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cancer drug resistance

Triple Negative Breast Cancer – What Every Patient Should Know

breast cancer ribbonA diagnosis of triple negative breast cancer (TNBC) can strike fear in the hearts of a patient and his or her family since such breast cancers tend to be both more aggressive and more difficult to treat than hormone-positive breast cancers.   

Nearly 15-20% of breast cancers are so-called “triple negative,” meaning such cancers have tested negative in pathology reports for estrogen receptors, progesterone receptors, and Her2/Neu.   The growth of these cancers are not fueled by estrogen and progesterone, as are most cancers, and therefore, do not respond to hormonal therapies such as Tamoxifen, Arimidex, Aromasin, Femara or Aromasin.  Further, such cancers do not respond to therapies that target HER2 receptors, such as Herceptin or Tykerb, rendering them more difficult to treat.   As a result, treatment for TNBC typically involves a combination of surgery, chemotherapy, and radiation.

Most studies have shown that TNBC is both more likely to metastasize and recur (in the early years) than hormone-positive breast cancers.   A 2007 study of 1,600 Canadian women found that TNBC patients were at much higher risk of reoccurrence outside of the breast area within the first 3-5 years post-diagnosis. Another 2007 study of more than 50,000 with all forms of breast cancer found 77 percent of women with TNBC survived 5 years, whereas 93 percent of women with other forms of cancer survived the same duration  Over the longer term, the TNBC relapse rate drops below that of hormone-positive breast cancers.   These conclusions have been supported by several studies, but also opposed by a smaller, 300-patent study.

TNBCs also tend to be higher “grade” than other types of breast cancer.  The grade measures how closely a cancer cell resembles a normal, healthy breast cell in terms of size, shape, and growth pattern/activity.   Most TNBCs are labeled Grade 3, the highest on the scale.

Younger African American and Hispanic women are at higher risk of TNBC than their Caucasian peers.  Furthermore, a 2009 study found that women who used oral contraceptives for more than one year were significantly more likely to develop TNBC than those that did not.

TNBC has become a core focus of the cancer research community.   Current research is focused on Angiogenesis and EGFR (HER-1) inhibitors, PARP inhibitors (which showed initial promise, but now, mixed results), and Glembatumumab vedotin (CDX-011).   Research in new target areas and new treatment options are being funded by the National Foundation for Cancer Research (NFCR).

NFCR-funded scientist Dr. Susan Horwitz, of the Albert Einstein College of Medicine, has been instrumental in the development of a successful class of anti-cancer drugs called Microtubule-Stabilizing Agents (MSAs) – a class that includes Taxol®.   MSAs work by binding microtubules, filamentous intracellular structures involved in cell and nucleic division and intracellular transport, promoting their polymerization, blocking mitosis (cell division/replication), and causing cell death.  According to Dr. Sujuan Ba, “NFCR is now funding a collaborative effort between Dr. Horwitz and Dr. Amos B. Smith, III, to develop another MSA agent designed to overcome the drug resistance triple-negative breast cancers exhibit to Taxol while limiting toxicity.”

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Research by NFCR Scientists Reveals New Insights into Treatment Resistance of Metastatic Breast Cancer

Oscillating expression of a key cancer gene may impact treatment approaches for patients

NFCR-supported scientist Dr. Daniel Haber and his team at the Massachusetts General Hospital Cancer Center have identified a dynamic gene expression in metastatic breast cancer that may contribute to disease progression and resistance to treatment experienced by many patients. Tumors can evolve in response to treatment and they may acquire new genetic features that may make them resistant to drugs and cause disease progression.

In their quest to find genetic changes in advanced breast cancer, the scientists utilized the rare circulating tumor cells (CTCs) found in a patient’s bloodstream – which have migrated away from a tumor and into blood vessels. CTCs offer a wealth of information to researchers and oncologists about the state of a patient’s cancer.

“I am thankful to the NFCR for their sustained support of our research to increase our understanding of the genes involved in the progression of cancer and to develop prevention and treatment strategies for metastatic cancer,” said Dr. Haber.

The Haber team used their device, the CTC-iChip, to collect viable CTCs from women initially diagnosed with primary breast tumors that are ER+/HER2-, meaning that their tumor cells expressed estrogen receptor genes (ER+) but did not express the HER2 gene (HER2–). Both ER and HER2 genes are known for their role in fueling breast cancer cells and promoting tumor growth. The patients had undergone multiple courses of treatment for recurrent metastatic cancer.

Intriguingly, molecular characterization of the isolated CTCs revealed not just ER+ / HER2– tumor cells, but also a second type: the ER+ / HER2+ cells that also express the HER2 gene.

Through a series of elegant laboratory experiments, the researchers delved deeper to characterize the CTCs and found a unique and dynamic interconversion of HER2 gene expression: ER+/HER2– cells could spontaneously become ER+/HER2+ and convert back to ER+/HER2–. In addition, researchers found that the two populations of tumor cells depended on different molecular signaling pathways for their proliferation and consequently, were sensitive to different anti-cancer drugs.

Because HER2 gene expression oscillates between on and off spontaneously in these tumors, researchers reasoned that the two separate signaling pathways may need to be simultaneously turned off to halt either cell group from repopulating one another and beginning new abnormal growth. Results of further experiments in cell cultures and more advanced tumor models proved that simultaneous treatment with chemotherapy paclitaxel and targeted therapeutic drugs that inhibit the NOTCH1 molecular signaling pathway achieved suppression of tumor cell growth expressing both ER+ / HER2– and HER2+ subpopulations.

This breakthrough discovery was published in the August 24 online edition of the journal Nature.

“Although more research is needed to uncover why HER2 has this dynamic on-and-off expression, these insights from our research are a positive development for a new treatment approach,” said Dr. Haber.

Dr. Haber also notes that clinical trials will now be needed to test whether these insights from experimental models will translate into better and more effective treatments for women with advanced breast cancer.

“The CTC research platform developed by Dr. Haber and his team continues to produce new knowledge about the intricate ways that cancer may grow and evade treatments,” said Franklin Salisbury, CEO of NFCR. “Metastatic disease causes more than 90% of the fatalities to cancer and the new insights from this research have opened the field for potential new treatment approaches so desperately needed for patients with metastatic breast cancer.”

 

 

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