Triple-Negative Breast Cancer

When Homa Sadat found a lump in her breast at age 27, her gynecologist told her she was too young to have breast cancer.

With the lump dismissed as a harmless cyst, Sadat didn’t think about it again until she felt a shooting pain. A biopsy of the lump confirmed breast cancer; a biopsy of a lymph node confirmed that the cancer had spread. Sadat was diagnosed with triple-negative breast cancer.

Pathologists who test breast cancer cells look for the presence of estrogen and progesterone hormone receptors and the overexpression of receptors for a type of protein called HER2. Breast cancer that is positive for one of the hormone receptors can be targeted with a tamoxifen or an aromatase inhibitor. Trastuzumab (Herceptin) and its newer versions are used to target HER2-positive breast cancers.

But breast cancers that are negative for all three receptors have no targets for these drugs, making them very difficult to treat. Fortunately, triple-negative breast cancer is rare — affecting approximately 15 percent of all women with breast cancer. It is diagnosed at a higher rate in patients with hereditary breast cancer associated with the BRCA1 gene, as well as in African-American women.

City of Hope researchers are fighting back by studying these cancers, in hopes of discovering more effective treatments.

“We offer several innovative clinical trials for newly diagnosed and Stage 4 triple-negative breast cancer patients that are part of a national effort to address these difficult-to-treat tumors,” says George Somlo, M.D., professor in the departments of Medical Oncology & Therapeutics Research and Hematology & Hematopoietic Cell Transplantation at City of Hope.

One such trial for newly diagnosed patients is evaluating the effect of destroying cancer cells with chemotherapy before patients have surgery. “Once the tumor is completely eliminated, or at least reduced in size, surgery follows. Patients with newly diagnosed triple-negative breast cancer who do not experience a recurrence within five years are likely cured,” says Somlo.

Sadat initially sought treatment at another center and came to City of Hope for a second opinion from Somlo. She enrolled in a City of Hope phase II clinical trial that offered chemotherapy prior to surgery and was treated with carboplatin and a novel nanoparticle drug called nab–paclitaxel (Abraxane).

After eight weeks on the chemotherapy regimen, the tumor had shrunk significantly. Sadat volunteered for a biopsy, and to her surprise, the tumor was gone.

Ongoing research, ongoing advances

Another eight weeks later, Sadat underwent surgery at City of Hope to remove the area of breast tissue that had contained the tumor, as well as several lymph nodes. No cancer cells were found in these tissues. Her cancer was in complete remission.
Somlo is close to completing this particular clinical trial, as well as a randomized, phase II, national study assessing the role of carboplatin and the PARP-inhibitor veliparib in patients with Stage 4 BRCA1- and BRCA2-associated breast cancer.

“We are learning that triple-negative breast cancer consists of at least a half-dozen subtypes, each of which may require personalized therapies,” says Somlo.

“We must intensify our current laboratory and translational research to improve next- generation clinical trials for much better control and eventual cure of triple-negative Stage 4 metastatic breast cancers. The next generation of trials will need to be more tumor-target specific, so we can help individual patients overcome their particular subtype of triple-negative breast cancer,” he adds.

Research reported in this study was supported in part by the National Cancer Institute of the National Institutes of Health under grant number NIH-NCI CA 33572. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Women’s Cancers: Basic research seeks new ways to attack cancer

Advances in immunotherapy
Peter P. Lee, M.D., chair of cancer immunotherapeutics and tumor immunology at City of Hope, is pursuing several projects that are part of a what he calls integrated immunotherapy. This concept advances the idea that effective cancer treatment must address each phase or action of the body’s complex immune system.

In one project, Lee is studying the role of stromal cells, which make up connective tissue. He has found that stromal cells support cancer by attracting and modulating immune cells. His team is currently developing three-dimensional microculture systems to study the interactions among stroma, cancer and immune cells in tumors, with a goal of learning how to disrupt cancer’s support system and restore immune function.

Lee is also advancing the use of spectral imaging. Using powerful new technology, Lee is able to see two- and three-dimensional images of the location of cells, making it possible to understand how immune cells and cancer cells interact within the tumor and sentinel nodes (lymph nodes found under the arm, and often the first site of metastasis for breast cancer). One of the leaders in this sophisticated imaging technique, Lee recently led a worldwide webinar to teach other researchers about spectral imaging.

A novel way to target cancer
Yuan Yuan, M.D., Ph.D., assistant professor of medical oncology, is studying how tumor cells use nutrients to grow and proliferate, and how this process differs from normal cell metabolism, so that she can selectively target cancer cells. Yuan is collaborating with David Ann, Ph.D., professor of molecular pharmacology, who found that some types of breast cancer cells lack a specific enzyme and, as a result, need the amino acid arginine to grow.

Together, their research demonstrates how to deprive these cells of arginine and suppress tumor growth. Yuan seeks to translate this novel research to the clinic, where it will be the focus of a first-of-its-kind study for women with breast cancer.

How genes help cancer spread
Emily Wang, Ph.D., associate professor of cancer biology, focuses her research on understanding how microRNAs (miRNAs) regulate gene expression to promote or prevent cancer. She has found that breast cancer cells secrete specific miRNAs that dictate gene expression in healthy cells at potential metastatic sites for breast cancer.

Wang’s studies also showed that treatment with a miRNA inhibitor significantly delayed metastasis — suggesting a novel therapeutic strategy to prevent or treat metastatic breast cancer. Wang is collaborating with Yuan to translate these findings to the clinic.

Photo: City of Hope’s fight against breast cancer, shown here, includes immunotherapy and an exploration of gene silencing.

Molecular imaging and disease
Tijana Jovanovic-Talisman, Ph.D., assistant professor of molecular medicine, recently joined City of Hope to advance her research using super resolution microscopy. Jovanovic-Talisman is using this sophisticated imaging method to see and quantify proteins on the cell membrane and inside cells. On a biological level, this method allows Jovanovic-Talisman to better understand protein signaling, both in normal cells and in cells affected by disease. She is also collaborating with other researchers at City of Hope to design new compounds to target cancer cells.

In one effort, Jovanovic-Talisman is studying the tumor marker called nucleoporins 88, which is overexpressed in solid tumors, including breast and ovarian cancers. She is currently designing mimics, down to the nanometer scale, of the biological processes that are occurring in cancer and healthy cells. These models will be used to further understand how nucleoporins 88 causes cancer and to test drugs that target the molecule.

The quest for a novel therapeutic
Linda Malkas, Ph.D., associate chair and professor of molecular and cellular biology and the deputy director of basic research, is focused on identifying compounds that selectively target cancer. Previously, Malkas found a target in cancer cells, called cancer-associated proliferating cell nuclear antigen, that plays a role in DNA repair and helps cancer survive and proliferate.

Now, she is collaborating with City of Hope’s molecular chemists to modify small molecules that selectively block the antigen. Together, they have created a highly active synthetic compound called AOH1160. Recent animal studies have shown that AOH1160 is effective at inhibiting tumor growth. This exciting new compound could lead to a novel therapeutic for women fighting breast cancer.

Silencing genes to target cancer
Carlotta Glackin, Ph.D., associate professor of neurosciences, studies a protein called Twist1, which is overexpressed in many aggressive cancers, including breast and ovarian cancers. She is working to develop targeted therapeutics that inhibit Twist1 and stop cancer.

In collaboration with John Rossi, Ph.D., Lidow Family Research Chair and chair and professor of molecular and cellular biology, Glackin is exploring the use of small-interfering RNA (siRNA) bound to nanoparticles to deliver gene-silencing materials to tumors and block the expression of Twist1. Glackin studied this approach in cell lines and found that it was effective. Now, she is studying this therapeutic in animal models, and hopes to open a clinical trial at City of Hope. Glackin’s research provides another promising approach to therapy that could bring healing to so many women battling cancer.

Next: Part 2: Studies of risk and prevention

New Program Offers Peer Support for Women

It has long been said that imitation is the sincerest form of flattery. At City of Hope, researchers are implementing this concept of imitation—of making one thing similar to another—in a leading-edge approach to treating difficult cancers.

City of Hope’s new chief of surgery and an enthusiastic researcher, Yuman Fong, M.D., has been developing a therapy that essentially makes resistant breast cancer respond like thyroid cancer, which is cured in 90 percent of patients.

Triple-negative breast cancer—named for its lack of three important receptors that can be targeted with common, effective therapies—remains a challenge for women, as well as for the oncologists who care for them. Fong is energized by this challenge and the promise of discovery. “If we can find something that can kill [these types of] cancer cells, it would be a big breakthrough for the field,” he says.

Fong has been developing a new approach to treating triple-negative breast cancer by starting with what he knows and loves: viral therapy. He has long studied how viruses can kill cancer. Happily, his expertise in viruses and affinity to the challenge of treatment-resistant cancers is a good fit.
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Exercise: Tackle Your Busy Schedule With Renewed Energy

Being a successful woman in the real estate industry means your days are most likely hectic and stressful. The last thing you probably want to do is go to the gym. If you can motivate yourself to go, you may end up on the treadmill the entire time because the weight area intimidates you and/or you’re scared to ask questions. Sure, you look and feel great in your designer power suit, but that feeling can quickly melt away once the suit comes off.

Now many of you know that you should use weights to reap maximum benefits for your body but perhaps you’re too busy to learn the right exercises. Or, maybe you’re against weights because you believe you’ll bulk up like one of those bodybuilders. This is where a personal trainer comes in.

Because the real estate business can be exhausting, hiring a personal trainer who’s experienced enough to know how to design customized workout routines can be just what you need. This can maximize your exercise results and help keep your heart rate up throughout your entire workout. It can also help you burn a great deal of fat, while sculpting your body.
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