Tykerb/Xeloda - continuing anti estrogen??

[doh2pa]

I have a question for my fellow warriors on Tykerb/Xeloda? Is your onc keeping you on anti-estrogen therapy also? Although I technically advanced on an AI, Lani's post of 5/2 regarding the triple targeted therapy approach to cure breast ca in mice got me thinking. So I asked my onc today about going back on Aromasin, and he said although it wasn't part of the original protocal, he didn't see any reason not to do it (except for the hot flashes and joint issues -which is all bearable). What about you? I'd love to hear what the rest of you are doing.

Donna

[hutchibk]

My onc took me off of Aromasin, too, before I started Ty/Xel. He felt that with progression, it wasn't doing anything for me. Hmmmm. I am glad you posted this as it had gotten past me about the triple targeted approach. I will ask my doc about going back on it.

Can you please reference Lani's post - I guess I missed it and would love to show it to my onc next week...

[doh2pa]

Hi Brenda,

It was originally posted by Lani on 5/2/07. I believe she has an update to it (search her posts) but here's the main body of the original post

her2 breast cancer cured (when transplanted in mice) using triple targetted therapy
vs her family:

Combination treatment stymies breast cancer growth [Eureka News Service]
HOUSTON (May 5, 2007)—A combination of three different drugs that block the HER-2 receptor, a critical cellular growth signal for some breast cancers, eradicated aggressive breast tumors in mice and could point the way toward developing better treatments inpatients, said researchers from the Breast Center at Baylor College of Medicine in a report that appears today in the Journal of the National Cancer Institute.
"For the first time, we were able to cure mice of a very aggressive human breast tumor," said Dr. Rachel Schiff, assistant professor in the Breast Center at Baylor College of Medicine and senior author of the report.

In prior such studies, treatment only slowed or delayed the growth of tumors, she said. In this case, the tumors disappear and do not come back, even when treatment is stopped.

The treatment involved is a new approach known as "targeted" therapy because the protein (in this case, HER-2) driving a tumor to grow is first identified in a patient's tumor and then specific drugs are used to block that particular growth pathway in the cells, said Dr. Kent Osborne director of the Breast Center and the Dan L. Duncan Cancer Center with BCM. He is also an investigator on the study.

"When you go after a specific target in a patient's tumor, the treatment is likely to be more effective and less toxic," said Schiff.

The tumors in question - nearly 25 percent of all breast cancers - have high levels of HER-2. While the HER-2 makes the tumors more aggressive, it also provides a target against which new drugs can act.

Previously, treatment for patients with HER-2 positive tumors was less effective.

"Now we have effective treatment, and survival is markedly improved," said Dr. Grazia Arpino, lead investigator of the study and a postdoctoral fellow at BCM.

"These tumors are initially highly sensitive to a drug known as trastuzumab or Herceptin, one of the drugs used in combination in the mouse study and which is approved by the FDA (U.S. Food and Drug Administration) for treatment," said Schiff.

However, the tumor is wily and can sometimes escape the drug's effects, resulting in resistance. Adding two other experimental drugs - gefitinib and pertuzumab — that inhibit HER-2 in different ways can more completely block the growth signals in the tumor, causing it to die.

In one of the tumors studied in this report, blocking the stimulatory effects of estrogen on the tumor was also necessary for optimal treatment, said Schiff. Completely blocking the HER pathway is critical, she said. Leaving out just one of the three drugs was much less effective.

A clinical study using drug combinations in newly diagnosed patients with HER-2 positive breast cancer will start soon under the direction of physicians at BCM's Breast Center, said Osborne.

"We are very excited to see if our laboratory results can be translated to patients with the more aggressive types of breast cancer," he said.

^^^^^^^^^^^^

Treatment of Human Epidermal Growth Factor Receptor 2-Overexpressing Breast Cancer Xenografts With Multiagent HER-Targeted Therapy [Journal of the National Cancer Institute]
Background: Human epidermal growth factor receptor 2 (HER2) is a member of the HER signaling pathway. HER inhibitors partially block HER signaling and tumor growth in preclinical breast cancer models. We investigated whether blockade of all HER homo- and heterodimer pairs by combined treatment with several inhibitors could more effectively inhibit tumor growth in such models.
Methods: Mice carrying xenograft tumors of HER2-overexpressing MCF7/HER2-18 (HER2-transfected) or BT474 (HER2-amplified) cells were treated with estrogen supplementation or estrogen withdrawal, alone or combined with tamoxifen. One to three HER inhibitors (pertuzumab, trastuzumab, or gefitinib) could also be added (n ?8 mice per group). Tumor volumes, HER signaling, and tumor cell proliferation and apoptosis were assessed. Results: were analyzed with the t test or Wilcoxon rank sum test and survival analysis methods. All statistical tests were two-sided.

Results: Median time to tumor progression was 21 days for mice receiving estrogen and 28 days for mice receiving estrogen and pertuzumab (difference = 7 days; P = .001; hazard ratio [HR] of progression in mice receiving estrogen and pertuzumab versus mice receiving estrogen = 0.27, 95% confidence interval [CI] = 0.09 to 0.77). Addition of gefitinib and trastuzumab to estrogen and pertuzumab increased this time to 49 days (difference = 21 days; P = .004; HR of progression = 0.28, 95% CI = 0.10 to 0.76). MCF7/HER2-18 tumors disappeared completely and did not progress (for ?189 days) after combination treatment with pertuzumab, trastuzumab, and gefitinib plus tamoxifen (19 of 20 mice) or plus estrogen withdrawal (14 of 15 mice). Both combination treatments induced apoptosis and blocked HER signaling and proliferation in tumor cells better than any single agent or dual combination. All BT474 tumors treated with pertuzumab, trastuzumab, and gefitinib disappeared rapidly, regardless of endocrine therapy, and no tumor progression was observed for 232 days.

Conclusion: Combined treatment with gefitinib, trastuzumab, and pertuzumab to block signals from all HER homo- and heterodimers inhibited growth of HER2-overexpressing xenografts statistically significantly better than single agents and dual combinations.

[lilyecuadorian]

C. Kent Osborne and Rachel Schiff Laboratory

Welcome

Our laboratory is a team effort between C. Kent Osborne, M.D. a clinical scientist and cell biologist, and Rachel Schiff, Ph.D., a molecular biologist, and is one of several basic/translational research laboratories comprising the Breast Center at Baylor College of Medicine and The Methodist Hospital in the Texas Medical Center in Houston, Texas. Both Drs. Osborne and Schiff have Faculty Appointments in the Department of Medicine and in the Department of Molecular and Cellular Biology. Dr. Osborne is the Director of the Breast Center and he has more than 25 years of experience in translational and clinical research in breast cancer. Dr. Schiff has much experience in molecular and cellular biology of breast cancer and is an expert in exploiting breast cancer preclinical models towards the development of novel approaches of targeted therapies.
The research objective of our laboratory is to understand the molecular mechanisms by which breast cancers become resistant to endocrine therapy and then to develop new treatment strategies to block or overcome this resistance. In this research, we combine molecular/genetic analyses with cell biology to answer important clinically relevant questions using cell culture and animal models that we developed two decades ago, along with newly developed ones. Major interests include the crosstalk that we and others have discovered between growth factor receptor and/or other cellular kinase signaling and estrogen receptor signaling pathways, and the role of ER coactivators and corepressors in the development of hormone therapy resistance. We have shown that growth factor receptor signaling such as that initiated by tyrosine kinase receptors of the EGF family play an important role in hormone therapy resistance and that blockade of these pathways represents a new strategy to prevent it. The ER coactivator AIB1 (SRC3) which is often either amplified and/or overexpressed in breast cancer, and the ER corepressor protein FKHR that is often lost in breast cancer are modulated by growth factor signaling and we believe are key to the resistant phenotype.
Various projects include: 1) determine the mechanisms by which receptor tyrosine and serine/ threonine kinases cause resistance to tamoxifen and other endocrine therapies, 2) investigate whether therapies that target these pathways can overcome resistance, 3) identify the role of AIB1 phosphorylation in ER function and hormone therapy resistance, 4) determine if the ER corepressor FKHR functions as a tumor suppressor gene in breast center, and 5) define molecular profiles in human breast cancer specimens that predict selective hormone therapy resistance and, then, identify new therapeutic targets to reverse it.

http://www.breastcenter.tmc.edu/labs/osborne/index.htm

[hutchibk]

Thanks! I did read this but didn't see any reference to lapatinib (Tykerb) so I didn't retain it...

I have already been on Herc w/ aromasin (which is double targeted, I suppose, not triple). It sounds like to me this triple threat is a combo of Iressa, Herceptin and pertuzamab (still in trials). The conclusion seems to be that the hormonal therapy is a non-player when using this combo... "All BT474 tumors treated with pertuzumab, trastuzumab, and gefitinib disappeared rapidly, regardless of endocrine therapy, and no tumor progression was observed for 232 days."

I know all about Kent Osborne. Luckily he is only 2.5 hours aways from me in Houston. He is on my list of "Where do I go next if this all gets REALLY complicated?" (because obviously we don't consider it very complicated yet, LOL) He was at the UT Health Science Center in San Antonio when my onc was in school there, so he knows him fairly well. He's a great researcher.