why lapatinib is likely to be effective for more patients than herceptin is

[Lani]

Cancer Res. 2007 Feb 1;67(3):1170-1175.
Lapatinib Antitumor Activity Is Not Dependent upon Phosphatase and Tensin Homologue Deleted on Chromosome 10 in ErbB2-Overexpressing Breast Cancers.

Xia W,
Husain I,
Liu L,
Bacus S,
Saini S,
Spohn J,
Pry K,
Westlund R,
Stein SH,
Spector NL.
Departments of Oncology Biology, Gene Interference, Clinical Pharmacology/Discovery Medicine, Exploratory Data Sciences, and Oncology Clinical Development, GlaxoSmithKline, Research Triangle Park, North Carolina and Targeted Molecular Diagnostics, Westmont, Illinois.
Trastuzumab antitumor activity in ErbB2-overexpressing breast cancers seems to be dependent upon the presence of phosphatase and tensin homologue deleted on chromosome 10 (PTEN), a phosphatase that dampens phosphatidylinositol 3-kinase-Akt signaling. Consequently, PTEN deficiency, which occurs in 50% of breast cancers, predicts for resistance to trastuzumab monotherapy. Here, we show that lapatinib, a small-molecule inhibitor of ErbB1 and ErbB2 tyrosine kinases, exerts its antitumor activity in a PTEN-independent manner. Steady-state phosphorylated ErbB2 (p-ErbB2) and p-Akt (S473) protein levels were inhibited within 30 min following lapatinib but not in response to trastuzumab in BT474 and Au565 cells (two ErbB2-overexpressing breast cancer cell lines that are sensitive to the proapoptotic effects of lapatinib). Whereas trastuzumab reportedly inhibits SRC phosphorylation (Y416), which in turn reduced SRC-ErbB2 protein interactions, lapatinib had no effect on either variable. To assess the potential functional role that PTEN might play in lapatinib antitumor activity, we selectively knocked down PTEN in BT474 and Au565 cells using small interfering RNA transfection. Loss of PTEN did not affect induction of tumor cell apoptosis by lapatinib in either cell line. In addition, lapatinib inhibited Akt phosphorylation in MDA-MB-468 cells, an ErbB1-expressing/ErbB2 non-overexpressing breast cancer line, despite their PTEN-null status. Moreover, patients with ErbB2-overexpressing inflammatory breast cancers responded to lapatinib monotherapy regardless of PTEN status. Thus, lapatinib seems to exert its antitumor activity in ErbB2-overexpressing breast cancers in a PTEN-independent manner. These data emphasize the importance of assessing PTEN status in tumors when selecting ErbB2-targeted therapies in patients with breast cancer. [Cancer Res 2007;67(3):1170-5].
PMID: 17283152 [PubMed - as supplied by publisher]

PTEN can be tested for. Perhaps in the future they will do a trial looking at whether the presence/absence of PTEN predicted who would be better treated with herceptin vs lapatinib as treating with both (which seems to be very effective) may prove exorbitantly expensive.

[Jean]

Thank you for this interesting article Lani.

I am a bit surprised that a trial is not on the drawing boards?

Jean

[Becky]

There is a trial for early bc on the drawing boards. It will be AC followed by TH (taxol and herceptin). AC followed by taxol and tykerb, and AC followed by taxol, herceptin and tykerb. This will be for newly diagnosed patients and will run very much like the Herceptin trials for early bc. Research oncologists (namely Eric Winer) have to wait until the FDA approves Tykerb for metastatic disease and then they will apply to begin this trial.

[StephN]

"PTEN can be tested for. Perhaps in the future they will do a trial looking at whether the presence/absence of PTEN predicted who would be better treated with herceptin vs lapatinib as treating with both (which seems to be very effective) may prove exorbitantly expensive."

Perhaps I SHOULD be tested for PTEN levels - if old, paraffin-fixed tissue is OK to use for that.

Then we would not be talking about my case (and a few others similar) in such an anecdotal setting. I know my doctors are interested in why I have done so well, and we are just making assumptions as my diagnosis was so far ahead of the availability of these tests.

I would LOVE it if something could be learned from those is us who are so many years out Stage IV and on Herceptin only as we are from the hormone negative bunch. That would help us understand our prognosis from here, as well as give others another treatment track to go down that would give them better odds. (I know that Tykerb and others are being tried based on good science, but I think the testing of our tumors should yield further information.)<!-- / message -->

[Jean]

Sorry for the confusion in my post Becky, I meant a trial for the PTEN.....

Regards,
Jean

[Lani]

It would be great if you could also be tested for phospho-her2 which is the activated form of her2 which supposedly herceptin is most active against, also c-myc because those who are both her2 and cmyc + do especially well with herceptin based on a paper Dr. Slamon presented at the 2005 San Antonio meeting.

There is so much to be learned.

They learned a lot about AIDS by looking at the few people who were infected with HIV who never got AIDS and those who lived in relative symbiosis with it for long periods of time.

Sometimes it is easier to learn about complicated processes by looking at a small subsegment of the population who did well and try to discover why.

I went to a fund-raiser for a new institute of Immunity, Transplantation, and Infection (I was just accompanying the invitee) where they described trying to look with all the wonderful new technology available at how the immune system actually behaves in health and disease. The equipment is there --what they need is samples and money and people to agree to give up privacy privileges written into the new HIPAA laws which do not allow researchers to have access to the medical records of those whose tumors they are looking at to see how they are doing!!!. I described how cooperative I felt people on this board would be if anyone were trying to discover the true behavior of how her2 eludes the immune system, how it is modified by radiation therapy, herceptin etc.

They would love to look at these things but...

Perhaps Cynthia could lobby in Washington. But looking at the Bush budget
and its effect on clinical trials...

We can only hope.

[Jean]

Research - I 've been thinking about that a lot. I would be so willing to share
my medical records and tumor slides. Knowledge is the power tool. There is so much work to be done Lani.

Regards,
Jean

[StephN]

... in getting some information from some of us long-termers on Herceptin.

Lani - if you ever DO come up with an opportunity for testing of our tissue for these othere components, just let me know.

ALso, my med onc mentioned that the HERIGISTER survey would be yielding some good info in the next year or two once there is enough data to compile on those several thousand participants.

But, I do not think it will answer our questions posed here. Unless they ARE doing some further testing on these people.

[Lani]

the tests I suggested (in the best of all possible worlds) are available from Targeted Molecular Diagnostics (google it) Robin P used them to test her PTEN, but on their site you can see that they also test pher2 and c-myc also I think. Perhaps you could show your onc the list of biomarkers. They are usually done for Clinical trials groups. Oncologists usually don't want to order the test unless it will change your treatment and insurance companies of course couldn't care less about helping you (and the world) to find out why you have done so well.

Hope this helps.