Donor Immune Cells Attack Metastatic Breast Cancer

New Approach Holds Promise

In patients with metastatic breast cancer, immune cells from a genetically matched donor can attack and shrink tumors, researchers from the National Cancer Institute (NCI) announced at the annual meeting of the American Society of Clinical Oncology.

This is the first time researchers have clearly demonstrated this type of immune response, known as a graft-versus-tumor effect, acting against breast cancer.

"Graft-versus-tumor effects have been shown to be useful in treating cancers of the blood, such as leukemia and lymphoma," says Dr. Michael Bishop, of NCI's Center for Cancer Research and the lead author on the study.

"Breast cancer, however, has generally been resistant to immune-based therapies," Dr. Bishop says. "Although the tumors of patients in this study were not completely eliminated by the treatment, the responses we saw provide hope that immunotherapies for breast cancer are worth pursuing."

Breast cancer is the most common cancer among women, excluding non-melanoma skin cancer. Currently, approximately 3 million women in the US are living with the disease, including 2 million who have already been diagnosed, and another 1 million who do not yet know they have the disease.

Approach Used in Metastatic Breast Cancer

Tumor regression has been observed in the past in some patients with metastatic breast cancer who received stem cell transplants, but it was unclear whether immune cells had attacked the tumor or the tumor was shrinking in response to chemotherapy drugs administered prior to the transplant.

The design of this clinical trial, however, allowed researchers to attribute tumor regression to a true graft-versus-tumor effect.

Each of the 13 patients in the Phase I trial had received multiple previous treatments for metastatic breast cancer.

In the study, patients first received conventional doses of chemotherapy to kill cancer cells and reduce the cells in their immune system so that donor cells could replace them.

They then received stem cells from the blood of HLA-matched siblings. HLA-matched donor cells, which have the same set of proteins (known as human leukocyte-associated antigens) on their surface as the patient's own cells, are much more likely to be accepted by the patient's body.

T cells, specialized immune cells that recognize and kill foreign cells that have invaded the body, were removed from the pool of donated stem cells prior to transplant.

These T cells were given to patients later, in an initial infusion 42 days after stem cell transplant, then in two follow-up infusions over the next two months.

Transplanted T Cells Led to Tumor Death

Because T cells were not given immediately following chemotherapy, researchers were able to attribute any tumor cell death to the transplanted T cells rather than to anti-tumor effects of the chemotherapy drugs.

In four patients, tumors shrunk at least 50 percent in response to the treatment. A minor response was seen in three of the other patients.

Although not all patients in the study responded to treatment, and none of the tumors was eliminated entirely, the results of the trial provide evidence that transplanted T cells can attack tumors in patients with metastatic breast cancer.

Researchers are optimistic that further study could lead to effective immunotherapies for women with breast cancer.

Always consult your physician for more information.

What Is Immunotherapy?

Immunotherapy (also called biological therapy, biological response modifier therapy, or biotherapy) uses the body's immune system to fight cancer.

The cells, antibodies, and organs of the immune system work to protect and defend the body against foreign invaders, such as bacteria or viruses.

Physicians and researchers have found that the immune system might also be able to both determine the difference between healthy cells and cancer cells in the body, and to eliminate the cancer cells.

Biological therapies are designed to boost the immune system, either directly or indirectly, by assisting in the following:

• making cancer cells more recognizable by the immune system, and therefore more susceptible to destruction by the immune system

• boosting the killing power of immune system cells

• changing the way cancer cells grow, so that they act more like healthy cells

• stopping the process that changes a normal cell into a cancerous cell

• enhancing the body's ability to repair or replace normal cells damaged or destroyed by other forms of cancer treatment, such as chemotherapy or radiation

• preventing cancer cells from spreading to other parts of the body

Always consult your physician for more information.

FDA-Approved Immunotherapy Drug for Breast Cancer

A immunotherapy drug approved in 1998 for recurrent breast cancer is called trastuzumab (Herceptin®). This monoclonal antibody works against a protein that encourages breast cancer cells to grow.

According to the American Cancer Society (ACS), Herceptin® attaches to a growth- promoting protein known as HER2/neu, which is present in small amounts on the surface of normal breast cells and most breast cancers.

About one-third of breast cancers have too much of this protein and tend to grow and spread more aggressively. Herceptin® can prevent the HER2/neu protein from making breast cancer cells grow and may also stimulate the immune system to more effectively attack the cancer.

This drug can shrink some breast cancer metastases that return after chemotherapy or continue to grow during chemotherapy. And treatment that combines Herceptin® with chemotherapy may be more effective than chemotherapy alone in some patients.

Treatment with Herceptin® is generally started after standard hormone therapy and/or chemotherapy is no longer effective, but clinical trials are now in progress to see if using it with adjuvant chemotherapy can reduce the risk of recurrence and help women live longer.

Always consult your physician for more information.

Online Resources

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American Cancer Society

American Society for Clinical Oncology

Centers for Disease Control and Prevention (CDC)

National Cancer Institute (NCI)

National Human Genome Research Institute

National Institutes of Health (NIH)

National Women's Health Information Center

July 2003

Donor Immune Cells Attack Metastatic Breast Cancer

Approach Used in Metastatic Breast Cancer

Transplanted T Cells Led to Tumor Death

What Is Immunotherapy?

FDA-Approved Immunotherapy Drug for Breast Cancer

Studies Suggest MRI an Effective Screening Tool for Women at High Risk for Breast Cancer

Reports from the Annual Meeting of the American Society for Clinical Oncology

Online Resources

Studies Suggest MRI an Effective Screening Tool for Women at High Risk for Breast Cancer

Physicians now know that the risk of breast cancer increases with a family history of the disease, including abnormalities in the BRCA genes. Mutations in the BRCA1 and BRCA2 are associated with about 5 percent to 10 percent of all breast cancers, according to press statement of the American Association of Clinical Oncology (ASCO).

For women with a high risk of breast cancer, experts recommend that they have their first mammogram at age 30, or five years before the earliest onset of the disease in their family.

However, while mammography is the best tool for detecting breast cancer in women at an average risk for the disease, experts are still debating the best type of imaging technique that should be used to screen women at high risk.

Some research has suggested the use of magnetic resonance imaging (MRI) in addition to mammography to screen women at high risk for breast cancer. An MRI uses a magnetic field to produce the image of an internal organ on a computer.

Reports from the Annual Meeting of the American Society for Clinical Oncology

Study 1: To determine whether MRI should be added as a screening method in high-risk populations, researchers led by Dr. Christiane Kuhl of the University of Bonn in Germany studied 462 women who were found to be carriers of BRCA1 or BRCA2 or who, based on their personal history or strong family history, were suspected to be carriers of BRCA1 or BRCA2.

In this study, a strong family history was defined as any of the following: a relative with a breast cancer diagnosis at age 35 or younger; a relative with ovarian cancer diagnosed at age 40 or younger; both breast and ovarian cancer in a relative; or at least two relatives with breast and/or ovarian cancer, one of whom was diagnosed at age 50 or younger.

All women in the study were screened with a clinical breast examination, mammography, high-resolution ultrasound of the breast - a technique that uses sound waves to detect abnormalities in body tissues - and an MRI. For the first five years of the study, researchers found 51 breast cancers in 45 patients.

MRI offered the highest sensitivity for diagnosing breast cancer at 96.1 percent, compared with 42.8 percent for mammography, 47 percent for ultrasound, and 25 percent during a clinical breast exam.

MRI was also associated with the lowest rate of unnecessary biopsies, a procedure that removes a small piece of tissue for examination under the microscope to help detect cancer.

Because of these findings, the researchers who conducted this study concluded that MRI of the breast should replace mammography to screen women with a strong family history of the disease or women who have known BRCA .

Study 2: A team of Dutch researchers reported similar findings. As part of the Dutch MRI Screening Study (MRISC), researchers evaluated the benefit of twice-yearly clinical breast examinations, yearly mammography, and yearly MRI in 1,905 women at high risk of breast cancer due to a mutation in the BRCA1 or BRCA2 gene or a strong family history of the disease.

Following the study, the researchers said, "We recommend the routine use of MRI in addition to mammography, especially in women with proven mutations in the BRCA1/2 genes, because these women generally develop rapidly growing tumors and show the lowest sensitivity to mammography because of their young age and dense breast tissue." Dr. Jan G.M. Klijn, chairman of the Rotterdam Family Cancer Clinic was a lead investigator of the study.

However, while MRI was found to be more effective at detecting tumors of the breast than both mammography and clinical breast examination, it was also found to be slightly less specific. Lower specificity means that it is more likely to produce false positive results. False positives can lead to unnecessary biopsies and anxiety for patients.

Study 3: Experts leading a third study evaluating the benefit of MRI for women at high risk for breast cancer said that MRI needs to be refined before its use can be recommended, even for women at high risk for the disease, due to a high rate of false positives.

"The psychological impact of a false-positive MRI is not trivial," said Dr. Mark E. Robson, of Memorial Sloan-Kettering Cancer Center and lead investigator of the study.

In a trial of 53 women with BRCA mutations who participated in MRI screening, researchers found that MRI was 100 percent sensitive for detecting both ductal carcinoma in situ - a precancerous breast condition - as well as breast cancer. However, it was only 81 percent specific.

"The improved sensitivity of MRI screening is very encouraging," said Dr. Robson. "MRI can clearly detect breast abnormalities that are not seen by mammography. Unfortunately, we are finding that many of these abnormalities are not cancers."

Until the specificity of an MRI can be improved, Dr. Robson recommends that women who are considering an MRI be aware of the significant risk of false-positive results.

Always consult your physician for more information.