Sounds Like Good News ??

[Joe]

IMPAKT: Solutions Possible for Anti-HER2 Drug Resistance
By Crystal Phend, Senior Staff Writer, MedPage Today
Published: May 11, 2010
Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston and
Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner
BRUSSELS -- Acquired resistance to HER2-targeted agents in breast cancer may be surmountable, based on new mechanistic clues, British researchers indicated.
Newer and novel agents that attack more types of HER receptors, such as lapatinib (Tykerb) or neratinib, could solve the problem of activation of alternative HER receptors via a negative feedback loop, according to a study led by Merel Gijsen, of the University of Oxford.
Another step in the loop -- ADAM17, which leads to activation of other HER receptors -- may also be a target through an experimental ADAM inhibitor, they reported here at the IMPAKT Breast Cancer Conference.
In a separate session at the conference, José Baselga, MD, of the Vall d'Hebron University Hospital in Barcelona, Spain, explained that resistance to trastuzumab (Herceptin) is no surprise. The emerging picture is one of a complex pathway with multiple places from which resistance can arise, he said.
Increasingly solid data suggest that about a third of the patients with HER2-positive tumors don't have the binding site trastuzumab would attack because of a truncated form of HER2 called p95. These fragments, which can be coexpressed with normal HER2 receptors, appear to be "bad actors," with more tumorogenic and more aggressive characteristics toward the tumors in which they are found, Baselga said. But this problem might be overcome by use of lapatinib, the subject of a study that is starting now, he said.
One mystery had been why trastuzumab is effective against HER2-overexpressing cancer but doesn't eliminate HER2 phosphorylation, which shows that the signaling pathway is activated, Gijsen said.
Her group showed that this is maintained by other HER receptors via upregulation of HER ligands. In a mouse cell line model of HER2+ breast cancer, levels of the HER2 and HER3 receptor activator heregulin rose with trastuzumab treatment, compared with untreated cells (P=0.0152 to P=0.0427).
This upregulation in turn was mediated by ADAM17, which almost doubled its relative gene expression level in the presence of trastuzumab in the same cell line (P=0.008). Combining ADAM17 inhibitors and trastuzumab dropped HER2 phosphorylation.
Inhibiting protein kinase B (PKB, also known as AKT), as trastuzumab does, increased heregulin (P=0.0127) and ADAM17 (P=0.016). Using an experimental agent that blocks all the HER receptors, either alone or in combination with trastuzumab, eliminated the rise in heregulin (P=0.42 and P=0.73 versus untreated, respectively) and ADAM17 (P=0.39 and P=0.09 versus untreated, respectively).
Based on these results, the researchers proposed that trastuzumab should be combined with a panHER inhibitor or ADAM inhibitor to overcome acquired drug resistance in this population, although no drug in either class is available commercially. Another mechanism of resistance that might be countered with drugs in the future is overexpression of cyclin E, for which CKD inhibitors could be effective, Baselga said.
However, he noted that loss of HER2 sensitivity can occur in tumors too.
"I'm not sure we can intervene, but we can monitor," he said.

Regards
Joe

[Ellie F]

I think it probably is good news. It reminded me of Dr Slamon now advocating less chemo and more targeted treatments in combo like herceptin and tykerb and less toxic ones such as T-DM1
Thanks for posting. Hope is so important for us all

Ellie

[weety]

So maybe it will end up that the standard of care for adjuvant therapy of HER2+ will be a low dose chemo with herceptin AND tykerb. I just wish there was a way we could know if we were one of the 30%who showed resistance to herceptin, so tykerb could be added from the start. SIGH. . . I don't like knowing that that many HER2+ tumors are resistant.

[vlcarr]

I guess this means I was very lucky to get in the trial for herceptin & tykerb? I guess time will tell.

[Midwest Alice]

Yes Vicki I think you are lucky too!

I have ask three different onc to give me Tykerb. All said no. So I am on Herceptin for 5 years.

When will the trials of the combo of Herceptin and Tykerb report results?
We can hope they will let those of us who didn't get Tykerb get it to help stay NED

[vlcarr]

Hey Alice,

I don't have the information in front of me but I believe it went on for a while. I know I was the first patient at my treatment center but if I remember Baylor had several participants.

I will look and see if I can locate that information. Looks like you are doing well.

[Ellie F]

Alice
Totally agree with you. I have also asked 2 oncs about tykerb. The answer is always NO! The cost is a big issue here but even if I offer to pay the answer is still a resounding NO.

Ellie

[pibikay]

I was under the impression that Tykerb is effective in cases where herceptin is not helpfull and that in some cases after a course of herceptin the patient is treated with tykerb
PBK