Tykerb Question

A reader of my blog e-mailed me today, and one thing she said is bothering me: She said that Tykerb, my new miracle drug, only works for six or seven months, typically, and then it stops working.

None of my doctors had told me this, and I sure hope it's not true, because I've been on Tykerb for four months already (since Thanksgiving Day, 2007), and that means it would stop working pretty darn soon.

Those of you who are on Tykerb--what do you know about this? Please give me your source, even if it's just "My oncologist said."

Thanks.

I've e-mailed Dr. L in Tucson to ask him, but of course it's Sunday morning, so he may not be checking e-mail today.

@ Jeanne Sather 2008.

Comments

[Dee]

One person to contact is Liz Kreger, over at www.lizkreger.com. I think she's been on the Xeloda/Tykerb regimen for over a year and is still doing relatively well, with no signs of the bone and liver metastases she'd had. Maybe her doctor has told her something?

[Dee]

Jeanne,
I just found the study results - here is an article about it:

http://www.medicalnewstoday.com/articles/65170.php

The study says that the median time to progression of metastases was 27.1 weeks, using Xeloda and Tykerb, versus 18 weeks on Xeloda alone. It was a statistically significant result. What that means is that, on AVERAGE, women with metastatic breast cancer had disease progression in 6-7 months (27 weeks divided by 4 is almost 7 months), which means that for some women it was less, and for some it was more (and if we read the actual medical article), it might actually mean that there were some women in the 399 who did NOT have disease progression.

We'd have to look at the actual profiles of women who participated in this study - just how bad was their metastatic disease?

I tend to think that my bone and skin mets may not be as bad as these other women who participated - we caught both fairly early in my case, so my belief is that I won't have recurrences on this regimen.

[jeanne]

Dee--thanks for digging this out. I still haven't gotten a reply from Dr. Livingston, and I will ask Dr. Lee when I see him this Friday.

Major bummer. But the women in the trial were probably sicker than you or I. I agree on that.

[Dee]

Did you hear from Dr. L yet?

A nurse said to me yesterday that since Tykerb is a lot like Herceptin, it may be able to be used long-term. How long were you on Herceptin?

[jeanne]

No answer from Dr. L yet. I may call him.

I was on Herceptin for six years, or a bit more. Initially, the Herceptin (plus zometa and hormonal treatments at the same time) put me into a fairly long clinical remission. Then when tumors started getting active again, we added different chemo drugs, typically for six months at a time, on top of the Herceptin and other drugs.

What I suspect is that if my tumor markers start to climb again on Tykerb, we will add oral cytoxan again. I'm OK with that, but I won't feel as well as I do now. Bummer. I'll know more after Friday's appt. with Dr. Lee.

But also, this is such a fairly new drug that there won't be a lot of clinical evidence yet ... meaning what our doctors are seeing with their patients, rather than what the clinical trial found.

So I'm holding on to these thoughts.

Jeanne

[Gregory D. Pawelski]

Why Do Some Breast Cancers Stop Responding to Targeted Therapy?

Targeted therapy halts the growth of certain cancers by zeroing in on a signaling molecule critical to the survival of those cancer cells. The drugs are effective in about 10-15% of patients. The drugs work specifically in patients whose cancers contain mutations in a gene that encodes the epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF) or some other pathway.

The EGFR stands at the origin of a major signaling pathway involved in the growth of breast cancer. Two of the four receptors in this pathway, epidermal growth factor receptor type 1 (HER1) and epidermal growth factor receptor type 2 (HER2, also referred to as HER2/neu or ErbB2), are promising targets for new treatments.

In about 20% of patients with breast cancer, the tumor overexpresses HER2. Herceptin, a humanized monoclonal antibody that targets the extracellular domain of HER2, is effective as adjuvant therapy and as treatment for metastatic disease in patients with HER2-positive breast cancer.

Tykerb, an orally administered small-molecule inhibitor of the tyrosine kinase domains of HER1 and HER2, has antitumor activity when used as a single agent in patients with HER2-positive inflammatory breast cancer or HER2-positive breast cancer with central nervous system (CNS) metastases that are refractory to Herceptin. This finding is important because HER2-positive tumors frequently spread to the CNS, where the tumor is sheltered from Herceptin and most chemotherapeutic agents.

Other targeted therapies also show great promise in the treatment of breast cancer. Avastin is a monoclonal antibody against the vascular endothelial growth factor (VEGF). Tumors can be effectively controlled by targeting the network of blood vessels that feed them. Tumor growth is dependent on angiogenesis. Angiogenesis is dependent on VEGF. Avastin directly binds to VEGF to directly inhibit angiogenesis. Within 24 hours of VEGF inhibition, endothelial cells have been shown to shrivel, retract, fragment and die by apoptosis. In addition to VEGF, researchers have identified a dozen other activators of angiogenesis, some of which are similar to VEGF.

Although these targeted therapies are initially effective in certain subsets of patients, the drugs eventually stop working, and the tumors begin to grow again. This is called acquired or secondary resistance. This is different from primary resistance, which means that the drugs never work at all. The change of a single base in DNA that encodes the mutant protein has been shown to cause drug resistance.

Initially, tumors have the kinds of mutations in the EGFR or VEGF gene that were previously associated with responsiveness to these drugs. But, sometime tumors grow despite continued therapy because an additional mutation in the gene, strongly implies that the second mutation was the cause of drug resistance. Biochemical studies have shown that this second mutation, which was the same as before, could confer resistance to the EGFR or VEGF mutants normally sensitive to these drugs.

It is especially interesting to note that the mutation is strictly analogous to a mutation that can make it tumor resistant. For example, mutations in a gene called KRAS, which encodes a signaling protein activated by EGFR, are found in 15 to 30 percent of certain cancers. The presence of a mutated KRAS gene in a biopsy sample is associated with primary resistance to drugs. Tumor cells from patients who develop secondary resistance to a drug like Tarceva after an initial response on therapy did not have mutations in KRAS. Rather, these tumor cells had new mutations in EGFR. This further indicates that secondary resistance is very different from primary resistance.

All the EGFR/VEGF mutation or amplification studies can tell us is whether or not the cells are potentially susceptible to this mechanism of attack. They don't tell you if one drug is better or worse than some other drug which may target this. There are differences. The drug has to get inside the cells in order to target anything.

EGFR/VEGF-targeted drugs are poorly-predicted by measuring the ostansible targets, but can be well-predicted by measuring the effect of the drug on the "function" of live cells.

Literature Citation:
PLoS Medicine, February 22, 2005
Eur J Clin Invest 37 (suppl. 1):60, 2007

[jeanne]

Gregory--WAY too much detail for this audience. Care to try to put it into everyday English?

Jeanne

[Gregory D. Pawelski]

Well, basically either one of two things happen. The original 'targeted' drug didn't work in the first place (primary resistance) or it worked but for the wrong gene mutation (acquired or secondary resistance). The change of a single base in DNA that encodes the mutant gene/protein has been shown to cause drug resistance.

If a particular gene/protein pathway was expressed (active) in cancer cells, you may take a drug that may shut down that gene/protein that was expressed, resulting in cancer cell death. Targeted therapy halts the growth of certain cancers by zeroing in on a signaling molecule critical to the survival of those cancer cells.

If that stopped working, sometimes tumors grow because another gene/protein was expressed that the original targeted drug did not take care of. It would be the second mutation that cause drug resistance, not the first mutation.

All the mutation or amplification studies can tell us is whether or not the cells are potentially susceptible to this mechanism (pathway) of attack. They don't tell you if one drug is better or worse than some other drug which may 'target' this. There are differences. The drug has to get inside the cells in order to 'target' anything.

'Targeted' drugs are poorly-predicted by measuring the ostensible 'targets' but these 'targeted' drugs can be well-predicted by measuring the effect of the drug on the 'function' of 'live' cells.

There is a new laboratory test that has accurately identified patients who would benefit from treatment with the molecularly-targeted anti-cancer therapies. These 'smart' drugs do not work for everyone and a test to determine the efficacy of these drugs in a patient could be the first crucial step in personalizing treatment to the individual.