Researchers are continually working to find better ways to treat all stages of breast cancer. The studies reviewed here are very early results on a number of new ways to treat breast cancer. The results were reported at the 2008 San Antonio Breast Cancer Symposium.
Some of these studies were phase I studies, which means the potential treatment is tested in a very small group of people (less than 100) to make sure it's safe and figure out a safe dosage, and to evaluate side effects. Some of the studies were phase II studies, which means the new treatment was given to between 100 and 300 people to make sure it works and to further study its safety. If the results from phase II trials look promising, researchers will conduct phase III trials, which means the new treatment is given to a larger group of people (more than 1,000) to confirm that it works and to see whether it's more effective than commonly used treatments. These phase I and phase II results, while promising, are very early results and the treatments reviewed here will not be available until more research is done.
New Treatments Shown to be Effective in Treating Breast Cancer
mTOR (Mammalian Target of Rapamycin) Inhibitors: Cancer cells need energy to grow and spread. A kinase is a kind of protein that helps all cells (both normal and cancer cells) get the energy they need. Doctors know that when kinases don't act normally they help certain breast cancers grow. Herceptin (chemical name: trastuzumab) treats breast cancer by interfering with this abnormal kinase activity.
mTOR is a kinase and doctors think it helps some breast cancers grow. RAD001 is an experimental targeted therapy that interferes with mTOR activity. In a phase I trial, 20 of 27 metastatic breast cancers responded to a combination of Taxol (chemical name: paclitaxel), Herceptin, and RAD001. But in a phase II trial, only 3 of 31 metastatic breast cancers responded to treatment with only RAD001.
TAS-108: Estrogen can make hormone-receptor-positive breast cancers grow and spread. Hormonal therapy medicines either reduce the amount of estrogen in the body or block estrogen's effect on breast cancer cells. Still, some advanced-stage breast cancers that have responded to available hormonal treatments can stop responding to those treatments.
TAS-108 is an experimental hormonal therapy medicine. In women diagnosed with advanced-stage breast cancer that had stopped responding to available hormonal therapy medicines, researchers found that some of the cancers did respond to TAS-108.
Zolinza (chemical name: vorinostat): Zolinza is a medicine that interferes with a protein that controls genetic activity inside a cancer cell. In a very small, very early study involving women diagnosed with advanced-stage breast cancer, researchers found that many of the cancers responded to a combination of Zolinza, Taxol, and Avastin (chemical name: bevacizumab).
Abraxane [chemical name: Nab-Paclitaxel (nanoparticle albumin-bound paclitaxel)]: Abraxane is a newer form of paclitaxel. Both Taxol and Abraxane are approved to treat advanced-stage breast cancer. Paclitaxel has to dissolve so it can enter the bloodstream. But paclitaxel does not dissolve in water. Taxol, the older form of paclitaxel, dissolves paclitaxel in a solvent called Cremaphor. But Cremaphor can cause an allergic-like reaction during treatment.
Instead of dissolving paclitaxel in Cremaphor, Abraxane surrounds the paclitaxel with albumin, a human protein. Because Abraxane doesn't use Cremaphor, it doesn't cause the allergic-like reaction seen with Taxol.
A small, early study found that most of the 123 women diagnosed with stage II or stage III breast cancer and treated with Abraxane and the chemotherapy medicines Gemzar (chemical name: gemcitabine) and Ellence (chemical name: epirubicin) got some benefits from the treatment.
Some breast cancers produce too much of a protein called SPARC. Researchers wondered if too much SPARC on the surface of breast cancer cells was connected to worse prognosis. SPARC can bind to albumin, so this study also looked to see if Abraxane would be more effective against cancers with too much SPARC because Abraxane surrounds paclitaxel with albumin. But the results showed no connection between too much SPARC and worse prognosis. The results also found that Abraxane wasn't more effective against breast cancers with too much SPARC.
Ixempra (chemical name: ixabepilone): Ixempra is approved to treat advanced-stage breast cancer after other chemotherapy treatments have stopped working. Ixempra is given alone or in combination with the chemotherapy medicine Xeloda (chemical name: capecitabine).
A small, early study looked at using Ixempra in combination with Herceptin to treat HER2-positive, metastatic breast cancer. Of 39 women treated with Ixempra and Herceptin, 20 of the women got some benefit from the combination. In 10 of the other women, the cancer stopped growing while being treated with Ixempra and Herceptin.
Potential New Breast Cancer Treatments
IGF Receptor Inhibitors: All cells have different types of receptors on their surfaces. These receptors tell the cell when to grow and divide based on chemical signals. But hormone receptors on the surface of many breast cancer cells can work with another receptor called IGF-R1 (insulin-like growth factor type 1). Together, these two receptors make breast cancers grow and spread. Doctors think that blocking the IGF receptor might make advanced-stage breast cancers respond better to hormonal therapy medicines.
An early safety study involving a small number of women diagnosed with advanced-stage hormone-receptor-positive breast cancer found that combining an experimental IGF receptor inhibitor called CP-751,871 with the hormonal therapy medicine Aromasin (chemical name: exemestane) didn't cause any severe side effects or problems. Some of the women treated with CP-751,871 developed high blood sugar, liver problems, or headaches. More research is needed to see if an IGF receptor inhibitor can effectively treat advanced-stage hormone-receptor-positive breast cancer.
PARP Inhibitors: DNA is the genetic code inside of a cell. Breast cancer cells are more likely than normal cells to have damaged DNA. Some chemotherapy medicines work by damaging breast cancer cells' DNA. Still, cells can repair the damage. A protein called PARP helps cells repair DNA damage. Researchers have found that PARP levels are higher than normal in some cancer cells, including breast cancer cells. This could make it easier for a breast cancer cell to recover from damage caused by chemotherapy.
BSI-201 is an experimental medicine that interferes with PARP's ability to repair DNA damage. An early safety study involving a small number of women diagnosed with advanced-stage, triple-negative (estrogen-receptor-negative, progesterone-receptor-negative, and HER2-negative) breast cancer found that adding BSI-201 to a combination of the chemotherapy medicines Gemzar and carboplatin didn't cause any more side effects than the chemotherapy medicines alone. More research is needed to determine if a PARP inhibitor can effectively treat advanced-stage, triple-negative breast cancer.
Nexavar (chemical name: sorafenib): Cancer cells need a steady blood supply to grow and spread. To ensure this steady supply, cancers can make new blood vessels grow into the tumor. This new blood vessel growth is called angiogenesis. The targeted therapy medicine Avastin works by blocking angiogenesis and starving the cancer. Nexavar is a new targeted therapy that also blocks angiogenesis. Nexavar also blocks the actions of other proteins that tell cancers to grow and spread. Nexavar has been approved to treat advanced-stage liver and kidney cancers.
An early study gave Nexavar with and after the chemotherapy medicines doxorubicin, cyclophosphamide, and paclitaxel to lower the risk of breast cancer coming back (recurrence) in a small number of women. The women had been diagnosed with early-stage breast cancer that had spread to the lymph nodes or were considered at high risk for the cancer coming back. The researchers found Nexavar caused a small increase in side effects compared to the chemotherapy medicines alone. More research is needed to see if Nexavar and chemotherapy can reduce the risk of breast cancer coming back after surgery.
Research on new treatments and new uses for current medicines offers hope for more effective breast cancer treatment options. Still, much more research is needed before any of these new medicines are widely available.
If you're being treated for breast cancer, especially advanced-stage breast cancer, you and your doctor might consider whether participating in a clinical trial makes sense for you. Clinical trials are designed to answer very specific questions about the new treatment, so your unique situation will be carefully considered before you're accepted into a trial. Besides the benefits you might get from the treatment being studied, being in a clinical trial allows you to help find better breast cancer treatments.
SAN ANTONIO, Jan. 23 (MedPage Today) -- Despite significant therapeutic advances, breast cancer remains the third leading cause of cancer mortality in the U.S., surpassed only by lung and colon cancer.
At the San Antonio Breast Cancer Symposium in December, dozens of presentations focused on how to maximize the benefits of existing therapies, but the symposium also provided a forum for the future.
Here's a look at the current state of clinical development for emerging breast cancer therapies.
mTOR Inhibitors
Mammalian target of rapamycin -- mTOR -- is a serine/thionine kinase involved in cell proliferation and angiogenesis. Laboratory studies have shown that activation of the mTOR pathway induces trastuzumab (Herceptin) resistance.
The mTOR inhibitor RAD001 was combined with paclitaxel and trastuzumab in a phase I study of patients with HER2-positive metastatic breast cancer with proven resistance to trastuzumab. A total of 27 patients received RAD001 at doses of 5 to 10 mg a day.
The combination therapy resulted in one complete response, eight partial responses, and stable disease in 11 patients, reported Ruth O'Regan, M.D., of Emory University in Atlanta.
The most common grade 3-4 adverse events were neutropenia (15 patients), lymphopenia (eight), stomatitis (seven), and leucopenia (five).
Investigators in a multinational European study reported similar results in 37 patients treated with RAD001, vinorelbine (Navelbine), and trastuzumab.
All patients had metastatic disease, HER2 overexpression, and demonstrated resistance to trastuzumab, reported Angela Fasolo, M.D., of the National Tumor Institute in Milan, Italy.
One patient had a complete response, five had partial responses, and 21 had stable disease. Grade 3-4 neutropenia occurred in all patients, but other grade 3-4 adverse events were infrequent.
Results of a phase II study of the mTOR inhibitor temsirolimus (Torisel) were less encouraging. Three of 31 patients with metastatic breast cancer had stable disease with single-agent treatment. No complete or partial responses occurred.
TAS-108
TAS-108 is a steroidal antiestrogen with potent estrogen receptor-alpha antagonist activity. Preclinical studies have shown that the agent inhibits both estrogen-dependent and estrogen-independent growth in tamoxifen- and aromatase inhibitor-resistant cell lines.
U.S. and Russian investigators reported findings from a phase II dose-finding study of TAS-108 in postmenopausal women with advanced breast cancer.
The study involved a total of 145 patients, who received 40 mg, 80, mg, or 120 mg of TAS-108 as second- or third-line endocrine therapy.
The primary endpoint was total clinical benefit, defined as the composite of complete and partial responses and stable disease ?24 weeks. The total benefit rate for all three groups was 18.7%, as determined by an independent clinical endpoint committee, and 25.2% as reported by investigators.
The drug was well tolerated at all three doses, reported Aman Buzdar, M.D., of the University of Texas M. D. Anderson Cancer Center in Houston. The most common adverse events were fatigue (28.3% of patients) and nausea (26.2%).
Japanese investigators reported slightly better findings from another phase II dose-finding study of TAS-108. A total of 97 postmenopausal women with advanced or metastatic breast cancer received 40, 80, or 120 mg of TAS-108 as single-agent therapy.
The overall rate of clinical benefit was 26.8%. Patients given the lowest dose had the highest rate of clinical benefit, 30.3% versus 25% for the 80- and 100-mg doses.
IGF Receptor Inhibitor
It's hypothesized that crosstalk occurs between estrogen receptors and insulin-like growth factor type 1 receptors (IGF-R1). In preclinical studies, inhibition of both leads to synergistic induction of apoptosis of estrogen receptor-dependent breast cancer cells.
The IGF-R1 inhibitor CP-751,871 is being evaluated with exemestane (Aromasin) in an ongoing randomized clinical trial involving patients with ER-positive advanced breast cancer. A total of 150 patients will be randomized to exemestane alone or to the combination of exemestane and CP-751,871. Thus far, 50 patients have received a total of 499 doses of the IGF-R1 inhibitor.
Paula Ryan, M.D., of Harvard, and colleagues reported safety data for 41 patients randomized to the CP-751,871 arm. The most common grade ?2 adverse events have been hyperglycemia (30%), elevated gamma glutamyl transferase (14%), and headache (12%).
The hyperglycemia was controlled with oral hypoglycemic agents or insulin, and elevated gamma glutamyl transferase appeared to be reversible.
PARP Inhibitor
Poly (ADP-ribose) polymerase (PARP) is a nuclear enzyme involved in DNA repair and is upregulated in several types of tumors, including breast cancer.
Preliminary safety data with the PARP inhibitor BSI-201 revealed no added or unexpected toxicity when BSI-201 was added to combination chemotherapy with gemcitabine (Gemzar) and carboplatin in patients with triple-negative breast cancer. The safety data pertained to 89 patients who received as many as 12 cycles of chemotherapy alone or combined with BSI-201.
Gene expression profiling of the first 50 patients enrolled in the study confirmed upregulation of PARP in tumors compared with normal breast tissue, as reported by Joyce O'Shaughnessy, M.D., of Baylor University Medical Center in Dallas, and colleagues.
Vorinostat
Histone deacetylase inhibitors enhance transcription of epigenetically silenced genes. Preclinical studies have shown that HDAC inhibitors enhance the anticancer activity of docetaxel (Taxotere) and inhibitors of vascular endothelial growth factor inhibitors.
Adding the HDAC inhibitor vorinostat (Zolinza) to paclitaxel and bevacizumab (Avastin) resulted in one complete response and 14 partial responses among 28 patients with metastatic breast cancer.
Additionally, 12 patients had stable disease for at least 12 weeks, including five who remained stable for at least six months, reported Bhuvaneswari Ramaswamy, M.D., of Ohio State University in Columbus.
Hematologic and nonhematologic toxicity was common, but severe toxicity (grade 3-4) was uncommon.
Nab-Paclitaxel
Nanoparticle albumin-bound paclitaxel (Abraxane) is a solvent-free formulation of the taxane. High-pressure homogenization of paclitaxel in the presence of serum albumin results in paclitaxel-containing nanoparticles that use endogenous albumin transport mechanisms to concentrate in tumors.
Investigators in a multicenter study evaluated nab-paclitaxel in combination with epirubicin and gemcitabine for patients with advanced breast cancer. The protocol included assessment of secreted protein acidic rich in cysteine (SPARC), an albumin-binding protein associated with poor prognosis.
Patients with stages IIa to IIIb breast cancer received six biweekly cycles of neoadjuvant therapy, followed by surgery or radiation therapy, and then four more cycles of chemotherapy. The primary objectives were the feasibility and toxicity of the regimen.
Of 123 evaluable patients, 18% had pathologic complete responses, 68% had partial responses, and 5% had stable disease, reported Denise Yardley, M.D., of the Sarah Cannon Research Institute in Nashville, Tenn.
Progression-free survival at 24 months was 71% and median PFS was 23 months.
SPARC staining results for 72 patients showed that 59 of 69 who had stable disease or better response were SPARC positive (including eight of nine pathologic complete responses), contradicting evidence linking SPARC overexpression to poor prognosis.
The regimen was generally well tolerated, as the most common grade 3-4 adverse effects were neutropenia (16%), arthralgia (11%), fatigue (10%), thrombocytopenia (9%), and infection (7%).
Sorafenib
The angiogenesis inhibitor sorafenib (Nexavar) was evaluated with standard adjuvant chemotherapy in patients with lymph node-positive or high-risk breast cancer.
Patients received four cycles of doxorubicin-cyclophosphamide, followed by 12 weeks of paclitaxel (administered every three weeks or weekly). Sorafenib was started concurrently with paclitaxel and continued as maintenance therapy from week 25 to week 64, reported David Spigel, M.D., of the Sarah Cannon Research Institute. The primary objective was the safety of the regimen.
Of 45 patients enrolled in the trial, all completed the doxorubicin-cyclophosphamide phase, but only 14 remained in the trial through completion of sorafenib maintenance therapy.
The most common reason for failure to complete the study was toxicity during the paclitaxel-sorafenib phase, although Dr. Spigel and colleagues said toxicity was not severe, as only rash and hand-foot syndrome were increased compared with the doxorubicin-cyclophosphamide phase.
Ixabepilone
A microtubule inhibitor, ixabepilone (Ixempra) was evaluated with trastuzumab in a phase II trial involving patients with metastatic HER2-positive breast cancer.
Sara M. Tolaney, M.D., of Dana-Farber Cancer Institute in Boston, presented data for 39 patients, 15 with no prior treatment for metastatic disease and 24 who had received one or two trastuzumab-containing regimens for metastatic disease.
Overall, 20 patients had partial responses, 12 of 15 with no prior treatment and eight of 24 treatment-experienced patients. Ten other patients had stable disease, all but one in the treatment-experienced group.
A pooled analysis of two phase II trials showed that the combination of ixabepilone and capecitabine (Xeloda) improved the response rate and progression-free survival in taxane-resistant metastatic breast cancer.
The analysis involved a total of 674 patients randomized to the combination and 663 randomized to capecitabine alone, as reported by Henri Roche, M.D., of Institut Claudius Regaud in Toulouse, France.
The combination was associated with an overall response rate of 39% versus 22% for capecitabine alone.
The median progression-free survival was 5.1 months with the combination and 3.7 months with monotherapy, representing a 19% improvement in the hazard ratio (95% CI 0.72-0.91).
Median overall survival was 13.3 months with the combination, which represented a nonsignificant improvement over the 11.6-month median with capecitabine alone.
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