From HER+ back to ER+: how to diagnostic?

[heblaj01]

A study has shown that a fraction of HER+ patients treated with Herceptin become resistant & they return to their original ER+ status & are then treated again with anti estrogen drugs such as Tamoxifen or Letrozole sometimes over several years.
How is the change of status detected? Is there a non invasive way to do the diagnostic? How often should this be checked?

(I am aware that in an other study readministering Herceptin to patients declared resistant shows renewed efficacy in some of them. My above questions are not related to the latter cases).

[Cathya]

I have read this as well and think that the word "resistant" will likely turn out to be inaccurate. However, if your disease progresses on herceptin this is thought to be true. I don't believe the process is understood. Joe posted a link to articles this morning I think and I was reading one which I believe could end up being useful in this regard and take away some of the worry the resistant theory brings to us all.

Lack of response to trastuzumab for breast cancer may reverse if PI3K inhibitor added

Cancer Weekly - May. 01, 2006
2006 MAY 1 - (NewsRx.com) -- Breast cancer patients with HER2-positive tumors who don't respond to Herceptin (trastuzumab) may benefit from cocktail therapy that includes Herceptin along with one or more PI3K inhibiting agents, according to researchers at The University of Texas M. D. Anderson Cancer Center.

Their findings, reported at the annual meeting of the American Association for Cancer Research (AACR), were made in cell culture and mice studies, but are so promising that a phase 1/2 clinical trial will start at M. D. Anderson in HER2-positive breast cancer patients whose disease has progressed despite Herceptin treatment. Herceptin is Genetech's formulation of the monoclonal antibody trastuzumab.

"More than half of patients with HER2-positive tumors don't respond to Herceptin as a single agent, and our research has shown us why that is and what might be done to help these patients," said lead author Dihua Yu, MD, PhD, professor in the Department of Surgical Oncology.

Combining PI3K inhibitors with existing therapies also might provide additional benefit in treating other breast tumor types.

In 2004, Yu and her research team reported that patients who don't respond to Herceptin have very low levels of PTEN in their breast tumors, whereas women who respond have higher levels of this protein. In normal cells, PTEN is a powerful tumor suppressor gene that helps control cell division. In about half of all of breast tumors (HER2-positive or not), however, PTEN levels are very low or the protein is completely missing.

It was known that when Herceptin, a monoclonal antibody, binds to the HER-2 protein on the outside of tumor cells it takes days for the protein to degrade. But Yu found that within 10 minutes of administration, Herceptin activated PTEN. This suggested that Herceptin works by rapidly mobilizing PTEN in addition to inhibiting HER-2 growth signals, she said.

PTEN is known to block the effect of a growth-promoting protein known as PI3K, which itself controls an oncogenic pathway that includes the cell proliferation kinases Akt and mTOR.

In this study, the research group tested seven different PI3K inhibitors that are either used or under development for clinical trials. They found that one, RAD001 (everolimus), had better antitumor activity when combined with Herceptin than did Herceptin or RAD001 alone.

Another PI3K inhibitor, TCN-P (triciribine), showed significant benefit when used in combination with Herceptin, Yu says. Even with a low dose of TCN-P, the combination therapy halted growth of PTEN-deficient HER2-positive breast tumors implanted in mice.

Based on preclinical data from Yu's team, Francisco Esteva, MD, PhD, an associate professor in the Department of Breast Medical Oncology, will be conducting the clinical trial.

This article was prepared by Cancer Weekly editors from staff and other reports. Copyright 2006, Cancer Weekly via NewsRx.com.

[al from Canada]

One thing we do know is that HER2 and ER status is variable and may change as the disease progresses. This has major implications for HER2 (-) BC as many may have HER2++ as the disease changes and do not know it and may have benefit grom herceptin. ER+ resistance can be reversed with administration of a HER1 inhibitor such as iressa, lapatinib or tarceva.

Al

[Cathya]

Al;

Why would it not be a good idea to give these drugs to all users of herceptin as it can't be known who isn't reacting to the drug until progression occurs? If they haven't been approved.... that would be one reason.... but other than that is it a good idea?

Cathy

[al from Canada]

Unfortunately, in this economy, there is much pressure on "cost / benefit analysis" Other than private care facilities, who can afford indiscriminate use of these very costly treatments without a very sound medical justification. I think the time has come for the drug manufacturers to re-assess their pricing structure, there committments to their share holders and balance that with the current mortality rate. For example, Avastin: $16,000 / month?? I thought there were laws against excessive profiteering but this sort of thing is going to bankrupt the Canadian public healthcare system.

trying hard not to be bitter and twisted,
Al