Do we know why....

[rinaina]

Do we have the reasons why herceptin works for some and not for others?

[Hopeful]

Rinaina,

I am not sure anyone knows for certain. I have a file at my office with a few articles I printed out that had some theories on it. I will try and find the links to those articles and post them for you if I do. From memory (which is not the best, these days!) one of them talked about whether the Her2+ receptor was on the cell surface or not (apparently there is some Her2+ with truncated forms) and that since the Herceptin binds to the outside of the cell, if there is nothing on the outside of the cell for it to bind to, it is not effective. Another article said that bc patients with cmyc expression have a very high response rate; another discussed if the tumor has not lost PTEN expression, the PTEN somehow gets the Herceptin into the center of the cell and causes it to die. With any luck, I'll get some of these links so you can read the reasearch.

Hopeful

[rinaina]

Thank you Hopeful, I appreciate both your response and your efforts in looking for those links.

[Lani]

Johnson PH, Esteva FJ. Related Articles, Links
The use of HER2 modulation in the adjuvant setting.
Curr Oncol Rep. 2007 Jan;9(1):9-16.
PMID: 17164042 [PubMed - in process]

6: Nahta R, Esteva FJ. Related Articles, Links
HER2 therapy: Molecular mechanisms of trastuzumab resistance.
Breast Cancer Res. 2006 Nov 6;8(6):215 [Epub ahead of print]
PMID: 17096862 [PubMed - as supplied by publisher]


10: Gonzalez-Angulo AM, Hortobagyi GN, Esteva FJ. Related Articles, Links
Adjuvant therapy with trastuzumab for HER-2/neu-positive breast cancer.
Oncologist. 2006 Sep;11(8):857-67. Review.
PMID: 16951389 [PubMed - indexed for MEDLINE]


14: Nahta R, Yu D, Hung MC, Hortobagyi GN, Esteva FJ. Related Articles, Links
Mechanisms of disease: understanding resistance to HER2-targeted therapy in human breast cancer.
Nat Clin Pract Oncol. 2006 May;3(5):269-80. Review.
PMID: 16683005 [PubMed - indexed for MEDLINE]
15: Pusztai L, Esteva FJ. Related Articles, Links
Continued use of trastuzumab (herceptin) after progression on prior trastuzumab therapy in HER-2-positive metastatic breast cancer.
Cancer Invest. 2006 Mar;24(2):187-91. Review.
PMID: 16619408 [PubMed - indexed for MEDLINE]

17: Nahta R, Esteva FJ. Related Articles, Links
Herceptin: mechanisms of action and resistance.
Cancer Lett. 2006 Feb 8;232(2):123-38. Review.
PMID: 16458110 [PubMed - indexed for MEDLINE]

19: Nahta R, Yuan LX, Zhang B, Kobayashi R, Esteva FJ. Related Articles, Links
Insulin-like growth factor-I receptor/human epidermal growth factor receptor 2 heterodimerization contributes to trastuzumab resistance of breast cancer cells.
Cancer Res. 2005 Dec 1;65(23):11118-28.
PMID: 16322262 [PubMed - indexed for MEDLINE]

[Hopeful]

Rinaina,

I was able to find some of the information I mentioned.

1. Here is a link to an article about the truncated form of Her2: http://clincancerres.aacrjournals.org/cgi/content/full/8/2/347. The authors state, "the full length receptor p185HER-2 undergoes a metalloprotease-dependent clevage producing a membrane-associated fragment (p95HER-2)in cultured cancer breast cells." They state "We report here that, in contrast to the full length receptor, p95HER-2 is more frequently expressed in lymph node metastatic tissue (45.7%) than in primary tumors (26.7%). If the truncated kinase p95 has a role in metastasis, as one study suggests, its presence may identify patients that are unlikely to respond to trastuzumab. Dmall molecule tyrosine kinase inhibitors may prove to be effective against p95-positive breast cancer."

2. Here is a link to the press release about the study on cymc: http://www.nsabp.pitt.edu/cMYC_Press_Release_121505.pdf. I have also read some comments about this relationship in the Breast Cancer Update materials - the links are generally posted in Articles of Interest.

3. Here is a link to an article about PTEN and Herceptin sensitivity: http://www.nature.com/bjc/journal/v94/n2/full/6602926a.html

I hope this helps.

Hopeful

[StephN]

In fact my hubby and I were discussing last night my good fortune with having Herceptin as a monotherapy last so long successfully in my case. I first heard about the PTEN connection on this board in the early days. I printed it out and showed it to my onc who replied that indeed we could assume that I had a high level of PTEN working in my favor. Have not been tested for this, but could now that I have my tumor blocks.

So, why OH why did my adjuvent treatment not work? Adria failed, so I assume my TOPOII is low - but that is recent research and not info we had when I was first treated.

And why did Taxotere fail me and TAXOL add to my success against my mets?
Was it the Taxol/Herceptin synergy??

If memory serves, Micheleu was tested for her PTEN level. You might search for a post on it. The following is from the article:

"PTEN activity might play an important and major role in its HER2/PI3K/Akt-mediated antitumour effect, and could be a useful biomarker for predicting the efficacy of trastuzumab in the treatment of breast cancer.

Keywords: breast cancer; erbB2; trastuzumab; PTEN; Akt"

Surely there are other bits of our pathology what play a big role, and that is why we have the Oncotype tests, which I also have not had.

If you have a progression, try hard to have a biopsy and the latest test done, for a better understanding of what will work in that case. It takes a very smart oncologist to keep up with all this now. Especially for us HER2's (HER@'s).

[AlaskaAngel]

Phosphorylated HER-2 tyrosine kinase and Her-2/neu gene amplification as predictive factors of response to trastuzumab in patients with HER-2 overexpressing metastatic breast cancer (MBC).

Giuliani R, Durbecq V, Di Leo A, Paesmans M, Larsimont D, Leroy JY, Borms M, Vindevoghel A, Jerusalem G, D'Hondt V, Dirix L, Canon JL, Richard V, Cocquyt V, Majois F, Reginster M, Demol J, Kains JP, Delree P, Keppens C, Sotiriou C, Piccart MJ, Cardoso F

Translational Research Unit, Jules Bordet Institute, 125, Boulevard de Waterloo, 1000 Brussels, Belgium.AIM:

Trastuzumab (T), a humanised monoclonal antibody against HER-2, is active in HER-2-positive MBC patients. However, nearly 60% of the patients do not benefit from T, stressing the need for additional predictive markers. The following markers could be implicated in response to T: (1) the magnitude of Her-2 gene amplification; (2) the co-expression of the other HER family receptors, possibly responsible for HER-2 trans-activation; (3) the activated status of HER-2; (4) the activated status of downstream effectors as mitogen-activated protein kinases (MAPKs), p38 and p27. METHODS: Medical files of patients with MBC treated with T either as a single agent or in combination with chemotherapy (CT) were reviewed. HER family members (EGFR, HER-2, HER-3, HER-4), the phosphorylated forms of EGFR (p-EGFR), HER-2 (p-HER-2) and of the downstream effectors were evaluated in the archival tumours. The correlation between clinical outcome and the expression of these markers was investigated.

RESULTS: (1) Increasing values of Her-2 amplification were associated with a higher probability of achieving an objective response; (2) no statistical significant correlation between the expression of the HER family receptors was found; (3) p-HER-2 was predictive of response in patients treated with T+CT; (4) a statistically significant correlation between p-ERK 1/2, p-p38 and p-HER-2 emerged, pointing to the activated vertical pathway p-HER-2-->p-MAPKs.

CONCLUSIONS: p-HER-2 and the magnitude of Her-2 amplification were predictive of response to T and their role deserves to be analysed in larger and more homogenous T-treated populations such as those from large phase III trials.

Published <?xml:namespace prefix = st1 ns = "urn:schemas-microsoft-com /><st1:date Year=25 January 2007</st1:date> in Eur J Cancer.

[Lani]

this means lapatinib may work for some of those that herceptin doesn't work for

[rinaina]

Thank you to all for your responses and help with this.

[michele u]

Steph and all,

yes i did check for PTEN. It was positive, so i have it to help the Herceptin. It was after the fact. I already had treatment and was done. I was just curiuos. I've never checked the TOPOII. Does anyone know if there is any thing out yet that could give PTEN to one that is negativae and have Herceptin help? I have a friend that failed Herceptin and Tykerb. Now she is on Taxotere. It is in her bone and lymph node in neck. she relapsed after 18months.