circumstances under which lapatinib, not herceptin, might be the drug of choice

[Lani]

Lapatinib Effective When Breast Tumors Express HER2 and P95HER2



NEW YORK (Reuters Health) May 07 - Lapatinib (Tykerb) is effective against breast cancers that express human epidermal growth factor receptor 2 (HER2), whether or not the tumors also express a truncated HER2 receptor called p95HER2, new studies show.

Tumor xenografts coexpressing p95HER2 are resistant to the HER2 inhibitor trastuzumab (Herceptin), the researchers said. They say p95HER2 is expressed in about 30% of HER2-positive breast cancers. It is associated with increased nodal metastasis and a shorter disease-free survival compared to patients who overexpress full-length HER2.

The studies, done in two animal models and then in tissues from clinical trial subjects, were reported in a single paper published online April 20th in Clinical Cancer Research.

Dr. Jose Baselga from Vall d'Hebron University Hospital, Barcelona, Spain and colleagues first studied the antitumor activity of lapatinib in two mouse models of p95HER2-positive tumors. Lapatinib -- an HER2 tyrosine kinase inhibitor -- markedly reduced tumor growth compared with placebo in trastuzumab-refractory breast tumors that coexpressed both full-length HER2 and p95HER2 and in p95HER2-dependent tumors.

Then the investigators analyzed the relationship between p95HER2 expression and response to lapatinib in HER2-positive patients who received the agent either as monotherapy or in combination with capecitabine (Xeloda).

Altogether, 20.5% of women in the monotherapy trial (14/68) and 28.5% of women in the capecitabine-plus-lapatinib study (45/156) had tumors that were p95HER2 positive. In both studies, progression-free survival did not differ significantly between p95HER2-positive and p95HER2-negative subgroups.

Moreover, the presence of p95HER2 did not alter the impact of lapatinib on clinical benefit rate or overall response rate in the 2 clinical trials.

"Taking in consideration that p95HER2 tumors are resistant to trastuzumab, our results suggest that lapatinib, as well as other tyrosine kinase inhibitors, may be a preferred therapeutic option for these tumors," the researchers conclude. "Hence, the presence of p95HER2 could determine the choice of anti-HER2 therapy if the results are further validated."

The current studies were supported in part by GlaxoSmithKline, the manufacturer of lapatinib.

Clin Cancer Res 2010;16:2688-2695.

[Rich66]

So..sounds like Lapatinib isn't more effective in tumors with or w/o p95, but that Herceptin is less effective in those tumors with p95. Maybe that's another reason some patients benefit from getting both. Without knowing whether the tumor has this quality, using both might cover the bases.
Any available test for p95 her2?

[Ellie F]

Good question Rich. I guess it's back to how well we understand individual tumour profiles.
Ellie

[Lani]

Bill i would interpret it as lapatinib is effective for her2 overexpressing tumors with or without p95, but herceptin is only effective in those without p95.(makes sense if you understand how lapatinib attacks the internal tyrosine kinase phosphorylation site, which doesn't depend on an extensive extracellular domain whereas herceptin's (many?) mechanism(s) of action are felt to revolve around sites on the extracellular domain which are not present on p95 shortened versions of the receptor

the test for p95 has not yet been made commercially available as far as i know

hope this helps

[Rich66]

I think we're saying the same thing in a different way. Too bad there isn't a test to guide therapy choice. While/if they develop that, it would be good to know what makes the difference between Herceptin and Lapatinib effectiveness in p95 positive tumors.