Finding

On Cancer: Studies Report on Latest Advances in Targeted Therapy for Breast Cancer

By Julie Grisham, MS, Science Writer/Editor  |  Tuesday, April 9, 2013
Pictured: José Baselga Physician-in-Chief José Baselga

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.”

Comments

Is ABRAXANE ever given in late stage metastatic breast cancers when Taxol and other chemo drugs were not effective?

Angelina, we spoke to Clifford Hudis, Chief of our Breast Cancer Medicine Service, and he said, "Abraxane (nanoparticle-bound paclitaxel) is a newer version of the older chemotherapy agent paclitaxel (Taxol). It is given to selected patients with breast cancer in a variety of settings, including in advanced or metastatic breast cancer." If you'd like to learn more about Memorial Sloan-Kettering's approach to treating breast cancer, you can go to http://www.mskcc.org/cancer-care/adult/breast. Thank you for your comment.

Is ABRAXANE given to patients at MSKCC?
The fact that paclitaxel in Abraxane reaches the tumor in higher concentrations and more rapidly than Taxol is a significant advantage. The active ingredient (paclitaxel) is bound and caught up in the bloodstream with Taxol, while in contrast the paclitaxel in Abraxane is rapidly transported to the tumor. A hallmark of Abraxane is its rapid response in terms of tumor reduction... this potential for rapid shrinkage is important when dealing with fast growing inoperative metastatic tumor which is what my sister is suffering with.

How does one get into clinical trial? Stage 2b or 3 Her2 Positive hormone positive grade 3- Neoadjuctive Taxol/Herceptin (stopped growth but pathology shows did nothing to turmor) Lumpectomy with Node dissection- doing 4 rounds A/C and it has not been decided what chemo to do next since I don't want to do more Taxol, since it did not work.

Mimi, if you'd like to learn more about participating in a clinical trial at Memorial Sloan-Kettering, please call 800-525-2225 or go to http://www.mskcc.org/cancer-care/appointment for more information. To view our current clinical trials in breast cancer, you can go to http://www.mskcc.org/cancer-care/clinical-trials/clinical-trial?keys=&field_trial_diseases_value=Breast+Cancer. Thank you for your comment.

Has there been any study done on the long-term use of denosumab ? What adverse effects have been coming up lately in cancer patients who use it?

Leonor, we forwarded your question to medical oncologist and breast cancer specialist Monica Fornier. She said that the pivotal randomized trials with denosumab — which included patients who had breast cancer, prostate cancer, and other solid tumors, as well as multiple myeloma — lasted for two years. The side effects that were seen in the study included a risk of hypocalcemia (low calcium) and a risk of developing osteonecrosis of the jaw. The risk for osteonecrosis was similar to what is seen with the use of bisphosphonates (zoledronic acid). Denosumab did not cause any kidney problems. Thank you for your comment.

My sister is stage IV metastatic breast cancer but is her2 negative- what is there for her? It is in her bones and she is on morphine for pain.
Is there anything to help her?

Shary, we're sorry but we are not able to answer individual medical questions on our blog. If you'd like to make an appointment to speak with a Memorial Sloan-Kettering physician, you can call 800-525-2225 or go to http://www.mskcc.org/cancer-care/appointment. Thank you for your comment.

Well all what i can say was it not for my radical mastectomy then my cancer would have spread to my bones!Biopsy show only one breast with cancer thanks to my Surgeon we chop of both.and the results was both with cancer and the same stage my left tumor was one cm bigger and both with positive lymph nodes.I am now four years cancer free on Tamoxifen only Lymphedema in my one arm.Charlotte

Anyone ever hear of fistula in breast after lumpectomy. I can't have radiation

Grace, unfortunately we are not able to answer questions about personal medical issues on our blog. We spoke to breast surgeon Tari King, who said that fistulae are a rare complication and that only your doctor can properly evaluate your personal situation. Thank you for your comment.

Is there a time span when surgical intervention is appropriate? This is generally speaking. Thank you. I can't find any literature on this subject.

If you'd like to speak to a doctor at Memorial Sloan-Kettering about your situation, please call 800-525-2225 or go to http://www.mskcc.org/cancer-care/appointment. Thank you for your comment.

Could you please clarify the meaning of PI3KCA mutations and how one is tested for it? Is this a genetic mutation similar to BRCA1 & BRCA2 or a protein mutation similar to HER2+?

Hi Neilene, the PI3KCA mutation is not an inherited mutation such as BRCA1 & BRCA2 but a mutation that occurs when a cell become cancerous. (It is similar to the HER2 mutation.) Therefore, a person would not be tested for a PI3KCA mutation as they might for a BRCA1 or BRCA2 mutation. Thank you for your comment.

What clinical trial would you recommend for PIK3R1 mutation in a triple negative metastatic scenario?

Karen, if you are interested in learning about clinical trials at MSKCC, you can call our Physician Referral Service at 800-525-2225. You may also want to reach out the National Cancer Institute's Cancer Information Service at 800-4CANCER. Thanks for your comment.

I was started on Kadcyla after having recurrence for Breast with mets to my liver. All liver lesions were gone after I started and have been on it one year this May. Most recent PET in Jan 2014... No lesions! It is a miracle drug in my book.

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