patients with metastatic breast cancer.
In another, Dr. Baselga and his colleagues will test whether T-DM1 might reduce the risk that cancer will recur in women with earlier-stage disease when it’s given to patients who also have surgery to remove their tumors.
“We think it could be beneficial in this setting especially because of the lack of serious side effects,” Dr. Baselga explains.
Targeting Additional Mutations
Dr. Baselga and his colleagues also presented data at the AACR meeting from two early-stage studies of new, experimental drugs that target PI3KCA mutations. The two drugs, called BYL719 and GDC-0032, both appear to shrink tumors in patients with metastatic breast cancers and some other solid tumors that carry the PI3KCA mutation. Further trials are planned with both drugs, testing them alone as well as in combination with other drugs such as HER2 inhibitors.
“The take-home message of these studies is that it is becoming increasingly important to check for PI3KCA mutations in patients with breast cancer,” Dr. Baselga concludes. “This testing is something we are already doing at Memorial Sloan-Kettering on a routine basis, because it informs us about which patients may be eligible to participate in these other trials.”