predicting resistance to herceptin therapy

[Lani]

I remember reading a thread started by someone whose breast cancer returned before they had even finished their herceptin treatment. I have previously given statistics quoted in the literature on how many her2+ patients respond vs. don't respond to herceptin given after chemo(usually quoted for patients with metastatic bc), and that, among those, the majority with become resistant within one year--again, don't panic. These numbers are quoted for Stage IV patients, and even for Stage IV patients I think the literature is lagging behind "facts on the ground" as evidenced by the many Stage IV posters here!

ANYWAY, here is a study where they looked at how resistance (do novo or acquired... I will be reading it in more detail) occurs. It had been noted that those with low PTEN values tended not to respond to herceptin de novo. But now it appears the PI3K pathway activation is the culprit. The good news--if that is the case, perhaps they could decide to treat patients differently upfront if they showed evidence of this problem, whether with Tykerb (unsure if the same would hold for them) or with combinations of herceptin with PI3K inhibitors they are working on, etc)

Lots more for me to read!!!

1: Cancer Cell. 2007 Oct;12(4):395-402.
A Functional Genetic Approach Identifies the PI3K Pathway as a Major Determinant of Trastuzumab Resistance in Breast Cancer.

Berns K, Horlings HM, Hennessy BT, Madiredjo M, Hijmans EM, Beelen K, Linn SC, Gonzalez-Angulo AM, Stemke-Hale K, Hauptmann M, Beijersbergen RL, Mills GB, van de Vijver MJ, Bernards R.
Division of Molecular Carcinogenesis and Center for Biomedical Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
A large-scale RNA interference screen to discover genes involved in trastuzumab resistance in breast cancer identified only PTEN as a modulator of drug sensitivity. Oncogenic mutants of PIK3CA (activator of the same pathway and frequently mutated in breast cancer) also conferred resistance to trastuzumab in cell culture. In a cohort of 55 breast cancer patients, activation of the PI3K pathway, as judged by the presence of oncogenic PIK3CA mutations or low PTEN expression, was associated with poor prognosis after trastuzumab therapy, and the combined analysis of PTEN and PIK3CA identified twice as many patients at increased risk for progression compared to PTEN alone. Thus, assessment of PI3K pathway activation may provide a biomarker to identify patients unlikely to respond to trastuzumab-based therapy.
PMID: 17936563 [PubMed - in process]