Info about A/C sensitivity in Her2 patients

I found this when checking my stock quote for Genentech (DNA)!

Chemo regimen can limit Herceptin heart risk-study
Thu Dec 8, 2005 10:44 AM ET
LOS ANGELES, Dec 8 (Reuters) - The breast cancer drug Herceptin, shown recently to improve survival in women with early-stage breast cancer, carries with it a risk of heart damage, but a chemotherapy regimen can limit the danger, researchers said on Thursday.
Genentech Inc.'s (DNA.N: Quote, Profile, Research) Herceptin has been on the market since 1998 as a treatment for the 25 percent to 30 percent of breast cancer patients, who have tumors that generate a protein called HER-2 and whose cancer has spread beyond the breast.

These tumors tend to grow faster and are more likely to recur than tumors that do not carry the protein.

Herceptin, given by injection, is an antibody-based drug designed to target tumor cells and spare normal cells, unlike chemotherapy which is toxic throughout the body.

Since the announcement earlier this year of positive trial results for Herceptin in combination with chemotherapy in earlier-stage cancer, physicians have begun to use the drug in these patients.

Genentech has said it plans to file in the first quarter of 2006 for regulatory approval of Herceptin in early-stage breast cancer after surgery.

A study conducted by the Breast Cancer International Research Group, early results of which were announced in September, found that Herceptin plus standard chemotherapy reduced the risk of disease recurrence in early breast cancer by 51 percent.

"The chemotherapy combinations we tested with Herceptin proved to be superior to the best available standard therapy for early breast cancer," Dr. Dennis Slamon, the study's principal investigator and director of clinical/translational research at UCLA's Jonsson Cancer Center, said in a statement.

He presented the full study results at the San Antonio Breast Cancer Symposium.

The 3,222 women enrolled in the trial received either standard treatment with Adriamycin and Carboplatin followed by Taxotere, an experimental regimen of Adriamycin and Carboplatin followed by Taxotere and one year of Herceptin or Taxotere and Carboplatin with one year of Herceptin.

Slamon said researchers knew that giving Herceptin with Adriamycin resulted in heart damage in some patients, the most severe of which was congestive heart failure. The study showed that the cardiac toxicity was significant and continued past the study's 18-month follow-up.

The trial found that 306 patients lost more than 10 percent of heart function. Of those, 91 received standard chemotherapy; 82 were in the arm that excluded Adriamycin; and 180 were in the arm which paired Adriamycin with Herceptin.

The good news, Slamon said, is that Herceptin given with the chemotherapy combination that eliminated Adriamycin is still significantly superior to the best available chemotherapy alone, reducing risk of relapse by 39 percent.

The study's other important finding is that a subset of HER-2 positive patients -- about 35 percent -- also have amplification of a gene called topo II, which makes them more likely to respond to Adriamycin. As Herceptin targets HER-2, Adriamycin targets topo II.

Patients who test positive for amplification of both HER-2 and topo II might opt for the drug regimen with Adriamycin, risking heart damage in exchange for a better response to therapy, Slamon said.

He said a test that indicates both HER-2 and topo II amplification is being developed so doctors will better be able to tell which patients should be on which drug regimen.

"Women will have the information they need to decide if the risk is worth the benefit," Slamon said.


© Reuters 2005. All Rights Reserved.

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[al from Canada]

Thanks Scott,
There was a session on this at SABCS and TOPO-II is one of the growing number of markers used to predict the efficacy of various treatments but also as a diagnostic tool to determine which targetted therapy should be used. It was very clear that the future of the traditional slash and burn chemos is questionable in light of the emergance of many targetted therapies which are based upon genetic profiling. What I didn't know was that adriamycin is actually treatment that targets the TOPO-II gene. Therefore, there is a co-relation between TOPO-II expression and the propencity towards cardiac (LVF) episodes. There was also a relationship between HER2 overexpression, TOPO-II overxpression and the response rate to herceptin both with and without adriamycin. As we know, current molecular targets that are cosely associated with the HER2 target are: HER1 & 3, ER, PR, COX2, P53, P13K, ALK, VEGF......just to mention a few. What is evident is a growing number of molecular targetted compounds, being introduced through the clinical trial pipeline.

Two of the most notable from the past few days are Lapatinib (TYKER), a HER1 and HER2 receptor antagonist and Avastin which is a Vascular epidermal growth factor (VEGF) anti-angiogenic compound. The results of Herceptin + avastin trial were nothing short of spectacular as their is a close co-relation between HER2 and VEGF. More on this later......
Regards,
Al

AL,

Was there any more positive data on Lapatinb? I've kind of given up on Lapatinib as the data has been so slow coming out.

Thanks for any info,
Scott

[al from Canada]

Scott,

Lapatinib has been approved for stage 3 trials. My understanding is that part of the hold-up has been due to zeroing on the parameters which wll result in the correct selection of patients; because they don't want to see the drug go down due to lousy project planning. For example, there were enough people trying to torpedo herceptin during the development stages that if the patients weren't properly selected herceptin would be history by now; never approved by the FDA. A better example of this is Iressa, another hopeful small molecule tyrosine kinase inhibitor, which was so successful in other cancer trials that they got sloppy in the BC trials and .....try to find it now. Targetted therapies are exactly what the name implies...VERY targetted; which means they work on a very select and TARGETTED group of patients.
Expect more on this drug, now called TYKERB, at ASCO next year.
Regards,
Al