Tykerb & Her2 signaling pathways explained

[1rarebird]

http://jjco.oxfordjournals.org/cgi/c...&pmid=20542996

I have found it difficult to understand the mechanisms in which Tykerb inhibits breast cancer cell proliferation in Her2+. This paper is the best I have found in summarizing the process. If you download the full (free) article, you'll find Figure 1. which diagrams the steps involved. It has helped me.

bird

Jpn J Clin Oncol. 2010 Jun 11. [Epub ahead of print]
Management of ErbB2-positive Breast Cancer: Insights from Preclinical and Clinical Studies with Lapatinib.

Vogel C, Chan A, Gril B, Kim SB, Kurebayashi J, Liu L, Lu YS, Moon H.
1Sylvester Comprehensive Cancer Center at Deerfield Beach, University of Miami Miller School of Medicine, Deerfield Beach, FL, USA.
Abstract

The management of human epidermal growth factor receptor 2-positive (ErbB2+) breast cancer is challenging; patients with ErbB2+ breast tumors have more aggressive disease and a poor prognosis. The increasing incidence of breast cancer in Asia and the limitations of existing treatments pose additional challenges. In this review, we summarize the preclinical and clinical evidence that indicates how lapatinib, a novel inhibitor that targets the human epidermal growth factor receptor (ErbB1) and ErbB2 may help clinicians address four particularly challenging issues in the management of ErbB2+ breast cancer. These issues are: (i) trastuzumab therapy failure, (ii) development of central nervous system metastases, (iii) minimizing toxicity and (iv) selecting the most appropriate partners (chemotherapy and non-chemotherapy) for combination therapy with lapatinib. Lapatinib, in combination with chemotherapeutic agents, such as capecitabine, provides clinical benefits to patients with ErbB2+ breast cancer, including patients who develop progressive disease on trastuzumab. Lapatinib, in combination with non-chemotherapeutic agents, such as letrozole, may also provide a chemotherapy-free treatment option for postmenopausal patients with estrogen receptor-positive/ErbB2+ metastatic breast cancer. Encouraging results have also emerged regarding the synergistic effects of lapatinib in combination with other agents for the treatment of ErbB2+ breast cancer. Promising findings have also been reported for the use of lapatinib to prevent and treat central nervous system metastases. Collectively, these results indicate that the judicious use of lapatinib, an effective oral therapy with a manageable toxicity profile, can enhance the management of patients with ErbB2+ breast cancer.

PMID: 20542996 [PubMed - as supplied by publisher]Free Article

[1rarebird]

There is both frightening and encouraging information on the high risks associated with a Her2+ diagnosis in this paper---particularly when it comes to CNS or brain metastases. Even though the paper was apparently mainly funded by GSK and is possibly biased to some degree, it gives a strong rationale for the use of lapatinib, Tykerb, in the management of the disease-- again, particularly in CNS metastasis settings. IMHO, I believe the hour or two needed to read the paper and many of its extensive references is time well spent. Well, it was for me anyway.

bird

[Rich66]

Due to potential brain/CNS met protection and Her1 inhibition, I suspect if Tykerb came along first it would be 1st line...maybe in combination with Herceptin. I am not aware of any studies comparing Tykerb to Herceptin. I imagine neither company wants to "go there".

[1rarebird]

Rich--I agree with you regarding Tykerb. If I knew a year ago what I now know about the CNS risks of Her2+ disease and the limitations of Herceptin and advantages of Tykerb, I would have not been as afraid of the ALTTO Trial. Now, for early-stage me, it's too late for ALTTO and a chance at Tykerb, and I am locked out of the Neratinib Trial because of my gender. As they say, you live and learn, but really, living is more important.

bird

[bejuce]

You know, as someone who got Tykerb daily for 12 weeks during the 2nd phase of my neo-adjuvant chemo, I'm really glad to have read this article
and to have it confirmed what my oncologist had told me about Tykerb's potential to help with CNS mets when she was trying to convince me to enroll in the trial.

I was deciding between the trial and the MD Anderson protocol
of Herceptin+Taxol and then FEC+Herceptin. I chose the trial so I could get Tykerb and Herceptin, albeit not simultaneously. I did get one loading dose of Herceptin before my surgery, and my giant tumor in the breast disappeared completely.

They were, however, cells left in 11/13 nodes, but they were very small and scattered. I wonder though - based on a recent posting of Herceptin given in a neo-adjuvant setting in the MD Anderson protocol - whether if I had done the MD Anderson protocol I would have ended up with clear nodes. Is Herceptin better than Tykerb at getting the cells in the lymph nodes? Probably doesn't matter that much as I'm getting
a year of it and got radiation as well. I do hope that Tykerb will
become standard of care together (concurrently? sequentially?) soon.